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Product Name
:
PHENYTOIN
Chemical Name
:
Phenytoin Soduim
Therapeutic Category
:
Central nervous system drugs
Pharmacologic Category
:
Anticonvulsant, Hydantoin
Pharmaceutical Form
:
Ampoule
Composition
:
Phenytoin Soduim 250mg/5ml
Dosing
 
Dosing: Adult
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.: 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.
Neurosurgery (prophylactic): 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: Pediatric

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

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Phenytoin level in serum may be difficult to interpret in renal failure. Monitoring of free (unbound) concentrations or adjustment to allow interpretation is recommended.

Dosing: Hepatic Impairment

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.
Use
 
Management of generalized tonic-clonic (grand mal), complex partial seizures; prevention of seizures following head trauma/neurosurgery
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
Contraindications
 
Hypersensitivity to phenytoin, other hydantoins, or any component of the formulation; pregnancy
Warnings / Precautions Drug
 
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.
Metabolism/Transport Effects
Substrate of CYP2C9 (major), 2C19 (major), 3A4 (minor); Induces CYP2B6 (strong), 2C8 (strong), 2C9 (strong), 2C19 (strong), 3A4 (strong)
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): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Allopurinol: May increase the serum concentration of Anticonvulsants (Hydantoin). Risk C: Monitor therapy
Amiodarone: Phenytoin may decrease the serum concentration of Amiodarone. Amiodarone may increase the serum concentration of Phenytoin. 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): May increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Antifungal Agents (Azole Derivatives, Systemic). Risk D: Consider therapy modification
Barbiturates: May decrease the serum concentration of Phenytoin. 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
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
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: Phenytoin may decrease the serum concentration of CarBAMazepine. CarBAMazepine may decrease the serum concentration of Phenytoin. CarBAMazepine may increase the serum concentration of Phenytoin. Possibly by competitive inhibition at sites of metabolism. 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. CYP3A4 Inducers (Strong) may decrease the serum concentration of Clarithromycin. Clarithromycin may increase the serum concentration of CYP3A4 Inducers (Strong). 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 (High risk): CYP2C8 Inducers (Highly Effective) may increase the metabolism of CYP2C8 Substrates (High risk). Risk C: Monitor therapy
CYP2C9 Inducers (Highly Effective): May increase the metabolism of CYP2C9 Substrates (High risk). Risk C: Monitor therapy
CYP2C9 Inhibitors (Moderate): May decrease the metabolism of CYP2C9 Substrates (High risk). Risk C: Monitor therapy
CYP2C9 Inhibitors (Strong): May decrease the metabolism of CYP2C9 Substrates (High risk). Risk D: Consider therapy modification
CYP2C9 Substrates (High risk): CYP2C9 Inducers (Highly Effective) may increase the metabolism of CYP2C9 Substrates (High risk). 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
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
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 (Highly Effective) may decrease the serum concentration of Diclofenac. Risk C: Monitor therapy
Disopyramide: Phenytoin may decrease the serum concentration of Disopyramide. Risk D: Consider therapy modification
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: Phenytoin may decrease the serum concentration of Divalproex. Divalproex may decrease the serum concentration of Phenytoin. 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: Phenytoin may decrease the serum concentration of Efavirenz. Efavirenz may increase the serum concentration of Phenytoin. Risk D: Consider therapy modification
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: Phenytoin may decrease the serum concentration of Felbamate. Felbamate may increase the serum concentration of Phenytoin. 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: Phenytoin may increase the serum concentration of Fosamprenavir. Specifically, phenytoin may increase the concentration of the active metabolite amprenavir. Fosamprenavir may decrease the serum concentration of Phenytoin. The active amprenavir metabolite is likely responsible for this effect. 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
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: Phenytoin may decrease the serum concentration of Lopinavir. Lopinavir may decrease the serum concentration of Phenytoin. 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
MetroNIDAZOLE: Phenytoin may decrease the serum concentration of MetroNIDAZOLE. MetroNIDAZOLE may increase the serum concentration of Phenytoin. Risk C: Monitor therapy
MetroNIDAZOLE (Systemic): Phenytoin may decrease the serum concentration of MetroNIDAZOLE (Systemic). MetroNIDAZOLE (Systemic) may increase the serum concentration of Phenytoin. 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
Nilotinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Nilotinib. Risk X: Avoid combination
OXcarbazepine: Phenytoin may decrease the serum concentration of OXcarbazepine. OXcarbazepine may increase the serum concentration of Phenytoin. 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 (High risk). 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
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: May decrease the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Ritonavir. Risk D: Consider therapy modification
Rivaroxaban: CYP3A4 Inducers (Strong) may decrease the serum concentration of Rivaroxaban. Management: Avoid concurrent use of rivaroxaban and strong CYP3A4 inducers when possible. If such a combination is used, the U.S. labeling recommends an increase in rivaroxaban dose; Canadian labeling does not make specific dose increase recommendations. Risk D: Consider therapy modification
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: May increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Rufinamide. 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: May increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Sertraline. Risk C: Monitor therapy
Sirolimus: Phenytoin may decrease the serum concentration of Sirolimus. Risk D: Consider therapy modification
SORAfenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of SORAfenib. Risk D: Consider therapy modification
Sulfonamide Derivatives: May increase the serum concentration of Phenytoin. Risk C: Monitor therapy
Tacrolimus: May increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Tacrolimus. Risk C: Monitor therapy
Tacrolimus (Systemic): May increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Tacrolimus (Systemic). 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: May decrease the serum concentration of Phenytoin. Telaprevir may increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Telaprevir. 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: Phenytoin may decrease the serum concentration of Theophylline Derivatives. Theophylline Derivatives may decrease the serum concentration of Phenytoin. 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: May decrease the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Tipranavir. 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: May increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Topiramate. Risk C: Monitor therapy
Treprostinil: CYP2C8 Inducers (Highly Effective) 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
Ethanol/Nutrition/Herb Interactions
Ethanol:
Acute use: Avoid or limit ethanol (inhibits metabolism of phenytoin). Ethanol may also increase CNS depression; monitor for increased effects with coadministration. Caution patients about effects.
Chronic use: Avoid or limit ethanol (stimulates metabolism of phenytoin).
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; hold tube feedings 1-2 hours before and 1-2 hours after phenytoin administration. May decrease calcium, folic acid, and vitamin D levels.
Herb/Nutraceutical: Avoid evening primrose (seizure threshold decreased). Avoid valerian, St John's wort, kava kava, gotu kola (may increase CNS depression).
Pregnancy
 
D
Pregnancy Implications
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.
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.
Monitoring Parameters
 
Blood pressure, vital signs (with I.V. use); plasma phenytoin level, CBC, liver function. Note: If available, free phenytoin concentrations should be obtained in patients with renal impairment and/or hypoalbuminemia. If free phenytoin levels are unavailable, the adjusted total level is based upon equations in adult patients. Monitor for suicidality (eg, suicidal thoughts, depression, behavioral changes).
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 (Clcr ≤10 mL/minute), it may not always be possible. If free phenytoin concentrations are unavailable, the following equations may be utilized in adult patients.

Adjustment of Serum Concentration in Adults With Low Serum Albumin


Measured Total Phenytoin Concentration
(mcg/mL)
Patient's Serum Albumin (g/dL)
 
3.5
3
2.5
2
 
Adjusted Total Phenytoin Concentration (mcg/mL)1
 

1Adjusted concentration = measured total concentration divided by [(0.2 x albumin) + 0.1].

 
5
6
7
8
10
 
10
13
14
17
20
 
15
19
21
25
30
 

Adjustment of Serum Concentration in Adults With Renal Failure (Clcr ≤10 mL/min)


Measured Total Phenytoin Concentration
(mcg/mL)
Patient's Serum Albumin (g/dL)
 
4
3.5
3
2.5
2
 
Adjusted Total Phenytoin Concentration (mcg/mL)1
 

1Adjusted concentration = measured total concentration divided by [(0.1 x albumin) + 0.1].

 
5
10
11
13
14
17
 
10
20
22
25
29
33
 
15
30
33
38
43
50
 
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
Distribution: Vd:
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), Clcr <25 mL/minute (unbound fraction is increased two- to threefold in uremia)
Metabolism: Follows dose-dependent capacity-limited (Michaelis-Menten) pharmacokinetics with increased Vmax in infants >6 months of age and children versus adults; major metabolite (via oxidation), HPPA, undergoes enterohepatic recirculation
Bioavailability: Form dependent
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
 
   
 
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