This information has been developed and provided by an independent third-party source. Merck & Co., Inc. does not endorse and is not responsible for the accuracy of the content, or for practices or standards of non-Merck sources.

ALERT: U.S. Boxed Warning

The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.

Pronunciation

(FEN i toyn)

Generic Available (U.S.)

Yes: Excludes chewable tablet

Index Terms

• Diphenylhydantoin
• DPH
• Phenytoin Sodium
• Phenytoin Sodium, Extended
• Phenytoin Sodium, Prompt

Medication Guide

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:

Dilantin®: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM241523.pdf

REMS Components

Dilantin® oral solution: Released from REMS requirement 5/27/2011

Brand Names: U.S.

• Dilantin-125®
• Dilantin®
• Phenytek®

Brand Names: Canada

• Dilantin®

Pharmacologic Category

• Anticonvulsant, Hydantoin

Pharmacologic Category Synonyms

• AED, Hydantoin
• Anti-epileptic Drug, Hydantoin
• Hydantoin Anticonvulsant

Use: Labeled Indications

Management of generalized tonic-clonic (grand mal), complex partial seizures; prevention of seizures following head trauma/neurosurgery

Pregnancy Risk Factor

D

Pregnancy Considerations

Phenytoin crosses the placenta. Congenital malformations (including a pattern of malformations termed the “fetal hydantoin syndrome” or “fetal anticonvulsant syndrome”) have been reported in infants. Isolated cases of malignancies (including neuroblastoma) and coagulation defects in the neonate following delivery have also been reported. Epilepsy itself, the number of medications, genetic factors, or a combination of these probably influence the teratogenicity of anticonvulsant therapy. Total plasma concentrations of phenytoin are decreased by 56% in the mother during pregnancy; unbound plasma (free) concentrations are decreased by 31%. Because protein binding is decreased, monitoring of unbound plasma concentrations is recommended. Concentrations should be monitored through the 8th week postpartum. The use of folic acid throughout pregnancy and vitamin K during the last month of pregnancy is recommended. Patients exposed to phenytoin during pregnancy are encouraged to enroll themselves into the AED Pregnancy Registry by calling 1-888-233-2334. Additional information is available at www.aedpregnancyregistry.org.

Lactation

Enters breast milk/not recommended (AAP rates “compatible”; AAP 2001 update pending)

Breast-Feeding Considerations

Phenytoin is excreted in breast milk; however, the amount to which the infant is exposed is considered small. The manufacturers of phenytoin do not recommend breast-feeding during therapy. Women should be counseled of the possible risks and benefits associated with breast-feeding while on phenytoin.

Contraindications

Hypersensitivity to phenytoin, other hydantoins, or any component of the formulation; pregnancy

Warnings/Precautions

Boxed warnings:

• Hypotension: See “Concerns related to adverse effects” below.

Concerns related to adverse effects:

• Blood dyscrasias: A spectrum of hematologic effects have been reported with use (eg, neutropenia, leukopenia, thrombocytopenia, pancytopenia, and anemias); patients with a previous history of adverse hematologic reaction to any drug may be at increased risk. Early detection of hematologic change is important; advise patients of early signs and symptoms including fever, sore throat, mouth ulcers, infections, easy bruising, petechial or purpuric hemorrhage.

• Dermatologic reactions: Severe reactions, including toxic epidermal necrolysis and Stevens-Johnson syndromes, although rarely reported, have resulted in fatalities; drug should be discontinued if there are any signs of rash. Data suggests a genetic susceptibility for serious skin reactions in patients of Asian descent (see "Special populations" below).

• Hypersensitivity syndrome: Acute hepatotoxicity associated with a hypersensitivity syndrome characterized by fever, skin eruptions, and lymphadenopathy has been reported to occur within the first 2 months of treatment; discontinue if skin rash or lymphadenopathy occurs.

• Hypotension: [U.S. Boxed Warning]: Phenytoin must be administered slowly. Intravenous administration should not exceed 50 mg/minute in adult patients. In neonates, intravenous administration rate should not exceed 1-3 mg/kg/minute (most clinicians use a lower maximum rate of infusion in neonates of 0.5-1 mg/kg/minute). Hypotension may occur with rapid administration.

• Osteomalacia: Has been reported.

• Suicidal ideation: Pooled analysis of trials involving various antiepileptics (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% treated patients compared to 0.24% of patients receiving placebo); risk observed as early as 1 week after initiation and continued through duration of trials (most trials ≤24 weeks). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression; notify healthcare provider immediately if symptoms occur.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with sinus bradycardia, SA block, or AV block.

• Hepatic impairment: Use with caution in patients with hepatic impairment.

• Hypoalbuminemia: Use with caution in patients with any condition associated with low serum albumin levels, which will increase the free fraction of phenytoin in the serum and, therefore, the pharmacologic response.

• Porphyria: Use with caution in patients with porphyria.

• Seizures: May increase frequency of petit mal seizures.

Concurrent drug therapy issues:

• Sedatives: Effects with other sedative drugs or ethanol may be potentiated.

Special populations:

• Asian ancestry: Asian patients with the variant HLA-B*1502 may be at an increased risk of developing Stevens-Johnson syndrome and/or toxic epidermal necrolysis.

• Debilitated patients: Use with caution in patients who are debilitated.

• Elderly: Use with caution in the elderly.

Dosage form specific issues:

• Injectable: I.V. form may cause hypotension, skin necrosis at I.V. site; avoid I.V. administration in small veins.

Other warnings/precautions:

• Serum concentrations: Sedation, confusional states, or cerebellar dysfunction (loss of motor coordination) may occur at higher total serum concentrations, or at lower total serum concentrations when the free fraction of phenytoin is increased.

• Withdrawal: Anticonvulsants should not be discontinued abruptly because of the possibility of increasing seizure frequency; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal.

Adverse Reactions

I.V. effects: Hypotension, bradycardia, cardiac arrhythmia, cardiovascular collapse (especially with rapid I.V. use), venous irritation and pain, thrombophlebitis

Effects not related to plasma phenytoin concentrations: Hypertrichosis, gingival hypertrophy, thickening of facial features, carbohydrate intolerance, folic acid deficiency, peripheral neuropathy, vitamin D deficiency, osteomalacia, systemic lupus erythematosus

Concentration-related effects: Nystagmus, blurred vision, diplopia, ataxia, slurred speech, dizziness, drowsiness, lethargy, coma, rash, fever, nausea, vomiting, gum tenderness, confusion, mood changes, folic acid depletion, osteomalacia, hyperglycemia

Related to elevated concentrations:

>20 mcg/mL: Far lateral nystagmus

>30 mcg/mL: 45° lateral gaze nystagmus and ataxia

>40 mcg/mL: Decreased mentation

>100 mcg/mL: Death

Cardiovascular: Hypotension, bradycardia, cardiac arrhythmia, cardiovascular collapse

Central nervous system: Psychiatric changes, slurred speech, dizziness, drowsiness, headache, insomnia

Dermatologic: Rash

Gastrointestinal: Constipation, nausea, vomiting, gingival hyperplasia, enlargement of lips

Hematologic: Leukopenia, thrombocytopenia, agranulocytosis

Hepatic: Hepatitis

Local: Thrombophlebitis

Neuromuscular & skeletal: Tremor, peripheral neuropathy, paresthesia

Ocular: Diplopia, nystagmus, blurred vision

Rarely seen effects: Blood dyscrasias, coarsening of facial features, dyskinesias, hepatitis, hypertrichosis, lymphadenopathy, lymphoma, pseudolymphoma, SLE-like syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis, venous irritation and pain

Metabolism/Transport Effects

Substrate of CYP2C19 (major), CYP2C9 (major), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Induces CYP2B6 (strong), CYP2C19 (strong), CYP2C8 (strong), CYP2C9 (strong), CYP3A4 (strong)

Drug Interactions

Acetaminophen: Anticonvulsants (Hydantoin) may increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy

Alcohol (Ethyl): May enhance the CNS depressant effect of Phenytoin. Alcohol (Ethyl) may increase the serum concentration of Phenytoin. This may be particularly applicable with acute, heavy alcohol consumption. Alcohol (Ethyl) may decrease the serum concentration of Phenytoin. This may be particularly applicable with chronic, heavy alcohol consumption. Risk C: Monitor therapy

Allopurinol: May increase the serum concentration of Anticonvulsants (Hydantoin). Risk C: Monitor therapy

Amiodarone: May increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Amiodarone. Risk C: Monitor therapy

Amphetamines: May decrease the serum concentration of Phenytoin. Risk C: Monitor therapy

Antacids: May decrease the serum concentration of Anticonvulsants (Hydantoin). Risk C: Monitor therapy

Antifungal Agents (Azole Derivatives, Systemic): Phenytoin may decrease the serum concentration of Antifungal Agents (Azole Derivatives, Systemic). Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Phenytoin. Risk D: Consider therapy modification

ARIPiprazole: CYP3A4 Inducers may decrease the serum concentration of ARIPiprazole. Management: Double aripiprazole dose when initiating concomitant therapy with a CYP3A4 inducer (e.g., carbamazepine). Monitor response and adjust aripiprazole dose as clinically indicated. If CYP3A4 inducer is discontinued, reduce aripiprazole dose to 10-15 mg/day. Risk D: Consider therapy modification

Axitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Axitinib. Risk X: Avoid combination

Barbiturates: Phenytoin may enhance the CNS depressant effect of Barbiturates. Barbiturates may decrease the serum concentration of Phenytoin. Phenytoin may increase the serum concentration of Barbiturates. Risk C: Monitor therapy

Benzodiazepines: May increase the serum concentration of Phenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy. Exceptions: ALPRAZolam. Risk C: Monitor therapy

Boceprevir: Phenytoin may decrease the serum concentration of Boceprevir. Risk X: Avoid combination

Bortezomib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Bortezomib. Risk X: Avoid combination

Brentuximab Vedotin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be decreased. Risk C: Monitor therapy

Busulfan: Phenytoin may decrease the serum concentration of Busulfan. Risk C: Monitor therapy

Calcium Channel Blockers: May increase the serum concentration of Phenytoin. Management: Monitor for phenytoin toxicity with concomitant use of a calcium channel blocker (CCB) or decreased phenytoin effects with CCB discontinuation. Monitor for decreased CCB therapeutic effects. Nimodipine Canadian labeling contraindicates use with phenytoin. Exceptions: Clevidipine. Risk D: Consider therapy modification

Capecitabine: May increase the serum concentration of Phenytoin. Risk D: Consider therapy modification

CarBAMazepine: May decrease the serum concentration of Phenytoin. CarBAMazepine may increase the serum concentration of Phenytoin. Possibly by competitive inhibition at sites of metabolism. Phenytoin may decrease the serum concentration of CarBAMazepine. Risk D: Consider therapy modification

Carbonic Anhydrase Inhibitors: May enhance the adverse/toxic effect of Anticonvulsants (Hydantoin). Specifically, osteomalacia and rickets. Exceptions: Brinzolamide; Dorzolamide. Risk C: Monitor therapy

Caspofungin: Inducers of Drug Clearance may decrease the serum concentration of Caspofungin. Management: Consider using an increased caspofungin dose of 70 mg daily in adults (or 70 mg/m², up to a maximum of 70 mg, daily in pediatric patients) when coadministered with known inducers of drug clearance. Risk D: Consider therapy modification

CeFAZolin: May decrease the protein binding of Phenytoin. Risk C: Monitor therapy

Chloramphenicol: May decrease the metabolism of Anticonvulsants (Hydantoin). Anticonvulsants (Hydantoin) may decrease the serum concentration of Chloramphenicol. Increased chloramphenicol concentrations have also been seen. Risk D: Consider therapy modification

Cimetidine: May enhance the adverse/toxic effect of Anticonvulsants (Hydantoin). Cimetidine may increase the serum concentration of Anticonvulsants (Hydantoin). Management: Consider using an alternative H₂-antagonist to avoid this interaction. Monitor for toxic effects of hydantoin anticonvulsants if cimetidine is initiated/dose increased. Risk D: Consider therapy modification

Ciprofloxacin: May decrease the serum concentration of Phenytoin. Risk C: Monitor therapy

Ciprofloxacin (Systemic): May decrease the serum concentration of Phenytoin. Risk C: Monitor therapy

CISplatin: May decrease the serum concentration of Phenytoin. Risk C: Monitor therapy

Clarithromycin: CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Clarithromycin. Clarithromycin may increase the serum concentration of CYP3A4 Inducers (Strong). CYP3A4 Inducers (Strong) may decrease the serum concentration of Clarithromycin. Risk D: Consider therapy modification

CloZAPine: Phenytoin may decrease the serum concentration of CloZAPine. Risk C: Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Exceptions: Levocabastine (Nasal). Risk C: Monitor therapy

Colesevelam: May decrease the serum concentration of Phenytoin. Risk D: Consider therapy modification

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (Low risk). Risk C: Monitor therapy

Contraceptives (Estrogens): Phenytoin may diminish the therapeutic effect of Contraceptives (Estrogens). Contraceptive failure is possible. Management: Use of an alternative, nonhormonal means of contraception is recommended. Risk D: Consider therapy modification

Contraceptives (Progestins): Phenytoin may diminish the therapeutic effect of Contraceptives (Progestins). Contraceptive failure is possible. Management: Contraceptive failure is possible. Use of an alternative, nonhormonal contraceptive is recommended. Risk D: Consider therapy modification

Crizotinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Crizotinib. Risk X: Avoid combination

CycloSPORINE: Phenytoin may decrease the serum concentration of CycloSPORINE. Risk D: Consider therapy modification

CycloSPORINE (Systemic): Phenytoin may increase the metabolism of CycloSPORINE (Systemic). Risk D: Consider therapy modification

CYP2B6 Substrates: CYP2B6 Inducers (Strong) may increase the metabolism of CYP2B6 Substrates. Risk C: Monitor therapy

CYP2C19 Inducers (Strong): May increase the metabolism of CYP2C19 Substrates. Risk C: Monitor therapy

CYP2C19 Inhibitors (Moderate): May decrease the metabolism of CYP2C19 Substrates. Risk C: Monitor therapy

CYP2C19 Inhibitors (Strong): May decrease the metabolism of CYP2C19 Substrates. Risk D: Consider therapy modification

CYP2C19 Substrates: CYP2C19 Inducers (Strong) may increase the metabolism of CYP2C19 Substrates. Risk C: Monitor therapy

CYP2C8 Substrates: CYP2C8 Inducers (Strong) may increase the metabolism of CYP2C8 Substrates. Risk C: Monitor therapy

CYP2C9 Inducers (Strong): May increase the metabolism of CYP2C9 Substrates. Risk C: Monitor therapy

CYP2C9 Inhibitors (Moderate): May decrease the metabolism of CYP2C9 Substrates. Risk C: Monitor therapy

CYP2C9 Inhibitors (Strong): May decrease the metabolism of CYP2C9 Substrates. Risk D: Consider therapy modification

CYP2C9 Substrates: CYP2C9 Inducers (Strong) may increase the metabolism of CYP2C9 Substrates. Risk C: Monitor therapy

CYP3A4 Substrates: CYP3A4 Inducers (Strong) may increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

Darunavir: Phenytoin may decrease the serum concentration of Darunavir. Risk X: Avoid combination

Dasatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dasatinib. Management: Avoid when possible. If such a combination cannot be avoided, consider increasing dasatinib dose and monitor clinical response and toxicity closely. Risk D: Consider therapy modification

Deferasirox: Phenytoin may decrease the serum concentration of Deferasirox. Management: Avoid combination when possible; if the combination must be used, consider an increase in initial deferasirox dose to 30 mg/kg, and monitor serum ferritin concentrations/clinical responses to guide further dosing. Risk D: Consider therapy modification

Delavirdine: May increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Delavirdine. Risk X: Avoid combination

Dexmethylphenidate: May increase the serum concentration of Phenytoin. Risk C: Monitor therapy

Diazoxide: May decrease the serum concentration of Phenytoin. Total phenytoin concentrations may be affected more than free phenytoin concentrations. Risk C: Monitor therapy

Diclofenac: CYP2C9 Inducers (Strong) may decrease the serum concentration of Diclofenac. Risk C: Monitor therapy

Disopyramide: Phenytoin may decrease the serum concentration of Disopyramide. Risk C: Monitor therapy

Disulfiram: May increase the serum concentration of Phenytoin. Management: Avoid concomitant use of disulfiram and phenytoin when possible. Phenytoin dose adjustment will likely be necessary when starting and/or stopping concurrent disulfiram. Monitor phenytoin response and concentrations closely. Risk D: Consider therapy modification

Divalproex: May decrease the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Divalproex. Risk C: Monitor therapy

Doxycycline: Phenytoin may decrease the serum concentration of Doxycycline. Risk D: Consider therapy modification

Dronedarone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dronedarone. Risk X: Avoid combination

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification

Efavirenz: May increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Efavirenz. Risk D: Consider therapy modification

Ethosuximide: May enhance the CNS depressant effect of Phenytoin. Ethosuximide may increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Ethosuximide. Risk C: Monitor therapy

Etoposide: Phenytoin may decrease the serum concentration of Etoposide. Risk C: Monitor therapy

Etoposide Phosphate: Phenytoin may decrease the serum concentration of Etoposide Phosphate. Phenytoin may increase the metabolism, via CYP isoenzymes, of etoposide phosphate. Risk C: Monitor therapy

Etravirine: Phenytoin may decrease the serum concentration of Etravirine. Management: The manufacturer of etravirine states these drugs should not be used in combination Risk X: Avoid combination

Everolimus: CYP3A4 Inducers (Strong) may decrease the serum concentration of Everolimus. Management: Avoid concurrent use of strong CYP3A4 inducers, but if strong CYP3A4 inducers cannot be avoided, consider gradually (in 5 mg increments) increasing the everolimus dose from 10 mg/day to 20 mg/day (adult doses). Risk X: Avoid combination

Exemestane: CYP3A4 Inducers (Strong) may decrease the serum concentration of Exemestane. Management: Exemestane prescribing information recommends using an increased dose (50 mg/day) in patients receiving concurrent strong CYP3A4 inducers. Monitor patients closely for evidence of toxicity and/or inadequate clinical response. Risk D: Consider therapy modification

Felbamate: May increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Felbamate. Management: Decreased phenytoin dose will likely be needed when adding felbamate; some reports suggest an empiric 20% decrease in phenytoin dose. Additional reductions may be needed if felbamate dose is increased or as otherwise guided by monitoring. Risk D: Consider therapy modification

Floxuridine: May increase the serum concentration of Phenytoin. Risk D: Consider therapy modification

Fluconazole: May increase the serum concentration of Phenytoin. Risk D: Consider therapy modification

Flunarizine: Phenytoin may decrease the serum concentration of Flunarizine. Risk C: Monitor therapy

Fluorouracil: May increase the serum concentration of Phenytoin. Risk D: Consider therapy modification

Fluorouracil (Systemic): May increase the serum concentration of Phenytoin. Risk D: Consider therapy modification

Fluorouracil (Topical): May increase the serum concentration of Phenytoin. Risk C: Monitor therapy

FLUoxetine: May increase the serum concentration of Phenytoin. Risk C: Monitor therapy

FluvoxaMINE: May increase the serum concentration of Phenytoin. Risk C: Monitor therapy

Folic Acid: May decrease the serum concentration of Phenytoin. Risk C: Monitor therapy

Fosamprenavir: May decrease the serum concentration of Phenytoin. The active amprenavir metabolite is likely responsible for this effect. Phenytoin may increase the serum concentration of Fosamprenavir. Specifically, phenytoin may increase the concentration of the active metabolite amprenavir. Risk C: Monitor therapy

Gefitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Gefitinib. Management: In the absence of severe adverse drug reactions, consider increasing gefitinib dose to 500 mg daily in patients receiving strong CYP3A4 inducers. Carefully monitor clinical response and development of adverse reactions. Risk D: Consider therapy modification

GuanFACINE: CYP3A4 Inducers (Strong) may decrease the serum concentration of GuanFACINE. Management: Consider increasing the guanfacine dose (within the labeled dosage range) when such a combination is used. Risk D: Consider therapy modification

Halothane: May increase the serum concentration of Phenytoin. Risk C: Monitor therapy

HMG-CoA Reductase Inhibitors: Phenytoin may decrease the serum concentration of HMG-CoA Reductase Inhibitors. Exceptions: Pitavastatin; Rosuvastatin. Risk D: Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Imatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Imatinib. Management: Avoid concurrent use of imatinib with strong CYP3A4 inducers when possible. If such a combination must be used, increase imatinib dose by at least 50% and monitor the patient's clinical response closely. Risk D: Consider therapy modification

Irinotecan: Phenytoin may decrease the serum concentration of Irinotecan. Concentrations of the active metabolite SN-38 may also be reduced. Management: Change to a non-enzyme inducing anticonvulsant, when clinically possible, at least 2 weeks prior to beginning irinotecan. Dosage increases for irinotecan may be needed when used with phenytoin, but specific dosing guidelines are not available. Risk D: Consider therapy modification

Isoniazid: May increase the serum concentration of Phenytoin. Management: Consider alternatives. If concomitant therapy cannot be avoided, monitor for increased phenytoin concentrations/effects with isoniazid initiation/dose increase, or decreased concentrations/effects with isoniazid discontinuation/dose decrease. Risk D: Consider therapy modification

Ixabepilone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ixabepilone. Management: Avoid this combination whenever possible. If this combination must be used, a gradual increase in ixabepilone dose from 40 mg/m² to 60 mg/m² (given as a 4-hour infusion), as tolerated, should be considered. Risk D: Consider therapy modification

Ketorolac: May diminish the therapeutic effect of Anticonvulsants. Risk C: Monitor therapy

Ketorolac (Nasal): May diminish the therapeutic effect of Anticonvulsants. Risk C: Monitor therapy

Ketorolac (Systemic): May diminish the therapeutic effect of Anticonvulsants. Risk C: Monitor therapy

Lacosamide: Phenytoin may decrease the serum concentration of Lacosamide. Risk C: Monitor therapy

LamoTRIgine: Phenytoin may decrease the serum concentration of LamoTRIgine. Risk D: Consider therapy modification

Lapatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lapatinib. Management: If therapy overlap cannot be avoided, consider titrating lapatinib gradually from 1,250 mg/day up to 4,500 mg/day (HER2 positive metastatic breast cancer) or 1,500 mg/day up to 5,500 mg/day (hormone receptor/HER2 positive breast cancer) as tolerated. Risk X: Avoid combination

Leucovorin Calcium-Levoleucovorin: May decrease the serum concentration of Phenytoin. Risk C: Monitor therapy

Levodopa: Phenytoin may diminish the therapeutic effect of Levodopa. Risk C: Monitor therapy

Levomefolate: May decrease the serum concentration of Phenytoin. Risk C: Monitor therapy

Linagliptin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Linagliptin. Management: Strongly consider using an alternative to any strong CYP3A4 inducer in patients who are being treated with linagliptin. If this combination is used, monitor patients closely for evidence of reduced linagliptin effectiveness. Risk D: Consider therapy modification

Lithium: Phenytoin may enhance the adverse/toxic effect of Lithium. Risk C: Monitor therapy

Loop Diuretics: Phenytoin may diminish the diuretic effect of Loop Diuretics. Risk C: Monitor therapy

Lopinavir: May decrease the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Lopinavir. Management: The manufacturer of lopinavir/ritonavir recommends avoiding once-daily administration if used together with phenytoin. Risk D: Consider therapy modification

Lurasidone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lurasidone. Risk X: Avoid combination

Maraviroc: CYP3A4 Inducers (Strong) may decrease the serum concentration of Maraviroc. Management: Increase maraviroc adult dose to 600 mg twice daily when used with strong CYP3A4 inducers. This does not apply to patients also receiving strong CYP3A4 inhibitors. Do not use maraviroc with strong CYP3A4 inducers in patients with Clcr less than 30 mL/min. Risk D: Consider therapy modification

Mebendazole: Phenytoin may decrease the serum concentration of Mebendazole. Risk C: Monitor therapy

Mefloquine: May diminish the therapeutic effect of Anticonvulsants. Mefloquine may decrease the serum concentration of Anticonvulsants. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of convulsions. Monitor anticonvulsant concentrations and treatment response closely with concurrent use. Risk D: Consider therapy modification

Meperidine: Phenytoin may decrease the serum concentration of Meperidine. Risk C: Monitor therapy

Methadone: Phenytoin may decrease the serum concentration of Methadone. Risk C: Monitor therapy

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Risk D: Consider therapy modification

Methylfolate: May decrease the serum concentration of Phenytoin. Risk C: Monitor therapy

Methylphenidate: May increase the serum concentration of Phenytoin. Risk C: Monitor therapy

MethylPREDNISolone: Phenytoin may decrease the serum concentration of MethylPREDNISolone. Management: Consider an alternative corticosteroid. If this combination cannot be avoided, monitor for diminished methylprednisolone effects during phenytoin treatment, and increased methylprednisolone effects following phenytoin discontinuation. Risk D: Consider therapy modification

MetroNIDAZOLE: May increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of MetroNIDAZOLE. Risk C: Monitor therapy

MetroNIDAZOLE (Systemic): May increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of MetroNIDAZOLE (Systemic). Risk C: Monitor therapy

Metyrapone: Phenytoin may decrease the serum concentration of Metyrapone. The oral metyrapone test would thus be unreliable unless the metapyrone dosage was substantially increased (e.g., 750 mg every 2 hours). Risk D: Consider therapy modification

Mexiletine: Phenytoin may decrease the serum concentration of Mexiletine. Risk C: Monitor therapy

Nelfinavir: May decrease the serum concentration of Phenytoin. Risk C: Monitor therapy

Nilotinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Nilotinib. Risk X: Avoid combination

OXcarbazepine: May increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of OXcarbazepine. Risk C: Monitor therapy

Pazopanib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Pazopanib. Risk X: Avoid combination

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2C9 Substrates. Risk C: Monitor therapy

Praziquantel: CYP3A4 Inducers (Strong) may decrease the serum concentration of Praziquantel. Management: Avoid concomitant use of praziquantel with strong CYP3A4 inducers. Discontinue rifampin 4 weeks prior to initiation of praziquantel therapy. Rifampin may be resumed the day following praziquantel completion. Risk X: Avoid combination

PrednisoLONE: Phenytoin may decrease the serum concentration of PrednisoLONE. Risk C: Monitor therapy

PrednisoLONE (Systemic): Phenytoin may decrease the serum concentration of PrednisoLONE (Systemic). Risk C: Monitor therapy

PredniSONE: Phenytoin may decrease serum concentrations of the active metabolite(s) of PredniSONE. Risk C: Monitor therapy

Prilocaine: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Prilocaine. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when prilocaine is used in combination with other agents associated with development of methemoglobinemia. Avoid lidocaine/prilocaine in infants receiving such agents. Risk C: Monitor therapy

Primidone: Phenytoin may increase the metabolism of Primidone. The ratio of primidone:phenobarbital is thus changed. Risk C: Monitor therapy

Proton Pump Inhibitors: May increase the serum concentration of Phenytoin. Exceptions: Dexlansoprazole; Esomeprazole; Lansoprazole; Pantoprazole; RABEprazole. Risk C: Monitor therapy

Pyridoxine: May increase the metabolism of Phenytoin. This is most apparent in high pyridoxine doses (e.g., 80 mg to 200 mg daily) Risk C: Monitor therapy

QUEtiapine: Phenytoin may decrease the serum concentration of QUEtiapine. Risk C: Monitor therapy

QuiNIDine: Phenytoin may decrease the serum concentration of QuiNIDine. Risk C: Monitor therapy

QuiNINE: Phenytoin may decrease the serum concentration of QuiNINE. Risk D: Consider therapy modification

Ranolazine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ranolazine. Risk X: Avoid combination

Rifamycin Derivatives: May decrease the serum concentration of Phenytoin. Risk C: Monitor therapy

Rilpivirine: Phenytoin may decrease the serum concentration of Rilpivirine. Risk X: Avoid combination

Ritonavir: Phenytoin may decrease the serum concentration of Ritonavir. Ritonavir may decrease the serum concentration of Phenytoin. Risk D: Consider therapy modification

Rivaroxaban: CYP3A4 Inducers (Strong) may decrease the serum concentration of Rivaroxaban. Risk X: Avoid combination

Roflumilast: CYP3A4 Inducers (Strong) may decrease the serum concentration of Roflumilast. Management: Roflumilast U.S. prescribing information recommends against combining strong CYP3A4 inducers with roflumilast. The Canadian product monograph makes no such recommendation but notes that such agents may reduce roflumilast therapeutic effects. Risk X: Avoid combination

RomiDEPsin: CYP3A4 Inducers (Strong) may decrease the serum concentration of RomiDEPsin. Risk X: Avoid combination

Rufinamide: Phenytoin may decrease the serum concentration of Rufinamide. Rufinamide may increase the serum concentration of Phenytoin. Risk C: Monitor therapy

Saxagliptin: CYP3A4 Inducers may decrease the serum concentration of Saxagliptin. Risk C: Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Risk C: Monitor therapy

Sertraline: Phenytoin may decrease the serum concentration of Sertraline. Sertraline may increase the serum concentration of Phenytoin. Risk C: Monitor therapy

Sirolimus: Phenytoin may decrease the serum concentration of Sirolimus. Management: Monitor for decreased sirolimus serum concentrations if phenytoin is intiated/dose increased. Monitor for increased sirolimus concentrations with phenytoin discontinuation/dose decrease. Sirolimus dose adjustments may be necessary. Risk D: Consider therapy modification

SORAfenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of SORAfenib. Risk X: Avoid combination

Sulfonamide Derivatives: May increase the serum concentration of Phenytoin. Risk C: Monitor therapy

SUNItinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of SUNItinib. Management: Avoid when possible. If such a combination cannot be avoided, consider increasing sunitinib dose and monitor clinical response and toxicity closely. Risk D: Consider therapy modification

Tacrolimus: Phenytoin may decrease the serum concentration of Tacrolimus. Tacrolimus may increase the serum concentration of Phenytoin. Risk C: Monitor therapy

Tacrolimus (Systemic): Phenytoin may decrease the serum concentration of Tacrolimus (Systemic). Tacrolimus (Systemic) may increase the serum concentration of Phenytoin. Risk C: Monitor therapy

Tadalafil: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tadalafil. Management: Erectile dysfunction: monitor for decreased effectiveness - no standard dose adjustments recommended. Avoid use of tadalafil for pulmonary arterial hypertension in patients receiving a strong CYP3A4 inducer. Risk D: Consider therapy modification

Telaprevir: Phenytoin may decrease the serum concentration of Telaprevir. Telaprevir may decrease the serum concentration of Phenytoin. Telaprevir may increase the serum concentration of Phenytoin. Risk X: Avoid combination

Temsirolimus: Phenytoin may decrease the serum concentration of Temsirolimus. Concentrations of the active metabolite, sirolimus, are also likely to be decreased (and maybe to an even greater degree). Management: Temsirolimus prescribing information recommends against coadministration with strong CYP3A4 inducers such as phenytoin; however, if concurrent therapy is necessary, an increase in temsirolimus adult dose to 50 mg/week should be considered. Risk D: Consider therapy modification

Teniposide: Phenytoin may decrease the serum concentration of Teniposide. Management: Consider alternatives to combined treatment with phenytoin and teniposide due to the potential for decreased teniposide concentrations. If the combination cannot be avoided, monitor teniposide response closely. Risk D: Consider therapy modification

Theophylline Derivatives: May decrease the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Theophylline Derivatives. Exceptions: Dyphylline. Risk C: Monitor therapy

Thyroid Products: Phenytoin may decrease the serum concentration of Thyroid Products. Phenytoin may also displace thyroid hormones from protein binding sites. Risk C: Monitor therapy

Ticagrelor: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Ticagrelor. CYP3A4 Inducers (Strong) may decrease the serum concentration of Ticagrelor. Risk X: Avoid combination

Ticlopidine: May increase the serum concentration of Phenytoin. Risk D: Consider therapy modification

Tipranavir: Phenytoin may decrease the serum concentration of Tipranavir. Tipranavir may decrease the serum concentration of Phenytoin. Risk D: Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Tolvaptan: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tolvaptan. Management: If concurrent use is necessary, increased doses of tolvaptan (with close monitoring for toxicity and clinical response) may be needed. Risk X: Avoid combination

Topiramate: Phenytoin may decrease the serum concentration of Topiramate. Topiramate may increase the serum concentration of Phenytoin. Risk C: Monitor therapy

Toremifene: CYP3A4 Inducers (Strong) may decrease the serum concentration of Toremifene. Risk X: Avoid combination

TraZODone: Phenytoin may decrease the serum concentration of TraZODone. TraZODone may increase the serum concentration of Phenytoin. Risk C: Monitor therapy

Treprostinil: CYP2C8 Inducers (Strong) may decrease the serum concentration of Treprostinil. Risk C: Monitor therapy

Trimethoprim: May increase the serum concentration of Phenytoin. Risk C: Monitor therapy

Ulipristal: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ulipristal. Risk C: Monitor therapy

Valproic Acid: Phenytoin may increase the metabolism of Valproic Acid. A hepatotoxic metabolite of valproic acid may result. Valproic Acid may decrease the serum concentration of Phenytoin. Continued therapy usually yields a normalization (or slight increase) of serum phenytoin concentrations. Free phenytoin concentrations, however, tend to remain relatively stable (possibly increased with continued therapy). Risk C: Monitor therapy

Vandetanib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vandetanib. Risk X: Avoid combination

Vecuronium: Phenytoin may enhance the therapeutic effect of Vecuronium. Phenytoin may diminish the therapeutic effect of Vecuronium. Phenytoin may decrease the serum concentration of Vecuronium. Risk C: Monitor therapy

Vemurafenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vemurafenib. Risk C: Monitor therapy

Vigabatrin: May decrease the serum concentration of Phenytoin. Risk C: Monitor therapy

Vitamin K Antagonists (eg, warfarin): Phenytoin may enhance the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists may increase the serum concentration of Phenytoin. Management: Anticoagulant dose adjustment will likely be necessary when phenytoin is initiated or discontinued. Monitor patients extra closely (INR and signs/symptoms of bleeding) when using this combination. Risk D: Consider therapy modification

Zonisamide: Phenytoin may decrease the serum concentration of Zonisamide. Risk C: Monitor therapy

Zuclopenthixol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Zuclopenthixol. Risk C: Monitor therapy

Ethanol/Nutrition/Herb Interactions

Ethanol:

Acute use: Ethanol inhibits metabolism of phenytoin and may also increase CNS depression. Management: Avoid or limit ethanol. Caution patients about effects.

Chronic use: Ethanol stimulates metabolism of phenytoin. Management: Avoid or limit ethanol.

Food: Phenytoin serum concentrations may be altered if taken with food. If taken with enteral nutrition, phenytoin serum concentrations may be decreased. Tube feedings decrease bioavailability. Phenytoin may decrease calcium, folic acid, and vitamin D levels. Supplementing folic acid may lower the seizure threshold. Management: Hold tube feedings 1-2 hours before and 1-2 hours after phenytoin administration. Do not supplement folic acid. Consider vitamin D supplementation. Take preferably on an empty stomach.

Herb/Nutraceutical: Evening primrose may decrease the seizure threshold; other herbal medications may increase CNS depression. Management: Avoid evening primrose, valerian, St John's wort, kava kava, and gotu kola.

Storage

Capsule, tablet: Store at controlled room temperature. Protect from light and moisture.

Oral suspension: Store at room temperature of 20°C to 25°C (68°F to 77°F); do not freeze. Protect from light.

Solution for injection: Store at room temperature of 15°C to 30°C (59°F to 86°F). Use only clear solutions free of precipitate and haziness; slightly yellow solutions may be used. Precipitation may occur if solution is refrigerated and may dissolve at room temperature.

Reconstitution

I.V.: Further dilution of the solution for I.V. infusion is controversial and no consensus exists as to the optimal concentration and length of stability. Stability is concentration and pH dependent. Based on limited clinical consensus, NS or LR are recommended diluents; dilutions of 1-10 mg/mL have been used and should be administered as soon as possible after preparation (some recommend to discard if not used within 4 hours). Do not refrigerate.

Compatibility

Incompatible with D₅NS, D₅W, fat emulsion 10%, LR, 1/2NS; variable stability (consult detailed reference) in NS.

Y-site administration: Compatible: Esmolol, famotidine, fluconazole, foscarnet. Incompatible: Amphotericin B cholesteryl sulfate complex, cefepime, ceftazidime, cimetidine, ciprofloxacin, diltiazem, enalaprilat, fenoldopam, fentanyl, heparin, heparin with hydrocortisone sodium succinate, hydromorphone, linezolid, methadone, micafungin, morphine, potassium chloride, propofol, sufentanil, theophylline, vasopressin, vitamin B complex with C. Variable (consult detailed reference): Pantoprazole, tacrolimus.

Compatibility in syringe: Incompatible: Hydromorphone, ondansetron, pantoprazole, sufentanil.

Mechanism of Action

Stabilizes neuronal membranes and decreases seizure activity by increasing efflux or decreasing influx of sodium ions across cell membranes in the motor cortex during generation of nerve impulses; prolongs effective refractory period and suppresses ventricular pacemaker automaticity, shortens action potential in the heart

Pharmacodynamics/Kinetics

Onset of action: I.V.: ~0.5-1 hour

Absorption: Oral: Slow

Distribution: V_d:

Neonates: Premature: 1-1.2 L/kg; Full-term: 0.8-0.9 L/kg

Infants: 0.7-0.8 L/kg

Children: 0.7 L/kg

Adults: 0.6-0.7 L/kg

Protein binding:

Neonates: ≥80% (≤20% free)

Infants: ≥85% (≤15% free)

Adults: 90% to 95%

Others: Decreased protein binding

Disease states resulting in a decrease in serum albumin concentration: Burns, hepatic cirrhosis, nephrotic syndrome, pregnancy, cystic fibrosis

Disease states resulting in an apparent decrease in affinity of phenytoin for serum albumin: Renal failure, jaundice (severe), other drugs (displacers), hyperbilirubinemia (total bilirubin >15 mg/dL), Cl_cr <25 mL/minute (unbound fraction is increased two- to threefold in uremia)

Metabolism: Follows dose-dependent capacity-limited (Michaelis-Menten) pharmacokinetics with increased V_max in infants >6 months of age and children versus adults; major metabolite (via oxidation), HPPA, undergoes enterohepatic recirculation

Bioavailability: Form dependent

Half-life elimination: Oral: 22 hours (range: 7-42 hours)

Time to peak, serum (form dependent): Oral: Extended-release capsule: 4-12 hours; Immediate release preparation: 2-3 hours

Excretion: Urine (<5% as unchanged drug); as glucuronides

Clearance: Highly variable, dependent upon intrinsic hepatic function and dose administered; increased clearance and decreased serum concentrations with febrile illness

Dosage

Note: Phenytoin base (eg, oral suspension, chewable tablets) contains ~8% more drug than phenytoin sodium (~92 mg base is equivalent to 100 mg phenytoin sodium). Dosage adjustments and closer serum monitoring may be necessary when switching dosage forms.

Status epilepticus: I.V.:

Infants and Children: Loading dose: 15-20 mg/kg in a single or divided dose; maintenance dose: Initial: 5 mg/kg/day in 2 divided doses; usual doses:

6 months to 3 years: 8-10 mg/kg/day

4-6 years: 7.5-9 mg/kg/day

7-9 years: 7-8 mg/kg/day

10-16 years: 6-7 mg/kg/day, some patients may require every 8 hours dosing

Adults: Loading dose: Manufacturer recommends 10-15 mg/kg, however, 15-20 mg/kg is generally recommended; maximum rate: 50 mg/minute; initial maintenance dose: I.V. or Oral: 100 mg every 6-8 hours

Anticonvulsant: Children and Adults: Oral:

Loading dose: 15-20 mg/kg; consider prior phenytoin serum concentrations and/or recent dosing history if available; administer oral loading dose in 3 divided doses given every 2-4 hours to decrease GI adverse effects and to ensure complete oral absorption

Maintenance dose:

Children: Initial maintenance dose: 5 mg/kg/day in 2-3 divided doses; usual maintenance dose range: 4-8 mg/kg/day

Adults: Initial maintenance dose: 300 mg/day in 3 divided doses; may also administer in 1-2 divided doses using extended release formulation; adjust dosage based on individual requirements; usual maintenance dose range: 300-600 mg/day

Dosage adjustment in obesity: Adults: Loading dose: Use adjusted body weight (ABW) correction based on a pharmacokinetic study of phenytoin loading doses in obese patients (Abernethy, 1985). The larger correction factor (ie, 1.33) is due to a doubling of V_d estimated in these obese patients.

ABW = [(Actual body weight – IBW) x 1.33] + IBW

Maximum loading dose: I.V.: 2000 mg (Erstad, 2004)

Maintenance doses should be based on ideal body weight, conventional daily doses with adjustments based upon therapeutic drug monitoring and clinical effectiveness. (Abernethy, 1985; Erstad, 2002; Erstad, 2004)

Neurosurgery (prophylactic): Adults: I.V.: 100-200 mg at ~4-hour intervals during surgery and the immediate postoperative period. Note: While the manufacturer recommends I.M. administration, this route should be avoided due to severe risk of local tissue destruction and necrosis; use fosphenytoin if I.M. administration necessary (Boucher, 1996; Meek, 1999).

Dosing adjustment/comments in renal impairment or hepatic disease: Safe in usual doses in mild liver disease; clearance may be substantially reduced in cirrhosis and plasma level monitoring with dose adjustment advisable. Free phenytoin levels should be monitored closely.

Administration: Oral

Suspension: Shake well prior to use. Absorption is impaired when phenytoin suspension is given concurrently to patients who are receiving continuous nasogastric feedings. A method to resolve this interaction is to divide the daily dose of phenytoin and withhold the administration of nutritional supplements for 1-2 hours before and after each phenytoin dose.

Administration: I.M.

Avoid this route (manufacturer recommends I.M. administration) due to severe risk of local tissue destruction and necrosis; use fosphenytoin if I.M. administration necessary (Boucher, 1996; Meek, 1999).

Administration: I.V.

Vesicant. Fosphenytoin may be considered for loading in patients who are in status epilepticus, hemodynamically unstable, or develop hypotension/bradycardia with I.V. administration of phenytoin. Although, phenytoin may be administered by direct I.V. injection, it is preferable that phenytoin be administered via infusion pump either undiluted or diluted in normal saline as an I.V. piggyback (IVPB) to prevent exceeding the maximum infusion rate (monitor closely for extravasation during infusion). The maximum rate of I.V. administration is 50 mg/minute in adults. Highly sensitive patients (eg, elderly, patients with pre-existing cardiovascular conditions) should receive phenytoin more slowly (eg, 20 mg/minute) (Meek, 1999). In neonates, the manufacturer recommends a maximum rate of 1-3 mg/kg/minute; however, a lower maximum rate of 0.5-1 mg/kg/minute is used clinically (Sankar, 2010; Shields, 1989). An in-line 0.22-5 micron filter is recommended for IVPB solutions due to the high potential for precipitation of the solution. Avoid extravasation. Following I.V. administration, NS should be injected through the same needle or I.V. catheter to prevent irritation.

Administration: Other

SubQ administration is not recommended because of the possibility of local tissue damage (due to high pH).

Administration: I.V. Detail

An in-line 0.22-5 micron filter is recommended for IVPB solutions due to the high potential for precipitation of the solution. Avoid extravasation. Following I.V. administration, NS should be injected through the same needle or I.V. catheter to prevent irritation.

pH: 10.0-12.3

Monitoring Parameters

CBC, liver function; suicidality (eg, suicidal thoughts, depression, behavioral changes); plasma phenytoin concentrations (if available, free phenytoin concentrations should be obtained in patients with renal impairment and/or hypoalbuminemia; if free phenytoin concentrations are unavailable, the adjusted total concentration may be determined based upon equations in adult patients). Trough concentrations are generally recommended for routine monitoring.

Additional monitoring with I.V. use: Continuous cardiac monitoring (rate, rhythm, blood pressure) and observation during administration recommended; blood pressure and pulse should be monitored every 15 minutes for 1 hour after administration (Meek, 1999); infusion site reactions

Reference Range

Timing of serum samples: Because it is slowly absorbed, peak blood levels may occur 4-8 hours after ingestion of an oral dose. The serum half-life varies with the dosage and the drug follows Michaelis-Menten kinetics. The average adult half-life is about 24 hours. Steady-state concentrations are reached in 5-10 days.

Children and Adults: Toxicity is measured clinically, and some patients require levels outside the suggested therapeutic range

Therapeutic range:

Total phenytoin: 10-20 mcg/mL (children and adults), 8-15 mcg/mL (neonates)

Concentrations of 5-10 mcg/mL may be therapeutic for some patients but concentrations <5 mcg/mL are not likely to be effective

50% of patients show decreased frequency of seizures at concentrations >10 mcg/mL

86% of patients show decreased frequency of seizures at concentrations >15 mcg/mL

Add another anticonvulsant if satisfactory therapeutic response is not achieved with a phenytoin concentration of 20 mcg/mL

Free phenytoin: 1-2.5 mcg/mL

Total phenytoin:

Toxic: >30 mcg/mL (SI: <120-200 micromole/L)

Lethal: >100 mcg/mL (SI: >400 micromole/L)

When to draw levels: This is dependent on the disease state being treated and the clinical condition of the patient

Key points:

Slow absorption of extended capsules and prolonged half-life minimize fluctuations between peak and trough concentrations, timing of sampling not crucial

Trough concentrations are generally recommended for routine monitoring. Daily levels are not necessary and may result in incorrect dosage adjustments. If it is determined essential to monitor free phenytoin concentrations, concomitant monitoring of total phenytoin concentrations is not necessary and expensive.

After a loading dose: If rapid therapeutic levels are needed, initial levels may be drawn after 1 hour (I.V. loading dose) or within 24 hours (oral loading dose) to aid in determining maintenance dose or need to reload.

Rapid achievement: Draw within 2-3 days of therapy initiation to ensure that the patient's metabolism is not remarkably different from that which would be predicted by average literature-derived pharmacokinetic parameters; early levels should be used cautiously in design of new dosing regimens

Second concentration: Draw within 6-7 days with subsequent doses of phenytoin adjusted accordingly

If plasma concentrations have not changed over a 3- to 5-day period, monitoring interval may be increased to once weekly in the acute clinical setting

In stable patients requiring long-term therapy, generally monitor levels at 3- to 12-month intervals

Adjustment of serum concentration: See tables.

Note: Although it is ideal to obtain free phenytoin concentrations to assess serum concentrations in patients with hypoalbuminemia or renal failure (Cl_cr ≤10 mL/minute), it may not always be possible. If free phenytoin concentrations are unavailable, the following equations may be utilized in adult patients.

Dietary Considerations

Folic acid: Phenytoin may decrease mucosal uptake of folic acid; to avoid folic acid deficiency and megaloblastic anemia, some clinicians recommend giving patients on anticonvulsants prophylactic doses of folic acid and cyanocobalamin. However, folate supplementation may increase seizures in some patients (dose dependent). Discuss with healthcare provider prior to using any supplements.

Calcium: Hypocalcemia has been reported in patients taking prolonged high-dose therapy with an anticonvulsant. Some clinicians have given an additional 4000 units/week of vitamin D (especially in those receiving poor nutrition and getting no sun exposure) to prevent hypocalcemia.

Vitamin D: Phenytoin interferes with vitamin D metabolism and osteomalacia may result; may need to supplement with vitamin D

Tube feedings: Tube feedings decrease phenytoin absorption. To avoid decreased serum levels with continuous NG feeds, hold feedings for 1-2 hours prior to and 1-2 hours after phenytoin administration, if possible. There is a variety of opinions on how to administer phenytoin with enteral feedings. Be consistent throughout therapy.

Injection may contain sodium.

Patient Education

Take preferably on an empty stomach. Do not crush, break, or chew extended release capsules. Shake liquid suspension well before using. Follow recommended diet, avoid alcohol, and maintain adequate hydration unless instructed to restrict fluid intake. May cause gum or mouth soreness, drowsiness, dizziness, nervousness, headache, nausea, or vomiting. Report chest pain, irregular heartbeat, or palpitations; slurred speech, unsteady gait, coordination difficulties, suicide ideation, or change in mentation; skin rash; unresolved nausea, vomiting, or constipation; swollen glands; swollen, sore, or bleeding gums; unusual bruising or bleeding; acute persistent fatigue; or vision changes.

Geriatric Considerations

Elderly may have reduced hepatic clearance due to age decline in phase I metabolism. Elderly may have low albumin which will increase free fraction and, therefore, pharmacologic response. Monitor closely in those who are hypoalbuminemic. Free fraction measurements advised, also elderly may display a higher incidence of adverse effects (cardiovascular) when using the I.V. loading regimen; therefore, recommended to decrease loading I.V. dose to 25 mg/minute.

Anesthesia and Critical Care Concerns/Other Considerations

Clinical Pearls/Comments: Because phenytoin induces the metabolism of many drugs, it may alter their effective blood concentration.

The vehicle, which contains propylene glycol and ethanol, may cause hypotension, bradycardia, arrhythmias (refractory to defibrillation), or asystole. Phenytoin 50 mg/mL contains propylene glycol 414.4 mg/mL (40% v/v). Rapid intravenous administration may cause hypotension. Infuse at a rate not exceeding 50 mg/minute in adults or 25 mg/minute in the elderly.

Patients on chronic phenytoin therapy (>7 days) require larger and more frequent doses of nondepolarizing neuromuscular blocking agents (NMBAs) to attain the same degree of muscle relaxation. The most likely reason for this reduced sensitivity is increased clearance of the NMBA due to hepatic enzyme induction (Hans, 1997; Richard, 2005; Wright, 2004).

Status Epilepticus: A randomized, double-blind trial (Treiman, 1998) evaluated the efficacy of four treatments in overt status epilepticus. Treatment arms were designed based upon accepted practices of North American neurologists. The treatments were: 1) lorazepam 0.1 mg/kg, 2) diazepam 0.15 mg/kg followed by phenytoin 18 mg/kg, 3) phenytoin 18 mg/kg alone, and 4) phenobarbital 15 mg/kg. Treatment was considered successful if the seizures were terminated (clinically and by EEG) within 20 minutes of start of therapy without seizure recurrence within 60 minutes from the start of therapy. Patients who failed the first treatment received a second and a third, if necessary. Patients did not receive randomized treatments after the first one but the treating physician remained blinded. Treatment success: Lorazepam 64.9%, phenobarbital 58.2%, diazepam/phenytoin 55.8%, and phenytoin alone 43.6%. Using an intention to treat analysis, there was no statistical difference between the groups. Results of subsequent treatments in patients who failed the first therapy indicated that response rate significantly dropped regardless of treatment. Aggregate response rate to the second treatment was 7% and third treatment 2.3%.

Dental Health: Effects on Dental Treatment

Gingival hyperplasia is a common problem observed during the first 6 months of phenytoin therapy appearing as gingivitis or gum inflammation. To minimize severity and growth rate of gingival tissue begin a program of professional cleaning and patient plaque control within 10 days of starting anticonvulsant therapy.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Nursing: Physical Assessment/Monitoring

When discontinuing oral formulation, taper dose gradually; abrupt discontinuance can cause exacerbation of seizures. I.V.: Monitor blood pressure. Infusion site should be monitored closely. Patient should be monitored closely for adverse/toxic results, including suicide ideation.

Oncology: Vesicant

Vesicant

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, extended release, oral, as sodium: 100 mg, 200 mg, 300 mg

Dilantin®: 30 mg, 100 mg

Phenytek®: 200 mg, 300 mg

Injection, solution, as sodium: 50 mg/mL (2 mL, 5 mL)

Suspension, oral: 100 mg/4 mL (4 mL); 125 mg/5 mL (237 mL, 240 mL)

Dilantin-125®: 125 mg/5 mL (240 mL) [contains ethanol ≤0.6%, sodium benzoate; orange-vanilla flavor]

Tablet, chewable, oral:

Dilantin®: 50 mg [scored]

Pricing: U.S. (www.drugstore.com)

Capsules (Dilantin)

30 mg (90): $54.99

100 mg (90): $58.99

Capsules (Phenytek)

200 mg (30): $42.89

300 mg (100): $175.00

Capsules (Phenytoin Sodium Extended)

100 mg (90): $31.99

Chewable (Dilantin Infatabs)

50 mg (90): $63.99

Suspension (Dilantin)

125 mg/5 mL (237): $82.99

Suspension (Phenytoin)

125 mg/5 mL (237): $28.98

References

Abernethy DR and Greenblatt DJ, “Phenytoin Disposition in Obesity. Determination of Loading Dose,” Arch Neurol, 1985, 42(5):468-71.

American Academy of Pediatrics Committee on Drugs, "Transfer of Drugs and Other Chemicals Into Human Milk," Pediatrics, 2001, 108(3):776-89.

Au Yeung SC and Ensom MH, “Phenytoin and Enteral Feedings: Does Evidence Support an Interaction?” Ann Pharmacother, 2000, 34(7-8):896-905.

Bauer LA and Blouin RA, “Phenytoin Michaelis-Menten Pharmacokinetics in Caucasian Pediatric Patients,” Clin Pharmacokinet, 1983, 8(6):545-9.

Berigan T and Watt TJ, “Dilantin® Toxicity Presenting as Mutism Following Severe Head Injury: Case Report,” Mil Med, 1994, 159(7):533-4.

Black J, Hannaman T, and Malone C, “The Relationship of Serum Albumin Level to Phenytoin Toxicity,” J Clin Pharmacol, 1987, 27(3):249-50.

Bleck TB, Seizures, Stroke, and Other Neurologic Emergencies. In: Zimmerman JL, Roberts PR, eds. Multidisciplinary Critical Care Review, Des Plains, IL: Society of Critical Care Medicine; 2003:325-34.

Boucher BA, Feler CA, Dean JC, et al, "The Safety, Tolerability, and Pharmacokinetics of Fosphenytoin After Intramuscular and Intravenous Administration in Neurosurgery Patients," Pharmacotherapy, 1996, 16(4):638-45.

Chapman MG, Smith M, and Hirsch NP, “Status Epilepticus,” Anaesthesia, 2001, 56(7):648-59.

Chiba K, Ishizaki T, Miura H, et al, “Michaelis-Menten Pharmacokinetics of Diphenylhydantoin and Application in the Pediatric Age Patient,” J Pediatr, 1980, 96(3 Pt 1):479-84.

Dela Cruz FG, Kanter MZ, Fischer JH, et al, “Efficacy of Individualized Phenytoin Sodium Loading Doses Administered by Intravenous Infusion,” Clin Pharm, 1988, 7(3):219-24.

Dooley G and Vasan N, “Dilantin® Hyperplasia: A Review of the Literature,” J N Z Soc Periodontol, 1989, 68:19-22.

Doyle MF, Anderson S, Cerrezuela C, et al, “Sezary Syndrome Associated With Phenytoin Therapy,” Acta Haematol, 1994, 92(4):204-7.

Erstad BL, “Dosing of Medications in Morbidly Obese Patients in the Intensive Care Unit Setting,” Intensive Care Med, 2004, 30(1):18-32.

Erstad BL, “Which Weight for Weight-Based Dosage Regimens in Obese Patients?” Am J Health-Syst Pharm, 2002, 59:(21)2105-10.

Hagg S and Spigset O, “Anticonvulsant Use During Lactation,” Drug Saf, 2000, 22(6):425-40.

Hans P, Brichant JF, Pieron F, et al, “Elevated Plasma Alpha 1-Acid Glycoprotein Levels: Lack of Connection to Resistance to Vecuronium Blockade Induced by Anticonvulsant Therapy,” J Neurosurg Anesthesiol, 1997, 9(1):3-7.

Iacopino AM, Doxey D, Cutler CW, et al, “Phenytoin and Cyclosporine A Specifically Regulate Macrophage Phenotype and Expression of Platelet-Derived Growth Factor and Interleukin-1 In Vitro and In Vivo: Possible Molecular Mechanism of Drug-Induced Gingival Hyperplasia,” J Periodontol, 1997, 68(1):73-83.

Kerrick JM, Wolff DL, and Graves NM, “Predicting Unbound Phenytoin Concentrations in Patients Receiving Valproic Acid: A Comparison of Two Prediction Methods,” Ann Pharmacother, 1995, 29(5):470-4.

Lombardi TP, Gailey RA, and Bryant BG, “Phenytoin Overdose in Neonate Attributable to Product Packaging Similarities,” Am J Hosp Pharm, 1989, 46(10):1999-2000.

Lowenstein DH, “Treatment Options for Status Epilepticus,” Curr Opin Pharmacol, 2005, 5(3):334-9.

Manno EM, “New Management Strategies in the Treatment of Status Epilepticus,” Mayo Clin Proc, 2003, 78(4):508-18.

Mansur LI, Murrow RW, Garrelts JC, et al, “Rebound of Plasma Free Phenytoin Concentration Following Plasmapheresis in a Patient With Thrombotic Thrombocytopenic Purpura,” Ann Pharmacother, 1995, 29(6):592-5.

McAuley JW and Anderson GD, “Treatment of Epilepsy in Women of Reproductive Age: Pharmacokinetic Considerations,” Clin Pharmacokinet, 2002, 41(8):559-79.

Meek PD, Davis SN, Collins DM, et al, "Guidelines for Nonemergency Use of Parenteral Phenytoin Products: Proceedings of an Expert Panel Consensus Process. Panel on Nonemergency Use of Parenteral Phenytoin Products," Arch Intern Med, 1999, 159(22):2639-44.

Nussinovitch M, Soen G, Volovitz B, et al, “Urinary Retention Related to Phenytoin Therapy,” Clin Pediatr (Phila), 1995, 34(7):382-3.

Pihlstrom BL, “Prevention and Treatment of Dilantin-Associated Gingival Enlargement,” Compendium, 1990, 14:S506-10.

“Practice Parameter: Management Issues for Women With Epilepsy (Summary Statement). Report of the Quality Standards Subcommittee of the American Academy of Neurology,” Epilepsia, 1998, 39(11):1226-31.

Rabinowicz AL, Hinton DR, Dyck P, et al, “High-Dose Tamoxifen in Treatment of Brain Tumors: Interaction With Antiepileptic Drugs,” Epilepsia, 1995, 36(5):513-5.

Richard A, Girard F, Girard DC, et al, “Cisatracurium-Induced Neuromuscular Blockade is Affected by Chronic Phenytoin or Carbamazepine Treatment in Neurosurgical Patients,” Anesth Analg, 2005, 100(2):538-44.

Rowden AM, Spoor JE, Bertino JS Jr, “The Effect of Activated Charcoal on Phenytoin Pharmacokinetics,” Ann Emerg Med, 1990, 19(10):1144-7.

Saito K, Mori S, Iwakura M, et al, “Immunohistochemical Localization of Transforming Growth Factor Beta, Basic Fibroblast Growth Factor and Heparin Sulphate Glycosaminoglycan in Gingival Hyperplasia Induced by Nifedipine and Phenytoin,” J Periodontal Res, 1996, 31(8):545-5.

Sankar JM, Agarwal R, Deorari A, et al, “Management of Neonatal Seizures,” Indian J Pediatr, 2010, 77(10):1129–35.

Shields WD, “Status Epilepticus,” Pediatr Clin of North Am, 1989, 36(2):383-93.

Soriano SG, Sullivan LJ, Venkatakrishnan K, et al, "Pharmacokinetics and Pharmacodynamics of Vecuronium in Children Receiving Phenytoin or Carbamazepine for Chronic Anticonvulsant Therapy," Br J Anaesth, 2001, 86(2):223-9.

Suzuki Y, Mimaki T, Cox S, et al, “Phenytoin Age-Dose-Concentration Relationship in Children,” Ther Drug Monit, 1994, 16(2):145-50.

“Treatment of Convulsive Status Epilepticus. Recommendations of the Epilepsy Foundation of America's Working Group on Status Epilepticus,” JAMA, 1993, 270(7):854-9.

Treiman DM, Meyers PD, Walton NY, et al, “A Comparison of Four Treatments for Generalized Convulsive Status Epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group,” N Engl J Med, 1998, 339(12):792-8.

Wright PM, McCarthy G, Szenohradszky J, et al, “Influence of Chronic Phenytoin Administration on the Pharmacokinetics and Pharmacodynamics of Vecuronium,” Anesthesiology, 2004, 100(3):626-33.

Zhou LX, Pihlstrom B, Hardwick JP, et al, “Metabolism of Phenytoin by the Gingiva of Normal Humans: The Possible Role of Reactive Metabolites of Phenytoin in the Initiation of Gingival Hyperplasia,” Clin Pharmacol Ther, 1996, 60(2):191-8.

International Brand Names

• Aleviatin (JP, TW)
• Antisacer (PT)
• Clerin (PY)
• Clerin LR (PY)
• Cumatil (CO)
• Di-Hydan (FR, LU)
• Difetoin (HR)
• Dilantin (AU, FR, HK, ID, IN, MY, PH, PK, TH, VE)
• Dintoina (IT)
• Diphedan (HU)
• Ditoin (HK, MY, TH)
• Epamin (BO, BR, CN, CR, DO, EC, GT, MX, NI, PA, PR, SV)
• Epanutin (AE, AT, BE, BF, BH, BJ, CI, CY, CZ, DE, EG, ES, ET, FI, GB, GH, GM, GN, GR, HN, HU, IE, IL, IQ, IR, JO, KE, KW, LB, LR, LU, LY, MA, ML, MR, MU, MW, NE, NG, NL, OM, PL, QA, SA, SC, SD, SE, SL, SN, SY, TN, TR, TZ, UG, UY, YE, ZA, ZM, ZW)
• Epilan-D (AT, BG, CZ)
• Epinat (NO)
• Eptoin (IN)
• Felantin (PE)
• Fenatoin NM (SE)
• Fenidantoin S (MX)
• Fenitin (PH)
• Fenitoina (ES)
• Fenitoina Rubio (ES)
• Fenitron (MX)
• Fenytoin (DE, DK)
• Fomiken (MX)
• Hidanil (CO)
• Hidantoína (MX)
• Hydantin (FI)
• Hydantoin (KP)
• Hydantol (JP)
• Ikaphen (ID)
• Kutoin (ID)
• Lantidin (PH)
• Lehydan (SE)
• Movileps (ID)
• Neosidantoina (ES)
• Pepsytoin-100 (TH)
• Phenhydan (AT, CH, DE, EE, HU, LU)
• Phenilep (ID)
• Phenlin (TW)
• Pyoredol (AR, FR)
• Sinergina (ES)
• Utoin (TH)

Lexi-Comp.com

Last full review/revision March 2012