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Fosphenytoin: Drug information

Fosphenytoin: Drug information
(For additional information see "Fosphenytoin: Patient drug information" and see "Fosphenytoin: Pediatric drug information")

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

The rate of fosphenytoin intravenous (IV) administration should not exceed 150 mg phenytoin sodium equivalent (PE)/minute because of the risk of severe hypotension and cardiac arrhythmias. Careful cardiac monitoring is needed during and after administering fosphenytoin IV. 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
  • Cerebyx
Brand Names: Canada
  • Cerebyx
Pharmacologic Category
  • Antiseizure Agent, Hydantoin
Dosing: Adult

Note: Dosing: Always prescribe and dispense fosphenytoin as phenytoin sodium equivalents (mg PE); 1 mg PE is equivalent to 1 mg phenytoin sodium. Safety: Before prescribing, 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) (Locharernkul 2008; Löscher 2009). IV administration: Continuous cardiac and blood pressure monitoring is recommended for rapid infusion in urgent indications (eg, status epilepticus). For nonurgent monitoring requirements when slow infusion is appropriate, refer to institutional protocol (Drislane 2019; Meek 1999; Siebert 2013).

Seizures

Seizures:

Craniotomy, seizure prophylaxis (alternative agent):

Loading dose: IV: 10 to 20 mg PE/kg at a rate of ≤150 mg PE/minute prior to incision (Iuchi 2015; Paisansathan 2019).

Postoperative prophylaxis: IV: 5 to 7.5 mg PE/kg/day in 2 to 3 divided doses, until postoperative day 7; usual daily dose: 300 to 400 mg PE; adjust dose based on response and serum concentrations (Iuchi 2015; Merli 2021; manufacturer's labeling). Note: Duration individualized based on underlying intracranial pathology and other clinical considerations (Iuchi 2015; Merli 2021).

Focal (partial) onset seizures and generalized onset seizures (short-term alternative to oral therapy): Note: Use of 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 observed in 1 to 3 weeks when steady-state serum concentrations are reached.

Loading dose (optional) (fosphenytoin/phenytoin naive): IV, IM: 10 to 20 mg PE/kg given in 1 to 3 divided doses over 24 hours; administer IV loading dose at a rate of 100 to 150 mg PE/minute; usual total loading dose is 1 to 1.5 g PE (AES [Glauser 2016]; Jirsch 2020); begin maintenance dose 8 to 12 hours after loading dose.

Maintenance dose: IV, IM: Initial: 4 to 7 mg PE/kg/day (usual daily dose: 300 to 400 mg PE) given in 2 to 4 divided doses; adjust dose based on response and serum concentrations (Murphy 2016). Some experts recommend initiating maintenance therapy with 5 mg PE/kg/day in 2 divided doses (Schachter 2020). A maximum dose has not been established; use caution when prescribing maintenance doses >600 mg PE/day.

Status epilepticus

Status epilepticus (convulsive and nonconvulsive): Note: Do not use the IM route due to delay in onset of action/bioavailability. Generally, fosphenytoin is administered as part of initial therapy with or immediately after a benzodiazepine (eg, lorazepam IV) (Drislane 2019; Jirsch 2020; NCS [Brophy 2012]).

Loading dose (fosphenytoin/phenytoin naive): IV: 20 mg PE/kg at a rate of 100 to 150 mg PE/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 5 to 10 mg PE/kg 10 minutes after the loading dose; maximum total loading dose: 30 mg PE/kg (AES [Glauser 2016]; Drislane 2019; Jirsch 2020; Inaba 2013; NCS [Brophy 2012]). Begin maintenance dose 8 to 12 hours after loading dose.

Maintenance dose: IV: Initial: 4 to 7 mg PE/kg/day (usual daily dose: 300 to 400 mg PE) given in 2 to 4 divided doses; adjust dose based on response and serum concentrations (Murphy 2016). Some experts recommend initiating maintenance therapy with 5 mg PE/kg/day in 2 divided doses (Schachter 2020). A maximum dose has not been established; use caution when prescribing maintenance doses >600 mg PE/day.

Traumatic brain injury, prevention of early posttraumatic seizure

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

Loading dose: IV: 17 to 20 mg PE/kg at a rate of 100 to 150 mg PE/minute; usual maximum dose: 2 g PE (Debenham 2011; Inaba 2013); begin maintenance dose 8 to 12 hours after loading dose.

Maintenance dose: IV: 100 mg PE every 8 hours or 5 mg PE/kg/day (round to the nearest 100 mg PE) given in divided doses every 8 hours (Debenham 2011; Inaba 2013). Note: Duration of prophylaxis varies, but is generally short term (eg, ~7 days) (BTF [Carney 2017]; Inaba 2013).

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 (Ho 2021).

IV: 250 mg to 1 g PE as a one-time dose or 15 mg/kg PE (maximum dose not established) over 30 to 120 minutes; administer at a rate ≤150 mg PE/minute (Cheshire 2001; Ho 2021; Vargas 2015).

Dosage form conversion: Use the same total daily dose when converting between oral/IV phenytoin and IV/IM fosphenytoin. Fosphenytoin is 100% bioavailable by both the IM and IV routes; oral phenytoin is 70% to 95% bioavailable (dependent on product and/or salt) (Lund 1974; Neuvonen 1979). Plasma phenytoin concentrations may modestly increase when switching from oral phenytoin to IM or IV fosphenytoin (or decrease when switching from fosphenytoin to oral phenytoin) due to differences in bioavailability.

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

There are no dosage adjustments provided in the manufacturer's labeling. Free (unbound) phenytoin levels should be monitored closely in patients with renal disease or in those with hypoalbuminemia; furthermore, fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance in these patients leading to increase frequency and severity of adverse events.

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling. Free (unbound) phenytoin levels should be monitored closely in patients with hepatic disease or in those with hypoalbuminemia or hyperbilirubinemia; furthermore, fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance in these patients leading to increased frequency and severity of adverse events.

Dosing: Pediatric

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

The dose, concentration in solutions, and infusion rates for fosphenytoin are expressed as PHENYTOIN SODIUM EQUIVALENTS (PE):

Fosphenytoin should ALWAYS be prescribed and dispensed in mg of PE; otherwise significant medication errors may occur.

Note: Based on pharmacokinetic studies, experts recommend the following (Fischer 2003): Use the pediatric IV phenytoin dosing guidelines to dose fosphenytoin using doses in PE equal to the phenytoin doses (ie, phenytoin 1 mg = fosphenytoin 1 mg PE). Dosage should be individualized based upon clinical response and serum concentrations. In pediatric patients, intravenous is the preferred route of administration. Due to the risks of cardiac and local toxicity, transition to oral phenytoin as soon as possible.

Seizures, maintenance therapy; short-term when oral route not available or appropriate

Seizures, maintenance therapy; short-term when oral route not available or appropriate:

Infants, Children, and Adolescents: IV (preferred), IM: Initial: 4 to 8 mg PE/kg/day in 2 divided doses; initiate maintenance dose ≥12 hours after loading dose. Based on data for phenytoin, some experts suggest higher maintenance doses (8 to 10 mg PE/kg/day) may be necessary in infants and young children (Guerrini 2006); in adult patients, treatment duration >5 days has not been evaluated.

Seizures, nonemergent

Seizures, nonemergent: Infants, Children, and Adolescents: Loading dose (if required): IV (preferred), IM: 10 to 15 mg PE/kg; then initiate maintenance doses ≥12 hours after loading dose.

Seizures, substitution for oral phenytoin therapy

Seizures, substitution for oral phenytoin therapy : Infants, Children, and Adolescents: IV (preferred), IM: May be substituted for oral phenytoin sodium at the same total daily dose; however, phenytoin capsules are ~90% bioavailable by the oral route; phenytoin, supplied as fosphenytoin, is 100% bioavailable by both the IM and IV routes; for this reason, plasma phenytoin concentrations may increase when IM or IV fosphenytoin is substituted for oral phenytoin sodium therapy; monitor serum concentrations closely; in adult clinical trials, IM fosphenytoin was administered as a single daily dose utilizing either 1 or 2 injection sites; some patients may require more frequent dosing.

Status epilepticus

Status epilepticus: Note: In management of status epilepticus, a benzodiazepine should be used for initial management; if seizures are refractory to benzodiazepines, fosphenytoin is a therapeutic option for second phase therapy along with levetiracetam and valproic acid; there is no preference on which agent and all 3 have been shown similarly effective (AES [Glauser 2016]; Kapur 2019).

Infants, Children, and Adolescents: Loading dose: IV (preferred), IM: 20 mg PE/kg/dose; maximum dose: 1,500 mg PE/dose; reported range: 15 to 20 mg PE/kg/dose; an additional load of 5 mg PE/kg administered 10 minutes after initial loading infusion has also been suggested if seizure activity continues (AAP [Shenoi 2020]; AES [Glauser 2016]; Kapur 2019; NCS [Brophy 2012]).

Traumatic brain injury; seizure prophylaxis

Traumatic brain injury; seizure prophylaxis: Limited data available:

Note: Current guidelines suggest 7 days of prophylactic phenytoin (fosphenytoin) may be considered to reduce the incidence of early posttraumatic seizures in pediatric patients with severe traumatic brain injuries; however, it has not been shown to reduce the risk of long-term seizures or improve neurologic outcome (BTS [Kochanek 2019]). Dosing based on experience with phenytoin.

Infants, Children, and Adolescents: IV: Initial: 18 mg PE/kg loading dose, followed by 6 mg PE/kg/day divided every 8 hours for 48 hours was used in a double-blind, placebo-controlled trial of 102 pediatric patients (n=46 treatment group; median age: 6.4 years) 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 (Young 2004). In a retrospective trial, reduced seizure frequency with prophylactic phenytoin use was described (Lewis 1993).

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

Infants, Children, and Adolescents: There are no dosage adjustments provided in the manufacturer's labeling. Free (unbound) phenytoin serum concentrations should be monitored closely in patients with renal disease or in those with hypoalbuminemia; free phenytoin serum concentrations may be increased; furthermore, fosphenytoin conversion to phenytoin may be increased without a similar increase in phenytoin conversion in these patients, leading to increased frequency and severity of adverse events.

Dosing: Hepatic Impairment: Pediatric

Infants, Children, and Adolescents: There are no dosage adjustments provided in the manufacturer's labeling. Free (unbound) phenytoin concentrations should be monitored closely in patients with hepatic disease or in those with hypoalbuminemia; free phenytoin concentrations may be increased; furthermore, fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance in these patients, leading to increased frequency and severity of adverse events.

Dosing: Older Adult

Refer to adult dosing; clearance is decreased in geriatric patients; lower doses or less frequent dosing may be required. In addition, older adults may have lower serum albumin, which may increase the free fraction and, therefore, pharmacologic response including adverse events.

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 (expert opinion). Refer to adult dosing for indication-specific doses.

Class 3 obesity (BMI ≥ 40 kg/m2):

Status epilepticus (convulsive and nonconvulsive):

Loading dose: IV: Initial: 15 mg PE/kg (using actual body weight; no maximum dose); administer at a rate of 100 to 150 mg PE/minute; doses up to 2.3 g PE have been reported (DasGupta 2019; Holder 2019; expert opinion); begin maintenance dose 8 to 12 hours after loading dose.

Maintenance dose: IV, IM: Initial: 4 to 7 mg PE/kg/day (using ideal body weight; usual dose: 300 to 400 mg PE/day) given in 2 to 4 divided doses; adjust dose based on response and serum concentrations (Erstad 2004; Murphy 2016). A maximum dose has not been established; use caution when prescribing maintenance doses >600 mg PE/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 ideal body weight (for maintenance doses) with subsequent appropriate therapeutic drug monitoring would apply (expert opinion).

Rationale for recommendations: For loading doses, use of actual body weight in patients with obesity 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 (expert opinion). There is a paucity of studies evaluating the influence of obesity on fosphenytoin dosing or pharmacokinetics. Evidence from one small pharmacokinetic study comparing patients with obesity to nonobese patients receiving phenytoin 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) (Abernethy 1985). 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 (Abernethy 1985; expert opinion).

Dosage Forms: US

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

Solution, Injection, as sodium:

Cerebyx: 100 mg PE/2 mL (2 mL); 500 mg PE/10 mL (10 mL)

Generic: 100 mg PE/2 mL (2 mL); 500 mg PE/10 mL (10 mL)

Generic Equivalent Available: US

Yes

Dosage Forms: Canada

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

Solution, Injection:

Cerebyx: 75 mg/mL (2 mL, 10 mL)

Product Availability

Sesquient: FDA approved November 2020; anticipated availability currently unknown.

Administration: Adult

IM: May be administered as a single daily dose using 1 to 4 injection sites (up to 20 mL per site well tolerated in adults) (Meek 1999; Pryor 2001).

IV: Rates of infusion: Do not exceed 150 mg PE/minute. Slower administration reduces incidence of cardiovascular events (eg, hypotension, arrhythmia) as well as severity of paresthesias and pruritus. For nonemergent situations, may administer loading dose more slowly (eg, over 30 minutes [~33 mg PE/minute for 1,000 mg PE] or 50 to 100 mg PE/minute [Fischer 2003]). Highly sensitive patients (eg, elderly, patients with preexisting cardiovascular conditions) should receive fosphenytoin more slowly (eg, 25 to 50 mg PE/minute) (Meek 1999).

Administration: Pediatric

Parenteral:

IV: Administer diluted solution as intermittent IV infusion; do not administer as a continuous infusion or IV push. Slower administration rates may reduce the incidence of cardiovascular events (eg, hypotension, arrhythmia), as well as severity of paresthesias and pruritus. In neonates, infusion over 10 to 30 minutes has been recommended (Domonoske 2017); in older patients, administration varies by patient condition and type of dose (eg, loading or maintenance). Highly sensitive patients (eg, patients with preexisting cardiovascular conditions) should receive fosphenytoin more slowly (Meek 1999).

Maximum rates of infusion:

Loading doses: Administer at 2 mg PE/kg/minute up to a maximum of 150 mg PE/minute.

Maintenance doses: Administer more slowly at 1 to 2 mg PE/kg/minute up to 100 mg PE/minute.

IM: Not the preferred route in neonatal and pediatric patients. May administer undiluted; the quadricep area has been recommended as an injection site; due to volume of dose, multiple injection sites may be necessary to administer a single dose; in adults, this has required 1 to 4 injection sites (Meek 1999; Pellock 1996; Pryor 2001).

Hazardous Drugs Handling Considerations

Hazardous agent (NIOSH 2016 [group 2]).

Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage.

NIOSH recommends double gloving, a protective gown, ventilated engineering controls (a class II biological safety cabinet or a compounding aseptic containment isolator), and closed system transfer devices (CSTDs) for preparation. Double gloving, a gown, and (if dosage form allows) CSTDs are required during administration (NIOSH 2016). Assess risk to determine appropriate containment strategy (USP-NF 2017).

Use: Labeled Indications

Seizures: Control of generalized tonic-clonic status epilepticus and the prevention and treatment of seizures occurring during neurosurgery (eg, prophylaxis during craniotomy); may be used for short-term parenteral administration (eg, focal [partial] onset seizures or generalized onset seizures) when oral phenytoin is not possible.

Use: Off-Label: Adult

Traumatic brain injury, prevention of early posttraumatic seizure; Trigeminal neuralgia, rescue therapy

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

Cerebyx may be confused with CeleBREX, CeleXA, Cerezyme, Cervarix

Fosphenytoin may be confused with fospropofol

Administration issues:

Overdoses have occurred due to confusion between the mg per mL concentration of fosphenytoin (50 mg phenytoin equivalent (PE)/mL) and total drug content per vial (either 100 mg PE/2 mL vial or 500 mg PE/10 mL vial). ISMP recommends that the total drug content per container is identified instead of the concentration in mg per mL to avoid confusion and potential overdoses. Additionally, since most errors have occurred with overdoses in children, ISMP recommends that pediatric hospitals consider stocking only the 2 mL vial.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Also refer to the phenytoin monograph for additional adverse reactions.

>10%:

Dermatologic: Pruritus (IM: 3%; IV: ≤49%; generally transient; often reported in groin area)

Nervous system: Ataxia (IM: ≤8%; IV: ≤11%), burning sensation (IV: ≤44%; often reported in groin area), dizziness (IM: 5%; IV: 31%), drowsiness (IM: 7%; IV: 20%), paresthesia (IM: 4%; IV: ≤44%; often reported in groin area)

Ophthalmic: Nystagmus disorder (IV: 44%; IM: 15%)

1% to 10%:

Cardiovascular: Atrial flutter (≤1%), bundle branch block (≤1%), cardiomegaly (≤1%), edema (≤1%), heart failure (≤1%), hypertension (>1%), hypotension (IV: 8%), orthostatic hypotension (≤1%), palpitations (≤1%), prolonged QT interval on ECG (≤1%), pulmonary embolism (≤1%), shock (≤1%), sinus bradycardia (≤1%), subdural hematoma (≤1%), syncope (≤1%), tachycardia (IV: 2%), thrombophlebitis (≤1%), vasodilation (IV: 6%), ventricular premature contractions (≤1%)

Dermatologic: Contact dermatitis (≤1%), cutaneous nodule (≤1%), diaphoresis (≤1%), ecchymoses (IM: 7%), maculopapular rash (≤1%), pustular rash (≤1%), skin discoloration (≤1%), skin photosensitivity (≤1%), skin rash (>1%), urticaria (≤1%)

Endocrine & metabolic: Acidosis (≤1%), albuminuria (≤1%), alkalosis (≤1%), cachexia (≤1%), dehydration (≤1%), diabetes insipidus (≤1%), hyperglycemia (≤1%), hyperkalemia (≤1%), hypokalemia (>1%), hypophosphatemia (≤1%), ketosis (≤1%)

Gastrointestinal: Ageusia (≤1%), anorexia (≤1%), constipation (>1%), diarrhea (≤1%), dysgeusia (IV: 3%), dyspepsia (≤1%), dysphagia (≤1%), flatulence (≤1%), gastritis (≤1%), gastrointestinal hemorrhage (≤1%), intestinal obstruction (≤1%), nausea (IM: 5%; IV: 9%), oral paresthesia (≤1%), sialorrhea (≤1%), tenesmus (≤1%), tongue disease (IV: 4%), vomiting (IM: 3%; IV: 2%), xerostomia (IV: 4%)

Genitourinary: Dysuria (≤1%), genital edema (≤1%), oliguria (≤1%), pelvic pain (IV: 4%), urethral pain (≤1%), urinary incontinence (≤1%), urinary retention (≤1%), vaginitis (≤1%), vulvovaginal candidiasis (≤1%)

Hematologic & oncologic: Anemia (≤1%), hypochromic anemia (≤1%), leukocytosis (≤1%), leukopenia (≤1%), lymphadenopathy (≤1%), petechia (≤1%), thrombocytopenia (≤1%)

Hepatic: Abnormal hepatic function tests (≤1%)

Hypersensitivity: Facial edema (>1%), tongue edema (≤1%)

Infection: Cryptococcosis (≤1%), infection (>1%), sepsis (≤1%)

Local: Bleeding at injection site (≤1%), inflammation at injection site (≤1%), injection-site reaction (>1%; including purple glove syndrome), pain at injection site (>1%), swelling at injection site (≤1%)

Nervous system: Abnormality in thinking (>1%), absent reflexes (IM: 3%), agitation (IV: 3%), akathisia (≤1%), altered sense of smell (≤1%), amnesia (≤1%), aphasia (≤1%), asthenia (IM: 9%; IV: 2%), brain edema (2%), central nervous system depression (≤1%), cerebral hemorrhage (≤1%), cerebral infarction (≤1%), chills (>1%), coma (≤1%), confusion (≤1%), delirium (≤1%), depersonalization (≤1%), depression (≤1%), dysarthria (≤2%), emotional lability (≤cerebral infarction (≤1%),1%), encephalitis (≤1%), encephalopathy (≤1%), extrapyramidal reaction (≤4%; more common with IV), headache (IM: 9%; IV: 2%), hemiplegia (≤1%), hostility (≤1%), hyperacusis (≤1%), hyperesthesia (≤1%), hyperreflexia (>1%), hypoesthesia (≤2%; more common with IV), hypotonia (≤1%), insomnia (≤1%), intracranial hypertension (>1%), malaise (≤1%), meningitis (≤1%), migraine (≤1%), myasthenia (>1%), myoclonus (≤1%), nervousness (>1%), neurosis (≤1%), paralysis (≤1%), personality disorder (≤1%), positive Babinski sign (≤1%), psychosis (≤1%), seizure (≤1%), speech disturbance (>1%), stupor (IV: 8%), tremor (IM: 10%; IV: 3%), twitching (≤1%), vertigo (IV: 2%)

Neuromuscular & skeletal: Arthralgia (≤1%), back pain (IV: 2%), hyperkinetic muscle activity (≤1%), hypokinesia (≤1%), lower limb cramp (≤1%), myalgia (≤1%), myopathy (≤1%)

Ophthalmic: Amblyopia (IV: 2%), conjunctivitis (≤1%), diplopia (IV: 3%), eye pain (≤1%), mydriasis (≤1%), photophobia (≤1%), visual field defect (≤1%)

Otic: Deafness (2%), otalgia (≤1%), tinnitus (IV: 9%)

Renal: Polyuria (≤1%), renal failure syndrome (≤1%)

Respiratory: Apnea (≤1%), aspiration pneumonia (≤1%), asthma (≤1%), atelectasis (≤1%), bronchitis (≤1%), cyanosis (≤1%), dyspnea (≤1%), epistaxis (≤1%), flu-like symptoms (≤1%), hemoptysis (≤1%), hyperventilation (≤1%), hypoxia (≤1%), increased bronchial secretions (≤1%), increased cough (≤1%), pharyngitis (≤1%), pneumonia (>1%), pneumothorax (≤1%), rhinitis (≤1%), sinusitis (≤1%)

Miscellaneous: Fever (>1%)

Frequency not defined: Cardiovascular: Cardiac arrhythmia, severe hypotension

Postmarketing (fosphenytoin or phenytoin):

Dermatologic: Acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, toxic epidermal necrolysis

Hematologic & oncologic: Pure red cell aplasia

Hypersensitivity: Anaphylaxis, angioedema

Immunologic: Drug reaction with eosinophilia and systemic symptoms

Neuromuscular & skeletal: Dyskinesia

Contraindications

Hypersensitivity to fosphenytoin, phenytoin, other hydantoins, or any component of the formulation; sinus bradycardia, sinoatrial block, second- and third-degree AV block, or Adams-Stokes syndrome; history of prior acute hepatotoxicity attributable to fosphenytoin or phenytoin; concurrent use with delavirdine.

Warnings/Precautions

Concerns related to adverse effects:

• Anemia: Macrocytosis, megaloblastic anemia, and pure red cell aplasia have occurred with phenytoin; macrocytosis and megaloblastic anemia can usually be treated with folic acid therapy.

• Blood dyscrasias: A spectrum of hematologic effects have been reported with phenytoin (eg, leukopenia, granulocytopenia, agranulocytosis, thrombocytopenia, and pancytopenia with or without bone marrow suppression) and may be fatal; patients with a previous history of adverse hematologic reaction to any drug may be at increased risk. Early detection of hematologic change is important; advise patients of early signs and symptoms including fever, sore throat, mouth ulcers, infections, easy bruising, petechial or purpuric hemorrhage.

• Cardiovascular events: [US Boxed Warning]: The rate of fosphenytoin IV administration should not exceed 150 mg phenytoin equivalents (PE)/minute in adults. In pediatric patients when treating status epilepticus, do not exceed a maximum IV administration rate of 2 mg PE/kg/minute (up to 150 mg PE/minute); for maintenance doses, the rate should not exceed 1 to 2 mg PE/kg/minute (up to 100 mg PE/minute). Severe hypotension and cardiac arrhythmias (eg, bradycardia, heart block, QT interval prolongation, ventricular tachycardia, ventricular fibrillation) may occur with rapid administration (may be fatal) and commonly occur in critically ill patients, elderly patients, and patients with hypotension and severe myocardial insufficiency. Careful cardiac (including respiratory) monitoring is necessary during and after administration of fosphenytoin IV; reduction in rate of administration or discontinuation of infusion may be necessary. 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.

• Dermatologic reactions: Severe cutaneous adverse reactions (some fatal), including acute generalized exanthematous pustulosis (AGEP), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and Stevens-Johnson syndrome (SJS) have been reported; the onset of symptoms is usually within 28 days, but can occur later. Data suggest a genetic susceptibility for serious skin reactions in patients of Asian descent (see "Special populations" below).

• Hepatotoxicity: Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with phenytoin. Other manifestations include jaundice, hepatomegaly, elevated serum transaminase levels, leukocytosis, and eosinophilia. The clinical course of acute phenytoin hepatotoxicity ranges from prompt recovery to fatal outcomes. Immediately discontinue fosphenytoin in patients who develop acute hepatotoxicity and do not readminister.

• Hypersensitivity: Hypersensitivity, including angioedema, has been reported; discontinue immediately if hypersensitivity reaction occurs. Consider alternative therapy in patients who have experienced hypersensitivity to structurally similar drugs such as carboxamides (eg, carbamazepine), barbiturates, succinimides, and oxazolidinediones (eg, trimethadione).

• Local toxicity: The "purple glove syndrome" (ie, discoloration with edema and pain of distal limb) may occur following peripheral IV administration of fosphenytoin. This syndrome may or may not be associated with drug extravasation. Symptoms may resolve spontaneously; however, skin necrosis and limb ischemia may occur. In general, fosphenytoin has significantly less venous irritation and phlebitis compared with an equimolar dose of phenytoin (Jamerson 1994).

• Lymphadenopathy: May occur (local or generalized), including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin disease. Discontinue if lymphadenopathy occurs.

• Multiorgan hypersensitivity reactions: Potentially serious, sometimes fatal multiorgan hypersensitivity reactions (also known as DRESS) have been reported with some antiseizure drugs; including fosphenytoin; monitor for signs and symptoms of possible manifestations associated with lymphatic, hepatic, renal, and/or hematologic organ systems; gradual discontinuation and conversion to alternate therapy may be required.

• Sensory disturbances: Severe burning or itching, and/or paresthesias, mostly perineal, may occur upon administration, usually at the maximum administration rate and last from minutes to hours; milder sensory disturbances may persist for as long as 24 hours; occurrence and intensity may be lessened by slowing or temporarily stopping the infusion.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with hypotension and/or severe myocardial insufficiency; use is contraindicated in patients with sinus bradycardia, sinoatrial block, second- and third-degree heart block or Adam-Stokes syndrome.

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

• Hepatic impairment: Use with caution in patients with hepatic impairment. Due to an increased fraction of unbound phenytoin in patients with hepatic impairment, interpret total plasma phenytoin concentrations with caution; unbound phenytoin concentrations may be more useful.

• Hyperbilirubinemia: Use with caution in patients with any condition associated with elevated serum bilirubin levels, which will increase the free fraction of phenytoin in the serum and, therefore, the pharmacologic response. Due to an increased fraction of unbound phenytoin in patients with hyperbilirubinemia, interpret total plasma phenytoin concentrations with caution; unbound phenytoin concentrations may be more useful.

• 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. Due to an increased fraction of unbound phenytoin in patients with hypoalbuminemia, interpret total plasma phenytoin concentrations with caution; unbound phenytoin concentrations may be more useful.

• Hypothyroidism: Use with caution in patients with hypothyroidism; phenytoin may alter thyroid (T4) hormone serum concentrations (with chronic administration).

• Porphyria: Use with caution in patients with porphyria.

• Renal impairment: Use with caution in patients with renal impairment; also consider the phosphate load of fosphenytoin (0.0037 mmol phosphate/mg PE fosphenytoin). Due to an increased fraction of unbound phenytoin in patients with renal impairment, interpret total plasma phenytoin concentrations with caution; unbound phenytoin concentrations may be more useful.

Special populations:

• Asian ancestry: Asian patients with the variant HLA-B*1502 and/or patients who are carriers for the variant CYP2C9*3 (intermediate or poor metabolizers) may be at an increased risk of developing SJS and/or TEN.

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

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

• Older adult: Use with caution in the elderly.

Dosage form specific issues:

• Phenytoin sodium equivalent: Doses of fosphenytoin are always expressed as their phenytoin sodium equivalent (PE). Thus, 1 mg PE is equivalent to 1 mg phenytoin sodium. Do not change the recommended doses when substituting fosphenytoin for phenytoin or vice versa as they are not equivalent on a mg to mg basis. Dosing errors have also occurred due to misinterpretation of vial concentrations resulting in two- or tenfold overdoses (some fatal); ensure correct volume of fosphenytoin is withdrawn from vial.

Other warnings/precautions:

• Appropriate use: Administer only when oral phenytoin administration is not possible. If rapid phenytoin loading is a primary goal, IV administration of fosphenytoin is preferred. As non-emergency therapy, fosphenytoin IV should be administered more slowly. Fosphenytoin is not indicated for the treatment of absence seizures or seizures due to hypoglycemia or other metabolic causes.

• 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 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 medications 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.

Warnings: Additional Pediatric Considerations

Pediatric patients may be at increased risk for vitamin D deficiency; with chronic therapy, phenytoin may cause catabolism of vitamin D; the daily vitamin D requirement may be increased in these patients (≥400 units/day); vitamin D status should be periodically monitored with laboratory data (Misra 2008; Wagner 2008).

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 Lexicomp 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: CYP3A4 Inducers (Strong) 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

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

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

Atazanavir: May decrease the serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may decrease the serum concentration of Atazanavir. Management: Coadministration of fosphenytoin or phenytoin and atazanavir without ritonavir is not recommended. If atazanavir and ritonavir are coadministered with fosphenytoin or phenytoin, fosphenytoin-phenytoin dose increases may be required. Risk D: Consider therapy modification

Atogepant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Atogepant. Management: The recommended dose of atogepant is 30 mg once daily or 60 mg once daily when combined with strong or moderate CYP3A4 inducers. 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: Fosphenytoin 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

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 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: Fosphenytoin 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

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

CeFAZolin: May increase the serum concentration of Fosphenytoin. 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): Fosphenytoin may decrease the serum concentration of Chloramphenicol (Systemic). Fosphenytoin may increase the serum concentration of Chloramphenicol (Systemic). Chloramphenicol (Systemic) may increase the serum concentration of Fosphenytoin. 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): Fosphenytoin may enhance the QTc-prolonging effect of Ciprofloxacin (Systemic). Ciprofloxacin (Systemic) may diminish the therapeutic effect of Fosphenytoin. Ciprofloxacin (Systemic) may decrease the serum concentration of Fosphenytoin. 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

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

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: Fosphenytoin may decrease the serum concentration of Deferasirox. Management: Avoid combination when possible; if the combination must be used, consider a 50% increase in initial deferasirox dose, with monitoring of serum ferritin concentrations and clinical responses 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: Fosphenytoin 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): Fosphenytoin may decrease the serum concentration of DexAMETHasone (Systemic). DexAMETHasone (Systemic) may decrease the serum concentration of Fosphenytoin. DexAMETHasone (Systemic) may increase the serum concentration of Fosphenytoin. Management: Consider dexamethasone dose increases when combined with fosphenytoin and monitor closely for reduced steroid efficacy. Monitor phenytoin levels closely, 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

Digoxin: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Digoxin. 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. Management: Avoid concomitant use of disulfiram and phenytoin when possible. Phenytoin dose adjustment will likely be necessary when starting and/or stopping concurrent disulfiram. Monitor phenytoin response and concentrations closely. Risk D: Consider therapy modification

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

DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of DOXOrubicin (Conventional). Risk X: Avoid combination

Doxycycline: Fosphenytoin may decrease the serum concentration of Doxycycline. Management: Consider increasing the dose of doxycycline when initiating phenytoin, or using another tetracycline derivative to avoid this interaction. If coadministered, monitor for decreased therapeutic effects of doxycyline. Risk D: Consider therapy modification

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

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

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

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: Fosphenytoin may decrease the serum concentration of Eslicarbazepine. (based on studies with phenytoin) Eslicarbazepine may increase the serum concentration of Fosphenytoin. (based on studies with 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

Ezogabine: Fosphenytoin-Phenytoin may decrease the serum concentration of Ezogabine. Management: Consider increasing the ezogabine dose when adding phenytoin. Patients using this combination should be monitored closely for evidence of adequate ezogabine therapy. 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: Fosphenytoin may decrease the serum concentration of Felbamate. Felbamate may increase the serum concentration of Fosphenytoin. 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 fosphenytoin 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

Flunarizine: Fosphenytoin 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: Fosphenytoin may decrease the serum concentration of Fosamprenavir. Fosamprenavir may decrease the serum concentration of Fosphenytoin. Specifically, fosamprenavir boosted with ritonavir may decrease phenytoin concentrations. 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

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

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

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

Halothane: May increase the serum concentration of Fosphenytoin. 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: Fosphenytoin may enhance the arrhythmogenic effect of LamoTRIgine. Fosphenytoin may decrease the serum concentration of LamoTRIgine. Management: Consider the risk of serious arrhythmias or death versus benefit of this combination. For patients taking fosphenytoin 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

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 Fosphenytoin. 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-Containing Products: Fosphenytoin-Phenytoin may diminish the therapeutic effect of Levodopa-Containing Products. 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

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

Lopinavir: Fosphenytoin may decrease the serum concentration of Lopinavir. Lopinavir may decrease the serum concentration of Fosphenytoin. 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

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

Miconazole (Oral): May increase the serum concentration of Fosphenytoin. 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. Risk X: Avoid combination

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

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). Fosphenytoin-Phenytoin may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing). Fosphenytoin-Phenytoin may decrease the serum concentration of Neuromuscular-Blocking Agents (Nondepolarizing). 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

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

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

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

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

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

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

PHENobarbital: Fosphenytoin may enhance the CNS depressant effect of PHENobarbital. Fosphenytoin may increase the serum concentration of PHENobarbital. PHENobarbital may decrease the serum concentration of Fosphenytoin. 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

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

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

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

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: Fosphenytoin 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

Ritonavir: Fosphenytoin may decrease the serum concentration of Ritonavir. Ritonavir may decrease the serum concentration of Fosphenytoin. Management: Consider avoiding when possible. Dose adjustments may be required. Monitor phenytoin concentrations, and for therapeutic response to fosphenytoin 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: Fosphenytoin may decrease the serum concentration of Rufinamide. Rufinamide may increase the serum concentration of Fosphenytoin. 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

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

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

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

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

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

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

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

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

Tepotinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tepotinib. 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 may decrease the serum concentration of Theophylline Derivatives. Theophylline Derivatives may decrease the serum concentration of Fosphenytoin. Management: Seek alternatives when possible. If used together, monitor for decreased concentrations/effects of phenytoin or theophylline if the other agent is initiated/dose increased, or increased concentrations/effects if the other is discontinued/dose decreased. Risk D: Consider therapy modification

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: Fosphenytoin 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: Fosphenytoin may decrease the serum concentration of Topiramate. Topiramate may increase the serum concentration of Fosphenytoin. 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: Fosphenytoin may decrease the serum concentration of TraZODone. TraZODone may increase the serum concentration of Fosphenytoin. Management: Consider increasing the trazodone dose during coadministration with strong CYP3A4 inducers, such as fosphenytoin. 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: Fosphenytoin may decrease the serum concentration of Trimethoprim. Trimethoprim may increase the serum concentration of Fosphenytoin. Management: Consider alternatives to this combination when possible, to avoid potential decreased trimethoprim efficacy and increased phenytoin concentrations/effects. Monitor patients receiving this combination closely for both of these possible effects. Risk D: Consider therapy modification

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 Fosphenytoin. 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

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

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

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

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

Females of reproductive potential who are not planning a pregnancy should use effective contraception; hormonal contraceptives may be less effective.

Pregnancy Considerations

Fosphenytoin is the prodrug of phenytoin. 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. 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.

Due to pregnancy-induced physiologic changes, the pharmacokinetics may be changed; additional monitoring is needed.

Also refer to the Phenytoin monograph for additional information.

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

Breastfeeding Considerations

Fosphenytoin is the prodrug of phenytoin. It is not known if fosphenytoin is present in breast milk prior to conversion to phenytoin. According to the manufacturer, the decision to continue or discontinue breastfeeding during therapy should take into account the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother. Refer to Phenytoin monograph for additional information.

Dietary Considerations

Provides 0.0037 mmol phosphate/mg PE fosphenytoin

Monitoring Parameters

Continuous blood pressure, heart rate, ECG, and respiratory function monitoring with loading dose and for ~10 to 20 minutes following infusion; CBC, hepatic function tests, plasma phenytoin concentration monitoring (plasma concentrations should not be measured until conversion to phenytoin is complete, ~2 hours after the end of an IV infusion or ~4 hours after an IM injection).

Note: If available, free (unbound) phenytoin concentrations should be obtained in patients with renal or hepatic impairment, and/or hypoalbuminemia or hyperbilirubinemia. If free (unbound) phenytoin concentrations are unavailable, the adjusted total phenytoin concentration may be determined based upon equations in adult patients; however, due to an increased fraction of unbound phenytoin in these patients, interpret total phenytoin concentrations with caution. Trough concentrations are generally recommended for routine monitoring.

Consult individual institutional policies and procedures.

Reference Range

Adults: Due to narrow safety margin and nonlinear pharmacokinetics (small dose increases can result in disproportionately large increases in serum concentrations), serum phenytoin concentration monitoring recommended.

Therapeutic range:

Total phenytoin: 10 to 20 mg/L (SI: 40 to 79 micromole/L) (Winter 2010).

Concentrations of 5 to 10 mg/L (SI: 20 to 40 micromole/L) may be therapeutic for some patients, but concentrations <5 mg/L (SI: <20 micromole/L) are not likely to be effective.

Free (unbound) phenytoin: 1 to 2.5 mg/L (SI: 4 to 10 micromole/L).

Total phenytoin:

Toxic: >30 mg/L (SI: >119 micromole/L).

Lethal: >100 mg/L (SI: >396 micromole/L).

Toxicity is measured clinically, and some patients require levels outside the suggested therapeutic range (refer to phenytoin monograph for additional information).

When to draw levels (Winter 2010):

Key points: Time of sampling is dependent on the disease state being treated and the clinical condition of the patient. Trough concentrations are generally recommended for routine monitoring.

After a loading dose:

First concentration: It is recommended that phenytoin concentrations NOT be monitored until conversion to phenytoin is complete. It is prudent to draw within 2 to 3 days of therapy initiation to ensure that the patient's metabolism is not remarkably altered. Alternatively, if rapid therapeutic levels are needed, a level may be drawn 2 hours after completion of an IV loading dose (Meek 1999; manufacturer's labeling) or 4 hours after an IM injection to aid in determining maintenance dose or need to reload (manufacturer's labeling).

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.

Mechanism of Action

Diphosphate ester salt of phenytoin that acts as a water-soluble prodrug of phenytoin; after administration, plasma esterases convert fosphenytoin to phosphate, formaldehyde (not expected to be clinically consequential [Fierro 1996]), and phenytoin as the active moiety. Phenytoin works by stabilizing neuronal membranes and decreasing seizure activity by increasing efflux or decreasing influx of sodium ions across cell membranes in the motor cortex during generation of nerve impulses

Pharmacokinetics

The pharmacokinetics of intravenous fosphenytoin in pediatric patients have been evaluated in 2 studies (n=49, age range: 1 day to 16.7 years; n=8, age range: 5 to 18 years) and found to be similar to the pharmacokinetics observed in young adults; the conversion rate of fosphenytoin to phenytoin was consistent throughout childhood (Fischer 2003; Pellock 1996). Also refer to Phenytoin monograph for additional information.

Distribution:

Fosphenytoin: Vd: 4.3 to 10.8 L; Vd of fosphenytoin increases with dose and rate of administration (Fischer 2003).

Phenytoin: 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 ± 0.22 L/kg.

Protein binding:

Fosphenytoin: 95% to 99% (primarily to albumin); binding of fosphenytoin to protein is saturable (the percent bound decreases as total concentration increases); fosphenytoin displaces phenytoin from protein binding sites; can displace phenytoin and increase free fraction (up to 30% unbound) during the period required for conversion of fosphenytoin to phenytoin. Note: In patients with renal and/or hepatic impairment or hypoalbuminemia, the fraction of unbound phenytoin may be increased.

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

Metabolism: Fosphenytoin is rapidly converted via hydrolysis to phenytoin; phenytoin is metabolized in the liver following dose-dependent (Michaelis-Menten) pharmacokinetics and forms metabolites.

Bioavailability: Fosphenytoin: IM: 100%.

Half-life elimination:

Fosphenytoin: Conversion half-life to Phenytoin:

Pediatric patients (ages: 1 day to 16.7 years): 8.3 minutes (range: 2.5 to 18.5 minutes) (Fischer 2003; Morton 1998).

Adults: IV: ~15 minutes; IM: ~30 minutes.

Phenytoin half-life: 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 (metabolic capacity) and Km (constant equal to the concentration at which the rate of metabolism is 1/2 of Vmax) (Patsalos 2008).

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; PNA >2 weeks: 7.6 ± 3.5 hours (Loughnan 1977).

Adults: Variable (mean: 12 to 29 hours); pharmacokinetics of phenytoin are saturable.

Time to peak, serum concentration: Phenytoin:

IV: Adults: ~30 to 60 minutes from start of IV infusion (Fischer 2003).

IM:

Neonates and infants ≤47 days: 1 to 2.4 hours was reported in a case series (n=3; GA 32 to 38 weeks; postnatal age: 15 to 47 days) (Hatzopoulos 1998).

Pediatric patients >7 months: Therapeutic concentrations within 30 minutes; time to maximum serum concentration not reported (Fischer 2003).

Adults: ~3 hours (manufacturer's labeling); therapeutic phenytoin concentrations may be achieved as early as 5 to 20 minutes following IM (gluteal) administration (Pryor 2001).

Excretion: Phenytoin: Urine (as inactive metabolites).

Pharmacokinetics: Additional Considerations

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

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

Older adult: Phenytoin clearance decreases ~20% in patients >70 years of age

Hyperbilirubinemia: Increased fraction of unbound phenytoin may occur.

Hypoalbuminemia: Increased fraction of unbound phenytoin may occur.

Pricing: US

Solution (Cerebyx Injection)

100 mg PE/2 mL (per mL): $16.07

500 mg PE/10 mL (per mL): $9.64

Solution (Fosphenytoin Sodium Injection)

100 mg PE/2 mL (per mL): $2.88 - $9.00

500 mg PE/10 mL (per mL): $2.70 - $5.76

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.

Brand Names: International
  • Cerebyx (KR);
  • Cereneu (TH);
  • Fosolin (IN);
  • Fosphen (IN);
  • Fostoin (JP);
  • Pro-Epanutin (AU, DK, FI, GB, IE, IS, NO, SE, SI);
  • ProDilantin (FR)


For country code abbreviations (show table)
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