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Fosphenytoin

Medically reviewed by Drugs.com. Last updated on Jun 26, 2020.

Pronunciation

(FOS fen i toyn)

Index Terms

  • Fosphenytoin Sodium

Dosage Forms

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)

Brand Names: U.S.

  • Cerebyx

Pharmacologic Category

  • Anticonvulsant, Hydantoin

Pharmacology

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

Distribution

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

Metabolism

Fosphenytoin is rapidly converted via hydrolysis to phenytoin; phenytoin is metabolized in the liver and forms metabolites

Excretion

Phenytoin: Urine (as inactive metabolites)

Time to Peak

Conversion to phenytoin:

IV: Adults: Following IV administration (maximum rate of administration): ~15 minutes.

IM:

Neonates and infants ≤6 months of age: 1 to 2.4 hours was reported in a case series (n=3; postnatal age: 15 to 47 days) (Hatzopoulos 1998).

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

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

Half-Life Elimination

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

Adults:

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

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

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.

Special Populations: Renal Function Impairment

Increased fraction of unbound phenytoin may occur.

Special Populations: Hepatic Function Impairment

Increased fraction of unbound phenytoin may occur.

Special Populations: Elderly

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

Special Populations Note

Hyperbilirubinemia: Increased fraction of unbound phenytoin may occur.

Hypoalbuminemia: Increased fraction of unbound phenytoin may occur.

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.

Off Label Uses

Traumatic brain injury, prevention of early posttraumatic seizure

Data from a randomized, double-blind, placebo-controlled trial in patients with serious head trauma support the use of phenytoin to prevent posttraumatic seizures (PTS) in patients who recently (within 7 days) experienced a traumatic brain injury (TBI). Phenytoin did not reduce the incidence of late (day 8 or later) PTS [Temkin 1990]. Similarly, a meta-analysis that included this controlled trial and several retrospective cohort studies also found a decrease in early PTS with phenytoin [Wilson 2018]. Dosing is based on phenytoin data.

Based on the Brain Trauma Foundation's guidelines for the management of severe traumatic brain injury and the American Association of Neurology’s practice parameter for antiepileptic drug prophylaxis in severe traumatic brain injury, phenytoin is effective and recommended to decrease the risk of PTS occurring within the first 7 days of TBI.

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.

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 Indians) (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:

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 2019). Note: Duration individualized based on underlying intracranial pathology and other clinical considerations (AAN [Glantz 2000]; Drappatz 2019; Iuchi 2015; Merli 2019).

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]; Gaspard 2019); 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 2019). A maximum dose has not been established; use caution when prescribing maintenance doses >600 mg PE/day.

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; Gaspard 2019; 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; Gaspard 2019; 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 2019). 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 (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).

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: Geriatric

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: Pediatric

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.

Status epilepticus: Infants, Children, and Adolescents: Loading dose: IV (preferred), IM: 15 to 20 mg PE/kg; maximum dose: 1,500 mg PE; experts recommend a loading dose of 20 mg PE/kg (AES [Glauser 2016]; NCS [Brophy 2012]). Note: Optimal therapy for refractory status epilepticus is not defined; if status epilepticus does not resolve, expert recommendations vary; some suggest an additional load of 5 mg PE/kg administered 10 minutes after initial loading infusion (NCS [Brophy 2012]); other experts recommend repeating initial loading dose or changing to another agent (AES [Glauser 2016])

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, 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. 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, 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

Traumatic brain injury; seizure prophylaxis: Limited data available; efficacy results variable; 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). Note: Current guidelines suggest that prophylactic phenytoin may be considered to reduce the incidence of early posttraumatic seizures in pediatric patients with severe traumatic brain injuries, but it does not reduce the risk of long-term seizures or improve neurologic outcome (Kochanek 2012).

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

Dosing: Obesity

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

Note: Evidence from one small comparator study evaluating phenytoin in adult patients (n=24) with obesity (124 ± 10 kg) demonstrated that the Vd was 0.68 ± 0.03 L/kg and distribution into weight in excess of ideal body weight (IBW) is disproportionately greater (by a factor of 1.33) (Abernethy 1985). However, a loading dose based on actual or total body weight (TBW) (dose = 15 mg/kg) compared to an approach based on IBW (dose = [14 × IBW] + [19 × (TBW − IBW)]) yielded similar dose estimates, when factoring population height and weight distributions (Abernethy 1985; expert opinion).

Loading dose: IV: Initial: 15 mg PE/kg (using actual body weight; no maximum dose) at a rate of 100 to 150 mg PE/minute; usual loading dose: 1.7 to 2.3 g PE; limited data from retrospective studies (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 IBW; 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.

Reconstitution

Must be diluted to concentrations of 1.5 to 25 mg PE/mL, in NS or D5W (maximum concentration: 25 mg PE/mL).

Administration

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).

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).

Dietary Considerations

Provides 0.0037 mmol phosphate/mg PE fosphenytoin

Storage

Store intact vials refrigerated at 2°C to 8°C (36°F to 46°F). Do not store at room temperature for more than 48 hours. After opening, discard any unused solution in vials.

Has been shown to be stable at 1, 8, and 20 mg PE/mL in normal saline or D5W at 25°C (77°F) for 30 days in glass container and at 4°C to 20°C (39°F to 68°F) for 30 days in PVC bag. Undiluted fosphenytoin injection (50 mg PE/mL) is stable in polypropylene syringes for 30 days at 25°C, 4°C, or frozen at -20°C. Fosphenytoin at concentrations of 1, 8, and 20 mg PE/mL prepared in D51/2NS, D51/2NS with KCl 20 mEq/L, D51/2NS with 40 mEq/L, LR, D5LR, D10W, amino acid 10%, mannitol 20%, hetastarch 6% in NS or Plasma-Lyte A injection is stable in polyvinyl chloride bags for 7 days when stored at 25°C (room temperature) (Fischer 1997).

Drug Interactions

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

Abiraterone Acetate: CYP3A4 Inducers (Strong) may decrease the serum concentration of Abiraterone Acetate. Management: Avoid whenever possible. If such a combination cannot be avoided, increase abiraterone acetate dosing frequency from once daily to twice daily during concomitant use. 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. Consider therapy modification

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

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. 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. 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. Consider therapy modification

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

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

Amiodarone: Fosphenytoin may decrease the serum concentration of Amiodarone. Amiodarone may increase the serum concentration of Fosphenytoin. Monitor therapy

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

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

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

Aprepitant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Aprepitant. 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. 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. Consider therapy modification

Artemether: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Artemether. Specifically, dihydroartemisinin concentrations may be reduced. CYP3A4 Inducers (Strong) may decrease the serum concentration of Artemether. Avoid combination

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

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

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

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

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

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. Monitor therapy

Bedaquiline: CYP3A4 Inducers (Strong) may decrease the serum concentration of Bedaquiline. Avoid combination

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

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

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

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

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

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

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

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

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

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

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

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

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

BuPROPion: CYP2B6 Inducers (Weak) may decrease the serum concentration of BuPROPion. 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. Consider therapy modification

Busulfan: Fosphenytoin may decrease the serum concentration of Busulfan. Monitor therapy

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

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 Consider therapy modification

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

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

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

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

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

CarBAMazepine: Fosphenytoin may decrease the serum concentration of CarBAMazepine. CarBAMazepine may decrease the serum concentration of Fosphenytoin. CarBAMazepine may increase the serum concentration of Fosphenytoin. Possibly by competitive inhibition at sites of metabolism. Monitor therapy

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

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

CeFAZolin: May decrease the protein binding of Fosphenytoin. Monitor therapy

Celiprolol: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Celiprolol. 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. Consider therapy modification

Ceritinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ceritinib. 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. Monitor therapy

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

ChlorproPAMIDE: CYP3A4 Inducers (Strong) may decrease the serum concentration of ChlorproPAMIDE. 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 anticonvulsants if cimetidine is initiated/dose increased. 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. Monitor therapy

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

Clarithromycin: CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Clarithromycin. Clarithromycin may increase the serum concentration of CYP3A4 Inducers (Strong). CYP3A4 Inducers (Strong) may decrease the serum concentration of Clarithromycin. Management: Consider alternative antimicrobial therapy for patients receiving a CYP3A inducer. Drugs that enhance the metabolism of clarithromycin into 14-hydroxyclarithromycin may alter the clinical activity of clarithromycin and may impair clarithromycin efficacy. Consider therapy modification

Clindamycin (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of Clindamycin (Systemic). Refer to the specific clindamycin (systemic) - rifampin drug interaction monograph for information concerning that combination. Monitor therapy

ClonazePAM: Fosphenytoin may decrease the serum concentration of ClonazePAM. Clonazepam may also alter concentrations of Phenytoin (active metabolite of Fosphenytoin). 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. Consider therapy modification

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

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

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

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

Corticosteroids (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of Corticosteroids (Systemic). Exceptions: Hydrocortisone (Systemic); PrednisoLONE (Systemic); PredniSONE. Monitor therapy

Crizotinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Crizotinib. 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. Consider therapy modification

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

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

CYP2C19 Inhibitors (Moderate): May increase the serum concentration of Fosphenytoin-Phenytoin. Exceptions: Cannabidiol; Cenobamate; Stiripentol; Voriconazole. Monitor therapy

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

CYP2C19 Inhibitors (Weak): May increase the serum concentration of Fosphenytoin-Phenytoin. Exceptions: Cimetidine; Elagolix; Elagolix, Estradiol, and Norethindrone; Eslicarbazepine; Felbamate; Ketoconazole (Systemic). Monitor therapy

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

CYP2C9 Inhibitors (Weak): May increase the serum concentration of Fosphenytoin-Phenytoin. Exceptions: Amiodarone; Ceritinib; Chloramphenicol (Systemic); FluvoxaMINE; MetroNIDAZOLE (Systemic); Rucaparib; Tamoxifen; Voriconazole. Monitor therapy

CYP3A4 Substrates (High risk with Inducers): CYP3A4 Inducers (Strong) may increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Exceptions: Benzhydrocodone; Bromperidol; Buprenorphine; CarBAMazepine; Dapsone (Systemic); Etizolam; HYDROcodone; Mirtazapine; Rivaroxaban; TraMADol; Zolpidem; Zonisamide. Consider therapy modification

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. Avoid combination

Dabrafenib: May decrease the serum concentration of CYP2C19 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP2C19 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

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

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

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

Darunavir: Fosphenytoin may decrease the serum concentration of Darunavir. Avoid combination

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

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

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

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

Delavirdine: Fosphenytoin may decrease the serum concentration of Delavirdine. Delavirdine may increase the serum concentration of Fosphenytoin. Avoid combination

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. Consider therapy modification

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

Dexmethylphenidate: May increase the serum concentration of Fosphenytoin. Monitor therapy

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

Dienogest: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dienogest. Management: Avoid use of dienogest for contraception when using medications that induce CYP3A4 and for at least 28 days after discontinuation of a CYP3A4 inducer. An alternative form of contraception should be used during this time. Avoid combination

Diethylstilbestrol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Diethylstilbestrol. Monitor therapy

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

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

Disopyramide: May enhance the QTc-prolonging effect of Fosphenytoin. Fosphenytoin may decrease the serum concentration of Disopyramide. Management: Seek alternatives when possible. Monitor patients receiving this combination closely for evidence of QT interval prolongation or changes in cardiac rhythm, as well as for decreased serum concentrations/therapeutic effects of disopyramide. Consider therapy modification

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. Consider therapy modification

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

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

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

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

DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of DOXOrubicin (Conventional). 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. Consider therapy modification

Dronabinol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dronabinol. Monitor therapy

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

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

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

Efavirenz: Fosphenytoin may decrease the serum concentration of Efavirenz. Efavirenz may increase the serum concentration of Fosphenytoin. Monitor therapy

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

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

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

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

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

Encorafenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Encorafenib. 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. Monitor therapy

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

Enzalutamide: May decrease the serum concentration of Fosphenytoin-Phenytoin. Avoid combination

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. Consider therapy modification

Erdafitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Erdafitinib. 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. Consider therapy modification

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) Monitor therapy

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

Estriol (Topical): CYP3A4 Inducers (Strong) may decrease the serum concentration of Estriol (Topical). Monitor therapy

Estrogen Derivatives (Contraceptive): Fosphenytoin may diminish the therapeutic effect of Estrogen Derivatives (Contraceptive). Contraceptive failure is possible. Management: Use of an alternative, nonhormonal means of contraception is recommended. Consider therapy modification

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

Etizolam: CYP3A4 Inducers (Strong) may decrease the serum concentration of Etizolam. 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. 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. Consider therapy modification

Etravirine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Etravirine. 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. Consider therapy modification

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

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

Fedratinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Fedratinib. Avoid combination

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

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

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

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

Flunarizine: Fosphenytoin may decrease the serum concentration of Flunarizine. Monitor therapy

Fluorouracil (Topical): May increase the serum concentration of Fosphenytoin. Monitor therapy

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

Folic Acid: May decrease the serum concentration of Fosphenytoin. 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. 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. Avoid combination

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

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

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

Gefitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Gefitinib. Management: In the absence of severe adverse reactions, increase 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. 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. Avoid combination

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

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

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

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

Grazoprevir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Grazoprevir. 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. Consider therapy modification

Halothane: May increase the serum concentration of Fosphenytoin. Monitor therapy

HMG-CoA Reductase Inhibitors (Statins): Fosphenytoin-Phenytoin may decrease the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Management: Consider avoiding coadministration of fosphenytoin/phenytoin and statins. If combined, monitor for decreased therapeutic effects of statins if fosphenytoin/phenytoin is initiated/dose increased. Exceptions: Fluvastatin. Consider therapy modification

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

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

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

Idelalisib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Idelalisib. 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. Monitor therapy

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

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. Avoid combination

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. Avoid combination

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

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

Itraconazole: CYP3A4 Inducers (Strong) may decrease the serum concentration of Itraconazole. Avoid combination

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

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

Ivosidenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ivosidenib. 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. Consider therapy modification

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

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. Consider therapy modification

Lacosamide: Antiepileptic 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. Monitor therapy

LamoTRIgine: Fosphenytoin may decrease the serum concentration of LamoTRIgine. Management: For patients taking fosphenytoin without valproate, lamotrigine dose adjustments are recommended for lamotrigine initiation. Recommendations vary based on lamotrigine indication and age. See full interact monograph for details. 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. 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. Consider therapy modification

Ledipasvir: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Ledipasvir. 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. 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. 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. 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. Consider therapy modification

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

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

Letermovir: May increase the serum concentration of UGT1A1 Inducers. Avoid combination

Leucovorin Calcium-Levoleucovorin: May decrease the serum concentration of Fosphenytoin. Monitor therapy

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

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

Levomefolate: May decrease the serum concentration of Fosphenytoin. Monitor therapy

Levomethadone: Fosphenytoin may decrease the serum concentration of Levomethadone. 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). 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. 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. Consider therapy modification

Lithium: Fosphenytoin may enhance the adverse/toxic effect of Lithium. Monitor therapy

Loop Diuretics: Fosphenytoin may diminish the diuretic effect of Loop Diuretics. Monitor therapy

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

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

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

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

Lumefantrine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lumefantrine. Avoid combination

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

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

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

Macitentan: CYP3A4 Inducers (Strong) may decrease the serum concentration of Macitentan. 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. Consider therapy modification

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

Mebendazole: Fosphenytoin may decrease the serum concentration of Mebendazole. Monitor therapy

Mefloquine: May diminish the therapeutic effect of Anticonvulsants. Mefloquine may decrease the serum concentration of Anticonvulsants. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of convulsions. If anticonvulsants are being used for another indication, monitor anticonvulsant concentrations and treatment response closely with concurrent use. Consider therapy modification

Meperidine: Fosphenytoin may decrease the serum concentration of Meperidine. Monitor therapy

Methadone: Fosphenytoin may decrease the serum concentration of Methadone. 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. Monitor therapy

Methylfolate: May decrease the serum concentration of Fosphenytoin. Monitor therapy

Methylphenidate: May increase the serum concentration of Fosphenytoin. 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. Consider therapy modification

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

MetyraPONE: Fosphenytoin may decrease the serum concentration of MetyraPONE. The oral metyrapone test would thus be unreliable unless the metapyrone dosage was substantially increased (eg, 750 mg every 2 hours). Management: Results of the metyrapone test may be unreliable in patients receiving phenytoin within 2 weeks of metyrapone. Consider doubling the dose of metyrapone to overcome increased metyrapone metabolism. Consider therapy modification

Mexiletine: Fosphenytoin may decrease the serum concentration of Mexiletine. Monitor therapy

Mianserin: May diminish the therapeutic effect of Fosphenytoin. Fosphenytoin may decrease the serum concentration of Mianserin. Monitor therapy

Miconazole (Oral): May increase the serum concentration of Fosphenytoin. Monitor therapy

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

MiFEPRIStone: CYP3A4 Inducers (Strong) may decrease the serum concentration of MiFEPRIStone. Avoid combination

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. Consider therapy modification

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

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

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

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

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

Nelfinavir: Fosphenytoin may decrease the serum concentration of Nelfinavir. Nelfinavir may decrease the serum concentration of Fosphenytoin. Monitor therapy

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

Netupitant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Netupitant. 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). Monitor therapy

NIFEdipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of NIFEdipine. Avoid combination

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

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

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

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

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

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

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

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

Palbociclib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Palbociclib. 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. Monitor therapy

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

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

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

Perampanel: Fosphenytoin may decrease the serum concentration of Perampanel. Management: Increase the perampanel starting dose to 4 mg/day when perampanel is used with phenytoin/fosphenytoin. Patients receiving this combination should be followed closely for response, especially with any changes to phenytoin/fosphenytoin therapy. Consider therapy modification

Pexidartinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Pexidartinib. 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. Monitor therapy

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

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

Piperaquine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Piperaquine. 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. Consider therapy modification

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

PONATinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of PONATinib. 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. 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. Consider therapy modification

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

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

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

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

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

Progestins (Contraceptive): Fosphenytoin may diminish the therapeutic effect of Progestins (Contraceptive). Contraceptive failure is possible. Management: Contraceptive failure is possible. Use of an alternative, nonhormonal contraceptive is recommended. Exceptions: Levonorgestrel (IUD). Consider therapy modification

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). Monitor therapy

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

Pyridoxine: May increase the metabolism of Fosphenytoin. This is most apparent in high pyridoxine doses (e.g., 80 mg to 200 mg daily) 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 7-14 days of discontinuing the inducer. Consider therapy modification

QuiNIDine: Fosphenytoin may enhance the QTc-prolonging effect of QuiNIDine. Fosphenytoin may decrease the serum concentration of QuiNIDine. Management: Consider alternatives when possible. Monitor patients receiving this combination closely forsigns and symptoms of excessive QTc interval prolongation and arrhythmia, as well as for decreased serum concentrations/therapeutic effects of quinidine. Consider therapy modification

QuiNINE: Fosphenytoin may decrease the serum concentration of QuiNINE. Management: Consider avoiding this combination due to the risk for impaired quinine effectiveness. If coadministered, monitor for reduced quinine effectiveness. 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. Consider therapy modification

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

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

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

Regorafenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Regorafenib. Avoid combination

Remdesivir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Remdesivir. Monitor therapy

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

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

Rilpivirine: Fosphenytoin may decrease the serum concentration of Rilpivirine. Avoid combination

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

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

RisperiDONE: CYP3A4 Inducers (Strong) may decrease the serum concentration of RisperiDONE. Management: Consider increasing the dose of oral risperidone (to no more than double the original dose) if a strong CYP3A4 inducer is initiated. For patients on IM risperidone, consider an increased IM dose or supplemental doses of oral risperidone. Consider therapy modification

Ritonavir: Fosphenytoin may decrease the serum concentration of Ritonavir. Ritonavir may decrease the serum concentration of Fosphenytoin. Management: Dose adjustments may be required. Monitor phenytoin concentrations, and for therapeutic reponse to fosphenytoin and ritonavir, particularly with any dose adjustments. Consider therapy modification

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

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

Rolapitant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Rolapitant. Management: Avoid rolapitant use in patients requiring chronic administration of strong CYP3A4 inducers. Monitor for reduced rolapitant response and the need for alternative or additional antiemetic therapy even with shorter-term use of such inducers. Consider therapy modification

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

Rufinamide: Fosphenytoin may decrease the serum concentration of Rufinamide. Rufinamide may increase the serum concentration of Fosphenytoin. Monitor therapy

Ruxolitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ruxolitinib. 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. Avoid combination

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

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

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

Sertraline: Fosphenytoin may decrease the serum concentration of Sertraline. Sertraline may increase the serum concentration of Fosphenytoin. Monitor therapy

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

Sirolimus: CYP3A4 Inducers (Strong) may decrease the serum concentration of Sirolimus. 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. Consider therapy modification

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

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

SORAfenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of SORAfenib. 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. Consider therapy modification

SUFentanil: CYP3A4 Inducers (Strong) may decrease the serum concentration of SUFentanil. Monitor therapy

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

Sulthiame: May increase the serum concentration of Fosphenytoin-Phenytoin. 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. Consider therapy modification

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. Consider therapy modification

Tadalafil: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tadalafil. Management: Erectile dysfunction or BPH: monitor for decreased effectiveness - no standard dose adjustments recommended. Avoid use of tadalafil for pulmonary arterial hypertension in patients receiving a strong CYP3A4 inducer. 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. Management: Consider alternatives to concomitant use of strong CYP3A4 inducers and tamoxifen. If the combination cannot be avoided, monitor for reduced therapeutic effects of tamoxifen. Consider therapy modification

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

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

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

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

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

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

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

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

Tezacaftor and Ivacaftor: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tezacaftor and Ivacaftor. 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. Exceptions: Dyphylline. 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. Consider therapy modification

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

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

TiaGABine: CYP3A4 Inducers (Strong) may decrease the serum concentration of TiaGABine. Management: Approximately 2-fold higher tiagabine doses and a more rapid dose titration will likely be required in patients concomitantly taking a strong CYP3A4 inducer. Consider therapy modification

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. Avoid combination

Tipranavir: Fosphenytoin may decrease the serum concentration of Tipranavir. Tipranavir may decrease the serum concentration of Fosphenytoin. Monitor therapy

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

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

Tolvaptan: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tolvaptan. Management: Avoid concurrent use of strong CYP3A4 inducers with the Jynarque brand of tolvaptan. For patients receiving the Samsca brand of tolvaptan, monitor patient response to tolvaptan and adjust tolvaptan dose if required. Consider therapy modification

Topiramate: Fosphenytoin may decrease the serum concentration of Topiramate. Topiramate may increase the serum concentration of Fosphenytoin. 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. Consider therapy modification

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

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

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

TraZODone: Fosphenytoin may decrease the serum concentration of TraZODone. TraZODone may increase the serum concentration of Fosphenytoin. Monitor therapy

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. Consider therapy modification

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

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

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

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

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

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

Valbenazine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Valbenazine. Avoid combination

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. Monitor therapy

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

Velpatasvir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Velpatasvir. 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. Consider therapy modification

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

Vigabatrin: May decrease the serum concentration of Fosphenytoin. 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. Consider therapy modification

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

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

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

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

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

Voriconazole: Fosphenytoin-Phenytoin may decrease the serum concentration of Voriconazole. Voriconazole may increase the serum concentration of Fosphenytoin-Phenytoin. Management: Increase voriconazole from 4 mg/kg to 5 mg/kg IV every 12 hours or from 200 mg to 400 mg orally every 12 hours (increase from 100 mg to 200 mg orally every 12 hours for patients who weigh less than 40 kg). Monitor for increased phenytoin concentrations. 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. 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 concomitant use is unavoidable, increase the voxelotor dose to 2,500 mg once daily. Consider therapy modification

Voxilaprevir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Voxilaprevir. 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 zalephon is combined with a strong CYP3A4 inducer, monitor for decreased effectiveness of zaleplon. Consider therapy modification

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

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

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

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

Test Interactions

Falsely high plasma phenytoin concentrations (due to cross-reactivity with fosphenytoin) when measured by immunoanalytical techniques (eg, TDX, TDXFLX, Emit 2000) prior to complete conversion of fosphenytoin to phenytoin. Phenytoin may produce falsely low results for dexamethasone or metyrapone tests. Phenytoin has the potential to lower serum folate levels.

Adverse Reactions

Also refer to the phenytoin monograph for additional adverse reactions.

>10%:

Central nervous system: Burning sensation (≤44%), paresthesia (≤44%), dizziness (IV: 31%; IM: 5%), drowsiness (IV: 20%; IM: 7%), ataxia (IV: 4% to 11%; IM: 8%)

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

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

1% to 10%:

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

Central nervous system: Headache (IM: 9%; IV: 2%), stupor (IV: 8%), paresthesia (4%; generally transient; often reported in groin area; may be more common with IV), extrapyramidal reaction (≤4%; more common with IV), absent reflexes (IM: 3%), agitation (IV: 3%), vertigo (IV: 2%), cerebral edema (≤2%; more common with IV), dysarthria (≤2%), hypoesthesia (≤2%; more common with IV), abnormality in thinking (>1%), chills (>1%), hyperreflexia (>1%), intracranial hypertension (>1%), myasthenia (>1%), nervousness (>1%), speech disturbance (>1%), akathisia (≤1%), altered sense of smell (≤1%), amnesia (≤1%), aphasia (≤1%), brain disease (≤1%), central nervous system depression (≤1%), cerebral hemorrhage (≤1%), coma (≤1%), confusion (≤1%), delirium (≤1%), depersonalization (≤1%), depression (≤1%), emotional lability (≤1%), encephalitis (≤1%), hemiplegia (≤1%), hostility (≤1%), hyperacusis (≤1%), hyperesthesia (≤1%), hypotonia (≤1%), insomnia (≤1%), malaise (≤1%), meningitis (≤1%), migraine (≤1%), myoclonus (≤1%), paralysis (≤1%), personality disorder (≤1%), positive Babinski sign (≤1%), psychoneurosis (≤1%), psychosis (≤1%), seizure (≤1%), twitching (≤1%)

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

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

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

Genitourinary: Pelvic pain (IV: 4%), dysuria (≤1%), genital edema (≤1%), oliguria (≤1%), 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: Tongue edema (≤1%)

Infection: Infection (>1%), cryptococcosis (≤1%), sepsis (≤1%)

Local: Injection site reaction (>1%), pain at injection site (>1%), bleeding at injection site (≤1%), inflammation at injection site (≤1%), swelling at injection site (≤1%)

Neuromuscular & skeletal: Tremor (IM: 10%; IV: 3%), asthenia (IM: 9%; IV: 2%), back pain (IV: 2%), arthralgia (≤1%), hyperkinetic muscle activity (≤1%), hypokinesia (≤1%), lower limb cramp (≤1%), myalgia (≤1%), myopathy (≤1%)

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

Otic: Tinnitus (IV: 9%), deafness (≤2%; more common with IV), otalgia (≤1%)

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

Respiratory: Pneumonia (>1%), 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%), pneumothorax (≤1%), rhinitis (≤1%), sinusitis (≤1%)

Miscellaneous: Fever (>1%)

Frequency not defined: Cardiovascular: Cardiac arrhythmia, severe hypotension

<1%, postmarketing, and/or case reports: Acute generalized exanthematous pustulosis, anaphylaxis, angioedema, drug reaction with eosinophilia and systemic symptoms, dyskinesia, severe dermatological reaction, signs and symptoms of injection site (purple glove syndrome), Stevens-Johnson syndrome, toxic epidermal necrolysis

ALERT: U.S. 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.

Warnings/Precautions

Concerns related to adverse effects:

• 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. Discontinue if there are any signs of rash or other signs and symptoms indicative of a severe cutaneous reaction. 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 antiepileptic 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 may be at an increased risk of developing Stevens-Johnson syndrome and/or TEN. Consider avoiding fosphenytoin as an alternative for carbamazepine patients positive for HLA-B*1502.

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

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

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

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.

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/.

Patient Education

What is this drug used for?

• It is used to help control certain kinds of seizures.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Dry mouth

• Nausea

• Vomiting

• Fatigue

• Headache

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes.

• High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit.

• Depression like thoughts of suicide, anxiety, emotional instability, or confusion.

• Low potassium like muscle pain or weakness, muscle cramps, or an abnormal heartbeat.

• Infection

• Severe dizziness

• Passing out

• Fast heartbeat

• Slow heartbeat

• Abnormal movements

• Twitching

• Change in balance

• Trouble swallowing

• Trouble speaking

• Confusion

• Noise or ringing in the ears

• Hearing loss

• Gingival pain or swelling

• Tremors

• Bruising

• Bleeding

• Involuntary eye movements

• Seizures

• Injection site swelling, irritation, or skin discoloration

• Burning or numbness feeling

• Swollen glands

• Chest pain

• Unable to pass urine

• Change in amount of urine passed

• Bone pain

• Severe loss of strength and energy

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.