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Phenytoin: Drug information

Phenytoin: Drug information
2024© UpToDate, Inc. and its affiliates and/or licensors. All Rights Reserved.
For additional information see "Phenytoin: Patient drug information" and "Phenytoin: Pediatric drug information"

For abbreviations, symbols, and age group definitions show table
ALERT: US Boxed Warning
Cardiovascular risk associated with rapid infusion (injection):

The rate of intravenous phenytoin administration should not exceed 50 mg/minute in adults and 1 to 3 mg/kg/minute (or 50 mg/minute, whichever is slower) in pediatric patients because of the risk of severe hypotension and cardiac arrhythmias. Careful cardiac monitoring is needed during and after administering intravenous phenytoin. Although the risk of cardiovascular toxicity increases with infusion rates above the recommended infusion rate, these events have also been reported at or below the recommended infusion rate. Reduction in rate of administration or discontinuation of dosing may be needed.

Brand Names: US
  • Dilantin;
  • Dilantin Infatabs;
  • Dilantin-125;
  • Phenytek;
  • Phenytoin Infatabs
Brand Names: Canada
  • Dilantin;
  • Dilantin Infatabs;
  • Dilantin-125;
  • Dilantin-30;
  • TARO-Phenytoin;
  • Tremytoine
Pharmacologic Category
  • Antiseizure Agent, Hydantoin
Dosing: Adult

Dosage guidance:

Safety: Before use, consider testing for HLA-B*1502 allele in patients at increased risk of developing serious cutaneous adverse reactions (ie, those of Asian ancestry, including South Asian Indian patients) (Ref).

Dosage form information: Doses for capsules (extended release) and injection are expressed as phenytoin sodium salt. Doses for oral suspension and chewable tablets are expressed as phenytoin base.

Seizures

Seizures:

Craniotomy, seizure prophylaxis (alternative agent):

Loading dose: IV: 15 mg/kg at a rate of ≤50 mg/minute prior to incision; maximum dose: 2 g (Ref).

Postoperative prophylaxis: IV, Oral: 5 to 6 mg/kg/day in 2 to 3 divided doses; usual daily dose: 300 to 400 mg; adjust dose based on response and serum concentrations (Ref). To ensure optimal absorption, individual oral doses should not exceed 400 mg (Ref). Note: Duration individualized based on underlying intracranial pathology and other clinical considerations (Ref).

Focal (partial) onset seizures and generalized onset seizures: Note: A loading dose is suggested for patients who require rapid attainment of a therapeutic serum level; in the absence of a loading dose, full effect is typically achieved after 1 to 3 weeks (ie, when steady-state serum concentrations are reached). FDA approved for generalized tonic-clonic and complex partial seizures; may be used off label for other seizure types.

Fixed (nonweight-based) dosing (manufacturer's labeling):

Loading dose (optional) (phenytoin naive): Oral (capsule [extended release]): 1 g divided into 3 doses (eg, 400 mg, 300 mg, 300 mg) administered at 2-hour intervals; begin maintenance dose 24 hours after first loading dose. To ensure optimal absorption, individual oral doses should not exceed 400 mg (Ref).

Maintenance dose: Oral (capsule [extended release]): Initial: 100 mg 3 to 4 times daily; adjust dose based on response and serum concentrations. After an effective maintenance dose is established, may consider converting stable patients to once-daily dosing. To ensure optimal absorption, individual oral doses should not exceed 400 mg (Ref).

Weight-based dosing (off-label): Note: May be used to individualize loading dose and estimate initial maintenance dose requirements according to body weight.

Loading dose (optional) (phenytoin naive): IV, Oral: 15 mg/kg given in 1 to 3 divided doses over 24 hours; usual total loading dose is 1 to 1.5 g (Ref); begin maintenance dose 8 to 12 hours after loading dose. To ensure optimal absorption, individual oral doses should not exceed 400 mg (Ref).

Maintenance dose: IV, Oral: Initial: 4 to 7 mg/kg/day (usual 300 to 400 mg/day) given in 2 to 4 divided doses; adjust dose based on response and serum concentrations (Ref). Some experts recommend initiating maintenance therapy with 5 mg/kg/day in 2 divided doses (Ref). After an effective maintenance dose is established, may consider converting stable patients to once-daily dosing (ER capsule). A maximum dose has not been established; caution should be used in prescribing maintenance doses >600 mg/day. To ensure optimal absorption, individual oral doses should not exceed 400 mg (Ref).

Traumatic brain injury, prevention of early posttraumatic seizure (alternative agent) (off-label use): Note: For use in select patients at elevated risk of early seizures with concerns for secondary complications. Dosing may be institution specific; refer to institutional protocols.

Loading dose: IV: 17 to 20 mg/kg at a rate of ≤50 mg/minute; maximum dose: 2 g (Ref); begin maintenance dose 8 to 12 hours after loading dose.

Maintenance dose: IV, Oral: 100 mg every 8 hours (Ref) or 5 mg/kg/day (round to the nearest 100 mg) divided every 8 hours (Ref). To ensure optimal absorption, individual oral doses should not exceed 400 mg (Ref). Note: Duration of prophylaxis varies, generally short-term use (eg, ~7 days) (Ref).

Status epilepticus

Status epilepticus (convulsive and nonconvulsive) (alternative agent): Note: If available, fosphenytoin is preferred because it is better tolerated and can be administered more rapidly than phenytoin (Ref). Generally administered as part of initial therapy with or immediately after a benzodiazepine (eg, lorazepam IV) (Ref).

Loading dose (phenytoin naive): IV: 20 mg/kg at a rate of 25 to 50 mg/minute in combination with a parenteral benzodiazepine (eg, lorazepam) under continuous cardiac and blood pressure monitoring; reduce infusion rate if significant adverse events occur; if necessary, may give an additional dose of 5 to 10 mg/kg 10 minutes after the loading dose; maximum total loading dose: 30 mg/kg (Ref). Begin maintenance dose 8 to 12 hours after loading dose.

Maintenance dose: IV, Oral: Initial: 4 to 7 mg/kg/day (usual 300 to 400 mg/day) given in 2 to 4 divided doses; adjust dose based on response and serum concentrations (Ref). Some experts recommend initiating maintenance therapy with 5 mg/kg/day in 2 divided doses (Ref). A maximum dose has not been established; caution should be used in prescribing maintenance doses >600 mg/day. (See Focal (partial) onset seizures and generalized onset seizures for nonweight-based maintenance dose). To ensure optimal absorption, individual oral doses should not exceed 400 mg (Ref).

Trigeminal neuralgia, rescue therapy

Trigeminal neuralgia, rescue therapy (off-label use):

Note: For use during oral medication titration and/or acute exacerbation of refractory trigeminal neuralgia (Ref).

IV: 250 mg to 1 g as a one-time dose or 15 mg/kg (maximum dose not established) over 30 to 120 minutes; administer at a rate ≤50 mg/minute (Ref).

Discontinuation of therapy: In chronic therapy, phenytoin should be withdrawn gradually over 2 to 6 months or gradually transitioned to another antiseizure agent to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal (Ref).

Dosage form conversions:

Between IV and oral capsule formulations: Convert using the same total daily dose. Oral capsules are ~10% less bioavailable than injectable formulation; dosage adjustments and closer serum monitoring may be necessary. To ensure optimal absorption, individual oral doses should not exceed 400 mg (Ref).

Between phenytoin base (oral suspension, chewable tablets) and phenytoin sodium (capsule): Dosage adjustments and closer serum monitoring may be necessary when switching between formulations.

Conversion: Phenytoin base ~92 mg is equivalent to phenytoin sodium 100 mg.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

Note: Phenytoin is primarily metabolized by the liver to inactive metabolites with <5% of active drug excreted unchanged in the urine (Ref), making routine dose adjustments for kidney dysfunction unnecessary (Ref). Monitoring total serum phenytoin concentrations in patients with severe kidney dysfunction is not recommended due to increased free (unbound) fraction secondary to displacement by uremic toxins. Instead, free serum concentrations should be monitored in patients with severe kidney dysfunction (eg, CrCl <25 mL/minute) or those receiving renal replacement therapies (Ref).

Altered kidney function: IV, Oral: No dosage adjustment necessary for any degree of kidney dysfunction (Ref).

Hemodialysis, intermittent (thrice weekly):

Extent of dialyzability is variable and may be dependent on filter type (Ref): IV, Oral: No dosage adjustment necessary (Ref).

Note: In general supplementation, posthemodialysis is not necessary. However, some patients (eg, those with documented low free serum concentrations posthemodialysis, those who have frequent seizures despite medication) may require supplemental doses postdialysis guided by free serum concentration monitoring (Ref).

Peritoneal dialysis: Not dialyzed (Ref): IV, Oral: No dosage adjustment necessary (Ref).

CRRT:

Note: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Recommendations are based on high-flux dialyzers and effluent flow rates of 20 to 25 mL/kg/hour (or ~1,500 to 3,000 mL/hour), unless otherwise noted. Appropriate dosing requires consideration of adequate drug concentrations and of initial loading doses. Close monitoring of response and adverse reactions (eg, neurotoxicity) is important.

IV, Oral: No initial dosage adjustment necessary. Monitor free phenytoin concentrations closely, as some removal by CRRT is expected (Ref).

PIRRT (eg, sustained, low-efficiency diafiltration):

Note: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Appropriate dosing requires consideration of adequate drug concentrations and of initial loading doses. Close monitoring of response and adverse reactions (eg, neurotoxicity) is important.

IV, Oral: No initial dosage adjustment necessary. Monitor free phenytoin concentrations closely, as some phenytoin removal by PIRRT may occur. Supplemental doses may be required in some patients (eg, those with documented low free serum concentrations post-PIRRT, those who have frequent seizures despite medication) guided by free serum concentration monitoring (Ref).

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling; undergoes hepatic metabolism and clearance may be decreased. Monitor free phenytoin levels closely. Dosage adjustments may be necessary.

Dosing: Obesity: Adult

The recommendations for dosing in patients with obesity are based upon the best available evidence and clinical expertise. Senior Editorial Team: Jeffrey F. Barletta, PharmD, FCCM; Manjunath P. Pai, PharmD, FCP; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC.

Class 1 or 2 obesity (BMI 30 to 39 kg/m2): No dosage adjustment necessary; use a standard, non–weight-based dose (based on indication) or actual body weight for weight-based dose calculations (Ref). Refer to adult dosing for indication-specific doses.

Class 3 obesity (BMI 40 kg/m2):

Status epilepticus (convulsive and nonconvulsive) (alternative agent):

Loading dose: IV: Initial: 15 mg/kg (using actual body weight; no maximum dose); administer at a rate of ≤50 mg/minute; doses up to 2.3 g have been reported (Ref); begin maintenance dose 8 to 12 hours after loading dose.

Maintenance dose: IV, Oral: Initial: 4 to 7 mg/kg/day (using ideal body weight; usual dose: 300 to 400 mg/day) given in 2 to 4 divided doses; adjust dose based on response and serum concentrations (Ref). A maximum dose has not been established; caution should be used in prescribing maintenance doses >600 mg/day.

Other indications: Evidence currently does not exist for other indications in patients with obesity; however, the same dosing principles and use of actual body weight (for loading doses) and IBW (for maintenance doses) with subsequent appropriate therapeutic drug monitoring would apply (Ref).

Rationale for recommendations:

For loading doses, use of actual body weight in patients who are obese is recommended to ensure adequate concentrations and efficacy. For maintenance doses, use of ideal body weight (IBW) for initial dosing is recommended to prevent toxicity (Ref). There is a paucity of studies evaluating the influence of obesity on phenytoin dosing or pharmacokinetics. Evidence from one small pharmacokinetic study comparing patients with obesity to nonobese patients demonstrated a slightly increased Vd (0.68 ± 0.03 L/kg vs 0.61 ± 0.02 L/kg) in patients with obesity and distribution into weight in excess of IBW was disproportionately greater (by a factor of 1.33) (Ref). Based on an unpublished comparison, a loading dose based on actual body weight (dose = 15 mg/kg) compared to an approach based on IBW (dose = [14 × IBW] + [19 × (actual body weight − IBW)]) yielded similar dose estimates, when factoring population height and weight distributions (Ref).

Dosing: Older Adult

Refer to adult dosing; clearance is decreased in geriatric patients; lower doses or less frequent dosing may be required.

Dosing: Pediatric

(For additional information see "Phenytoin: Pediatric drug information")

Dosage guidance:

Dosing: Doses for capsules (extended release) and injection are expressed as phenytoin sodium salt. Doses for oral suspension and chewable tablets are expressed as phenytoin base.

Dosage form information: Phenytoin base (eg, oral suspension, chewable tablets) contains ~8% more active drug than phenytoin sodium (~92 mg base is equivalent to 100 mg phenytoin sodium).

Clinical considerations: When converting from IV phenytoin/fosphenytoin to phenytoin oral suspension, increased serum concentration monitoring and dosages may be necessary, especially in patients receiving administration via a feeding tube. Dosage adjustments for non-acute seizures should typically be made no more frequently than every 7 days.

Status epilepticus

Status epilepticus: Infants, Children, and Adolescents: Loading dose: IV: 20 mg/kg in a single or divided doses; maximum dose: 1,000 mg/dose; begin maintenance therapy usually 12 hours after dose (Ref). An additional load of 5 to 10 mg/kg if status epilepticus is not resolved has been used; however, some experts recommend trying another agent once a total loading dose of 20 mg/kg has been given (Ref).

Seizures, focal onset seizures and generalized onset seizures

Seizures, focal (partial) onset seizures and generalized onset seizures:

Infants, Children, and Adolescents:

Loading dose (optional, not routinely used; reserved for patients if not currently on phenytoin): IV, Oral: 15 to 20 mg/kg; if currently on phenytoin, reloading dose should be based upon serum concentrations and recent dosing history; an oral loading dose should be divided into 3 doses and administered every 2 to 4 hours to decrease GI adverse effects and to maximize oral absorption.

Maintenance therapy: IV, Oral: Initial: 5 mg/kg/day in divided doses (based upon dosage form, see below); usual range: 4 to 8 mg/kg/day; maximum daily dose: 300 mg/day. Some experts suggest higher maintenance doses (8 to 10 mg/kg/day) may be necessary in infants and young children (Ref).

Usual dosing range (Ref):

6 months to 3 years: IV, Oral: 8 to 10 mg/kg/day.

4 to 6 years: IV, Oral: 7.5 to 9 mg/kg/day.

7 to 9 years: IV, Oral: 7 to 8 mg/kg/day.

10 to 16 years: IV, Oral: 6 to 7 mg/kg/day.

Dosing interval (product specific):

Immediate-release preparations (including injection, suspension, and chewable tablets): Divide daily dose into 2 to 3 doses per day.

Extended-release preparations: In most pediatric patients, usually dosed every 12 hours; however, in adolescent patients with sufficiently long half-life, may be dosed every 24 hours.

Seizure prophylaxis, traumatic brain injury

Seizure prophylaxis, traumatic brain injury (TBI): Limited data available; efficacy results variable (Ref):

Note: Current guidelines suggest that prophylactic fosphenytoin/phenytoin may be considered to reduce the incidence of early (within 7 days) posttraumatic seizures in pediatric patients with severe traumatic brain injuries; it has not been shown to reduce mortality, the risk of long-term seizures nor improve neurologic outcome (Ref); fosphenytoin is preferred over phenytoin if available due to lower risk of adverse effects (Ref).

Infants, Children, and Adolescents: IV: Initial: 18 to 20 mg/kg over 20 minutes, followed by 6 mg/kg/day divided every 8 hours (Young 2004; manufacturer's labeling); dosing reported in a double-blind, placebo-controlled trial of 102 pediatric patients (n=46 treatment group; median age: 6.4 years); prophylaxis was used for 48 hours in the trials and showed no significant difference in seizure frequency between groups; however, the trial was stopped early due to a very low seizure frequency among both study groups (Ref). One retrospective review including 133 TBI patients who received antiseizure prophylaxis (large majority received either fosphenytoin/phenytoin) reported efficacy (ie, no seizure or impact only seizure) in 125 (94%) of patients (Ref). In another retrospective trial, reduced seizure frequency with prophylactic phenytoin use was described (Ref).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling; <5% excreted as unchanged drug. Phenytoin serum concentrations may be difficult to interpret in renal failure. Monitoring of free (unbound) concentrations or adjustment to allow interpretation is recommended.

Hemodialysis: Based on adult experience, dose supplementation may be required with high-efficiency dialyzers; monitor serum concentrations. Serum concentration may be difficult to interpret in renal failure (Ref).

Dosing: Hepatic Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling; undergoes hepatic metabolism and clearance may be decreased. Monitor free phenytoin levels closely. Dosage adjustments may be necessary.

Adverse Reactions (Significant): Considerations
Blood dyscrasias

Hematologic effects, including agranulocytosis, granulocytopenia, leukopenia, macrocytosis, megaloblastic anemia, pancytopenia, pure red cell aplasia, and thrombocytopenia with or without bone marrow depression, have infrequently been reported with phenytoin and are rarely fatal in adult and pediatric patients. Additionally, hyper-homocystinemia has been reported in pediatric patients receiving phenytoin (Ref). The exact incidence of blood dyscrasias is unknown (Ref).

Mechanism: Time-related; megaloblastic anemia may occur due to folic acid deficiency. Aplastic anemia and leukopenia may occur due to direct suppression of bone marrow cell precursors. Thrombocytopenia usually occurs within the setting of other blood dyscrasias (Ref).

Onset: Delayed; blood dyscrasias in general typically occur weeks to months after initiation (Ref). Thrombocytopenia may occur within 2 to 4 weeks after initiation (Ref).

Risk factors:

• Prolonged duration of therapy (Ref)

• Folic acid deficiency (Ref)

• Vitamin B12 deficiency (Ref)

• Patients ≥60 years of age (Ref)

• Concurrent use of medications that cause bone marrow suppression

• Previous history of adverse hematologic reaction to any drug

Cardiovascular effects

Hypotension and severe cardiac arrhythmia, such as bradycardia, heart block, ventricular tachycardia, and ventricular fibrillation progressing to asystole, cardiac arrest, and death, may occur with rapid IV administration in all ages; adverse cardiac events have also been reported at or below the recommended infusion rate (Ref). The incidence of hypotension and bradycardia reported with IV phenytoin in an international drug monitoring program was 0.8% and 0.02%, respectively (Ref). Cardiovascular adverse reactions were uncommon in cases of overdose of oral phenytoin (Ref).

Mechanism: Phenytoin, a Vaughan-Williams class IB antiarrhythmic drug, inhibits sodium currents, which then widens the QRS complex and slows conduction. In addition, the refractory period is shortened, and ventricular automaticity is suppressed (Ref). It also has peripheral vasodilatory and negative inotropic effects, which can lower blood pressure. Rapid IV infusion rates and propylene glycol in IV phenytoin formulations at toxic dosages may lead to bradycardia and asystole (Ref).

Onset: Rapid; related to IV infusion rate (Ref).

Risk factors:

• IV infusion rate (should not exceed 50 mg/minute in adults [or slower in certain adults] and 1 to 3 mg/kg/minute [or 50 mg/minute, whichever is slower] in pediatric patients) (Ref). See "Administration" for more information.

• Older patients (>50 years) (Ref)

• Comorbid cardiac and/or metabolic disorders (Ref)

CNS effects

CNS effects of phenytoin are concentration-dependent and can range from mild symptoms of drowsiness, fatigue, and nystagmus disorder to ataxia, incoordination, and slurred speech in all ages. At very high concentrations, drug-induced seizure activity has been reported (Ref).

Mechanism: At higher serum concentrations, saturation of protein binding occurs and the amount of free phenytoin in the serum is increased. In addition, phenytoin exhibits dose-dependent, non-linear (zero-order) elimination pharmacokinetics. The enzyme system responsible for phenytoin’s hepatic metabolism is saturable at higher serum concentrations resulting in capacity limited metabolism. As a result, small increases in doses can result in substantial elevations in serum concentrations (Ref).

Onset: Varied, related to serum phenytoin concentrations; mostly acute (hours to days) but chronic toxicity may also occur with prolonged use (~ years) (Ref).

Risk factors:

• Higher serum concentrations (Ref)

• Hypoalbuminemia of any cause (eg, kidney or hepatic failure, malnutrition) and uremia (Ref)

• Concurrent administration with CYP2C9 and 2C19 inhibitors (Ref)

• CYP2C9 and 2C19 genetic polymorphisms (Ref)

Gingival hyperplasia or overgrowth

Gingival hyperplasia or overgrowth, also referred to as gingival enlargement, can occur in all ages (Ref). Clinical presentation includes aesthetic changes of the gingival tissues with the potential for pain, tenderness, bleeding, speech disturbances, abnormal tooth movement, problems with dental occlusions, increased dental caries, and periodontal disorders (Ref). The reported prevalence is ~50% in patients with long-term use (Ref).

Mechanism: Time-related; alters extracellular matrix metabolism resulting in increased cell proliferation (Ref). The underlying cause is unclear but is hypothesized to be multifactorial involving the drug, plaque-induced inflammatory changes in the gingival tissues, and genetic factors (Ref).

Onset: Delayed; may occur after 1 month of treatment but occurs most often after 3 months (Ref).

Risk factors:

• Increased plaque index (oral hygiene) (Ref)

• Pediatric patients (Ref)

Hepatotoxicity

Hepatotoxicity including acute hepatitis and acute hepatic failure have been reported in all ages (Ref). Phenytoin is associated with transient increased serum transaminases, which seem to be mostly benign (Ref). Most cases of hepatotoxicity involve hypersensitivity features (eg, rash, fever, lymphadenopathy, eosinophilia) and occur as part of drug reaction with eosinophilia and systemic symptoms (DRESS) (Ref). Hepatotoxicity is generally reversible upon discontinuation of therapy and resolves within 1 to 2 months (Ref).

Mechanism: Unknown; liver injury as part of DRESS may be caused by immune-mediated mechanisms triggered by arene oxide metabolite formation (Ref).

Onset: Varied; typically after 2 to 8 weeks of therapy (Ref), one study reported a median onset of 4 weeks after initiating treatment (Ref).

Risk factors:

• Ethnicity: Black patients (Ref)

• Cross-reactivity: High degree of cross-reactivity exists between aromatic antiseizure medications, including phenytoin, carbamazepine, phenobarbital, primidone, and oxcarbazepine (Ref)

• Family history: Increased probability of hepatotoxicity (as part of DRESS) in family members who develop DRESS (Ref)

Hypersensitivity reactions (delayed)

Phenytoin is associated with a variety of delayed hypersensitivity reactions in all ages, ranging from mild with maculopapular eruption (MPE) (also known as morbilliform rash) to severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) (often referred to as antiseizure medication hypersensitivity syndrome), and acute generalized exanthematous pustulosis (Ref).

Mechanism: Non–dose-related; immunologic. Delayed hypersensitivity reactions, including maculopapular eruptions and SCARs, are T-cell-mediated (Ref).

Onset: Delayed hypersensitivity reactions: varied. Maculopapular rash usually occurs 3 to 20 days after start of therapy (Ref). SCARs usually occur 1 to 12 weeks after initiation (Ref); reexposure may lead to more rapid onset (usually with 1 to 4 days) (Ref).

Risk factors:

• Females: Increased risk for development of maculopapular rash (Ref)

• Genetic factors: Presence of HLA-B*1502 allele increases risk of SJS/TEN in south Asian population (Ref). Other HLA alleles, including HLA-B*1301 and HLA-B*51:01 have been identified as potential risk factors (Ref). CYP2C9 polymorphism may increase the risk of DRESS and SJS/TEN (Ref).

• Family history of DRESS (Ref)

• Reactivation of viruses: Viral reactivation, in particular human herpesvirus 6 (HHV-6) reactivation may be associated with a prolonged and more severe course of DRESS (Ref)

• Cross-reactivity: High degree of cross-reactivity exists between aromatic antiseizure medications, including phenytoin, carbamazepine, phenobarbital, primidone, and oxcarbazepine (Ref). Although chemically distinct, lamotrigine is also associated with DRESS and SJS/TEN, and may be cross-reactive to phenytoin, as shown in patch test studies (Ref).

• Age: Younger pediatric patients <12 years and older adult patients may be at risk for severe SCARs associated with aromatic antiseizure medications, including phenytoin (Ref)

• Cranial irradiation: May increase the risk of TEN/SJS (Ref)

Suicidal ideation/tendencies

Antiseizure medications have been associated with suicidal ideation and tendencies in adult and pediatric patients. From trials of various antiseizure medications across multiple indications, a pooled analysis showed an increased risk of suicidal thoughts/behavior, with an incidence rate of 0.43% in treated patients, regardless of indication, as compared to 0.24% of patients receiving placebo. However, the FDA meta-analysis has been criticized due to several limitations (Ref). The risk of suicide is increased in epilepsy (Ref), but the occurrence of suicidal ideation/tendencies in epilepsy is multifactorial (Ref). While some antiseizure medications (but not all) have been associated with treatment-emergent psychiatric effects such as anxiety and depression, other factors such as post-ictal suicidal behavior and pertinent patient history must also be evaluated to provide an accurate assessment of risk for any individual drug (Ref).

Onset: Varied; peak incidence of suicidality across antiseizure medications (not specific to individual agents) has been noted to occur between 1 and 12 weeks of drug therapy (Ref). A review of clinical trials noted that risk extended from 1 week to 24 weeks of therapy, corresponding to the duration of most trials.

Risk factors:

• History of depression (Ref)

• Use in conditions other than epilepsy or bipolar disorder (Ref)

• In patients with bipolar disorder, risk for repeat suicide attempt was increased in patients with alcohol/substance abuse disorder, rapid cycling, and earlier age at onset of first manic episode (Ref)

• Higher serum concentrations (Ref)

• History of suicidal ideation (Ref)

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

Frequency not defined:

Cardiovascular: Cardiac conduction disorder (depression), circulatory shock

Dermatologic: Bullous dermatitis, exfoliative dermatitis, morbilliform rash, scarlatiniform rash, skin or other tissue necrosis

Endocrine & metabolic: Decreased T4, increased gamma-glutamyl transferase, vitamin D deficiency (associated with chronic treatment)

Gastrointestinal: Constipation, dysgeusia, nausea, swelling of lips, vomiting

Genitourinary: Peyronie's disease

Hematologic & oncologic: Macrocytosis, megaloblastic anemia, purpuric dermatitis

Local: Injection site reaction (“purple glove syndrome”; edema, discoloration, and pain distal to injection site), local inflammation, local irritation, local tissue necrosis, localized tenderness

Nervous system: Cerebral atrophy (elevated serum levels and/or long-term use), cerebral dysfunction (elevated serum levels and/or long-term use), confusion, dizziness, headache, insomnia, nervousness, paresthesia, peripheral neuropathy (associated with chronic treatment), twitching, vertigo

Miscellaneous: Fever, tissue sloughing

Postmarketing:

Cardiovascular: Bradycardia (Earnest 1983), cardiac arrhythmia (Earnest 1983), hypotension (Earnest 1983), polyarteritis nodosa (Yermakov 1983), ventricular fibrillation (Earnest 1983)

Dermatologic: Acute generalized exanthematous pustulosis (Aziz 2010), hypertrichosis, skin rash (Kim 2020), Stevens-Johnson syndrome (Kim 2020), toxic epidermal necrolysis (Frey 2017), urticaria (Kim 2020)

Endocrine & metabolic: Exacerbation of porphyria (Larson 1978, Vidaurre 2017), homocysteinemia (Chandrasekaran 2017), hyperglycemia

Gastrointestinal: Gingival hyperplasia (Arya 2011, Neelathil 2014, Perlik 1995)

Hematologic & oncologic: Agranulocytosis, bone marrow depression, granulocytopenia, hemolytic anemia (Blackburn 1998), Hodgkin lymphoma, homocystinemia (hyperhomocystinemia) (Chandrasekaran 2017), immunoglobulin abnormality, leukopenia, lymphadenopathy, malignant lymphoma, neutropenia (Blackburn 1998), pancytopenia, pseudolymphoma (Riyaz 2015), pure red cell aplasia (Paul 2011), thrombocytopenia (Blackburn 1998)

Hepatic: Acute hepatic failure (Chalasani 2021), cholestatic hepatitis (Chalasani 2021), hepatitis (Chalasani 2021), hepatocellular hepatitis (Chalasani 2021), hepatotoxicity (Chalasani 2021), increased serum transaminases

Hypersensitivity: Anaphylaxis (Polat 2015), angioedema (Duke 2017, Polat 2015)

Immunologic: Drug reaction with eosinophilia and systemic symptoms (Kim 2020)

Nervous system: Asterixis (Chi 2000), ataxia (Farrokh 2018), chorea (Gill 2018), drowsiness (Farrokh 2018), dystonia (Acar 2018), seizure (paradoxical) (Farrokh 2018), slurred speech (Farrokh 2018), suicidal ideation (Pandey 2012), suicidal tendencies (Pandey 2012)

Neuromuscular & skeletal: Bone fracture (Lee 2013), decreased bone mineral density (Lee 2013, Meier 2011), dyskinesia (Montenegro 1999), enlargement of facial features (including coarsening of facial features) (Lefebvre 1972), osteomalacia (Palmer 1977), osteoporosis (Patil 2015), systemic lupus erythematosus (Atwater 2008), tremor

Ophthalmic: Nystagmus disorder (Farrokh 2018)

Contraindications

Hypersensitivity to phenytoin, other hydantoins, or any component of the formulation; concurrent use of delavirdine; history of prior acute hepatotoxicity attributable to phenytoin.

Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Injection: Additional contraindications: Sinus bradycardia, sinoatrial block, second- and third-degree heart block, Adams-Stokes syndrome

Canadian labeling (oral formulation): Additional contraindications (not in US labeling): Sick sinus syndrome, sinus bradycardia, sinoatrial block, second- and third-degree heart block; QT interval prolongation; Adams-Stokes syndrome; or other heart rhythm disorders

Warnings/Precautions

Concerns related to adverse effects:

• Extravasation: Vesicant (intravenous administration); ensure proper catheter or needle position prior to and during infusion. Avoid extravasation. IV formulation may cause soft tissue irritation and inflammation, and skin necrosis at IV site; avoid IV administration in small veins. The "purple glove syndrome" (ie, discoloration with edema and pain of distal limb) may occur following peripheral IV administration of phenytoin. This syndrome may or may not be associated with drug extravasation. Symptoms may resolve spontaneously; however, skin necrosis and limb ischemia may occur; interventions such as fasciotomies, skin grafts, and amputation (rare) may be required. To decrease the risk of this syndrome, inject phenytoin slowly and directly into a large vein through a large gauge needle or IV catheter; follow with NS flushes through the same needle or IV catheter.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with underlying cardiac disease; IV use is contraindicated in patients with sinus bradycardia, sinoatrial block, or second- and third-degree heart block. Bradycardia and cardiac arrest have been reported with oral phenytoin administration, usually in patients with underlying cardiac disease, and have occurred at recommended doses and levels and associated with toxicity.

• Diabetes: Use with caution in patients with diabetes mellitus; phenytoin may inhibit insulin release and increase serum glucose in patients with diabetes.

• Hepatic impairment: Use with caution in patients with hepatic impairment; use free (unbound) serum concentrations to monitor.

• 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. Use free (unbound) serum concentrations to monitor.

• Hypothyroidism: Use with caution in patients with hypothyroidism; phenytoin may alter thyroid hormone serum concentrations (with chronic administration).

• Myasthenia gravis: Use with caution in patients with myasthenia gravis; may exacerbate condition (Mehrizi 2012).

• Porphyria: May cause exacerbation of porphyria; use with caution in patients with porphyria.

• Renal impairment: Use with caution in patients with renal impairment; use free (unbound) serum concentrations to monitor.

Special populations:

• Critically ill patients: Use with caution in critically ill patients.

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

• Pediatric patients: In neonatal and pediatric patients in emergent situations, fosphenytoin is preferred over phenytoin (AAP [Shenoi 2020]).

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer's labeling.

• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures and respiratory depression; use caution (AAP 1997; Zar 2007).

Other warnings/precautions:

• Appropriate use: Not indicated for the treatment of absence seizures, myoclonic seizures, or seizures due to hypoglycemia or other metabolic causes. Phenytoin may increase seizure frequency in patients with childhood or juvenile absence epilepsy, juvenile myoclonic epilepsy, and Dravet Syndrome; use should be avoided in these conditions (Chaves 2005).

• Sustained serum concentrations: Plasma concentrations of phenytoin sustained above the optimal range may produce confusional states referred to as delirium, psychosis, or encephalopathy, or rarely, irreversible cerebellar dysfunction and/or cerebellar atrophy. Measure plasma phenytoin concentrations at the first sign of acute toxicity; dosage reduction is indicated if phenytoin concentrations are excessive; if symptoms persist, discontinue administration.

• Withdrawal: Antiseizure 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.

Dosage Forms Considerations

The capsule dosage form represents Extended Phenytoin Sodium Capsules, USP, a designation differentiating the drug from Prompt Phenytoin Sodium Capsules, USP (no longer available) as the extended form was characterized by a slow and extended rate of absorption when the two were compared.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule, Oral, as extended phenytoin sodium:

Dilantin: 30 mg [contains quinoline yellow (d&c yellow #10)]

Dilantin: 100 mg

Phenytek: 200 mg, 300 mg [contains fd&c blue #1 (brill blue) aluminum lake, fd&c blue #1 (brilliant blue), fd&c blue #2 (indigo carm) aluminum lake, fd&c red #40(allura red ac)aluminum lake, quinoline (d&c yellow #10) aluminum lake]

Generic: 100 mg, 200 mg, 300 mg

Solution, Injection, as sodium:

Generic: 50 mg/mL (2 mL, 5 mL)

Suspension, Oral:

Dilantin: 125 mg/5 mL (237 mL) [contains alcohol, usp, fd&c yellow #6 (sunset yellow), sodium benzoate]

Dilantin-125: 125 mg/5 mL (237 mL) [contains alcohol, usp, fd&c yellow #6 (sunset yellow), sodium benzoate; orange-vanilla flavor]

Generic: 100 mg/4 mL (4 mL [DSC]); 125 mg/5 mL (4 mL [DSC], 237 mL)

Tablet Chewable, Oral:

Dilantin Infatabs: 50 mg [scored]

Phenytoin Infatabs: 50 mg [scored; contains fd&c yellow #6(sunset yellow)alumin lake, quinoline (d&c yellow #10) aluminum lake, saccharin sodium]

Generic: 50 mg

Generic Equivalent Available: US

Yes

Pricing: US

Capsules (Dilantin Oral)

30 mg (per each): $1.74

100 mg (per each): $2.02

Capsules (Phenytek Oral)

200 mg (per each): $1.68

300 mg (per each): $2.51

Capsules (Phenytoin Sodium Extended Oral)

100 mg (per each): $0.34 - $1.19

200 mg (per each): $1.51

300 mg (per each): $2.26

Chewable (Dilantin Infatabs Oral)

50 mg (per each): $1.89

Chewable (Phenytoin Infatabs Oral)

50 mg (per each): $0.53

Chewable (Phenytoin Oral)

50 mg (per each): $1.57

Solution (Phenytoin Sodium Injection)

50 mg/mL (per mL): $0.70 - $2.08

Suspension (Dilantin Oral)

125 mg/5 mL (per mL): $1.01

Suspension (Dilantin-125 Oral)

125 mg/5 mL (per mL): $1.01

Suspension (Phenytoin Oral)

125 mg/5 mL (per mL): $0.16

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Dosage Forms: Canada

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

Capsule, Oral, as extended phenytoin sodium:

Dilantin: 30 mg [contains quinoline yellow (d&c yellow #10)]

Dilantin: 100 mg [contains fd&c yellow #6 (sunset yellow)]

Generic: 100 mg

Solution, Injection, as sodium:

Tremytoine: 50 mg/mL (2 mL, 5 mL)

Generic: 50 mg/mL (2 mL, 5 mL)

Suspension, Oral:

Dilantin-30: 30 mg/5 mL (250 mL) [contains alcohol, usp, fd&c yellow #6 (sunset yellow), sodium benzoate]

Dilantin-125: 125 mg/5 mL (250 mL) [contains alcohol, usp, fd&c yellow #6 (sunset yellow), sodium benzoate]

Generic: 125 mg/5 mL (237 mL)

Tablet Chewable, Oral:

Dilantin Infatabs: 50 mg

Administration: Adult

IM: Avoid IM administration due to severe risk of local tissue destruction and necrosis; use fosphenytoin if IM administration necessary (Ref). The manufacturer's labeling includes IM administration; however, in general the IM route should be avoided and should NOT be used for status epilepticus.

IV: For patients who are in status epilepticus, hemodynamically unstable, or develop hypotension/bradycardia with IV administration of phenytoin, consider the use of fosphenytoin when loading instead. Although phenytoin may be administered by direct IV injection, it is preferable that phenytoin be administered via infusion pump either undiluted or diluted in NS as an IV piggyback (IVPB) to prevent exceeding the maximum infusion rate (monitor closely for extravasation during infusion). Administer directly into a large peripheral or central vein through a large-gauge catheter. Infusion must be completed within 4 hours after dilution in NS. The maximum rate of IV administration is 50 mg/minute. Highly sensitive patients (eg, elderly patients, patients with preexisting cardiovascular conditions) should receive phenytoin more slowly (eg, 20 mg/minute) (Ref). When using IV route for oral replacement, administer at slower rate as either a loading dose or by intermittent infusion. An in-line 0.22- to 0.55-micron filter is recommended for IVPB solutions due to the potential for precipitation of the solution. Following IV administration, NS should be injected through the same needle or IV catheter to prevent irritation.

Oral:

Immediate release: Divide daily dose into 2 to 3 doses per day; if the daily dosage cannot be divided equally, take the larger dose before retiring.

Chewable tablets: May chew thoroughly before swallowing or swallow whole.

Suspension: Shake well prior to use; measure and administer dose using a calibrated oral dosing syringe (or other accurate dose-measuring device).

Extended release: Usually dosed every 12 hours; however, in patients with sufficiently long half-life, may be dosed every 24 hours.

Bariatric surgery: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. ER capsule should be swallowed whole. Do not crush, cut, or chew. IR chewable tablet and oral suspension formulations are available. If safety and efficacy can be effectively monitored, no change in formulation or administration is required after bariatric surgery; however, close clinical monitoring is advised in the immediate postoperative phase for the theoretical circumstance of altered absorption after bariatric surgery. Conversion to IR formulation should be considered for high-risk labeled and off-label clinical indications.

Enteral feeding tube

The following recommendations are based upon the best available evidence and clinical expertise. Senior editorial team: Joseph I. Boullata, PharmD, RPh, CNS-S, FASPEN, FACN; Peggi A. Guenter PhD, RN, FASPEN; Kathleen Gura, PharmD, BCNSP, FASHP, FASPEN, FPPA, FMSHP; Mark G. Klang MS, RPh, BCNSP, PhD, FASPEN; Linda Lord, NP, ACNP-BC, CNSC, FASPEN.

Note: Maintain consistent administration practices (eg, route, dosage form) as able throughout therapy. Monitor clinical response and serum phenytoin concentrations frequently (Ref).

Oral capsules:

Gastric tubes (eg, NG, G-tube ) (≥8 French): Open powder-containing capsule(s) and disperse contents in 10 mL purified water; some capsule contents may need to stand for up to 5 minutes in purified water, followed by stirring, to disperse well. Draw up mixture into enteral dosing syringe and administer via feeding tube (Ref).

Dosage form information: Additional flushes may be required; contents from opened powder-containing capsules were reported to adhere to the feeding tube (Ref). One manufacturer’s capsules (Phenytek) contain ER tablets within the capsule; do not use this product for feeding tube administration; crushing the tablets may result in release of excessive doses, variable serum concentrations, and risk of severe adverse effects (Ref).

General guidance: Hold enteral nutrition (EN) during phenytoin administration (Ref). Flush feeding tube with an appropriate volume of purified water (eg, 15 mL) before administration (Ref). Following administration, rinse container used for preparation with purified water; draw up rinse and administer contents to ensure delivery of entire dose (Ref). Flush feeding tube with an appropriate volume of purified water (eg, 15 mL) and restart EN (Ref).

Oral suspension (commercially available):

Note: Avoidance of jejunal administration has been recommended due to erratic absorption. If jejunal administration is necessary, monitor plasma concentrations to assess need for dose adjustment (Ref).

Gastric (eg, NG, G-tube) or post-pyloric (eg, J-tube) tubes (≥8 French): Shake suspension well prior to drawing up dose for dilution. Dilute dose with at least an equivalent volume of purified water immediately prior to administration to reduce osmolality and viscosity; some experts recommend diluting in a volume of purified water that is 3 times the phenytoin suspension volume (eg, 10 mL phenytoin suspension diluted in 30 mL purified water). Draw up diluted suspension into enteral dosing syringe and administer via feeding tube (Ref).

Dosage form information: Some undiluted formulations have been reported to have osmolalities of 1,500 to ~3,100 mOsm/kg (Ref). Oral suspensions with an osmolality >600 mOsm/kg may increase the probability of adverse GI effects (eg, diarrhea, cramping, abdominal distention, slowed gastric emptying), particularly if administered post-pylorically, inadequately diluted, and/or used in at-risk patients (eg, neonates and infants, patients with short bowel syndrome) (Ref).

General guidance: Hold EN during phenytoin administration (Ref). Flush feeding tube with an appropriate volume of purified water (eg, 15 mL) before administration (Ref). Following administration, rinse container used for preparation with purified water; draw up rinse and administer contents to ensure delivery of entire dose (Ref). Flush feeding tube with an appropriate volume of purified water (eg, 15 mL) and restart EN (Ref).

Oral tablets (chewable):

Gastric tubes (eg, NG, G-tube): Crush tablet(s) into a fine powder and disperse in purified water prior to administration. Draw up mixture into enteral dosing syringe and administer via feeding tube (Ref).

Dosage form information: Crushed tablets do not disperse easily in water. Administration of chewable phenytoin tablets via enteral tube may increase the risk of clogging the tube (Ref).

General guidance: Hold EN during phenytoin administration (Ref). Flush feeding tube with an appropriate volume of purified water (eg, 15 mL) before administration (Ref). Following administration, rinse container used for preparation with purified water; draw up rinse and administer contents to ensure delivery of entire dose (Boullata 2019, White 2015). Flush feeding tube with an appropriate volume of purified water (eg, 15 mL) and restart EN (Ref).

Enteral nutrition considerations: Administration of phenytoin with EN via an enteral feeding tube may decrease phenytoin absorption; maintain consistent administration practices throughout therapy. Hold EN during phenytoin administration, flush feeding tube before and after phenytoin administration, monitor clinical response and serum phenytoin concentrations frequently, and reevaluate phenytoin dose following EN discontinuation. (Ref).

Although several studies have demonstrated that holding EN for an extended period before and after phenytoin administration may not improve phenytoin absorption, some continue to recommend holding EN for 1 to 2 hours prior to and 1 to 2 hours following phenytoin administration; see institution-specific protocols (Ref). This approach requires interruption of enteral feeding for extended periods; impact on nutrition may be minimized by consolidating total daily dose into fewer divided doses as appropriate (Ref). If EN is not held for 1 to 2 hours before and after phenytoin administration, increased phenytoin doses based on frequent serum concentration monitoring may be necessary to overcome decreased absorption (Ref).

Note: Recommendations may not account for differences in inactive ingredients, osmolality, or other formulation properties among manufacturers.

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

Vesicant; ensure proper needle or catheter placement prior to and during IV infusion. Avoid extravasation.

Extravasation management: If extravasation occurs, stop infusion immediately; leave needle/cannula in place temporarily but do NOT flush the line; gently aspirate extravasated solution, then remove needle/cannula; elevate extremity and apply dry warm compresses; closely monitor for tissue sloughing or compartment syndrome (Ref). There is conflicting information regarding an antidote; some sources recommend not to use an antidote (Ref) or to use hyaluronidase in refractory cases (Ref).

Hyaluronidase (if appropriate): Intradermal or SUBQ: Inject a total of 1 mL (15 units/mL) as 5 separate 0.2 mL injections (using a tuberculin syringe) around the site of extravasation; if IV catheter remains in place, administer IV through the infiltrated catheter; may repeat in 30 to 60 minutes if no resolution (Ref)

Administration: Pediatric

Oral:

Immediate release: If the daily dosage cannot be divided equally, administer the larger dose before bedtime.

Chewable tablets: May chew thoroughly before swallowing or swallow whole.

Suspension: Shake well prior to use; measure and administer dose using a calibrated oral dosing syringe (or other accurate dose-measuring device). 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 to 2 hours before and after each phenytoin dose. In patients who cannot have enteral feeds held and phenytoin therapy cannot be avoided, frequent serum concentration monitoring and increased dosages may be required.

Extended-release capsules: May be administered without regard to meals.

Parenteral: Note: Fosphenytoin may be considered for loading in patients who are in status epilepticus, hemodynamically unstable, or develop hypotension/bradycardia with IV administration of phenytoin.

IV: Phenytoin may be administered IV directly into a large vein through a large gauge needle or IV catheter; however, it is preferred that phenytoin be administered via infusion pump either undiluted or diluted in NS to prevent exceeding the maximum infusion rate (monitor closely for extravasation during infusion). An in-line 0.22 to 0.55 micron filter is recommended for IV piggyback (IVPB) solutions due to the potential for precipitation of the solution.

Neonates: Administer slowly, usual maximum recommended rate: 0.5 to 1 mg/kg/minute (Ref). Note: Although the manufacturer recommends a maximum rate: 1 to 3 mg/kg/minute, a lower maximum rate of infusion of 1 mg/kg/minute has been recommended (Ref).

Infants, Children, and Adolescents: Administer slowly, maximum recommended rate: 1 to 3 mg/kg/minute or maximum rate: 50 mg/minute, whichever is slower.

Following IV administration, NS should be injected through the same needle or IV catheter to prevent irritation. Avoid IM use due to erratic absorption, pain on injection, and precipitation of drug at injection site.

Vesicant; ensure proper needle or catheter placement prior to and during IV infusion. Avoid extravasation. If extravasation occurs, stop infusion immediately and disconnect (leave needle/cannula in place); gently aspirate extravasated solution (do NOT flush the line); remove needle/cannula; elevate extremity. There is conflicting information regarding an antidote; some sources recommend not to use an antidote (Ref), while other sources recommend hyaluronidase (see Management of Drug Extravasations for more details).

IM: Although the manufacturer's labeling includes IM administration, in general the IM route is not a recommended route of administration in neonatal and pediatric patients and should be avoided (Ref); IM should NOT be used for status epilepticus (Ref). Avoid IM administration due to severe risk of local tissue destruction and necrosis; use fosphenytoin if IM administration necessary (Ref).

Hazardous Drugs Handling Considerations

Hazardous agent (NIOSH 2016 [group 2]).

Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).

Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.

Medication Guide and/or Vaccine Information Statement (VIS)

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

Dilantin chewable tablets: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/084427s039s041lbl.pdf#page=17

Dilantin extended release capsules: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/084349s085lbl.pdf#page=19

Dilantin-125 oral suspension: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/008762s066lbl.pdf#page=19

Use: Labeled Indications

Focal (partial) onset seizures and generalized onset seizures: Treatment of patients with focal and generalized onset seizures and prevention of seizures following craniotomy. May be used off-label for other seizure types.

Status epilepticus: Treatment of patients with convulsive and nonconvulsive status epilepticus.

Use: Off-Label: Adult

Seizures, posttraumatic (prevention); Trigeminal neuralgia, rescue therapy

Medication Safety Issues
Sound-alike/look-alike issues:

Phenytoin may be confused with phenelzine, phentermine, PHENobarbital

Dilantin may be confused with Dilaudid, dilTIAZem, Dipentum

High alert medication:

The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Community/Ambulatory Care and Long-Term Care Settings).

International issues:

Dilantin [US, Canada, and multiple international markets] may be confused with Dolantine brand name for pethidine [Belgium]

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 CYP1A2 (weak), CYP2B6 (weak), CYP3A4 (strong), P-glycoprotein/ABCB1, UGT1A1, UGT1A4

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.

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

Abiraterone Acetate: CYP3A4 Inducers (Strong) may decrease the serum concentration of Abiraterone Acetate. Management: Avoid when possible. If the combination cannot be avoided, increase abiraterone acetate dosing frequency from once daily to twice daily during combined use. Reduce abiraterone dose back to the prior dose and frequency once strong inducer is discontinued. Risk D: Consider therapy modification

Acalabrutinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Acalabrutinib. Management: Avoid co-administration of strong CYP3A inducers in patients taking acalabrutinib. If strong CYP3A inducers cannot be avoided, increase the dose of acalabrutinib to 200 mg twice daily. Risk D: Consider therapy modification

Acemetacin: May increase the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy

Acetaminophen: Fosphenytoin-Phenytoin may decrease the serum concentration of Acetaminophen. Specifically, serum concentrations of acetaminophen may be decreased (leading to decreased efficacy), but the formation of the toxic N-acetyl-p-benzoquinone imine (NAPQI) metabolite may be increased (leading to increased hepatotoxicity). Risk C: Monitor therapy

Adagrasib: May increase the serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may decrease the serum concentration of Adagrasib. Risk X: Avoid combination

Afatinib: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Afatinib. Management: Increase the afatinib dose by 10 mg as tolerated in patients requiring chronic coadministration of P-gp inducers with afatinib. Reduce afatinib dose back to the original afatinib dose 2 to 3 days after discontinuation of the P-gp inducer. Risk D: Consider therapy modification

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

Alcohol (Ethyl): May decrease the serum concentration of Fosphenytoin-Phenytoin. Alcohol (Ethyl) may increase the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy

Aldesleukin: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy

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

ALfentanil: CYP3A4 Inducers (Strong) may decrease the serum concentration of ALfentanil. Management: If concomitant use of alfentanil and strong CYP3A4 inducers is necessary, consider dosage increase of alfentanil until stable drug effects are achieved. Monitor patients for signs of opioid withdrawal. Risk D: Consider therapy modification

Aliskiren: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Aliskiren. Risk C: Monitor therapy

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

ALPRAZolam: CYP3A4 Inducers (Strong) may decrease the serum concentration of ALPRAZolam. 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

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

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

Apixaban: Inducers of CYP3A4 (Strong) and P-glycoprotein may decrease the serum concentration of Apixaban. Risk X: Avoid combination

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

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

ARIPiprazole: CYP3A4 Inducers (Strong) may decrease the serum concentration of ARIPiprazole. Management: For indications other than major depressive disorder: double the oral aripiprazole dose over 1 to 2 weeks and closely monitor. Avoid use of strong CYP3A4 inducers for more than 14 days with extended-release injectable aripiprazole. Risk D: Consider therapy modification

ARIPiprazole Lauroxil: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of ARIPiprazole Lauroxil. Management: Patients taking the 441 mg dose of aripiprazole lauroxil increase their dose to 662 mg if used with a strong CYP3A4 inducer for more than 14 days. No dose adjustment is necessary for patients using the higher doses of aripiprazole lauroxil. Risk D: Consider therapy modification

Artemether and Lumefantrine: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Artemether and Lumefantrine. Specifically, concentrations of dihydroartemisinin (DHA), the active metabolite of artemether may be decreased. CYP3A4 Inducers (Strong) may decrease the serum concentration of Artemether and Lumefantrine. Risk X: Avoid combination

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

Atazanavir: May decrease the serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may decrease the serum concentration of Atazanavir. Risk X: Avoid combination

Atogepant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Atogepant. Management: For treatment of episodic migraine, the recommended dose of atogepant is 30 mg once daily or 60 mg once daily when combined with CYP3A4 inducers. When used for treatment of chronic migraine, use of atogepant with CYP3A4 inducers should be avoided. Risk D: Consider therapy modification

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

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

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

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

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

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

Bazedoxifene: Phenytoin may decrease the serum concentration of Bazedoxifene. This may lead to loss of efficacy or, if bazedoxifene is combined with estrogen therapy, an increased risk of endometrial hyperplasia. Risk C: Monitor therapy

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

Belumosudil: CYP3A4 Inducers (Strong) may decrease the serum concentration of Belumosudil. Management: Increase the dose of belumosudil to 200 mg twice daily when coadministered with strong CYP3A4 inducers. Risk D: Consider therapy modification

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

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

Benzhydrocodone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Benzhydrocodone. Specifically, the serum concentrations of hydrocodone may be reduced. Risk C: Monitor therapy

Berotralstat: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Berotralstat. Risk X: Avoid combination

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

Bictegravir: Fosphenytoin-Phenytoin may decrease the serum concentration of Bictegravir. Management: When possible consider using an alternative antiseizure drug with concurrent bictegravir, emtricitabine, and tenofovir alafenamide. If the combination must be used, monitor closely for evidence of reduced antiviral effectiveness. Risk D: Consider therapy modification

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

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

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

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

Bosutinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Bosutinib. 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

Brexpiprazole: CYP3A4 Inducers (Strong) may decrease the serum concentration of Brexpiprazole. Management: If brexpiprazole is used together with a strong CYP3A4 inducer, the brexpiprazole dose should gradually be doubled over the course of 1 to 2 weeks. Decrease brexpiprazole to original dose over 1 to 2 weeks if the strong CYP3A4 inducer is discontinued. Risk D: Consider therapy modification

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

Brivaracetam: May increase the serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may decrease the serum concentration of Brivaracetam. Risk C: Monitor therapy

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

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

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

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

BuPROPion: CYP2B6 Inducers (Weak) may decrease the serum concentration of BuPROPion. Risk C: Monitor therapy

BusPIRone: CYP3A4 Inducers (Strong) may decrease the serum concentration of BusPIRone. Management: Consider alternatives to this combination. If coadministration of these agents is deemed necessary, monitor patients for reduced buspirone effects and increase buspirone doses as needed. Risk D: Consider therapy modification

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

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

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

Cabotegravir: UGT1A1 Inducers may decrease the serum concentration of Cabotegravir. Risk X: Avoid combination

Cabozantinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Cabozantinib. Management: Avoid use of strong CYP3A4 inducers with cabozantinib if possible. If combined, increase cabozantinib capsules (Cometriq) by 40 mg from previous dose, max 180 mg daily. Increase cabozantinib tablets (Cabometyx) by 20 mg from previous dose, max 80 mg daily Risk D: Consider therapy modification

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

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

Calcium Channel Blockers (Nondihydropyridine): May increase the serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may decrease the serum concentration of Calcium Channel Blockers (Nondihydropyridine). Management: Consider alternatives to this combination when possible. If combined, monitor for increased phenytoin concentrations and toxicities and monitor for decreased calcium channel blocker efficacy. Risk D: Consider therapy modification

Canagliflozin: Phenytoin may decrease the serum concentration of Canagliflozin. Management: Consider increasing canagliflozin dose to 200 mg/day in patients tolerating 100 mg/day. A further increase to 300 mg/day can be considered in patients with an estimated glomerular filtration rate (GFR) of 60 mL/min/1.73 m2 or greater. Risk D: Consider therapy modification

Cannabidiol: May increase the serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may decrease the serum concentration of Cannabidiol. Risk C: Monitor therapy

Cannabis: CYP3A4 Inducers (Strong) may decrease the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be decreased. Risk C: Monitor therapy

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

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

CarBAMazepine: Fosphenytoin-Phenytoin may decrease the serum concentration of CarBAMazepine. CarBAMazepine may decrease the serum concentration of Fosphenytoin-Phenytoin. CarBAMazepine may increase the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy

Carbonic Anhydrase Inhibitors: May enhance the adverse/toxic effect of Fosphenytoin-Phenytoin. Specifically, the risk for osteomalacia or rickets may be increased. Risk C: Monitor therapy

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

Carmustine: May decrease the serum concentration of Fosphenytoin-Phenytoin. Management: Consider alternatives to fosphenytoin-phenytoin in carmustine treated patients. If combined, monitor closely for reduced phenytoin concentrations and increase fosphenytoin-phenytoin doses as needed. Risk D: Consider therapy modification

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 increase the serum concentration of Phenytoin. Specifically, the ratio of free phenytoin to total phenytoin may be increased. Risk C: Monitor therapy

Celiprolol: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Celiprolol. Risk C: Monitor therapy

Cenobamate: Fosphenytoin-Phenytoin may decrease the serum concentration of Cenobamate. Cenobamate may increase the serum concentration of Fosphenytoin-Phenytoin. Management: Gradually reduce the dose of fosphenytoin/phenytoin by up to 50% as the dose of cenobamate is being titrated up. Monitor phenytoin levels closely; higher doses of cenobamate may be required. Risk D: Consider therapy modification

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

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

ChlordiazePOXIDE: May increase the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy

Chlorpheniramine: May increase the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy

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

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

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

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

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

Cladribine: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Cladribine. 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. Management: Consider alternative antimicrobial therapy for patients receiving a CYP3A4 inducer. Drugs that enhance the metabolism of clarithromycin into 14-hydroxyclarithromycin may alter the clinical activity of clarithromycin and may impair clarithromycin efficacy. Risk D: Consider therapy modification

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

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

CloZAPine: CYP3A4 Inducers (Strong) may decrease the serum concentration of CloZAPine. Management: Avoid use with strong CYP3A4 inducers when possible. If combined, monitor patients closely and consider clozapine dose increases. Clozapine dose reduction and further monitoring may be required when strong CYP3A4 inducers are discontinued. Risk D: Consider therapy modification

Cobicistat: Fosphenytoin-Phenytoin may decrease the serum concentration of Cobicistat. Risk X: Avoid combination

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

Codeine: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Codeine. Risk C: Monitor therapy

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

Colesevelam: May decrease the serum concentration of Phenytoin. Management: Administer phenytoin at least 4 hours prior to colesevelam. Risk D: Consider therapy modification

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

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

CycloSPORINE (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of CycloSPORINE (Systemic). Management: Monitor closely for reduced cyclosporine concentrations when combined with strong CYP3A4 inducers. Cyclosporine dose increases will likely be required to maintain adequate serum concentrations. Risk D: Consider therapy modification

CYP2C19 Inducers (Moderate): May decrease the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy

CYP2C19 Inducers (Strong): May decrease the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy

CYP2C19 Inhibitors (Moderate): May increase the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy

CYP2C19 Inhibitors (Strong): May increase the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy

CYP2C19 Inhibitors (Weak): May increase the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy

CYP2C9 Inhibitors (Moderate): May increase the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy

CYP2C9 Inhibitors (Weak): May increase the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy

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

Dabigatran Etexilate: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Dabigatran Etexilate. Management: Avoid concurrent use of dabigatran with P-glycoprotein inducers whenever possible. Risk X: Avoid combination

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

Dapsone (Systemic): May enhance the adverse/toxic effect of CYP3A4 Inducers (Strong). CYP3A4 Inducers (Strong) may decrease the serum concentration of Dapsone (Systemic). Risk C: Monitor therapy

Dapsone (Topical): May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Risk C: Monitor therapy

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

Darolutamide: Inducers of CYP3A4 (Strong) and P-glycoprotein may decrease the serum concentration of Darolutamide. Risk X: Avoid combination

Darunavir: May decrease the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy

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

Dasatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dasatinib. Management: Avoid concurrent use of dasatinib with strong CYP3A4 inducers 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: UGT1A1 Inducers may decrease the serum concentration of Deferasirox. Management: Avoid concomitant use of deferasirox and UGT1A1 inducers when possible. If combined, consider a 50% increase in the initial deferasirox dose, with monitoring of serum ferritin concentrations and clinical response to guide further dosing. Risk D: Consider therapy modification

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

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

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

Desmopressin: Hyponatremia-Associated Agents may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy

DexAMETHasone (Systemic): Phenytoin may decrease the serum concentration of DexAMETHasone (Systemic). DexAMETHasone (Systemic) may decrease the serum concentration of Phenytoin. DexAMETHasone (Systemic) may increase the serum concentration of Phenytoin. Management: Consider dexamethasone dose increases when combined with phenytoin and monitor closely for reduced steroid efficacy. Monitor phenytoin levels closely when combined with dexamethasone, both increased and decreased phenytoin levels have been reported. Risk D: Consider therapy modification

Dexketoprofen: May enhance the adverse/toxic effect of Fosphenytoin-Phenytoin. Risk C: Monitor therapy

DiazePAM: Fosphenytoin-Phenytoin may decrease the serum concentration of DiazePAM. DiazePAM may increase the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy

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

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

Digoxin: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Digoxin. Risk C: Monitor therapy

Dinutuximab Beta: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy

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

Disulfiram: May increase the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy

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

Dolutegravir: Fosphenytoin-Phenytoin may decrease the serum concentration of Dolutegravir. Risk X: Avoid combination

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

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

Doxercalciferol: CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Doxercalciferol. Risk C: Monitor therapy

Doxofylline: Fosphenytoin-Phenytoin may decrease the serum concentration of Doxofylline. Risk C: Monitor therapy

DOXOrubicin (Conventional): Phenytoin may decrease the serum concentration of DOXOrubicin (Conventional). DOXOrubicin (Conventional) may decrease the serum concentration of Phenytoin. Risk X: Avoid combination

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

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

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

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

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

Ebastine: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Ebastine. CYP3A4 Inducers (Strong) may decrease the serum concentration of Ebastine. Risk C: Monitor therapy

Edoxaban: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Edoxaban. Management: Avoid coadministration of edoxaban and P-glycoprotein (P-gp) inducers if possible. If concomitant use is required, be aware the edoxaban efficacy may be decreased. Risk D: Consider therapy modification

Efavirenz: Fosphenytoin-Phenytoin may decrease the serum concentration of Efavirenz. Efavirenz may decrease the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy

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

Elagolix: Fosphenytoin-Phenytoin may decrease the serum concentration of Elagolix. Elagolix may increase the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy

Elagolix, Estradiol, and Norethindrone: May increase the serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may decrease the serum concentration of Elagolix, Estradiol, and Norethindrone. Risk C: Monitor therapy

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

Elexacaftor, Tezacaftor, and Ivacaftor: CYP3A4 Inducers (Strong) may decrease the serum concentration of Elexacaftor, Tezacaftor, and Ivacaftor. Risk X: Avoid combination

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

Elranatamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy

Elvitegravir: Fosphenytoin-Phenytoin may decrease the serum concentration of Elvitegravir. Risk X: Avoid combination

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

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

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

Enzalutamide: May decrease the serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may decrease the serum concentration of Enzalutamide. Management: Avoid concurrent use of phenytoin/fosphenytoin and enzalutamide whenever possible. If combined, increase enzalutamide dose to 240 mg daily. Additionally, monitor for reduced phenytoin serum concentrations and effects. Risk D: Consider therapy modification

Epcoritamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy

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

Eravacycline: CYP3A4 Inducers (Strong) may decrease the serum concentration of Eravacycline. Management: Increase the eravacycline dose to 1.5 mg/kg every 12 hours when combined with strong CYP3A4 inducers. Risk D: Consider therapy modification

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

Erlotinib: May increase the serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may decrease the serum concentration of Erlotinib. Management: Avoid use of erlotinib with phenytoin when possible. If required, increase erlotinib dose by 50 mg increments at 2 week intervals, as tolerated, to a max of 450 mg/day. Also monitor for increased phenytoin concentrations and toxicities. Risk D: Consider therapy modification

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

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

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

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

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

Ethosuximide: May increase the serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may decrease the serum concentration of Ethosuximide. Risk C: Monitor therapy

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

Etoposide: CYP3A4 Inducers (Strong) may decrease the serum concentration of Etoposide. Management: When possible, seek alternatives to strong CYP3A4-inducing medications in patients receiving etoposide. If combined, monitor patients closely for diminished etoposide response and need for etoposide dose increases. Risk D: Consider therapy modification

Etoposide Phosphate: CYP3A4 Inducers (Strong) may decrease the serum concentration of Etoposide Phosphate. Management: When possible, seek alternatives to strong CYP3A4-inducing medications in patients receiving etoposide phosphate. If these combinations cannot be avoided, monitor patients closely for diminished etoposide phosphate response. Risk D: Consider therapy modification

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

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

Everolimus: Inducers of CYP3A4 (Strong) and P-glycoprotein may decrease the serum concentration of Everolimus. Management: Afinitor: Double the everolimus daily dose, using increments of 5 mg or less, with careful monitoring; multiple increments may be necessary. Zortress: Avoid if possible and monitor for decreased everolimus concentrations if combined. Risk D: Consider therapy modification

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

Exemestane: CYP3A4 Inducers (Strong) may decrease the serum concentration of Exemestane. Management: Increase the exemestane dose to 50 mg once daily in patients receiving concurrent strong CYP3A4 inducers. Monitor patients closely for evidence of toxicity or inadequate clinical response. Risk D: Consider therapy modification

Fedratinib: May increase the serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may decrease the serum concentration of Fedratinib. Risk X: Avoid combination

Felbamate: May increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Felbamate. Management: Initiate felbamate at typical doses (1,200 mg/day in 3 or 4 divided doses for adults and children 14 years of age or older; 15 mg/kg/day in 3 or 4 divided doses in children 2 to 14 years of age) while reducing the phenytoin dose by 20%. Risk D: Consider therapy modification

Felodipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Felodipine. Management: Consider alternatives to this combination when possible. If combined, monitor for reduced felodipine efficacy and the need for felodipine dose increases. Risk D: Consider therapy modification

Fenfluramine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Fenfluramine. Management: Avoid concurrent use of strong CYP3A4 inducers with fenfluramine when possible. If combined use cannot be avoided, consider increasing the fenfluramine dose, but do not exceed the fenfluramine maximum daily dose. Risk D: Consider therapy modification

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

Fesoterodine: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Fesoterodine. Risk C: Monitor therapy

Fexinidazole: CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Fexinidazole. Risk X: Avoid combination

Fexofenadine: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Fexofenadine. Risk C: Monitor therapy

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

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

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

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

Fluvastatin: May increase the serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may increase the serum concentration of Fluvastatin. Risk C: Monitor therapy

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

Fosamprenavir: May decrease the serum concentration of Phenytoin. Specifically, fosamprenavir boosted with ritonavir may decrease phenytoin concentrations. Phenytoin may decrease the serum concentration of Fosamprenavir. Specifically, phenytoin may decrease the concentration of the active metabolite amprenavir. Risk C: Monitor therapy

Fosaprepitant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Fosaprepitant. Specifically, CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite aprepitant. Risk X: Avoid combination

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

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

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

Fotemustine: Fosphenytoin-Phenytoin may decrease the serum concentration of Fotemustine. Fotemustine may decrease the serum concentration of Fosphenytoin-Phenytoin. Specifically, fotemustine may decrease concentrations of orally administered phenytoin. Risk X: Avoid combination

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

Furosemide: Fosphenytoin-Phenytoin may diminish the diuretic effect of Furosemide. Risk C: Monitor therapy

Futibatinib: Inducers of CYP3A4 (Strong) and P-glycoprotein may decrease the serum concentration of Futibatinib. Risk X: Avoid combination

Ganaxolone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ganaxolone. Management: Avoid concomitant use of ganaxolone and strong CYP3A4 inducers whenever possible. If combined, consider increasing the dose of ganaxolone, but do not exceed the maximum recommended daily dose. Risk D: Consider therapy modification

Gefitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Gefitinib. Management: In the absence of severe adverse reactions, increase the gefitinib dose to 500 mg daily in patients receiving strong CYP3A4 inducers; resume 250 mg dose 7 days after discontinuation of the strong inducer. Carefully monitor clinical response. Risk D: Consider therapy modification

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

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

Gestrinone: Fosphenytoin-Phenytoin may decrease the serum concentration of Gestrinone. Risk C: Monitor therapy

Gilteritinib: Inducers of CYP3A4 (Strong) and P-glycoprotein may decrease the serum concentration of Gilteritinib. Risk X: Avoid combination

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

Glecaprevir and Pibrentasvir: Fosphenytoin-Phenytoin may decrease the serum concentration of Glecaprevir and Pibrentasvir. Risk X: Avoid combination

Glofitamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy

GuanFACINE: CYP3A4 Inducers (Strong) may decrease the serum concentration of GuanFACINE. Management: Increase extended-release guanfacine dose by up to double when initiating guanfacine in patients taking CYP3A4 inducers or if initiating a CYP3A4 inducer in a patient already taking extended-release guanfacine. Monitor for reduced guanfacine efficacy. Risk D: Consider therapy modification

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

Hormonal Contraceptives: CYP3A4 Inducers (Strong) may decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing a strong CYP3A4 inducer to ensure contraceptive reliability. Risk D: Consider therapy modification

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

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

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

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

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

Ifosfamide: CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Ifosfamide. CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. Risk C: Monitor therapy

Imatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Imatinib. Management: Avoid use of imatinib and 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. Doses up to 1200 mg/day (600 mg twice daily) have been used. Risk D: Consider therapy modification

Indinavir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Indinavir. Management: Consider avoiding the combination of indinavir and strong CYP3A4 inducers whenever possible due to the risk for decreased indinavir concentrations, reduced efficacy, and development of resistance. If combined, monitor for indinavir treatment failure Risk D: Consider therapy modification

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

Irinotecan Products: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, serum concentrations of SN-38 may be reduced. CYP3A4 Inducers (Strong) may decrease the serum concentration of Irinotecan Products. Management: Avoid administration of strong CYP3A4 inducers during irinotecan treatment, and substitute non-CYP3A4 inducing agents at least 2 weeks prior to irinotecan initiation, whenever possible. If combined, monitor for reduced irinotecan efficacy. Risk D: Consider therapy modification

Isavuconazonium Sulfate: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Isavuconazonium Sulfate. Specifically, CYP3A4 Inducers (Strong) may decrease isavuconazole serum concentrations. Risk X: Avoid combination

Isoniazid: May increase the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy

Isradipine: May increase the serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may decrease the serum concentration of Isradipine. Risk C: Monitor therapy

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

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

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

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

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

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

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

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

Ketoconazole (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of Ketoconazole (Systemic). Management: The use of ketoconazole concurrently with or within 2 weeks of a strong CYP3A4 inducer is not recommended. If such a combination cannot be avoided, monitor patients closely for evidence of diminished clinical response to ketoconazole. Risk D: Consider therapy modification

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

Lacosamide: Antiseizure Agents (Sodium Channel Blockers) may enhance the adverse/toxic effect of Lacosamide. Specifically the risk for bradycardia, ventricular tachyarrhythmias, or a prolonged PR interval may be increased. Risk C: Monitor therapy

LamoTRIgine: Phenytoin may enhance the arrhythmogenic effect of LamoTRIgine. Phenytoin may decrease the serum concentration of LamoTRIgine. Management: Consider the risk of serious arrhythmias or death versus benefit of this combination. For patients taking phenytoin without valproate, lamotrigine dose adjustments are recommended for lamotrigine initiation. See full interact monograph for details. Risk D: Consider therapy modification

Lapatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lapatinib. Management: If concomitant use cannot be avoided, titrate 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 D: Consider therapy modification

Larotrectinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Larotrectinib. Management: Avoid use of strong CYP3A4 inducers with larotrectinib. If this combination cannot be avoided, double the larotrectinib dose. Reduced to previous dose after stopping the inducer after a period of 3 to 5 times the inducer's half-life. Risk D: Consider therapy modification

Ledipasvir: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Ledipasvir. Risk X: Avoid combination

Lefamulin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin with strong CYP3A4 inducers unless the benefits outweigh the risks. Risk D: Consider therapy modification

Lefamulin: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin with P-glycoprotein/ABCB1 inducers unless the benefits outweigh the risks. Risk D: Consider therapy modification

Lefamulin (Intravenous): CYP3A4 Inducers (Strong) may decrease the serum concentration of Lefamulin (Intravenous). Management: Avoid concomitant use of lefamulin intravenous infusion with strong CYP3A4 inducers unless the benefits outweigh the risks. Risk D: Consider therapy modification

Lefamulin (Intravenous): P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Lefamulin (Intravenous). Management: Avoid concomitant use of lefamulin (intravenous) with P-glycoprotein/ABCB1 inducers unless the benefits outweigh the risks. Risk D: Consider therapy modification

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

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

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

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

Letermovir: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Letermovir. Risk X: Avoid combination

Letermovir: UGT1A1 Inducers may decrease the serum concentration of Letermovir. Risk X: Avoid combination

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

Leuprolide and Norethindrone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Leuprolide and Norethindrone. Specifically, norethindrone concentrations may be decreased. Risk C: Monitor therapy

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

LevETIRAcetam: Fosphenytoin-Phenytoin may decrease the serum concentration of LevETIRAcetam. Risk C: Monitor therapy

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

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

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

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

Levonorgestrel (IUD): CYP3A4 Inducers (Strong) may diminish the therapeutic effect of Levonorgestrel (IUD). CYP3A4 Inducers (Strong) may decrease the serum concentration of Levonorgestrel (IUD). Risk C: Monitor therapy

Lidocaine (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of Lidocaine (Systemic). 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

LinaGLIPtin: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of LinaGLIPtin. Management: Strongly consider using an alternative to any P-glycoprotein 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: Fosphenytoin-Phenytoin may enhance the adverse/toxic effect of Lithium. Risk C: Monitor therapy

Local Anesthetics: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Local Anesthetics. Specifically, the risk for methemoglobinemia may be increased. Risk C: Monitor therapy

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

Lopinavir: Phenytoin may decrease the serum concentration of Lopinavir. Lopinavir may decrease the serum concentration of Phenytoin. Management: Avoid once-daily administration of lopinavir/ritonavir if used together with phenytoin. If twice daily lopinavir/ritonavir is coadministered with phenytoin, monitor phenytoin levels and response to both agents. Risk D: Consider therapy modification

Lorlatinib: CYP3A4 Inducers (Strong) may enhance the hepatotoxic effect of Lorlatinib. CYP3A4 Inducers (Strong) may decrease the serum concentration of Lorlatinib. Risk X: Avoid combination

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

Lumacaftor and Ivacaftor: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lumacaftor and Ivacaftor. Specifically, the serum concentration of ivacaftor may be decreased. Risk X: Avoid combination

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

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

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

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

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

Manidipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Manidipine. Management: Consider avoiding concomitant use of manidipine and strong CYP3A4 inducers. If combined, monitor closely for decreased manidipine effects and loss of efficacy. Increased manidipine doses may be required. Risk D: Consider therapy modification

Maraviroc: CYP3A4 Inducers (Strong) may decrease the serum concentration of Maraviroc. Management: Increase maraviroc adult dose to 600 mg twice/day, but only if not receiving a strong CYP3A4 inhibitor. Not recommended for pediatric patients not also receiving a strong CYP3A4 inhibitor. Contraindicated in patients with CrCl less than 30 mL/min. Risk D: Consider therapy modification

Maribavir: Fosphenytoin-Phenytoin may decrease the serum concentration of Maribavir. Management: Increase the dose of maribavir to 1,200 mg twice daily with concomitant use of fosphenytoin or phenytoin. Risk D: Consider therapy modification

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

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

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

Mefloquine: May diminish the therapeutic effect of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may decrease the serum concentration of Mefloquine. Mefloquine may decrease the serum concentration of Fosphenytoin-Phenytoin. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of seizures. If fosphenytoin/phenytoin is being used for another indication, monitor for decreased concentrations and efficacy of both phenytoin and mefloquine. Risk D: Consider therapy modification

Meperidine: CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Meperidine. Specifically, concentrations of normeperidine, the CNS stimulating metabolite, may be increased. CYP3A4 Inducers (Strong) may decrease the serum concentration of Meperidine. Risk C: Monitor therapy

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

Methotrexate: May decrease the serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may increase the serum concentration of Methotrexate. Specifically, fosphenytoin-phenytoin may displace methotrexate from serum proteins, increasing the concentration of free, unbound drug. Risk C: Monitor therapy

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

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

MethylPREDNISolone: CYP3A4 Inducers (Strong) may decrease the serum concentration of MethylPREDNISolone. Management: Consider methylprednisolone dose increases in patients receiving strong CYP3A4 inducers and monitor closely for reduced steroid efficacy. Risk D: Consider therapy modification

MetroNIDAZOLE (Systemic): May enhance the adverse/toxic effect of Phenytoin. A disulfiram-like reaction may occur if combined with phenytoin dosage forms that contain propylene glycol. Phenytoin may decrease the serum concentration of MetroNIDAZOLE (Systemic). MetroNIDAZOLE (Systemic) may increase the serum concentration of Phenytoin. Risk C: Monitor therapy

MetyraPONE: Antiseizure Agents may diminish the diagnostic effect of MetyraPONE. Management: Consider alternatives to the use of the metyrapone test in patients taking antiseizure agents. Risk D: Consider therapy modification

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

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

Miconazole (Oral): May increase the serum concentration of Phenytoin. Risk C: Monitor therapy

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

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

MiFEPRIStone: CYP3A4 Inducers (Strong) may decrease the serum concentration of MiFEPRIStone. Management: Avoid combined use in patients treated for Cushing's disease. When used for pregnancy termination, mifepristone efficacy may be reduced and an alternative pregnancy termination procedure may be warranted. Ensure a follow-up assessment after combined use. Risk D: Consider therapy modification

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

Mirodenafil: CYP3A4 Inducers (Strong) may decrease the serum concentration of Mirodenafil. Management: Consider avoiding the concomitant use of mirodenafil and strong CYP3A4 inducers. If combined, monitor for decreased mirodenafil effects. Mirodenafil dose increases may be required to achieve desired effects. Risk D: Consider therapy modification

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

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

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

Mosunetuzumab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy

Multivitamins/Minerals (with ADEK, Folate, Iron): May decrease the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy

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

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

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

Nelfinavir: Fosphenytoin-Phenytoin may decrease the serum concentration of Nelfinavir. Nelfinavir may decrease the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy

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

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

Neuromuscular-Blocking Agents (Nondepolarizing): Fosphenytoin-Phenytoin may diminish the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing). Specifically, this effect is observed with chronic phenytoin administration. Fosphenytoin-Phenytoin may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing). Specifically, this effects is observed with acute/short term phenytoin administration. Risk C: Monitor therapy

Nevirapine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Nevirapine. Management: Consider alternatives to this combination when possible. If combined, monitor for reduced nevirapine efficacy. Risk D: Consider therapy modification

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

NIFEdipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of NIFEdipine. Management: Avoid coadministration of nifedipine with strong CYP3A4 inducers when possible and if combined, monitor patients closely for clinical signs of diminished nifedipine response. Risk D: Consider therapy modification

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

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

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

Nintedanib: Inducers of CYP3A4 (Strong) and P-glycoprotein may decrease the serum concentration of Nintedanib. Risk X: Avoid combination

Nirmatrelvir and Ritonavir: Fosphenytoin-Phenytoin may decrease the serum concentration of Nirmatrelvir and Ritonavir. Nirmatrelvir and Ritonavir may decrease the serum concentration of Fosphenytoin-Phenytoin. Risk X: Avoid combination

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

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

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

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

Nitric Oxide: May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Risk C: Monitor therapy

OLANZapine: CYP1A2 Inducers (Weak) may decrease the serum concentration of OLANZapine. Risk C: Monitor therapy

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

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

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

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

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

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

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

Orlistat: May decrease the serum concentration of Antiseizure Agents. Risk C: Monitor therapy

Ornidazole: May enhance the adverse/toxic effect of Products Containing Propylene Glycol. Specifically, a disulfiram-like reaction may occur. Risk X: Avoid combination

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

Osimertinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Osimertinib. Management: Avoid coadministration of osimertinib and strong CYP3A4 inducers if possible. If coadministration is unavoidable, increase osimertinib to 160 mg daily. Reduce osimertinib to 80 mg daily 3 weeks after discontinuation of the strong CYP3A4 inducer. Risk D: Consider therapy modification

OXcarbazepine: Fosphenytoin-Phenytoin may decrease serum concentrations of the active metabolite(s) of OXcarbazepine. Specifically, concentrations of the major active 10-monohydroxy metabolite may be reduced. OXcarbazepine may increase the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy

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

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

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

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

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

Paliperidone: Inducers of CYP3A4 (Strong) and P-glycoprotein may decrease the serum concentration of Paliperidone. Management: Monitor for reduced paliperidone effects when combined with strong inducers of both CYP3A4 and P-gp. Avoid use of these inducers with extended-release injectable paliperidone and instead manage patients with paliperidone extended-release tablets. Risk C: Monitor therapy

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

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

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

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

Perampanel: Phenytoin may decrease the serum concentration of Perampanel. Management: Increase perampanel starting dose to 4 mg/day if used with phenytoin. Increase perampanel dose by 2 mg/day no more than once weekly based on response and tolerability. Dose adjustments may be needed if phenytoin is discontinued. Risk D: Consider therapy modification

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

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

Phenylbutazone: May increase the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy

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

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

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

Pitolisant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Pitolisant. Management: If on a stable pitolisant dose of 8.9 mg or 17.8 mg/day and starting a strong CYP3A4 inducer, double the pitolisant dose over 7 days (ie, to either 17.8 mg/day or 35.6 mg/day, respectively). Reduce pitolisant dose by 50% when the inducer is discontinued. Risk D: Consider therapy modification

Platinum Derivatives: May decrease the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy

Polatuzumab Vedotin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Polatuzumab Vedotin. Exposure to unconjugated MMAE, the cytotoxic small molecule component of polatuzumab vedotin, may be decreased. Risk C: Monitor therapy

PONATinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of PONATinib. Management: Avoid coadministration of ponatinib with strong CYP3A4 inducers unless the potential benefit of concomitant treatment outweighs the risk of reduced ponatinib exposure. Monitor patients for reduced ponatinib efficacy if combined. Risk D: Consider therapy modification

Ponesimod: UGT1A1 Inducers may decrease the serum concentration of Ponesimod. Risk X: Avoid combination

Posaconazole: Fosphenytoin-Phenytoin may decrease the serum concentration of Posaconazole. Management: Concomitant use of posaconazole and fosphenytoin/phenytoin should be avoided unless the benefit to the patient outweighs the risk. If concomitant administration is required, close monitoring for breakthrough fungal infections is recommended. Risk D: Consider therapy modification

Pralsetinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Pralsetinib. Management: Avoid concomitant use of pralsetinib with strong CYP3A4 inducers when possible. If combined, increase the starting dose of pralsetinib to double the current pralsetinib dosage starting on day 7 of coadministration. Risk D: Consider therapy modification

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

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

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

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

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 for signs of methemoglobinemia when prilocaine is used in combination with other agents associated with development of methemoglobinemia. Avoid use of these agents with prilocaine/lidocaine cream in infants less than 12 months of age. Risk C: Monitor therapy

Primidone: May enhance the adverse/toxic effect of Fosphenytoin-Phenytoin. Specifically, the risk for agranulocytosis may be increased. Fosphenytoin-Phenytoin may increase serum concentrations of the active metabolite(s) of Primidone. Risk C: Monitor therapy

Propacetamol: Fosphenytoin-Phenytoin may decrease serum concentrations of the active metabolite(s) of Propacetamol. Specifically, serum concentrations of acetaminophen may be decreased (leading to decreased efficacy), but the formation of its toxic N-acetyl-p-benzoquinone imine (NAPQI) metabolite may be increased (leading to increased hepatotoxicity). Risk C: Monitor therapy

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

Pyridoxine: May decrease the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy

QUEtiapine: CYP3A4 Inducers (Strong) may decrease the serum concentration of QUEtiapine. Management: An increase in quetiapine dose (as much as 5 times the regular dose) may be required to maintain therapeutic benefit. Reduce the quetiapine dose back to the previous/regular dose within 7 to 14 days of discontinuing the inducer. Risk D: Consider therapy modification

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

QuiNINE: CYP3A4 Inducers (Strong) may decrease the serum concentration of QuiNINE. Management: Consider alternatives to this combination when possible. If combined, monitor for reduced quinine efficacy and treatment failure. Risk D: Consider therapy modification

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

Radotinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Radotinib. Management: Consider alternatives to this combination when possible as the risk of radotinib treatment failure may be increased. Risk D: Consider therapy modification

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

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

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

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

Relugolix: Inducers of CYP3A4 (Strong) and P-glycoprotein may decrease the serum concentration of Relugolix. Management: Avoid use of relugolix with drugs that are both strong CYP3A4 and P-glycoprotein (P-gp) inducer. If combined, increase the dose of relugolix to 240 mg once daily. Reduce back to 120 mg daily once the combined inducer is discontinued. Risk D: Consider therapy modification

Relugolix, Estradiol, and Norethindrone: Inducers of CYP3A4 (Strong) and P-glycoprotein may decrease the serum concentration of Relugolix, Estradiol, and Norethindrone. Risk X: Avoid combination

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

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

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

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

Rifapentine: May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Risk C: Monitor therapy

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

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

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

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

RisperiDONE: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of RisperiDONE. CYP3A4 Inducers (Strong) may decrease the serum concentration of RisperiDONE. Management: Careful monitoring for reduced risperidone efficacy and possible dose adjustment are recommended when combined with strong CYP3A4 inducers. See full interaction monograph for details. Risk D: Consider therapy modification

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

Ritonavir: Phenytoin may decrease the serum concentration of Ritonavir. Ritonavir may decrease the serum concentration of Phenytoin. Management: Consider avoiding when possible. Dose adjustments may be required. Monitor phenytoin concentrations, and for therapeutic response to phenytoin and ritonavir, particularly with any dose adjustments. Risk D: Consider therapy modification

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

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

Rolapitant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Rolapitant. 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

Ruxolitinib (Systemic): CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Ruxolitinib (Systemic). CYP3A4 Inducers (Strong) may decrease the serum concentration of Ruxolitinib (Systemic). Risk C: Monitor therapy

Sacituzumab Govitecan: UGT1A1 Inducers may decrease serum concentrations of the active metabolite(s) of Sacituzumab Govitecan. Specifically, concentrations of SN-38 may be decreased. Risk X: Avoid combination

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

Saquinavir: Fosphenytoin-Phenytoin may decrease the serum concentration of Saquinavir. Risk X: Avoid combination

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

Secnidazole: Products Containing Propylene Glycol may enhance the adverse/toxic effect of Secnidazole. Risk X: Avoid combination

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

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

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

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

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

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

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

Sirolimus (Conventional): CYP3A4 Inducers (Strong) may decrease the serum concentration of Sirolimus (Conventional). Management: Avoid concomitant use of strong CYP3A4 inducers and sirolimus if possible. If combined, monitor for reduced serum sirolimus concentrations. Sirolimus dose increases will likely be necessary to prevent subtherapeutic sirolimus levels. Risk D: Consider therapy modification

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

Sodium Nitrite: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Sodium Nitrite. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Risk C: Monitor therapy

Sofosbuvir: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Sofosbuvir. Risk X: Avoid combination

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

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

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

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

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

Stiripentol: Fosphenytoin-Phenytoin may decrease the serum concentration of Stiripentol. Stiripentol may increase the serum concentration of Fosphenytoin-Phenytoin. Management: Avoid this combination when possible. If combined, monitor for decreased stiripentol concentrations and effects and monitor for increased phenytoin concentrations and effects. Dose adjustments of either medication may be needed. Risk D: Consider therapy modification

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

SUFentanil: CYP3A4 Inducers (Strong) may decrease the serum concentration of SUFentanil. Management: If a strong CYP3A4 inducer is initiated in a patient on sufentanil, consider a sufentanil dose increase and monitor for decreased sufentanil effects and opioid withdrawal symptoms. Risk D: Consider therapy modification

SulfADIAZINE: May increase the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy

Sulfamethoxazole: May increase the serum concentration of Phenytoin. Management: Avoid coadministration of phenytoin and sulfamethoxazole. If coadministered, monitor phenytoin concentrations and for evidence of phenytoin toxicity. Risk of toxicity is increased with sulfamethoxazole/trimethoprim combination product. Risk D: Consider therapy modification

Sulthiame: May increase the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy

SUNItinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of SUNItinib. Management: Avoid when possible. If combined, increase sunitinib dose to a max of 87.5 mg daily when treating GIST or RCC. Increase sunitinib dose to a max of 62.5 mg daily when treating PNET. Monitor patients for both reduced efficacy and increased toxicities. Risk D: Consider therapy modification

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

Tacrolimus (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of Tacrolimus (Systemic). Management: Monitor for decreased tacrolimus concentrations and effects when combined with strong CYP3A4 inducers. Tacrolimus dose increases will likely be needed during concomitant use. Risk D: Consider therapy modification

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

Talquetamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy

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

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

Taurursodiol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Taurursodiol. Specifically, the concentrations of phenylbutyrate may be decreased. Risk C: Monitor therapy

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

Teclistamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy

Temsirolimus: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Temsirolimus. Specifically, concentrations of sirolimus may be decreased. CYP3A4 Inducers (Strong) may decrease the serum concentration of Temsirolimus. Management: Avoid concomitant use of temsirolimus and strong CYP3A4 inducers. If coadministration is unavoidable, increase temsirolimus dose to 50 mg per week. Resume previous temsirolimus dose after discontinuation of the strong CYP3A4 inducer. Risk D: Consider therapy modification

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

Tenofovir Alafenamide: Fosphenytoin-Phenytoin may decrease the serum concentration of Tenofovir Alafenamide. Risk X: Avoid combination

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

Tetrahydrocannabinol and Cannabidiol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tetrahydrocannabinol and Cannabidiol. Management: Avoid use of the tetrahydrocannabinol/cannabidiol oromucosal spray and strong CYP3A4 inducers when possible. If combined use is necessary, careful titration is recommended, notably within the two weeks following discontinuation of the inducer. Risk D: Consider therapy modification

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

Theophylline Derivatives: Fosphenytoin-Phenytoin may decrease the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy

Thiotepa: CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Thiotepa. CYP3A4 Inducers (Strong) may decrease the serum concentration of Thiotepa. Management: Thiotepa prescribing information recommends avoiding concomitant use of thiotepa and strong CYP3A4 inducers. If concomitant use is unavoidable, monitor for adverse effects. Risk D: Consider therapy modification

Thiothixene: Fosphenytoin-Phenytoin may decrease the serum concentration of Thiothixene. 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

TiaGABine: CYP3A4 Inducers (Strong) may decrease the serum concentration of TiaGABine. 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

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

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

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

TOLBUTamide: May decrease the protein binding of Fosphenytoin-Phenytoin. Specifically concentrations of free phenytoin may be increased. Risk C: Monitor therapy

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

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

Topotecan: Fosphenytoin-Phenytoin may decrease the serum concentration of Topotecan. Management: Monitor topotecan response closely, and consider alternatives to phenytoin when possible. Systemic concentrations and effects of topotecan may be reduced. No specific guidelines for topotecan dose adjustment are available. Risk D: Consider therapy modification

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

Torsemide: May enhance the adverse/toxic effect of Fosphenytoin-Phenytoin. Risk C: Monitor therapy

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

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

TraZODone: Phenytoin may decrease the serum concentration of TraZODone. TraZODone may increase the serum concentration of Phenytoin. Management: Consider increasing the trazodone dose during coadministration with strong CYP3A4 inducers, such as phenytoin. In addition, monitor for increased phenytoin concentrations and effects during coadministration with trazodone. Risk D: Consider therapy modification

Treosulfan: May increase the serum concentration of CYP2C19 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination

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

Triazolam: CYP3A4 Inducers (Strong) may decrease the serum concentration of Triazolam. Management: Consider alternatives to this combination when possible. If combined, monitor for reduced triazolam efficacy. Substantial triazolam dose increases will likely be required. Risk D: Consider therapy modification

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

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

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

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

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

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

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

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

Valproate Products: Fosphenytoin-Phenytoin may enhance the adverse/toxic effect of Valproate Products. Specifically, the risk of hepatotoxicity or hyperammonemia may be increased. Valproate Products may decrease the protein binding of Fosphenytoin-Phenytoin. This appears to lead to an initial increase in the percentage of unbound (free) phenytoin and to a decrease in total phenytoin concentrations. Whether concentrations of free phenytoin are increased is unclear. With long-term concurrent use, total phenytoin concentrations may increase. Fosphenytoin-Phenytoin may decrease the serum concentration of Valproate Products. Risk C: Monitor therapy

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

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

Vemurafenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vemurafenib. Management: Avoid coadministration of vemurafenib and strong CYP3A4 inducers if possible. If coadministration is unavoidable, increase the vemurafenib dose by 240 mg as tolerated. Resume prior vemurafenib dose 2 weeks after discontinuation of strong CYP3A4 inducer. Risk D: Consider therapy modification

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

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

Vilazodone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vilazodone. Management: Consider increasing vilazodone dose by as much as 2-fold (do not exceed 80 mg/day), based on response, in patients receiving strong CYP3A4 inducers for > 14 days. Reduce to the original vilazodone dose over 1 to 2 weeks after inducer discontinuation. Risk D: Consider therapy modification

Viloxazine: May increase the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy

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

VinCRIStine: May decrease the serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may decrease the serum concentration of VinCRIStine. Risk C: Monitor therapy

VinCRIStine (Liposomal): May decrease the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of VinCRIStine (Liposomal). Risk X: Avoid combination

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

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

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

Vitamin K Antagonists (eg, warfarin): Fosphenytoin-Phenytoin may enhance the anticoagulant effect of Vitamin K Antagonists. Fosphenytoin-Phenytoin may diminish the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists may increase the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy

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

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

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

Voriconazole: Fosphenytoin-Phenytoin may decrease the serum concentration of Voriconazole. Voriconazole may increase the serum concentration of Fosphenytoin-Phenytoin. Management: Increase maintenance dose of voriconazole from 4 mg/kg to 5 mg/kg IV every 12 hours or from 200 mg to 400 mg orally every 12 hours in patients who weigh 40 kg or more or from 100 mg to 200 mg orally every 12 hours for patients who weigh less than 40 kg. Risk D: Consider therapy modification

Vortioxetine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vortioxetine. Management: Consider increasing the vortioxetine dose to no more than 3 times the original dose when used with a strong drug metabolism inducer for more than 14 days. The vortioxetine dose should be returned to normal within 14 days of stopping the strong inducer. Risk D: Consider therapy modification

Voxelotor: CYP3A4 Inducers (Strong) may decrease the serum concentration of Voxelotor. Management: Avoid concomitant use of voxelotor and strong CYP3A4 inducers. If unavoidable, increase the voxelotor dose to 2,500 mg once daily. For children ages 4 to less than 12 years, weight-based dose adjustments are required. See full monograph for details. Risk D: Consider therapy modification

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

Zaleplon: CYP3A4 Inducers (Strong) may decrease the serum concentration of Zaleplon. Management: Consider the use of an alternative hypnotic that is not metabolized by CYP3A4 in patients receiving strong CYP3A4 inducers. If zaleplon is combined with a strong CYP3A4 inducer, monitor for decreased effectiveness of zaleplon. Risk D: Consider therapy modification

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

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

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

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

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

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

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

Food Interactions

Ethanol:

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

Chronic use: Ethanol stimulates metabolism of phenytoin. Management: Monitor patients.

Reproductive Considerations

Effective contraception is recommended for females of reproductive potential who are not planning a pregnancy. Phenytoin may decrease the efficacy of hormonal contraceptives; consult drug interactions database for more detailed information.

Females with epilepsy who are planning a pregnancy should have baseline serum concentrations measured once or twice prior to pregnancy during a period when seizure control is optimal (Patsalos 2008).

Pregnancy Considerations

Phenytoin crosses the placenta (Harden 2009a). An increased risk of congenital malformations and adverse outcomes may occur following in utero phenytoin exposure. Reported malformations include orofacial clefts, cardiac defects, dysmorphic facial features, nail/digit hypoplasia, growth abnormalities including microcephaly, and mental deficiency. Isolated cases of malignancies (including neuroblastoma) and coagulation defects in the neonate (may be life threatening) following delivery have also been reported. Maternal use of phenytoin should be avoided when possible to decrease the risk of cleft palate and poor cognitive outcomes. Polytherapy may also increase the risk of congenital malformations; monotherapy is recommended (Harden 2009b). The maternal use of folic acid throughout pregnancy is recommended to reduce the risk of major congenital malformations (Harden 2009a). Potentially life-threatening bleeding disorders in the newborn may also occur due to decreased concentrations of vitamin K-dependent clotting factors following phenytoin exposure in utero; vitamin K administration to the mother prior to delivery and the newborn after birth is recommended.

Total plasma concentrations of phenytoin are decreased in the mother during pregnancy; unbound plasma (free) concentrations are also decreased and plasma clearance is increased. Due to pregnancy-induced physiologic changes, women who are pregnant may require dose adjustments of phenytoin in order to maintain clinical response; monitoring during pregnancy should be considered (Harden 2009a). For women with epilepsy who are planning a pregnancy in advance, baseline serum concentrations should be measured once or twice prior to pregnancy during a period when seizure control is optimal. Monitoring can then be continued once each trimester during pregnancy and postpartum; more frequent monitoring may be needed in some patients. Monitoring of unbound plasma concentrations is recommended (Patsalos 2008; Patsalos 2018).

Patients exposed to phenytoin during pregnancy are encouraged to enroll themselves in the North American Antiepileptic Drug Pregnancy Registry by calling 1-888-233-2334. Additional information is available at http://aedpregnancyregistry.org.

Breastfeeding Considerations

Phenytoin is excreted in breast milk. According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.

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 antiseizure medications prophylactic doses of folic acid and cyanocobalamin (Belcastro 2012). Folic acid 0.5 mg/day has been shown to reduce the incidence of phenytoin-induced gingival overgrowth in children (Arya 2011). However, folate supplementation may increase seizures in some patients (dose dependent). Discuss with health care provider prior to using any supplements.

Calcium: Hypocalcemia has been reported in patients taking prolonged high-dose therapy with an antiseizure medication. Some clinicians have given an additional 4,000 units/week of vitamin D (especially in those receiving poor nutrition and getting no sun exposure) to prevent hypocalcemia.

Vitamin B: Phenytoin use has been associated with low serum concentrations of vitamin B2 (riboflavin), B6 (pyridoxine) and B12 (cyanocobalamin), which may contribute to hyperhomocysteinemia. Hyperhomocysteinemia may contribute to cardiovascular disease, venous thromboembolic disease, dementia, neuropsychiatric symptoms and poor seizure control. Some clinicians recommend administering riboflavin, pyridoxine and cyanocobalamin supplements in patients taking phenytoin (Apeland 2003; Apeland 2008; Belcastro 2012; Bochyńska 2012).

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

Injection may contain sodium.

Monitoring Parameters

CBC, comprehensive metabolic profile, liver function; 25-hydroxyvitamin D levels (chronic use); suicidality (eg, suicidal thoughts, depression, behavioral changes); signs/symptoms of hematological change (early detection important; eg, fever, sore throat, mouth ulcers, infections, easy bruising, petechial or purpuric hemorrhage); signs/symptoms of hypersensitivity reactions, including DRESS (manifestations associated with lymphatic, hepatic, renal, and/or hematologic organ systems); plasma phenytoin concentrations (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; timing of trough sampling is not as critical in patients receiving the ER oral dosage form because the slow absorption minimizes the fluctuations between peak and trough concentrations (Winter 2010).

Plasma phenytoin concentrations (Winter 2010):

First concentration: Consider obtaining within 2 to 3 days of therapy initiation, especially in patients requiring rapid achievement and maintenance of therapeutic concentrations, to ensure the patient's metabolism is not remarkably altered. Alternatively, a level may be drawn 2 hours after completion of an IV loading dose or 6 to 12 hours after administration of an oral loading dose (Meek 1999; Ratanakorn 1997; Swadron 2004) to aid in determining maintenance dose or need to reload.

Second concentration: Draw within 5 to 8 days of therapy initiation 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.

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

Consult individual institutional policies and procedures.

Reference Range

Adult:

Time of sampling is dependent on the disease state being treated and the clinical condition of the patient. In general, trough concentrations should be assessed after treatment initiation, dosage changes, or the addition or subtraction of interacting drugs; timing of sampling is not as critical in patients receiving the ER oral dosage form because the slow absorption minimizes the fluctuations between peak and trough concentrations (Winter 2010). Steady-state levels are reached in 5 to 10 days (5 to 7 half-lives) after initiation of therapy; however, the half-life is concentration dependent and increases in dose produce increases in the half-life. With loading-dose regimens, a level may be drawn 2 hours after an IV loading dose or 6 to12 hours after an oral loading dose (Meek 1999; Ratanakorn 1997; Swadron 2004). Peak concentrations may also be drawn if clinically necessary (eg, concentration-related toxicity).

Consider using total phenytoin levels (protein-bound plus free unbound phenytoin) only in patients without any disorders or drug interactions that would alter the degree of protein binding; this measurement may be more readily available and less expensive (von Winckelmann 2008). Use free phenytoin levels in patients with renal or hepatic disorders or hypoalbuminemia because the amount of free phenytoin may be increased.

Total phenytoin:

Therapeutic: Seizure disorders: 10 to 20 mg/L (SI: 39.6 to 79.2 micromole/L). Some patients may require levels outside the suggested therapeutic range (Hiemke 2018; Patsalos 2018).

Supratherapeutic: >20 mg/L (SI: >79.2 micromole/L). Lateral nystagmus usually appears at 20 mg/L (SI: 79.2 micromole/L), ataxia at 30 mg/L (SI: 118.8 micromole/L), and dysarthria and lethargy at >40 mg/L (SI: >158.4 micromole/L).

Free phenytoin: Therapeutic: Seizure disorders: 1 to 2 mg/L (SI: 4 to 7.9 micromole/L).

Estimate free phenytoin levels:

If free phenytoin concentrations are unavailable, predictive equations may be used in adult patients to estimate free phenytoin levels and help guide dosage adjustments, along with the assessment of patient response and tolerability. The most common predictive equation is the Winter-Tozer equation (also known as Sheiner-Tozer); however, other equations exist. Overall predictive performance of the equations varies (Cheng 2016; Kiang 2016). Note: Many centers use 25°C assay temperatures; consult individual institution laboratory information.

General medicine, critical care, or neurology patients without end-stage renal disease:

Cheng revised Winter-Tozer equation (Cheng 2016): Note: For use when phenytoin assays are performed at room temperature (25°C).

Predicted free phenytoin = (Measured total phenytoin divided by [(0.275 × albumin) + 0.1]) × 0.1

End-stage renal disease on hemodialysis:

Renal failure Winter-Tozer equation (Soriano 2017): Note: For use when phenytoin assays are performed at normal physiologic temperatures of 37ºC.

Predicted free phenytoin = (Measured total phenytoin divided by [(0.1 × albumin) + 0.1]) × 0.1

Soriano revised Winter-Tozer equation (Soriano 2017): Note: For use when phenytoin assays are performed at room temperature (25°C).

Predicted free phenytoin = (Measured total phenytoin divided by [(0.2 × albumin) + 0.1]) × 0.1

Hypoalbuminemia (serum albumin <3 g/dL [SI: <30 g/L]; hospitalized, noncritically ill patients) (Khan 2017):

Traditional Winter-Tozer equation: Note: For use when phenytoin assays are performed at normal physiologic temperatures of 37°C.

Predicted free phenytoin = (Measured total phenytoin divided by [(0.2 × albumin) + 0.1]) × 0.1

Anderson revised Winter-Tozer equation (Anderson 1997): Note: For use when phenytoin assays are performed at room temperature (25°C).

Predicted free phenytoin = (Measured total phenytoin divided by [(0.25 × albumin) + 0.1]) × 0.1

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

Pharmacokinetics (Adult Data Unless Noted)

Onset of action: IV: ~0.5 to 1 hour.

Absorption: Oral: Slow, variable; dependent on product formulation; decreased in neonates.

Distribution: Vd:

Neonates (Painter 1978):

GA 27 to 30 weeks: 1.2 ± 0.11 L/kg.

GA 31 to 36 weeks: 1.17 ± 0.21 L/kg.

GA ≥37 weeks: 1.22 ± 0.21 L/kg.

Infants: 0.62 to 1.04 L/kg (Loughnan 1977).

Children <7 years: Mean: 0.56 L/kg (Curless 1976).

Adults: 0.52 to 0.78 L/kg (Cranford 1978; Lund 1974).

Protein binding:

Neonates: GA 25 to 43 weeks: 61% to 91% (Painter 1994).

Infants: ≥85% (≤15% free).

Adults: 87.8% to 91.9% (Richens 1979).

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), CrCl <25 mL/minute (free fraction is increased 2- to 3-fold in uremia).

Metabolism: Follows dose-dependent (Michaelis-Menten) pharmacokinetics; "apparent” or calculated half-life is dependent upon serum concentration, therefore, metabolism is best described in terms of Vmax (metabolic capacity) and Km (constant equal to the concentration at which the rate of metabolism is 1/2 of Vmax); Vmax is increased in infants >6 months and children compared to adults; major metabolite (via oxidation) HPPA undergoes enterohepatic recycling and elimination in urine as glucuronides.

Bioavailability: Formulation dependent.

IM: 83% to ~100% (single dose) (Kostenbauder 1975).

IV: 100%.

Oral (dependent on product and/or salt): Capsules: 70% to 95% (Lund 1974; Neuvonen 1979); Oral suspension: Neonates: Variable, compared to adults, absolute enteral bioavailability reduced by 25% (Al Za'abi 2006).

Half-life elimination: Note: Elimination is not first-order (ie, follows Michaelis-Menten pharmacokinetics); half-life increases with increasing phenytoin concentrations; best described using parameters such as Vmax and Km (Patsalos 2008).

IV:

Neonates: Prolonged and highly variable particularly during the first week of life and in premature neonates; reported range varies from 6.9 to 194 hours (Bourgeois 1983; Loughnan 1977; Painter 1978; Painter 1981).

Preterm neonates: 75.4 ± 64.5 hours (Loughnan 1977).

Term neonates PNA ≤1 week: 20.7 ± 11.6 hours (Loughnan 1977).

Term neonates PNA >2 weeks and Infants: 7.6 ± 3.5 hours (Loughnan 1977).

Adults: 10 to 12 hours.

Oral:

Capsule, oral suspension: Average 22 hours (range: 7 to 42 hours).

Chewable tablet: Average 14 hours (range: 7 to 29 hours).

Time to peak, serum (formulation dependent): Oral: Extended-release capsule: 4 to 12 hours; Immediate-release preparation: 1.5 to 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. Note: In newborns (PNA <7 days), clearance is low but rapidly accelerates to older infant levels by 4 or 5 weeks of life (Patsalos 2008).

Pharmacokinetics: Additional Considerations (Adult Data Unless Noted)

Altered kidney function: Increased fraction of free phenytoin may occur.

Hepatic function impairment: Increased fraction of free phenytoin may occur.

Older adult: Clearance decreases ~20% in patients >70 years of age.

Brand Names: International
International Brand Names by Country
For country code abbreviations (show table)

  • (AE) United Arab Emirates: Epanutin | Phentolep;
  • (AR) Argentina: Aprocom | Epamin | Etoina | Fenigramon | Fenitenk | Fenitoina denver farma | Lotoquis simple;
  • (AT) Austria: Epanutin | Phenhydan;
  • (AU) Australia: Dilantin | Phenytoin | Phenytoin Sandoz;
  • (BD) Bangladesh: Phentin | Phenyton;
  • (BE) Belgium: Diphantoine;
  • (BG) Bulgaria: Epilan d | Phenhydan;
  • (BR) Brazil: Epelin;
  • (CH) Switzerland: Epanutin;
  • (CL) Chile: Dilantin | Epamin;
  • (CO) Colombia: Blask | Epamin | Epamin xr | Fenaten | Fenitoina | Fenitoina sodica;
  • (CZ) Czech Republic: Phenhydan;
  • (DE) Germany: Phenhydan;
  • (DO) Dominican Republic: Dilantin | Epamin | Fenitoina;
  • (EC) Ecuador: Epamin | Fenitenk | Fenitoina nifa;
  • (EE) Estonia: Epanutin | Phenhydan;
  • (EG) Egypt: Epanutin | Epilog | Ipanten | Pharotoin | Phenytin | Phenytion sodium | Phenytoin;
  • (ES) Spain: Epanutin | Fenitoina combino | Fenitoina ges;
  • (GB) United Kingdom: Epanutin | Phenytoin | Phenytoin cox | Phenytoin hikma;
  • (GR) Greece: Epanutin;
  • (HK) Hong Kong: Dilantin | Ditoin | Phenytoin;
  • (HU) Hungary: Epanutin | Phenhydan;
  • (ID) Indonesia: Curelepz | Decatona | Dilantin | Ikaphen | Kutoin | Movileps | Natrium fenitoina | Phenilep | Phenytoin;
  • (IE) Ireland: Epanutin | Phenytoin;
  • (IL) Israel: Dilantin | Epanutin;
  • (IN) India: C Toin | Dilantin | Epsotoin | Eptoin | Fentoin | Gentoin | Phenykem | Phenytoin;
  • (IT) Italy: Fenitoina Hikma;
  • (JO) Jordan: Epanutin | Phentolep | Phenytoin;
  • (KE) Kenya: Epanutin;
  • (KR) Korea, Republic of: Epatoina | Peniton | Peton | Phenytoin;
  • (KW) Kuwait: Epanutin | Phentolep;
  • (LB) Lebanon: Epanutin | Phentolep;
  • (LT) Lithuania: Epanutin | Phenhydan;
  • (LU) Luxembourg: Diphantoine;
  • (LV) Latvia: Epanutin | Phenhydan;
  • (MX) Mexico: Epamin | Fenaten | Feniffler | Fenitoina | Hidantoina;
  • (MY) Malaysia: Dilantin | Ditoin | Epanutin | Phenytoin;
  • (NL) Netherlands: Diphantoine | Epanutin;
  • (NO) Norway: Epanutin | Epinat;
  • (NZ) New Zealand: Dilantin | Dilantin infatabs | Dilantin paediatric;
  • (PE) Peru: Epamin | Epamin xr | Fenitoina | Phenostal 100;
  • (PH) Philippines: Dilantin | Sriphen;
  • (PK) Pakistan: Dilantin | Epitoin | Phenton-s;
  • (PL) Poland: Dilantin | Epanutin;
  • (PR) Puerto Rico: Dilantin | Extended phenytoin sodium | Phenytek | Phenytoin;
  • (PT) Portugal: Epanutin | Fenitoina;
  • (PY) Paraguay: Clerin | Epamin;
  • (QA) Qatar: Dilantin | Epanutin | Epanutin OS | Epanutin Ready-Mixed | Epitoin | Fentex | Phentolep;
  • (SA) Saudi Arabia: Epanutin | Phenytoin;
  • (SE) Sweden: Epanutin;
  • (SG) Singapore: Dilantin | Phenytoin;
  • (SI) Slovenia: Epanutin | Hydanphen | Phenhydan;
  • (SK) Slovakia: Phenhydan;
  • (TH) Thailand: Dantoin | Denyl | Dilantin | Diphenylhydantoin | Ditoin | Ditomed | Fenitoina rubio | Molantin | Pepsytoin | Phenytoin | Phenytoin KP;
  • (TN) Tunisia: Phentolep;
  • (TR) Turkey: Epanutin;
  • (TW) Taiwan: Aleviatin sodium | Dilantin | Epileptin | Hydantin;
  • (UG) Uganda: Tophen;
  • (UY) Uruguay: Antepil | Comitoina Simple | Difenilhidantoina | Epanutin | Fenitoina;
  • (VE) Venezuela, Bolivarian Republic of: Difenilhidantoina | Dilantin | Epamin | Fenitoina | Fentoinal;
  • (ZA) South Africa: Epanutin;
  • (ZW) Zimbabwe: Epanutin
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