phenytoin (Rx)

Brand and Other Names:Dilantin, Dilantin 125, more...Phenytek
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

capsule, immediate-release

  • 30mg
  • 100mg

capsule, extended-release

  • 100mg
  • 200mg
  • 300mg

tablet, chewable

  • 50mg

oral suspension

  • 125mg/5mL

injectable solution

  • 50mg/mL

Seizures

Status epilepticus

  • Load 10-15 mg/kg or 15-20 mg/kg at 25-50 mg/min, THEN  
  • Maintenance: 100 mg IV/PO q6-8hr PRN
  • Administer IV slowly; not to exceed 50 mg/min

Anticonvulsant

  • Tablet
    • 100 mg PO TID
    • Maintenance: 300-400 mg/day; increase to 600 mg/day if necessary
    • May adjust dose no sooner than 7-10 day intervals when indicated
  • Suspension
    • 125 mg PO TID, initially
    • Increase to 625 mg/day if necessary
    • May adjust dose no sooner than 7-10 day intervals when indicated
  • Extended release
    • Loading dose: 1 g divided into 3 doses (400, 300, 300 mg) administered at 2 hr intervals; initiate dosage 24 hr after loading dose
    • Loading dose not for administration to patients with a history of renal or hepatic disease; reserve for patients who require rapid steady serum levels, when IV administration not desirable, and for patients in a clinic or hospital setting where phenytoin levels can be closely monitored
    • Treatment (naive): 100 mg PO TID initially
    • May adjust dose no sooner than 7-10 day intervals
  • Therapeutic range: 10-20 mcg/mL (total) or 1-2 mcg/mL free drug

Dosage Forms & Strengths

capsule, immediate-release

  • 30mg
  • 100mg

capsule, extended-release

  • 100mg
  • 200mg
  • 300mg

tablet

  • 50mg

oral suspension

  • 125mg/5mL

injectable solution

  • 50mg/mL

Status Epilepticus

15-20 mg/kg IV in single or divided dose; if necessary may administer additional dose of 5-10 mg/kg 10 min after loading dose  

Maintenance: 4-8 mg/kg/day IV divided twice daily

Control of Tonic-Clonic and Complex Partial Seizures

Initial dosage

  • Neonates: 5 mg/kg/day in 2 divided doses  
  • 6 months to 16 years: 5 mg/kg/day in 2-3 divided doses

Neonates (<28 days)

  • Initial: 5-8 mg/kg/day IV/PO divided q8-12hr

Age-based maintenance dose

  • 6 months-4 years: Usual range, 8-10 mg/kg/day IV/PO divided two to three times daily
  • 4-7 years: Usual range, 7.5-9 mg/kg/day IV/PO divided two to three times daily
  • 7-10 years: Usual range, 7-8 mg/kg/day IV/PO divided two to three times daily
  • 10-16 years: Usual range, 6-7 mg/kg/day IV/PO divided two to three times daily

Anticonvulsant (Nonemergent)

Children and adolescents

Immediate release

  • Tablet and suspension
  • 5 mg/kg/day PO in 2-3 divided doses, initially; may make dose adjustments no sooner than 7-10 day intervals
  • Maintenance: 4-8 mg/kg/day PO; not to exceed 300 mg/day; higher doses may be considered in infant and young children (range: 8-10 mg/kg/day in divided doses)

Extended release

  • 5 mg/kg/day PO, initially in 2-3 equally divided doses; may adjust dose no sooner than 7-10-day intervals  
  • Maintenance: 4-8 mg/kg/day PO not to exceed 300 mg/day

Dosing Considerations

<6 years: Potential toxic dose, 20 mg/kg

Therapeutic range: 10-20 mcg/mL (total) or 1-2 mcg/mL free drug

ALWAYS administer IV slowly; not to exceed 1-3 mg/kg/min

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Interactions

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            Contraindicated (28)

            • apixaban

              phenytoin will decrease the level or effect of apixaban by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Reduces anticoagulant effect by decreasing apixaban systemic exposure

            • artemether/lumefantrine

              phenytoin will decrease the level or effect of artemether/lumefantrine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Coadministration with strong CYP3A4 inducers can result in decreased serum concentrations and loss of antimalarial efficacy

            • atazanavir

              phenytoin will decrease the level or effect of atazanavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.

            • cabotegravir

              phenytoin will decrease the level or effect of cabotegravir by increasing metabolism. Contraindicated. Cabotegravir is metabolized by UGT1A1 and UGT1A9. Strong UGT1A1 or UGT1A9 inducers decrease cabotegravir systemic exposure, thereby increasing potential for loss of virologic response.

            • cariprazine

              phenytoin will decrease the level or effect of cariprazine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. CYP3A4 is responsible for the formation and elimination of cariprazine's active metabolites. The effect of CYP3A4 inducers on cariprazine exposure has not been evaluated and the net effect is unclear.

            • cobimetinib

              phenytoin will decrease the level or effect of cobimetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Avoid coadministration. Strong or moderate CYP3A inducers may decrease cobimetinib systemic exposure by >80% and reduce its efficacy.

            • darunavir

              phenytoin will decrease the level or effect of darunavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Coadministration with phenytoin may result in loss of therapeutic effect and development of resistance to darunavir

            • dienogest/estradiol valerate

              phenytoin will decrease the level or effect of dienogest/estradiol valerate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Women should not choose estradiol valerate/dienogest as their contraceptive while using strong CYP3A4 inducers due to potential decrease in contraceptive efficacy. Estradiol valerate/dienogest should not be used for at least 28 days after discontinuation of the inducer due to possibility of decreased contraceptive efficacy.

            • dofetilide

              phenytoin, dofetilide. Either increases effects of the other by pharmacodynamic synergism. Contraindicated. Additive cardiac effects.

            • doravirine

              phenytoin will decrease the level or effect of doravirine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Coadministration of doravirine with a strong CYP3A inducer may decrease doravirine plasma concentrations and/or effects. Potential for loss of virologic response and possible resistance to doravirine.

            • elbasvir/grazoprevir

              phenytoin will decrease the level or effect of elbasvir/grazoprevir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. The therapeutic effect of elbasvir/grazoprevir may be reduced if coadministered with strong CYP3A inducers and is therefore contraindicated.

            • elvitegravir/cobicistat/emtricitabine/tenofovir DF

              phenytoin decreases levels of elvitegravir/cobicistat/emtricitabine/tenofovir DF by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. May lead to loss of virologic response and possible resistance.

            • fostemsavir

              phenytoin will decrease the level or effect of fostemsavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Coadministration of fostemsavir (prodrug) with strong CYP3A4 inducers significantly decreases temsavir (active moiety) plasma concentrations, which may lead to loss of virologic response and resistance.

            • isavuconazonium sulfate

              phenytoin will decrease the level or effect of isavuconazonium sulfate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.

            • ledipasvir/sofosbuvir

              phenytoin will decrease the level or effect of ledipasvir/sofosbuvir by P-glycoprotein (MDR1) efflux transporter. Contraindicated. P-gp inducers decrease sofosbuvir levels, and therefore decrease conversion to sofosbuvir's active metabolite (GS-331007) responsible for 90% of pharmacologic effect

            • lonafarnib

              phenytoin will decrease the level or effect of lonafarnib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Lonafarnib is a sensitive CYP3A4 substrate. Coadministration with strong or moderate CYP3A4 inducers is contraindicated.

            • lorlatinib

              phenytoin will decrease the level or effect of lorlatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Coadministration of lorlatinib with strong CYP3A inducers is contraindicated. Discontinue the strong CYP3A inducer for 3 plasma half-lives before initiating lorlatinib.

            • lumacaftor/ivacaftor

              phenytoin will decrease the level or effect of lumacaftor/ivacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Strong CYP3A inducers have minimal effect on lumacaftor exposure, but decreased ivacaftor exposure (AUC) by 57%. This may reduce the effectiveness of lumacaftor/ivacaftor. Therefore, coadministration is not recommended.

            • lumefantrine

              phenytoin will decrease the level or effect of lumefantrine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Coadministration with strong CYP3A4 inducers can result in decreased serum concentrations and loss of antimalarial efficacy

            • lurasidone

              phenytoin decreases levels of lurasidone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Contraindicated.

            • naloxegol

              phenytoin will decrease the level or effect of naloxegol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Use of naloxegol with strong CYP3A4 inducers is not recommended

            • ombitasvir/paritaprevir/ritonavir & dasabuvir

              phenytoin will decrease the level or effect of ombitasvir/paritaprevir/ritonavir & dasabuvir by increasing metabolism. Contraindicated. Strong CYP2C8 inducers may reduce dasabuvir levels, and therefore decreased efficacy of Viekira Pak

              phenytoin will decrease the level or effect of ombitasvir/paritaprevir/ritonavir & dasabuvir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Strong CYP3A4 inducers may reduce partiaprevir and ritonavir levels, and therefore decreased efficacy of Viekira Pak

            • panobinostat

              phenytoin decreases levels of panobinostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Strong CYP3A4 inducers can reduce panobinostat levels by ~70% and lead to treatment failure.

            • praziquantel

              phenytoin decreases levels of praziquantel by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Strong CYP450 inducers significantly decrease praziquantel blood levels.

            • regorafenib

              phenytoin, regorafenib. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Strong CYP3A4 inducers decrease regorafenib levels and increase exposure of the active metabolite M-5.

            • rilpivirine

              phenytoin decreases levels of rilpivirine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Contraindicated. Rilpivirine should not be co-administered with strong CYP 3A4 inducers. Potential for loss of virologic response and possible resistance to rilpivirine or to the NNRTI class.

            • roflumilast

              phenytoin will decrease the level or effect of roflumilast by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Coadministration not recommended; strong cytochrome P450 enzyme inducers decrease systemic exposure to roflumilast and may reduce the therapeutic effectiveness

            • vandetanib

              phenytoin decreases levels of vandetanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Avoid coadministration with potent CYP3A4 inducers; these drugs reduce exposure to vandetanib by up to 40%.

            Serious - Use Alternative (159)

            • abemaciclib

              phenytoin will decrease the level or effect of abemaciclib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of abemaciclib with strong CYP3A4 inducers reduces plasma concentration of abemaciclib and its metabolites.

            • acalabrutinib

              phenytoin will decrease the level or effect of acalabrutinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of acalabrutinib with strong CYP3A inducers. If a strong CYP3A inducer must be used, increase acalabrutinib dose to 200 mg twice daily.

            • afatinib

              phenytoin decreases levels of afatinib by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. Increase afatinib daily dose by 10 mg as tolerated if chronic therapy with P-gp inducer required; resume previous afatinib dose 2-3 days after P-gp inducer discontinued.

            • alpelisib

              phenytoin will decrease the level or effect of alpelisib by pharmacodynamic synergism. Avoid or Use Alternate Drug. Avoid coadministration of alpelisib (CYP3A4 substrate) with strong CYP3A4 inducers.

              phenytoin will decrease the level or effect of alpelisib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • apalutamide

              apalutamide will decrease the level or effect of phenytoin by affecting hepatic enzyme CYP2C19 metabolism. Avoid or Use Alternate Drug. Coadministration of apalutamide, a strong CYP2C19 inducer, with drugs that are CYP2C19 substrates can result in lower exposure to these medications. Avoid or substitute another drug for these medications when possible. Evaluate for loss of therapeutic effect if medication must be coadministered.

            • apremilast

              phenytoin will decrease the level or effect of apremilast by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration with strong CYP inducers results in a significant decrease of systemic exposure of apremilast, which may result in loss of efficacy

            • avapritinib

              phenytoin will decrease the level or effect of avapritinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • axitinib

              phenytoin decreases levels of axitinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Selection of concomitant medication with no or minimal CYP3A4 induction potential is recommended.

            • bedaquiline

              phenytoin will decrease the level or effect of bedaquiline by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of bedaquiline with strong CYP3A4 inducers due to potential for decreased therapeutic effect

            • berotralstat

              phenytoin decreases levels of berotralstat by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug.

            • bictegravir

              phenytoin will decrease the level or effect of bictegravir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of strong CYP3A and UGT1A1 inducers can substantially decrease bictegravir plasma concentrations. This may result in the loss of therapeutic effect and development of resistance to bictegravir. Coadministration with another anticonvulsant should be considered.

            • bosutinib

              phenytoin decreases levels of bosutinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Strong CYP3A4 inducers decreased bosutinib plasma concentration by ~85%.

            • bremelanotide

              bremelanotide will decrease the level or effect of phenytoin by Other (see comment). Avoid or Use Alternate Drug. Bremelanotide may slow gastric emptying and potentially reduces the rate and extent of absorption of concomitantly administered oral medications. Avoid use when taking any oral drug that is dependent on threshold concentrations for efficacy. Interactions listed are representative examples and do not include all possible clinical examples.

            • brigatinib

              phenytoin will decrease the level or effect of brigatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration with strong CYP3A4 inducers may decrease brigatinib efficacy.

            • cabozantinib

              phenytoin will decrease the level or effect of cabozantinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of cabozantinib with strong CYP3A4 inducers. If a strong CYP3A4 inducer is required, increase cabozantinib dose by 40 mg/day (Cometriq) or by 20 mg/day (Cabometyx). Resume previous dose 2-3 days after strong CYP3A4 inducer discontinued.

            • calcium/magnesium/potassium/sodium oxybates

              phenytoin, calcium/magnesium/potassium/sodium oxybates. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

            • capmatinib

              phenytoin will decrease the level or effect of capmatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • ceritinib

              phenytoin decreases levels of ceritinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              ceritinib increases levels of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Avoid or Use Alternate Drug. Avoid concurrent use of CYP2C9 substrates known to have narrow therapeutic indices or substrates primarily metabolized by CYP2C9 during treatment with ceritinib; if use of these medications is unavoidable, consider dose.

            • cobicistat

              phenytoin will decrease the level or effect of cobicistat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration is necessary, monitor for lack or loss of virologic response from cobicistat

            • copanlisib

              phenytoin will decrease the level or effect of copanlisib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of copanlisib with strong CYP3A4 inducers.

            • cyclosporine

              phenytoin decreases levels of cyclosporine by increasing metabolism. Avoid or Use Alternate Drug.

            • dabigatran

              phenytoin will decrease the level or effect of dabigatran by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. Avoid coadministration. P-gp inducers reduce systemic exposure of dabigatran

            • dabrafenib

              phenytoin decreases levels of dabrafenib by increasing metabolism. Avoid or Use Alternate Drug. Strong CYP2C8 inducers may decrease dabrafenib levels.

              phenytoin decreases levels of dabrafenib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • dantrolene

              phenytoin will decrease the level or effect of dantrolene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • darolutamide

              phenytoin will decrease the level or effect of darolutamide by Other (see comment). Avoid or Use Alternate Drug. Darolutamide is a P-gp and CYP3A4 substrate. Avoid coadminstration of darolutamide with combined P-gp and strong or moderate CYP3A4 inducers.

            • deflazacort

              phenytoin will decrease the level or effect of deflazacort by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of deflazacort with moderate or strong CYP3A4 inducers.

            • dihydroergotamine

              phenytoin will decrease the level or effect of dihydroergotamine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.

            • dihydroergotamine intranasal

              phenytoin will decrease the level or effect of dihydroergotamine intranasal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.

            • dolutegravir

              phenytoin will decrease the level or effect of dolutegravir by increasing metabolism. Avoid or Use Alternate Drug. Avoid coadministration; insufficient data to recommend dosage adjustment

            • dopamine

              phenytoin, dopamine. Mechanism: pharmacodynamic synergism. Avoid or Use Alternate Drug. Increased risk of hypotension.

            • dronedarone

              phenytoin will decrease the level or effect of dronedarone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.

            • duvelisib

              phenytoin will decrease the level or effect of duvelisib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration with a strong CYP3A inducer decreases duvelisib area under the curve (AUC), which may reduce duvelisib efficacy.

            • edoxaban

              phenytoin will decrease the level or effect of edoxaban by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. Avoid coadministration of edoxaban with potent P-gp inducers

            • eliglustat

              phenytoin will decrease the level or effect of eliglustat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Strong CYP3A inducers significantly decreases eliglustat exposure; coadministration not recommended

            • elvitegravir

              phenytoin will decrease the level or effect of elvitegravir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid; coadministration with CYP3A inducers may result in decreased plasma concentrations of elvitegravir and/or a concomitantly administered protease inhibitor and lead to loss of therapeutic effect and to possible resistance

            • encorafenib

              phenytoin will decrease the level or effect of encorafenib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • entrectinib

              phenytoin will decrease the level or effect of entrectinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • enzalutamide

              phenytoin will decrease the level or effect of enzalutamide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • erdafitinib

              phenytoin will decrease the level or effect of erdafitinib by altering metabolism. Avoid or Use Alternate Drug. Avoid coadministration of strong CYP2C9 or CYP3A4 inducers with erdafitinib.

            • ergotamine

              phenytoin will decrease the level or effect of ergotamine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.

            • erythromycin base

              phenytoin will decrease the level or effect of erythromycin base by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.

            • erythromycin ethylsuccinate

              phenytoin will decrease the level or effect of erythromycin ethylsuccinate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.

            • erythromycin lactobionate

              phenytoin will decrease the level or effect of erythromycin lactobionate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.

            • erythromycin stearate

              phenytoin will decrease the level or effect of erythromycin stearate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.

            • ethinylestradiol

              phenytoin will decrease the level or effect of ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. The efficacy of hormonal contraceptives may be reduced. Use of a nonhormonal contraceptive is recommended.

            • etravirine

              phenytoin will decrease the level or effect of etravirine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Etravirine and phenytoin should not be coadministered. Concomitant use of etravirine and phenytoin may result in decreased etravirine plasma concentrations and loss of therapeutic effect of etravirine.

              phenytoin will decrease the level or effect of etravirine by increasing metabolism. Avoid or Use Alternate Drug. Concomitant use of etravirine and phenytoin may result in decreased etravirine plasma concentrations and loss of therapeutic effect of etravirine.

              etravirine will increase the level or effect of phenytoin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Etravirine and phenytoin should not be coadministered. Concomitant use of etravirine and phenytoin may result in decreased etravirine plasma concentrations and loss of therapeutic effect of etravirine. In addition, etravirine may inhibit the CYP metabolism of phenytoin, resulting in increased phenytoin concentrations.

              phenytoin will decrease the level or effect of etravirine by affecting hepatic enzyme CYP2C9/10 metabolism. Avoid or Use Alternate Drug.

            • everolimus

              phenytoin will decrease the level or effect of everolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.

              phenytoin will decrease the level or effect of everolimus by P-glycoprotein (MDR1) efflux transporter. Contraindicated.

            • fedratinib

              phenytoin will decrease the level or effect of fedratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Effect of coadministering a strong CYP3A4 inducer with fedratinib has not been studied.

            • fexinidazole

              phenytoin will increase the level or effect of fexinidazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. CYP450 inducers may significantly increase plasma concentrations of fexinidazole?s active metabolites: fexinidazole sulfoxide (M1) and fexinidazole sulfone (M2). M2 plasma concentrations associated with increased QT prolongation risks.

            • finerenone

              phenytoin will decrease the level or effect of finerenone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • fostamatinib

              phenytoin will decrease the level or effect of fostamatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • gilteritinib

              phenytoin will decrease the level or effect of gilteritinib by Other (see comment). Avoid or Use Alternate Drug. Gilteritinib is a P-gp and CYP3A4 substrates. Coadministration of gilteritinib with a combined P-gp and strong CYP3A inducer decreases gilteritinib exposure and efficacy.

            • glasdegib

              phenytoin will decrease the level or effect of glasdegib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of glasdegib with strong CYP3A inducers.

            • glecaprevir/pibrentasvir

              phenytoin will decrease the level or effect of glecaprevir/pibrentasvir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • haloperidol

              phenytoin will decrease the level or effect of haloperidol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • ibrutinib

              phenytoin decreases levels of ibrutinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Strong CYP3A inducers decrease ibrutinib plasma concentrations by ~10-fold.

            • idelalisib

              phenytoin will decrease the level or effect of idelalisib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration; strong CYP3A4 inducers significantly decrease idelalisib systemic exposure

            • infigratinib

              phenytoin will decrease the level or effect of infigratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • irinotecan

              phenytoin will decrease the level or effect of irinotecan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • irinotecan liposomal

              phenytoin will decrease the level or effect of irinotecan liposomal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • isosorbide dinitrate

              phenytoin will decrease the level or effect of isosorbide dinitrate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • isosorbide mononitrate

              phenytoin will decrease the level or effect of isosorbide mononitrate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • istradefylline

              phenytoin will decrease the level or effect of istradefylline by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of istradefylline with strong CYP3A4 inducers.

            • itraconazole

              phenytoin decreases levels of itraconazole by increasing metabolism. Avoid or Use Alternate Drug.

            • ivabradine

              phenytoin will decrease the level or effect of ivabradine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of ivabradine with moderate CYP3A4 inducers.

            • ivacaftor

              phenytoin decreases levels of ivacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration with strong CYP3A4 inducers; systemic exposure of ivacaftor substantially reduced (ie, ~9-fold).

            • ivosidenib

              phenytoin will decrease the level or effect of ivosidenib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of ivosidenib with strong CYP3A4 inducers decreased ivosidenib plasma concentrations.

              ivosidenib will decrease the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of sensitive CYP2C9 substrates with ivosidenib or replace with alternate therapies. If coadministration is unavoidable, monitor patients for loss of therapeutic effect of these drugs.

            • ixazomib

              phenytoin will decrease the level or effect of ixazomib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of ixazomib with strong CYP3A inducers. Strong inducers have been shown to decrease ixazomib Cmax by 54% and AUC by 74%.

            • lansoprazole

              phenytoin will decrease the level or effect of lansoprazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Consider alternative for one of the interacting drugs

              phenytoin will decrease the level or effect of lansoprazole by affecting hepatic enzyme CYP2C19 metabolism. Avoid or Use Alternate Drug. Consider alternative for one of the interacting drugs

            • larotrectinib

              phenytoin will decrease the level or effect of larotrectinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration of larotrectinib with strong CYP3A4 inducers is unavoidable, double larotrectinib dose. Resume prior larotrectinib dose once CYP3A4 inducer discontinued for 3-5 half-lives

            • lefamulin

              phenytoin will decrease the level or effect of lefamulin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of lefamulin with strong or moderate CYP3A inducers unless the benefit outweighs risks. Monitor for reduced efficacy.

            • lemborexant

              phenytoin will decrease the level or effect of lemborexant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • letermovir

              phenytoin will decrease the level or effect of letermovir by Other (see comment). Avoid or Use Alternate Drug. Coadministration of letermovir with UCT1A1/3 inducers is not recommended.

              phenytoin will decrease the level or effect of letermovir by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. Coadministration of letermovir with P-gp inducers is not recommended.

            • lidocaine

              phenytoin decreases levels of lidocaine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • lomitapide

              phenytoin will decrease the level or effect of lomitapide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • losartan

              phenytoin will decrease the level or effect of losartan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • lovastatin

              phenytoin will decrease the level or effect of lovastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.

            • lurbinectedin

              phenytoin will decrease the level or effect of lurbinectedin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • macimorelin

              phenytoin will decrease the level or effect of macimorelin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Potential for false positive test results if macimorelin and strong CYP3A4 inducers are coadministered. Discontinue strong CYP3A4 inducer, allowing for sufficient washout time, before testing.

            • macitentan

              phenytoin will decrease the level or effect of macitentan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministering macitentan with strong CYP3A4 inducers

            • mebendazole

              phenytoin decreases levels of mebendazole by increasing metabolism. Contraindicated.

            • mefloquine

              phenytoin will decrease the level or effect of mefloquine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • mestranol

              phenytoin decreases levels of mestranol by increasing metabolism. Avoid or Use Alternate Drug. May result in contraceptive failure.

            • methadone

              phenytoin decreases levels of methadone by increasing metabolism. Contraindicated.

            • metoclopramide intranasal

              phenytoin, metoclopramide intranasal. Either increases effects of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Avoid use of metoclopramide intranasal or interacting drug, depending on importance of drug to patient.

            • midostaurin

              phenytoin will decrease the level or effect of midostaurin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Strong CYP3A4 inducers may decrease midostaurin concentrations resulting in reduced efficacy.

            • mobocertinib

              phenytoin will decrease the level or effect of mobocertinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • naldemedine

              phenytoin will decrease the level or effect of naldemedine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration with strong CYP3A4 inducers.

            • neratinib

              phenytoin will decrease the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inducers.

            • netupitant/palonosetron

              phenytoin will decrease the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Netupitant is mainly metabolized by CYP3A4; avoid use in patients who are chronically using a strong CYP3A4 inducer

            • nifedipine

              phenytoin will decrease the level or effect of nifedipine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Phenytoin decreases systemic exposure of nifedipine by about 70%

            • nintedanib

              phenytoin decreases levels of nintedanib by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. Avoid coadministration, particularly for P-gp inducers that are also CYP3A4 inducers; nintedanib is a substrate of P-gp and to a less extent CYP3A4.

            • nitazoxanide

              nitazoxanide, phenytoin. Either increases levels of the other by Mechanism: plasma protein binding competition. Avoid or Use Alternate Drug.

            • norethindrone

              phenytoin will decrease the level or effect of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia).

            • norethindrone acetate

              phenytoin will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia).

            • norethindrone transdermal

              phenytoin will decrease the level or effect of norethindrone transdermal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia).

            • norgestrel

              phenytoin will decrease the level or effect of norgestrel by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Use of nonhormonal contraceptives advised

            • olaparib

              phenytoin will decrease the level or effect of olaparib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of olaparib with strong CYP3A4 inducers.

            • osimertinib

              phenytoin will decrease the level or effect of osimertinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid concomitant use of osimertinib with strong CYP3A inducers.

            • ozanimod

              phenytoin will decrease the level or effect of ozanimod by Other (see comment). Avoid or Use Alternate Drug. Coadministration of ozanimod (a CYP2C8 substrate) with strong CYP2C8 inducers decreases the exposure of the active metabolites (CC112273 and CC1084037) of ozanimod, which may decrease the effiicacy of ozanimod. Therefore, coadministration of ozanimod with strong CYP2C8 inducers is not recommended.

            • palbociclib

              phenytoin will decrease the level or effect of palbociclib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Strong CYP3A inducers decrease palbociclib plasma exposure by ~85%.

            • pemigatinib

              phenytoin will decrease the level or effect of pemigatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • perampanel

              phenytoin will decrease the level or effect of perampanel by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • pexidartinib

              phenytoin will decrease the level or effect of pexidartinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              phenytoin and pexidartinib both increase Other (see comment). Avoid or Use Alternate Drug. Pexidartinib can cause hepatotoxicity. Avoid coadministration of pexidartinib with other products know to cause hepatoxicity.

            • pomalidomide

              phenytoin decreases levels of pomalidomide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • ponatinib

              phenytoin decreases levels of ponatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid unless the coadministration outweighs the possible risk of ponatinib underexposure; monitor for signs of reduced efficacy.

            • ponesimod

              phenytoin will decrease the level or effect of ponesimod by Other (see comment). Avoid or Use Alternate Drug. Not recommended. Based on limited data, coadministration of strong CYP3A4 and UGT1A1 inducers (eg, rifampin, phenytoin, carbamazepine) may decrease systemic exposure of ponesimod. The clinical relevance is unclear.

            • posaconazole

              phenytoin will decrease the level or effect of posaconazole by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug.

            • pralsetinib

              phenytoin will decrease the level or effect of pralsetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If unable to avoid, double current pralsetinib dose starting on Day 7 of coadministration with strong CYP3A inducer. After inducer has been discontinued for at least 14 days, resume previous pralsetinib dose.

            • pretomanid

              phenytoin will decrease the level or effect of pretomanid by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Pretomanid is a CYP3A4 substrate. Avoid coadministration of strong or moderate CYP3A4 inducers.

              phenytoin, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.

            • progesterone intravaginal gel

              phenytoin will decrease the level or effect of progesterone intravaginal gel by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Use of nonhormonal contraceptives advised

            • progesterone micronized

              phenytoin will decrease the level or effect of progesterone micronized by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Use of nonhormonal contraceptives advised

            • progesterone, natural

              phenytoin will decrease the level or effect of progesterone, natural by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Use of nonhormonal contraceptives advised

            • rabeprazole

              phenytoin will decrease the level or effect of rabeprazole by affecting hepatic enzyme CYP2C19 metabolism. Avoid or Use Alternate Drug. Consider alternative for one of the interacting drugs

            • ranolazine

              phenytoin will decrease the level or effect of ranolazine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.

            • ribociclib

              phenytoin will decrease the level or effect of ribociclib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of ribociclib with strong CYP3A inducers should be avoided.

            • rifabutin

              phenytoin will decrease the level or effect of rifabutin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • rimegepant

              phenytoin will decrease the level or effect of rimegepant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • ripretinib

              phenytoin will decrease the level or effect of ripretinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration with a strong CYP3A inhibitor will decrease systemic exposure to ripretinib and its active metabolite (DP-5439), which may decrease risk of adverse reactions.

            • rolapitant

              phenytoin will decrease the level or effect of rolapitant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Long-term coadministration of strong CYP3A4 inducers with rolapitant may significantly decrease rolapitant efficacy.

            • romidepsin

              phenytoin will decrease the level or effect of romidepsin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of romidepsin and phenytoin, a potent CYP3A4 inducer, as this may decrease romidepsin concentrations and efficacy.

            • selpercatinib

              phenytoin will decrease the level or effect of selpercatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • selumetinib

              phenytoin will decrease the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • sildenafil

              phenytoin will decrease the level or effect of sildenafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Potent CYP3A4 inducers are expected to cause substantial decreases in sildenafil plasma levels

            • silodosin

              phenytoin will decrease the level or effect of silodosin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.

            • simvastatin

              phenytoin will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.

            • siponimod

              phenytoin will decrease the level or effect of siponimod by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of siponimod with a drug that causes moderate CYP2C9 plus a moderate or strong CYP3A4 inducer is not recommended. Coadministration with moderate or strong CYP3A4 inducers alone is not recommended for patients with CYP2C9*1/*3 and*2/*3 genotype.

            • sirolimus

              phenytoin will decrease the level or effect of sirolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.

            • sodium oxybate

              phenytoin, sodium oxybate. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Profound sedation, respiratory depression, coma, and death may result if coadministered. Reserve concomitant prescribing of these drugs in patients for whom other treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation.

            • sofosbuvir

              phenytoin will decrease the level or effect of sofosbuvir by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. P-gp inducers decrease sofosbuvir levels, and therefore decrease conversion to sofosbuvir's active metabolite (GS-331007) responsible for 90% of pharmacologic effect

            • sofosbuvir/velpatasvir

              phenytoin will decrease the level or effect of sofosbuvir/velpatasvir by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. Sofosbuvir and velpatasvir are substrates of the drug transporter P-gp. Potent P-gp inducers may significantly decrease sofosbuvir and velpatasvir plasma concentrations, leading to potentially reduced therapeutic effect.

              phenytoin will decrease the level or effect of sofosbuvir/velpatasvir by affecting hepatic enzyme CYP2B6 metabolism. Avoid or Use Alternate Drug. Velpatasvir is a substrate of CYP2B6, CYP2C8, and CYP3A4. Drugs that are moderate-to-potent inducers of CYP2B6, CYP2C8, or CYP3A4 may significantly decrease velpatasvir plasma concentrations, leading to potentially reduced therapeutic effect.

              phenytoin will decrease the level or effect of sofosbuvir/velpatasvir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Velpatasvir is a substrate of CYP2B6, CYP2C8, and CYP3A4. Drugs that are moderate-to-potent inducers of CYP2B6, CYP2C8, or CYP3A4 may significantly decrease velpatasvir plasma concentrations, leading to potentially reduced therapeutic effect.

            • sonidegib

              phenytoin will decrease the level or effect of sonidegib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of sonidegib with strong or moderate CYP3A4 inducers.

            • sorafenib

              phenytoin will decrease the level or effect of sorafenib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • sotorasib

              phenytoin will decrease the level or effect of sotorasib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • stiripentol

              phenytoin will decrease the level or effect of stiripentol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If unable to avoid coadministration of stiripentol with strong CYP3A4 inducers, increase stiripentol dose.

              phenytoin will decrease the level or effect of stiripentol by affecting hepatic enzyme CYP2C19 metabolism. Avoid or Use Alternate Drug. If unable to avoid coadministration of stiripentol with strong CYP1A2 inducers, increase stiripentol dose.

            • tamsulosin

              phenytoin will decrease the level or effect of tamsulosin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • tazemetostat

              phenytoin will decrease the level or effect of tazemetostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • tepotinib

              phenytoin will decrease the level or effect of tepotinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • tetracycline

              phenytoin will decrease the level or effect of tetracycline by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • tezacaftor

              phenytoin will decrease the level or effect of tezacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • tivozanib

              phenytoin will decrease the level or effect of tivozanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • tolvaptan

              phenytoin will decrease the level or effect of tolvaptan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.

            • trabectedin

              phenytoin will decrease the level or effect of trabectedin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • trimipramine

              phenytoin will decrease the level or effect of trimipramine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • tucatinib

              phenytoin will decrease the level or effect of tucatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              phenytoin will decrease the level or effect of tucatinib by Other (see comment). Avoid or Use Alternate Drug. Coadministration of tucatinib (a CYP2C8 substrate) with a strong or moderate CYP2C8 inducer decreases tucatinib plasma concentrations.

            • ubrogepant

              phenytoin will decrease the level or effect of ubrogepant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • ulipristal

              phenytoin will decrease the level or effect of ulipristal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • upadacitinib

              phenytoin will decrease the level or effect of upadacitinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid upadacitinib coadministration with strong CYP3A4 inducers.

            • valbenazine

              phenytoin will decrease the level or effect of valbenazine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Concomitant use not recommended.

            • velpatasvir

              phenytoin will decrease the level or effect of velpatasvir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.

            • vemurafenib

              phenytoin decreases levels of vemurafenib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • venetoclax

              phenytoin will decrease the level or effect of venetoclax by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of venetoclax with strong or moderate CYP3A inducers. Consider alternative treatment with agents that have less CYP3A induction.

            • voclosporin

              phenytoin will decrease the level or effect of voclosporin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • vorapaxar

              phenytoin decreases levels of vorapaxar by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • voriconazole

              phenytoin will decrease the level or effect of voriconazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • vortioxetine

              phenytoin will decrease the level or effect of vortioxetine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • voxelotor

              phenytoin will decrease the level or effect of voxelotor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Voxelotor is primarily metabolized by CYP3A4. Avoid coadministration with moderate or strong CYP3A4 inducers. If unable to avoid coadministration, increase voxelotor dose (see Dosage Modifications).

            • voxilaprevir

              phenytoin will decrease the level or effect of voxilaprevir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.

            • zanubrutinib

              phenytoin will decrease the level or effect of zanubrutinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            Monitor Closely (334)

            • abiraterone

              phenytoin decreases levels of abiraterone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of abiraterone with strong CYP3A4 inducers; if a strong CYP3A4 inducer must be used, increase abiraterone dosage frequency from once daily to twice daily.

            • albendazole

              phenytoin decreases levels of albendazole by increasing metabolism. Use Caution/Monitor. Phenytoin decreases levels of albendazole active metabolites; monitor for decreased efficacy.

            • alitretinoin

              phenytoin will decrease the level or effect of alitretinoin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • almotriptan

              phenytoin will decrease the level or effect of almotriptan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • alpelisib

              alpelisib will decrease the level or effect of phenytoin by pharmacodynamic synergism. Modify Therapy/Monitor Closely.

            • alprazolam

              phenytoin will decrease the level or effect of alprazolam by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • amikacin

              phenytoin will decrease the level or effect of amikacin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • amiodarone

              amiodarone will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

              phenytoin will decrease the level or effect of amiodarone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. An increased risk of phenytoin toxicity (ataxia, hyperreflexa, nystagmus, tremor) and/or decreased amiodarone concentrations. Because of the long half-life of amiodarone, the full extent of this interaction may not be evident for several weeks; careful monitoring is required.

            • amitriptyline

              phenytoin will decrease the level or effect of amitriptyline by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor therapeutic efficacy of amitriptyline; an increased dose may be required. Serum phenytoin levels should be obtained when tricyclic antidepressant agents are added to therapy due to the potential for impaired phenytoin metabolism and decreased seizure threshold. Tricyclic antidepressants when given concomitantly with anticonvulsants can increase CNS depression.

              phenytoin will decrease the level or effect of amitriptyline by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Monitor therapeutic efficacy of amitriptyline; an increased dose may be required. Serum phenytoin levels should be obtained when tricyclic antidepressant agents are added to therapy due to the potential for impaired phenytoin metabolism and decreased seizure threshold. Tricyclic antidepressants when given concomitantly with anticonvulsants can increase CNS depression.

            • amlodipine

              amlodipine will increase the level or effect of phenytoin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely.

            • amobarbital

              amobarbital will decrease the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            • antithrombin alfa

              antithrombin alfa increases levels of phenytoin by unknown mechanism. Use Caution/Monitor.

              phenytoin, antithrombin alfa. Other (see comment). Use Caution/Monitor. Comment: Hydantoin anticonvulsants increase anticoagulant effects at first, then decrease those effects with continued use (2+ wks). There are multiple mechanisms involved, including enzyme induction, plasma protein binding site competition, and additive effects on prothrombin time.

            • antithrombin III

              antithrombin III increases levels of phenytoin by unknown mechanism. Use Caution/Monitor.

              phenytoin, antithrombin III. Other (see comment). Use Caution/Monitor. Comment: Hydantoin anticonvulsants increase anticoagulant effects at first, then decrease those effects with continued use (2+ wks). There are multiple mechanisms involved, including enzyme induction, plasma protein binding site competition, and additive effects on prothrombin time.

            • apalutamide

              apalutamide will decrease the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor. Coadministration of apalutamide, a weak CYP2C9 inducer, with drugs that are CYP2C9 substrates can result in lower exposure to these medications. Evaluate for loss of therapeutic effect if medication must be coadministered.

            • aprepitant

              phenytoin will decrease the level or effect of aprepitant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • argatroban

              argatroban increases levels of phenytoin by unknown mechanism. Use Caution/Monitor.

              phenytoin, argatroban. Other (see comment). Use Caution/Monitor. Comment: Hydantoin anticonvulsants increase anticoagulant effects at first, then decrease those effects with continued use (2+ wks). There are multiple mechanisms involved, including enzyme induction, plasma protein binding site competition, and additive effects on prothrombin time.

            • aripiprazole

              phenytoin will decrease the level or effect of aripiprazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • artesunate

              phenytoin will decrease the level or effect of artesunate by increasing metabolism. Use Caution/Monitor. Coadministration may decrease AUC and peak plasma concentration of active artesunate metabolite (DHA) by inducing UGT. Monitor for decreased efficacy.

            • atorvastatin

              phenytoin will decrease the level or effect of atorvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • avanafil

              phenytoin will decrease the level or effect of avanafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. For patients with ED, monitor response carefully because of potential for decreased effectiveness.

            • avatrombopag

              phenytoin will decrease the level or effect of avatrombopag by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. When treating ITP, coadministration of avatrombopag with a moderate or strong dual CYP2C9/3A4 inducer requires an increased avatrombopag starting dose. Refer to drug monograph for specific recommendations.

            • bazedoxifene/conjugated estrogens

              phenytoin will decrease the level or effect of bazedoxifene/conjugated estrogens by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              phenytoin will decrease the level or effect of bazedoxifene/conjugated estrogens by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. If the estrogen is being used for contraception then loss of contraception may occur.

              phenytoin decreases levels of bazedoxifene/conjugated estrogens by increasing metabolism. Use Caution/Monitor. A reduction in bazedoxifene exposure may be associated with an increase risk of endometrial hyperplasia.

            • bemiparin

              bemiparin increases levels of phenytoin by unknown mechanism. Use Caution/Monitor.

              phenytoin, bemiparin. Other (see comment). Use Caution/Monitor. Comment: Hydantoin anticonvulsants increase anticoagulant effects at first, then decrease those effects with continued use (2+ wks). There are multiple mechanisms involved, including enzyme induction, plasma protein binding site competition, and additive effects on prothrombin time.

            • benzhydrocodone/acetaminophen

              phenytoin will decrease the level or effect of benzhydrocodone/acetaminophen by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Caution when discontinuing CYP3A4 inducers that are coadministered with benzhydrocodone (prodrug of hydrocodone); plasma concentrations of hydrocodone may increase and can result in potentially fatal respiratory depression.

            • bexarotene

              phenytoin will decrease the level or effect of bexarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • bivalirudin

              bivalirudin increases levels of phenytoin by unknown mechanism. Use Caution/Monitor.

              phenytoin, bivalirudin. Other (see comment). Use Caution/Monitor. Comment: Hydantoin anticonvulsants increase anticoagulant effects at first, then decrease those effects with continued use (2+ wks). There are multiple mechanisms involved, including enzyme induction, plasma protein binding site competition, and additive effects on prothrombin time.

            • bleomycin

              bleomycin decreases levels of phenytoin by increasing metabolism. Use Caution/Monitor.

            • blinatumomab

              blinatumomab increases levels of phenytoin by decreasing metabolism. Modify Therapy/Monitor Closely. Treatment initiation causes transient release of cytokines that may suppress CYP450 enzymes; highest drug-drug interaction risk is during the first 9 days of the first cycle and the first 2 days of the 2nd cycle in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index.

            • bortezomib

              phenytoin will decrease the level or effect of bortezomib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • bosentan

              bosentan will decrease the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            • brentuximab vedotin

              phenytoin decreases levels of brentuximab vedotin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • brexanolone

              brexanolone, phenytoin. Either increases toxicity of the other by sedation. Use Caution/Monitor.

            • brexpiprazole

              phenytoin will decrease the level or effect of brexpiprazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Double brexpiprazole dose over 1-2 weeks if administered with a strong CYP3A4 inducer.

            • brivaracetam

              phenytoin will decrease the level or effect of brivaracetam by affecting hepatic enzyme CYP2C19 metabolism. Use Caution/Monitor. Brivaracetam plasma concentration decreased by 21%.

              brivaracetam increases levels of phenytoin by decreasing metabolism. Use Caution/Monitor. Up to 20% increase in phenytoin plasma concentrations observed. Monitor phenytoin levels when brivaracetam is coadministered or discontinued from ongoing phenytoin therapy. .

            • brodalumab

              brodalumab, phenytoin. Other (see comment). Use Caution/Monitor. Comment: Formation of CYP450 enzymes can be altered by increased levels of certain cytokines during chronic inflammation; thus, brodalumab could normalize the formation of CYP450 enzymes. Upon initiation or discontinuation of brodalumab in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for therapeutic effect.

            • bromocriptine

              phenytoin will decrease the level or effect of bromocriptine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • budesonide

              phenytoin will decrease the level or effect of budesonide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              phenytoin will decrease the level or effect of budesonide by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • buprenorphine

              phenytoin will decrease the level or effect of buprenorphine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • buprenorphine buccal

              phenytoin will decrease the level or effect of buprenorphine buccal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • buprenorphine subdermal implant

              phenytoin will decrease the level or effect of buprenorphine subdermal implant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Monitor patients already on buprenorphine subdermal implant who require newly-initiated treatment with CYP3A4 inducer for signs and symptoms of withdrawal. If the dose of the concomitant CYP3A4 inducer cannot be reduced or discontinued, implant removal may be necessary and the patient should then be treated with a buprenorphine dosage form that permits dose adjustments. If a CYP3A4 inducer is discontinued in a patient who has been stabilized on buprenorphine, monitor the patient for overmedication.

            • buprenorphine transdermal

              phenytoin will decrease the level or effect of buprenorphine transdermal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • buprenorphine, long-acting injection

              phenytoin will decrease the level or effect of buprenorphine, long-acting injection by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Patients who transfer to buprenorphine long-acting injection from transmucosal buprenorphine coadministered with CYP3A4 inducers should be monitored to ensure buprenorphine plasma levels are adequate. If the buprenorphine dose is inadequate and the CYP3A4 inducer cannot be reduced or discontinued, transition the patient back to a buprenorphine formulation that permits dose adjustments.

            • buspirone

              phenytoin will decrease the level or effect of buspirone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • busulfan

              phenytoin decreases levels of busulfan by increasing hepatic clearance. Use Caution/Monitor.

              phenytoin will decrease the level or effect of busulfan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • butabarbital

              butabarbital will decrease the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            • butalbital

              butalbital will decrease the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            • cabazitaxel

              phenytoin will decrease the level or effect of cabazitaxel by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration of strong CYP3A4 inducers may decrease cabazitaxel concentrations. Avoid coadministration.

            • calcifediol

              phenytoin, calcifediol. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Drugs that stimulate microsomal hydroxylation reduce the half-life of calcifediol.

            • calcitriol

              phenytoin will decrease the level or effect of calcitriol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely.

            • canagliflozin

              phenytoin decreases levels of canagliflozin by increasing metabolism. Use Caution/Monitor. Coadministration with potent UGT enzyme inducers: Consider increasing dose to 300 mg qDay if 100 mg/day tolerate and additional glycemic control required (eGFR must be >60 mL/min/1.73 m2 to increase dose); if eGFR <60 mL/min/1.73 m2, consider using a different antihyperglycemic agent.

            • cannabidiol

              phenytoin will decrease the level or effect of cannabidiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Consider an increase in cannabidiol dosage (based on clinical response and tolerability) when coadministered with a strong CYP3A4 inducer.

              cannabidiol will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C19 metabolism. Modify Therapy/Monitor Closely. Consider reducing the dose of sensitive CYP2C19 substrates, as clinically appropriate, when coadministered with cannabidiol.

              cannabidiol will increase the level or effect of phenytoin by decreasing metabolism. Modify Therapy/Monitor Closely. Cannabidiol may potentially inhibit CYP2C9 activity. Consider reducing the dose when concomitantly using CYP2C9 substrates.Cannabidiol may potentially inhibit CYP2C9 activity. Consider reducing the dose when concomitantly using CYP2C9 substrates.

            • capecitabine

              capecitabine increases levels of phenytoin by unknown mechanism. Use Caution/Monitor. Based on case reports.

            • carbamazepine

              carbamazepine will decrease the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

              phenytoin will decrease the level or effect of carbamazepine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • carboplatin

              carboplatin decreases levels of phenytoin by unknown mechanism. Use Caution/Monitor.

            • carmustine

              carmustine decreases levels of phenytoin by unknown mechanism. Use Caution/Monitor.

            • cenobamate

              cenobamate will increase the level or effect of phenytoin by unspecified interaction mechanism. Modify Therapy/Monitor Closely. Concomitant use of phenytoin with multiple doses of cenobamate 200 mg qDay increased phenytoin mean Cmax and AUC by 70% and 80. Gradually decrease phenytoin dosage by up to 50% when used concomitantly with cenobamate.

              cenobamate will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C19 metabolism. Modify Therapy/Monitor Closely. Consider a dose reduction of CYP2C19 substrates, as clinically appropriate, when used concomitantly with cenobamate.

              cenobamate, phenytoin. Either increases effects of the other by sedation. Use Caution/Monitor.

            • chloramphenicol

              chloramphenicol increases levels of phenytoin by decreasing metabolism. Use Caution/Monitor.

            • chlordiazepoxide

              phenytoin will decrease the level or effect of chlordiazepoxide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely.

            • chloroquine

              phenytoin will decrease the level or effect of chloroquine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • cilostazol

              phenytoin will decrease the level or effect of cilostazol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • cimetidine

              cimetidine will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            • cinacalcet

              phenytoin will decrease the level or effect of cinacalcet by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • ciprofloxacin

              ciprofloxacin decreases effects of phenytoin by unknown mechanism. Use Caution/Monitor. Ciprofloxacin has been reported to both increase and decrease phenytoin concentrations. Additional clinical evidence is needed however; phenytoin serum concentrations should be monitored in patients.

            • cisatracurium

              phenytoin decreases effects of cisatracurium by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Monitor closely for more rapid recovery from neuromuscular blockade than expected; infusion rate requirements may be higher.

            • cisplatin

              cisplatin decreases levels of phenytoin by unknown mechanism. Use Caution/Monitor.

            • citalopram

              phenytoin will decrease the level or effect of citalopram by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • clobetasone

              phenytoin will decrease the level or effect of clobetasone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              phenytoin will decrease the level or effect of clobetasone by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • clomipramine

              phenytoin will decrease the level or effect of clomipramine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • clonazepam

              phenytoin will decrease the level or effect of clonazepam by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • clopidogrel

              phenytoin will increase the level or effect of clopidogrel by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. CYP3A4 inducers may increase the metabolism of clopidogrel to its active metabolite. Monitor patients for potential increase in antiplatelet effects when CYP3A4 inducers are used in combination with clopidogrel

            • clorazepate

              phenytoin will decrease the level or effect of clorazepate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • clozapine

              phenytoin will decrease the level or effect of clozapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. When adding phenytoin therapy to patients stabilized on clozapine, monitor patient closely for worsening of psychotic symptoms. If needed, increase the clozapine dose cautiously on basis of psychotic symptoms. Conversely, when phenytoin is discontinued, levels of clozapine may significantly increase.

            • colchicine

              phenytoin will decrease the level or effect of colchicine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • colesevelam

              colesevelam will decrease the level or effect of phenytoin by Mechanism: inhibition of GI absorption. Applies only to oral form of both agents. Modify Therapy/Monitor Closely. Administer phenytoin at least 4 hr before colesevelam

            • conivaptan

              phenytoin will decrease the level or effect of conivaptan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • conjugated estrogens

              phenytoin will decrease the level or effect of conjugated estrogens by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              phenytoin will decrease the level or effect of conjugated estrogens by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. If the estrogen is being used for contraception then loss of contraception may occur.

            • conjugated estrogens, vaginal

              phenytoin will decrease the level or effect of conjugated estrogens, vaginal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              phenytoin will decrease the level or effect of conjugated estrogens, vaginal by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. If the estrogen is being used for contraception then loss of contraception may occur.

            • cortisone

              phenytoin will decrease the level or effect of cortisone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              phenytoin will decrease the level or effect of cortisone by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • crizotinib

              phenytoin decreases levels of crizotinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Concomitant use of strong CYP3A inducers should be avoided. .

              crizotinib increases levels of phenytoin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration of crizotinib with CYP3A substrates with narrow therapeutic indices should be avoided.

            • cyclosporine

              phenytoin will decrease the level or effect of cyclosporine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              phenytoin will decrease the level or effect of cyclosporine by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • dalteparin

              dalteparin increases levels of phenytoin by unknown mechanism. Use Caution/Monitor.

              phenytoin, dalteparin. Other (see comment). Use Caution/Monitor. Comment: Hydantoin anticonvulsants increase anticoagulant effects at first, then decrease those effects with continued use (2+ wks). There are multiple mechanisms involved, including enzyme induction, plasma protein binding site competition, and additive effects on prothrombin time.

            • dapsone topical

              phenytoin increases toxicity of dapsone topical by altering metabolism. Modify Therapy/Monitor Closely. May induce methemoglobinemia.

            • darifenacin

              phenytoin will decrease the level or effect of darifenacin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • dasatinib

              phenytoin will decrease the level or effect of dasatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Concomitant use will lead to decreased dasatinib plasma concentrations. Consider using alternative therapeutic agents with low enzyme induction potential for coadministration with dasatinib. However, if concomitant use with phenytoin is required, consider increasing the dasatinib dose and monitor the patient closely for dasatinib toxicity (myelosuppression, fluid retention, diarrhea, hemorrhage, or skin rash).

            • deferasirox

              phenytoin decreases levels of deferasirox by Other (see comment). Use Caution/Monitor. Comment: Avoid concomitant use of potent UGT inducers with deferasirox. If co-administration is required then consider increasing initial dose of deferasirox to 30 mg/kg and monitor ferritin levels and clinical response.

            • deflazacort

              phenytoin will decrease the level or effect of deflazacort by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • desipramine

              phenytoin will decrease the level or effect of desipramine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Consider phenytoin serum levels if a tricyclic antidepressant is added to therapy or if the patient begins to exhibit signs of toxicity; lower doses of phenytoin may be required. If phenytoin is added to tricyclic antidepressant therapy, monitor for clinical efficacy of the tricyclic agent. Tricyclic antidepressants when given concomitantly with anticonvulsants can increase CNS depression.

            • deutetrabenazine

              phenytoin and deutetrabenazine both increase sedation. Use Caution/Monitor.

            • dexamethasone

              phenytoin will decrease the level or effect of dexamethasone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              phenytoin will decrease the level or effect of dexamethasone by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • dexlansoprazole

              phenytoin will decrease the level or effect of dexlansoprazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • diazepam

              phenytoin will decrease the level or effect of diazepam by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • diazepam intranasal

              phenytoin will decrease the level or effect of diazepam intranasal by affecting hepatic enzyme CYP2C19 metabolism. Use Caution/Monitor. Strong or moderate CYP2C19 inducers may increase rate of diazepam elimination; therefore, efficacy of diazepam may be decreased.

              phenytoin will decrease the level or effect of diazepam intranasal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Strong or moderate CYP3A4 inducers may increase rate of diazepam elimination; therefore, efficacy of diazepam may be decreased.

            • digoxin

              phenytoin will decrease the level or effect of digoxin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • diltiazem

              phenytoin will decrease the level or effect of diltiazem by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • disopyramide

              phenytoin will decrease the level or effect of disopyramide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Phenytoin decreases the levels of disopyramide but can also increase the toxicity.

              phenytoin increases toxicity of disopyramide by increasing metabolism. Use Caution/Monitor. Hydantoins decreases the level, but increases the toxicity, of disopyramide.

            • disulfiram

              disulfiram will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            • docetaxel

              phenytoin will decrease the level or effect of docetaxel by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              docetaxel decreases levels of phenytoin by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              docetaxel decreases levels of phenytoin by increasing metabolism. Use Caution/Monitor.

            • doxorubicin

              phenytoin will decrease the level or effect of doxorubicin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              doxorubicin decreases levels of phenytoin by increasing metabolism. Use Caution/Monitor.

            • doxorubicin liposomal

              phenytoin will decrease the level or effect of doxorubicin liposomal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              doxorubicin liposomal decreases levels of phenytoin by increasing metabolism. Use Caution/Monitor.

            • dronabinol

              phenytoin will decrease the level or effect of dronabinol by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor. Dronabinol is a CYP2C9 substrate.

              phenytoin will decrease the level or effect of dronabinol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Dronabinol is a CYP3A4 substrate.

              dronabinol increases levels of phenytoin by plasma protein binding competition. Modify Therapy/Monitor Closely. Dronabinol is highly bound to plasma proteins and may displace and increase the free fraction of other concomitantly administered highly protein-bound drugs. This has not been confirmed in vivo. Caution with narrow therapeutic index drugs that are highly protein bound when initiating or increasing the dose of dronabinol.

            • dulaglutide

              dulaglutide, phenytoin. Other (see comment). Use Caution/Monitor. Comment: Dulaglutide slows gastric emptying and may impact absorption of concomitantly administered oral medications; be particularly cautious when coadministered with drugs that have a narrow therapeutic index.

            • dupilumab

              dupilumab, phenytoin. Other (see comment). Use Caution/Monitor. Comment: Formation of CYP450 enzymes can be altered by increased levels of certain cytokines during chronic inflammation; thus, dupilumab could normalize the formation of CYP450 enzymes. Upon initiation or discontinuation of dupilumab in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for therapeutic effect.

            • duvelisib

              phenytoin will decrease the level or effect of duvelisib by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • efavirenz

              efavirenz will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

              phenytoin will decrease the level or effect of efavirenz by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. When given together, periodic monitoring for reduced efavirenz efficacy and phenytoin plasma concentrations are recommended .

              phenytoin will increase the level or effect of efavirenz by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            • elagolix

              elagolix will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C19 metabolism. Modify Therapy/Monitor Closely. Elagolix is a weak CYP2C19 inhibitor. Caution with sensitive CYP2C19 substrates.

              phenytoin will decrease the level or effect of elagolix by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • eletriptan

              phenytoin will decrease the level or effect of eletriptan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • eliglustat

              eliglustat increases levels of phenytoin by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. Monitor therapeutic drug concentrations, as indicated, or consider reducing the dosage of the P-gp substrate and titrate to clinical effect.

            • elvitegravir/cobicistat/emtricitabine/tenofovir DF

              elvitegravir/cobicistat/emtricitabine/tenofovir DF decreases levels of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor. Elvitegravir is a moderate CYP2C9 inducer.

            • enfortumab vedotin

              phenytoin will decrease the level or effect of enfortumab vedotin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • enoxaparin

              enoxaparin increases levels of phenytoin by unknown mechanism. Use Caution/Monitor.

              phenytoin, enoxaparin. Other (see comment). Use Caution/Monitor. Comment: Hydantoin anticonvulsants increase anticoagulant effects at first, then decrease those effects with continued use (2+ wks). There are multiple mechanisms involved, including enzyme induction, plasma protein binding site competition, and additive effects on prothrombin time.

            • erlotinib

              phenytoin will decrease the level or effect of erlotinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Avoid concomitant use because there is a potential for decreased erlotinib exposure and efficacy. However, if concomitant use is clinically warranted, consider an increase in erlotinib dose as tolerated at 2 week intervals and monitor patient's safety. If the erlotinib dose is increased, reduce it immediately to the indicated starting dose upon discontinuation of phenytoin.

              phenytoin will decrease the level or effect of erlotinib by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • escitalopram

              phenytoin will decrease the level or effect of escitalopram by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • esketamine intranasal

              esketamine intranasal, phenytoin. Either increases toxicity of the other by sedation. Modify Therapy/Monitor Closely.

            • eslicarbazepine acetate

              phenytoin will decrease the level or effect of eslicarbazepine acetate by increasing metabolism. Use Caution/Monitor. Higher dosage of eslicarbazepine may be necessary and dose adjustment may be needed for phenytoin

              eslicarbazepine acetate will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C19 metabolism. Use Caution/Monitor.

            • esomeprazole

              esomeprazole will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C19 metabolism. Use Caution/Monitor.

              phenytoin will decrease the level or effect of esomeprazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • estradiol

              phenytoin will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              phenytoin will decrease the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • estradiol vaginal

              phenytoin will decrease the level or effect of estradiol vaginal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • estrogens conjugated synthetic

              phenytoin will decrease the level or effect of estrogens conjugated synthetic by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              phenytoin will decrease the level or effect of estrogens conjugated synthetic by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. If the estrogen is being used for contraception then loss of contraception may occur.

            • estrogens esterified

              phenytoin will decrease the level or effect of estrogens esterified by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. If the estrogen is being used for contraception then loss of contraception may occur.

            • estropipate

              phenytoin will decrease the level or effect of estropipate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              phenytoin will decrease the level or effect of estropipate by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. If the estrogen is being used for contraception then loss of contraception may occur.

            • eszopiclone

              phenytoin will decrease the level or effect of eszopiclone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • ethanol

              ethanol decreases levels of phenytoin by increasing metabolism. Use Caution/Monitor. Decreased phenytoin levels may be seen with chronic alcohol ingestion.

              ethanol increases levels of phenytoin by decreasing metabolism. Use Caution/Monitor. Increased phenytoin levels may be seen with acute alcohol ingestion.

            • ethosuximide

              phenytoin, ethosuximide. Other (see comment). Use Caution/Monitor. Comment: Ethosuximide may enhance CNS depressant effects and may increase serum concentrations of phenytoin. Phenytoin, a CYP3A4 inducer, may decrease plasma levels of ethosuximide (a CYP3A4 substrate.).

            • etonogestrel

              phenytoin will decrease the level or effect of etonogestrel by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • etoposide

              phenytoin will decrease the level or effect of etoposide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • exemestane

              phenytoin will decrease the level or effect of exemestane by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. For patients receiving exemestane with a potent CYP3A4 inducer the recommended dose of exemestane is 50 mg daily after a meal.

            • felbamate

              felbamate will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

              phenytoin will decrease the level or effect of felbamate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Felbamate may increase serum concentrations of phenytoin. Phenytoin, a CYP3A4 inducer, may decrease plasma levels of felbamate (a CYP3A4 substrate).

            • felodipine

              phenytoin will decrease the level or effect of felodipine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. When possible, avoid coadministration of these drugs and consider alternative therapy. When an alternative therapy is not possible, patients should be monitored for the desired cardiovascular effects such as heart rate, chest pain, or blood pressure.

              phenytoin decreases levels of felodipine by increasing metabolism. Use Caution/Monitor.

            • fentanyl

              phenytoin will decrease the level or effect of fentanyl by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Coadministration of fentanyl with CYP3A4 inducers could lead to a decrease in fentanyl plasma concentrations, lack of efficacy or, possibly, development of a withdrawal syndrome in a patient who has developed physical dependence to fentanyl. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase which could increase or prolong both the therapeutic and adverse effects.

            • fentanyl intranasal

              phenytoin will decrease the level or effect of fentanyl intranasal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Coadministration of fentanyl with CYP3A4 inducers could lead to a decrease in fentanyl plasma concentrations, lack of efficacy or, possibly, development of a withdrawal syndrome in a patient who has developed physical dependence to fentanyl. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase which could increase or prolong both the therapeutic and adverse effects.

            • fentanyl transdermal

              phenytoin will decrease the level or effect of fentanyl transdermal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Coadministration of fentanyl with CYP3A4 inducers could lead to a decrease in fentanyl plasma concentrations, lack of efficacy or, possibly, development of a withdrawal syndrome in a patient who has developed physical dependence to fentanyl. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase which could increase or prolong both the therapeutic and adverse effects.

            • fentanyl transmucosal

              phenytoin will decrease the level or effect of fentanyl transmucosal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Coadministration of fentanyl with CYP3A4 inducers could lead to a decrease in fentanyl plasma concentrations, lack of efficacy or, possibly, development of a withdrawal syndrome in a patient who has developed physical dependence to fentanyl. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase which could increase or prolong both the therapeutic and adverse effects.

            • ferric maltol

              ferric maltol, phenytoin. Either increases levels of the other by unspecified interaction mechanism. Modify Therapy/Monitor Closely. Coadministration of ferric maltol with certain oral medications may decrease the bioavailability of either ferric maltol and some oral drugs. For oral drugs where reductions in bioavailability may cause clinically significant effects on its safety or efficacy, separate administration of ferric maltol from these drugs. Duration of separation may depend on the absorption of the medication concomitantly administered (eg, time to peak concentration, whether the drug is an immediate or extended release product).

            • fesoterodine

              phenytoin will decrease the level or effect of fesoterodine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • fexinidazole

              fexinidazole will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C19 metabolism. Use Caution/Monitor.

            • fleroxacin

              fleroxacin decreases effects of phenytoin by unknown mechanism. Use Caution/Monitor. There are also case reports of quinolones increasing phenytoin levels.

            • flibanserin

              phenytoin will decrease the level or effect of flibanserin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Strong CYP3A4 inducers substantially decrease flibanserin systemic exposure.

            • floxuridine

              floxuridine increases levels of phenytoin by unknown mechanism. Use Caution/Monitor. Based on case reports.

            • fluconazole

              fluconazole will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            • fludrocortisone

              phenytoin will decrease the level or effect of fludrocortisone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              phenytoin will decrease the level or effect of fludrocortisone by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • fluorouracil

              fluorouracil increases levels of phenytoin by unknown mechanism. Use Caution/Monitor. Based on case reports.

            • fluoxetine

              fluoxetine will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            • flurazepam

              phenytoin will decrease the level or effect of flurazepam by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • fluticasone furoate

              phenytoin will decrease the level or effect of fluticasone furoate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • fluticasone inhaled

              phenytoin will decrease the level or effect of fluticasone inhaled by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • fluvastatin

              fluvastatin increases levels of phenytoin by decreasing metabolism. Use Caution/Monitor.

            • fluvoxamine

              fluvoxamine will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            • fondaparinux

              fondaparinux increases levels of phenytoin by unknown mechanism. Use Caution/Monitor.

              phenytoin, fondaparinux. Other (see comment). Use Caution/Monitor. Comment: Hydantoin anticonvulsants increase anticoagulant effects at first, then decrease those effects with continued use (2+ wks). There are multiple mechanisms involved, including enzyme induction, plasma protein binding site competition, and additive effects on prothrombin time.

            • fosamprenavir

              phenytoin, fosamprenavir. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration of phenytoin and fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite; when given with the combination of fosamprenavir and ritonavir an increased concentration of amprenavir is observed.

            • gefitinib

              phenytoin will decrease the level or effect of gefitinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Increase gefitinib to 500 mg daily if coadministered with a strong CYP3A4 inducer. Resume gefitinib dose at 250 mg/day 7 days after discontinuing the strong inducer.

            • gemifloxacin

              gemifloxacin decreases effects of phenytoin by unknown mechanism. Use Caution/Monitor. There are also case reports of quinolones increasing phenytoin levels.

            • gentamicin

              phenytoin will decrease the level or effect of gentamicin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • glyburide

              phenytoin decreases levels of glyburide by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor. Strong CYP2C9 inducers may increase glyburide metabolism.

            • green tea

              phenytoin decreases levels of green tea by increasing metabolism. Use Caution/Monitor. (Caffeine). Potential for decreased effects of caffeine in green tea. .

            • guanfacine

              phenytoin will decrease the level or effect of guanfacine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Strong or moderate CYP3A4 inducers significantly reduce guanfacine plasma concentrations and elimination half-life. If coadministered, more frequent dosing of the IR product may be required to achieve or maintain the desired hypotensive response. For patients with ADHD, FDA-approved labeling for ER guanfacine recommends that, if coadministered, doubling the recommended dose of guanfacine should be considered.

            • guselkumab

              guselkumab, phenytoin. Other (see comment). Use Caution/Monitor. Comment: Formation of CYP450 enzymes can be altered by increased levels of certain cytokines during chronic inflammation; thus, normalizing the formation of CYP450 enzymes. Upon initiation or discontinuation of guselkumab in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for therapeutic effect.

            • hawthorn

              hawthorn increases effects of phenytoin by pharmacodynamic synergism. Use Caution/Monitor.

            • heparin

              heparin increases levels of phenytoin by unknown mechanism. Use Caution/Monitor.

              phenytoin, heparin. Other (see comment). Use Caution/Monitor. Comment: Hydantoin anticonvulsants increase anticoagulant effects at first, then decrease those effects with continued use (2+ wks). There are multiple mechanisms involved, including enzyme induction, plasma protein binding site competition, and additive effects on prothrombin time.

            • hyaluronidase

              hyaluronidase, phenytoin. Other (see comment). Use Caution/Monitor. Comment: Drug combination has been found to be incompatible.

            • hydrocodone

              phenytoin will decrease the level or effect of hydrocodone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Caution when discontinuing CYP3A4 inducers that are coadministered with hydrocodone; plasma concentrations of hydrocodone may increase and can result in potentially fatal respiratory depression.

            • hydrocortisone

              phenytoin will decrease the level or effect of hydrocortisone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              phenytoin will decrease the level or effect of hydrocortisone by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • hydroxyprogesterone caproate

              phenytoin will decrease the level or effect of hydroxyprogesterone caproate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • ifosfamide

              phenytoin increases effects of ifosfamide by affecting hepatic enzyme CYP2B6 metabolism. Use Caution/Monitor. Coadministration of ifosfamide with CYP2B6 inducers may increase metabolism of ifosfamide to its metabolite. Monitor for increased effects/toxicities if combined with CYP2B6 inducers.

              phenytoin increases toxicity of ifosfamide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. CYP3A4 inducers may increase the metabolism of ifosfamide to its active alkylating metabolites. CYP3A4 inducers may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde. Closely monitor patients taking ifosfamide with CYP3A4 inducers for toxicities and consider dose adjustment.

            • iloperidone

              phenytoin will decrease the level or effect of iloperidone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • imatinib

              imatinib will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

              phenytoin will decrease the level or effect of imatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Alternatives to phenytoin, with less enzyme induction potential, should be considered. Combo may decrease imatinib levels and efficacy.

              phenytoin will decrease the level or effect of imatinib by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • imipramine

              phenytoin will decrease the level or effect of imipramine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Consider phenytoin serum levels if a tricyclic antidepressant is added to therapy or if the patient begins to exhibit signs of toxicity; lower doses of phenytoin may be required. If phenytoin is added to tricyclic antidepressant therapy, monitor for clinical efficacy of the tricyclic agent. Tricyclic antidepressants when given concomitantly with anticonvulsants can increase CNS depression.

            • indinavir

              phenytoin will decrease the level or effect of indinavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              phenytoin will decrease the level or effect of indinavir by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • itraconazole

              phenytoin will decrease the level or effect of itraconazole by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Antifungal failure may occur due to clinically significant decreases in itraconazole serum concentrations when given with phenytoin. Increased itraconazole dosage may be needed.

            • ivermectin

              phenytoin will decrease the level or effect of ivermectin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • ixabepilone

              phenytoin will decrease the level or effect of ixabepilone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • ixekizumab

              ixekizumab, phenytoin. Other (see comment). Use Caution/Monitor. Comment: Formation of CYP450 enzymes can be altered by increased levels of certain cytokines during chronic inflammation; thus, ixekizumab could normalize the formation of CYP450 enzymes. Upon initiation or discontinuation of ixekizumab in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for therapeutic effect.

            • ketoconazole

              ketoconazole will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            • L-methylfolate

              L-methylfolate decreases levels of phenytoin by unspecified interaction mechanism. Use Caution/Monitor.

            • lamotrigine

              phenytoin decreases levels of lamotrigine by increasing metabolism. Use Caution/Monitor.

            • lapatinib

              phenytoin will decrease the level or effect of lapatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              phenytoin will decrease the level or effect of lapatinib by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. A reduction in therapeutic effectiveness of lapatinib may occur. Concomitant use of phenytoin with dasatinib, nilotinib, lapatinib, or pazopanib should be avoided.

            • lasmiditan

              lasmiditan, phenytoin. Either increases effects of the other by sedation. Use Caution/Monitor. Coadministration of lasmiditan and other CNS depressant drugs, including alcohol have not been evaluated in clinical studies. Lasmiditan may cause sedation, as well as other cognitive and/or neuropsychiatric adverse reactions.

            • leflunomide

              leflunomide will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            • lemborexant

              lemborexant, phenytoin. Either increases effects of the other by sedation. Modify Therapy/Monitor Closely. Dosage adjustment may be necessary if lemborexant is coadministered with other CNS depressants because of potentially additive effects.

            • lesinurad

              phenytoin will decrease the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.

            • letermovir

              letermovir will decrease the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor. Monitor phenytoin levels.

            • levamlodipine

              phenytoin will decrease the level or effect of levamlodipine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. No information is available on the quantitative effects of CYP3A4 inducers on amlodipine. Closely monitor blood pressure when amlodipine is coadministered with CYP3A4 inducers.

            • levodopa

              phenytoin decreases effects of levodopa by unknown mechanism. Use Caution/Monitor.

            • levofloxacin

              levofloxacin decreases effects of phenytoin by unknown mechanism. Use Caution/Monitor. There are also case reports of quinolones increasing phenytoin levels.

            • levonorgestrel intrauterine

              phenytoin decreases levels of levonorgestrel intrauterine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • levonorgestrel oral

              phenytoin decreases levels of levonorgestrel oral by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • levonorgestrel oral/ethinylestradiol/ferrous bisglycinate

              phenytoin will decrease the level or effect of levonorgestrel oral/ethinylestradiol/ferrous bisglycinate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. The efficacy of hormonal contraceptives may be reduced. Use an alternative method of contraception or a backup method when enzyme inducers are used with combined hormonal contraceptives (CHCs), and continue backup contraception for 28 days after discontinuing enzyme inducer to ensure contraceptive reliability.

            • linagliptin

              phenytoin will decrease the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Use of alternative treatments is strongly recommended when linagliptin is to be administered with a CYP3A4 inducer.

            • lomustine

              phenytoin will decrease the level or effect of lomustine by increasing metabolism. Use Caution/Monitor. Coadministration of enzyme inducing antiepileptics with lomustine may cause a decrease in plasma concentration and reduced efficacy of lomustine.

              lomustine will increase the level or effect of phenytoin by decreasing metabolism. Use Caution/Monitor. Coadministration of lomustine with phenytoin may decrease of phenytoin levels and seizure control.

            • loperamide

              phenytoin will decrease the level or effect of loperamide by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • lopinavir

              phenytoin will decrease the level or effect of lopinavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • loratadine

              phenytoin will decrease the level or effect of loratadine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • lumacaftor/ivacaftor

              lumacaftor/ivacaftor, phenytoin. affecting hepatic enzyme CYP2C19 metabolism. Use Caution/Monitor. In vitro studies suggest that lumacaftor may induce and ivacaftor may inhibit CYP2C19 substrates. .

              lumacaftor/ivacaftor, phenytoin. affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor. In vitro studies suggest that lumacaftor may induce and ivacaftor may inhibit CYP2C9 substrates. .

            • lurasidone

              lurasidone, phenytoin. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Potential for increased CNS depressant effects when used concurrently; monitor for increased adverse effects and toxicity.

            • maraviroc

              phenytoin will decrease the level or effect of maraviroc by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              phenytoin will decrease the level or effect of maraviroc by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. The plasma concentrations and pharmacologic effects of maraviroc may be increased by phenytoin. Maraviroc dosage adjustment is recommended during concomitant therapy with phenytoin. Coadministration of maraviroc and phenytoin is contraindicated in patients with severe renal impairment.

            • marijuana

              phenytoin will decrease the level or effect of marijuana by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • medroxyprogesterone

              phenytoin will decrease the level or effect of medroxyprogesterone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Contraceptirve failure possible

            • mestranol

              phenytoin will decrease the level or effect of mestranol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              phenytoin will decrease the level or effect of mestranol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              mestranol decreases effects of phenytoin by decreasing metabolism. Use Caution/Monitor.

            • metformin

              phenytoin decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.

            • methadone

              phenytoin will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • methotrexate

              phenytoin increases toxicity of methotrexate by Other (see comment). Use Caution/Monitor. Comment: Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by certain drugs, such as phenytoin.

            • methylphenidate

              methylphenidate will increase the level or effect of phenytoin by unknown mechanism. Use Caution/Monitor. Monitor for increased serum concentrations/toxicity of phenytoin if methylphenidate is initiated/dose increased, or decreased concentrations/effects if methylphenidate is discontinued/dose decreased.

            • methylprednisolone

              phenytoin will decrease the level or effect of methylprednisolone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              phenytoin will decrease the level or effect of methylprednisolone by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • metronidazole

              metronidazole will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            • metyrapone

              phenytoin decreases levels of metyrapone by increasing metabolism. Use Caution/Monitor.

            • mexiletine

              phenytoin decreases levels of mexiletine by increasing metabolism. Use Caution/Monitor.

            • miconazole vaginal

              miconazole vaginal will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            • midazolam

              phenytoin will decrease the level or effect of midazolam by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • midazolam intranasal

              midazolam intranasal, phenytoin. Either increases toxicity of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Concomitant use of barbiturates, alcohol, or other CNS depressants may increase the risk of hypoventilation, airway obstruction, desaturation, or apnea and may contribute to profound and/or prolonged drug effect.

            • mifepristone

              phenytoin will decrease the level or effect of mifepristone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. CYP3A4 inducers have not been studied, coadministration not recommended by manufacturer

            • mipomersen

              mipomersen, phenytoin. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Both drugs have potential to increase hepatic enzymes; monitor LFTs.

            • mirtazapine

              phenytoin will decrease the level or effect of mirtazapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • mitoxantrone

              mitoxantrone decreases levels of phenytoin by increasing metabolism. Use Caution/Monitor.

            • modafinil

              phenytoin will decrease the level or effect of modafinil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • moxifloxacin

              moxifloxacin decreases effects of phenytoin by unknown mechanism. Use Caution/Monitor. There are also case reports of quinolones increasing phenytoin levels.

            • nateglinide

              nateglinide will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

              phenytoin will decrease the level or effect of nateglinide by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor. Inducers of CYP2C9 decrease levels of nateglinide by increasing its metabolism. Coadministration may reduce nateglinide's hypoglycemic action.

            • nefazodone

              phenytoin will decrease the level or effect of nefazodone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • nelfinavir

              phenytoin will decrease the level or effect of nelfinavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              phenytoin will decrease the level or effect of nelfinavir by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • neomycin PO

              phenytoin will decrease the level or effect of neomycin PO by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • nevirapine

              phenytoin will decrease the level or effect of nevirapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • nicardipine

              phenytoin will decrease the level or effect of nicardipine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • nilotinib

              nilotinib will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor. Avoid concomitant use of phenytoin with nilotinib.

              phenytoin will decrease the level or effect of nilotinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              phenytoin will decrease the level or effect of nilotinib by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. A reduction in therapeutic effectiveness of nilotinib may occur. Concomitant use of phenytoin with lapatinib, nilotinib, lapatinib, or pazopanib should be avoided.

            • nilutamide

              nilutamide will increase the level or effect of phenytoin by decreasing metabolism. Use Caution/Monitor.

            • nisoldipine

              phenytoin will decrease the level or effect of nisoldipine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • nitisinone

              nitisinone will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor. Nitisinone inhibits CYP2C9. Caution if CYP2C9 substrate coadministered, particularly those with a narrow therapeutic index.

            • ofloxacin

              ofloxacin decreases effects of phenytoin by unknown mechanism. Use Caution/Monitor. There are also case reports of quinolones increasing phenytoin levels.

            • oliceridine

              phenytoin will decrease the level or effect of oliceridine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. If coadministration with a CYP3A4 inducer is necessary, consider increasing oliceridine dose until stable drug effects are achieved; monitor for signs of opioid withdrawal. If inducer is discontinued, consider oliceridine dosage reduction and monitor for signs of respiratory depression.

            • omeprazole

              omeprazole will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

              phenytoin will decrease the level or effect of omeprazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • ondansetron

              phenytoin will decrease the level or effect of ondansetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. No dosage adjustment for ondansetron is recommended for patients on these drugs.

            • oritavancin

              oritavancin will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor. Oritavancin is a weak CYP2C9 inhibitor; caution if coadministered with CYP2C9 substrates that have a narrow therapeutic index

            • orlistat

              orlistat decreases levels of phenytoin by inhibition of GI absorption. Applies only to oral form of both agents. Modify Therapy/Monitor Closely. Risk of convulsions.

            • osilodrostat

              phenytoin will decrease the level or effect of osilodrostat by Other (see comment). Modify Therapy/Monitor Closely. Osilodrostat is a CYP3A4 and CYP2B6 subtrate. Monitor cortisol concentration and patient?s signs and symptoms during coadministration and discontinuation with strong CYP3A4 and/or CYP2B6 inducers. Adjust dose of osilodrostat if necessary.

            • ospemifene

              phenytoin decreases levels of ospemifene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              phenytoin decreases levels of ospemifene by affecting hepatic enzyme CYP2C19 metabolism. Use Caution/Monitor.

              phenytoin decreases levels of ospemifene by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

              phenytoin, ospemifene. Either increases levels of the other by plasma protein binding competition. Modify Therapy/Monitor Closely.

            • oxaliplatin

              oxaliplatin decreases levels of phenytoin by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              oxaliplatin decreases levels of phenytoin by increasing metabolism. Use Caution/Monitor.

              oxaliplatin will decrease the level or effect of phenytoin by unknown mechanism. Use Caution/Monitor. Monitor phenytoin concentrations/effects during treatment with oxaliplatin. Adjust phenytoin/fosphenytoin dose as necessary to maintain concentrations in the desired range.

            • oxcarbazepine

              oxcarbazepine increases levels of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor. Oxcarbazepine increases levels of phenytoin at doses >1200 mg/day; monitor phenytoin levels during oxcarbazepine titration period and dosage modification; may require a decrease in phenytoin dose.

            • oxycodone

              phenytoin decreases levels of oxycodone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • paclitaxel

              paclitaxel decreases levels of phenytoin by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              paclitaxel decreases levels of phenytoin by increasing metabolism. Use Caution/Monitor.

              phenytoin will decrease the level or effect of paclitaxel by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              phenytoin will decrease the level or effect of paclitaxel by Other (see comment). Use Caution/Monitor. Paclitaxel levels/efficacy may decrease when coadministered with CYP2C8 inducers

            • paclitaxel protein bound

              paclitaxel protein bound decreases levels of phenytoin by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              paclitaxel protein bound decreases levels of phenytoin by increasing metabolism. Use Caution/Monitor.

              phenytoin will decrease the level or effect of paclitaxel protein bound by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              phenytoin will decrease the level or effect of paclitaxel protein bound by Other (see comment). Use Caution/Monitor. Paclitaxel levels/efficacy may decrease when coadministered with CYP2C8 inducers

            • paliperidone

              phenytoin will decrease the level or effect of paliperidone by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • pancuronium

              phenytoin decreases effects of pancuronium by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Monitor closely for more rapid recovery from neuromuscular blockade than expected; infusion rate requirements may be higher.

            • pantoprazole

              phenytoin will decrease the level or effect of pantoprazole by affecting hepatic enzyme CYP2C19 metabolism. Use Caution/Monitor.

            • paricalcitol

              phenytoin will decrease the level or effect of paricalcitol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • paromomycin

              phenytoin will decrease the level or effect of paromomycin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • pazopanib

              phenytoin will decrease the level or effect of pazopanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • peginterferon alfa 2b

              peginterferon alfa 2b decreases levels of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor. When patients are administered peginterferon alpha-2b with CYP2C9 substrates, the therapeutic effect of these drugs may be altered. .

            • pentobarbital

              pentobarbital will decrease the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            • phenindione

              phenindione increases levels of phenytoin by unknown mechanism. Use Caution/Monitor.

              phenytoin, phenindione. Other (see comment). Use Caution/Monitor. Comment: Hydantoin anticonvulsants increase anticoagulant effects at first, then decrease those effects with continued use (2+ wks). There are multiple mechanisms involved, including enzyme induction, plasma protein binding site competition, and additive effects on prothrombin time.

            • phenobarbital

              phenobarbital will decrease the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            • pimavanserin

              phenytoin will decrease the level or effect of pimavanserin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Avoid coadministration if possible. Monitor for reduced pimavanserin efficacy. An increase in pimavanserin dosage may be needed.

            • pitolisant

              phenytoin will decrease the level or effect of pitolisant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Pitolisant exposure is decreased by 50% if coadministered with strong CYP3A4 inducers. For patients stable on pitolisant 8.9 mg/day or 17.8 mg/day, double the pitolisant dose (ie, 17.8 mg or 35.6 mg, respectively) over 7 days. If the strong CYP3A4 inducer is discontinued, reduce pitolisant dosage by half.

            • polatuzumab vedotin

              phenytoin will decrease the level or effect of polatuzumab vedotin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Polatuzumab undergoes catabolism to small peptides, amino acids, monomethyl auristatin E (MMAE), and unconjugated MMAE-related catabolites. MMAE is a CYP3A4 substrate. Coadministration of polatuzumab vedotin with a strong CYP3A4 inducer may decrease unconjugated MMAE AUC.

            • posaconazole

              phenytoin decreases levels of posaconazole by increasing metabolism. Use Caution/Monitor.

            • prednisolone

              phenytoin will decrease the level or effect of prednisolone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              phenytoin will decrease the level or effect of prednisolone by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • prednisone

              phenytoin will decrease the level or effect of prednisone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              phenytoin will decrease the level or effect of prednisone by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • primidone

              primidone will decrease the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

              phenytoin increases effects of primidone by increasing metabolism. Use Caution/Monitor. Phenytoin enhances the conversion of primidone to phenobarbital.

            • protamine

              protamine increases levels of phenytoin by unknown mechanism. Use Caution/Monitor.

              phenytoin, protamine. Other (see comment). Use Caution/Monitor. Comment: Hydantoin anticonvulsants increase anticoagulant effects at first, then decrease those effects with continued use (2+ wks). There are multiple mechanisms involved, including enzyme induction, plasma protein binding site competition, and additive effects on prothrombin time.

            • quazepam

              phenytoin will decrease the level or effect of quazepam by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • quetiapine

              phenytoin will decrease the level or effect of quetiapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Increased doses of quetiapine may be required to maintain control of psychotic symptoms in patients receiving quetiapine and phenytoin. Caution should be taken if phenytoin is withdrawn from therapy or replaced with a non-inducing anticonvulsant.

            • quinidine

              phenytoin will decrease the level or effect of quinidine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              phenytoin decreases levels of quinidine by increasing metabolism. Use Caution/Monitor.

            • quinine

              phenytoin will decrease the level or effect of quinine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Use caution when prescribing phenytoin and quinine together due to a decrease in quinine plasma concentrations and potential lack of efficacy.

            • repaglinide

              phenytoin will decrease the level or effect of repaglinide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • rifampin

              rifampin will decrease the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            • rifapentine

              rifapentine will decrease the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            • riociguat

              phenytoin will decrease the level or effect of riociguat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Data not available for dose adjustment

            • risperidone

              phenytoin will decrease the level or effect of risperidone by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • ritonavir

              phenytoin will decrease the level or effect of ritonavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              phenytoin will decrease the level or effect of ritonavir by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • rivaroxaban

              phenytoin decreases levels of rivaroxaban by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Avoid concomitant use of rivaroxaban with drugs that are combined P-gp and strong CYP3A4 inducers. Consider increasing the rivaroxaban dose if these drugs must be coadministered.

            • rocuronium

              phenytoin decreases effects of rocuronium by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Monitor closely for more rapid recovery from neuromuscular blockade than expected; infusion rate requirements may be higher.

            • rufinamide

              rufinamide increases levels of phenytoin by decreasing renal clearance. Use Caution/Monitor.

              phenytoin decreases levels of rufinamide by increasing metabolism. Use Caution/Monitor.

            • ruxolitinib

              phenytoin will decrease the level or effect of ruxolitinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • saquinavir

              phenytoin will decrease the level or effect of saquinavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Clinicians may want to consider using alternative medication to phenytoin in patients on saquinavir therapy. However, if it becomes necessary to give these agents concurrently, upward adjustments in saquinavir dosing may be needed to maintain antiviral effectiveness.

              phenytoin will decrease the level or effect of saquinavir by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • sarilumab

              sarilumab, phenytoin. Other (see comment). Use Caution/Monitor. Comment: Formation of CYP450 enzymes can be altered by increased levels of cytokines such as IL-6. Elevated IL-6 concentration may down-regulate CYP activity, such as in patients with RA, and, hence, increase drug levels compared with subjects without RA. Blockade of IL-6 signaling by IL-6 antagonists (eg, sarilumab) might reverse the inhibitory effect of IL-6 and restore CYP activity, leading to decreased drug concentrations. Caution when initiating or discontinuing sarilumab if coadministered with CYP450 substrates, especially those with a narrow therapeutic index.

            • secobarbital

              secobarbital will decrease the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            • secukinumab

              secukinumab, phenytoin. Other (see comment). Use Caution/Monitor. Comment: Formation of CYP450 enzymes can be altered by increased levels of certain cytokines during chronic inflammation; thus, secukinumab could normalize the formation of CYP450 enzymes. Upon initiation or discontinuation of secukinumab in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for therapeutic effect.

            • selexipag

              phenytoin will decrease the level or effect of selexipag by increasing metabolism. Modify Therapy/Monitor Closely. Increase selexipag dose (up to 2-fold) if coadministered with strong CYP2C8 inducers.

            • sertraline

              sertraline increases levels of phenytoin by decreasing metabolism. Use Caution/Monitor.

            • sevelamer

              sevelamer decreases levels of phenytoin by increasing elimination. Use Caution/Monitor.

            • silodosin

              phenytoin will decrease the level or effect of silodosin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • sirolimus

              phenytoin will decrease the level or effect of sirolimus by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • sodium sulfate/?magnesium sulfate/potassium chloride

              sodium sulfate/?magnesium sulfate/potassium chloride increases toxicity of phenytoin by Other (see comment). Use Caution/Monitor. Comment: Coadministration with medications that cause fluid and electrolyte abnormalities may increase the risk of adverse events of seizure, arrhythmias, and renal impairment.

            • sodium sulfate/potassium sulfate/magnesium sulfate

              sodium sulfate/potassium sulfate/magnesium sulfate increases toxicity of phenytoin by Other (see comment). Use Caution/Monitor. Comment: Coadministration with medications that cause fluid and electrolyte abnormalities may increase the risk of adverse events of seizure, arrhythmias, and renal impairment.

            • solifenacin

              phenytoin will decrease the level or effect of solifenacin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • sorafenib

              phenytoin decreases levels of sorafenib by increasing metabolism. Use Caution/Monitor.

            • stiripentol

              stiripentol will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C19 metabolism. Modify Therapy/Monitor Closely. Consider reducing the dose of CYP2C19 substrates, if adverse reactions are experienced when administered concomitantly with stiripentol.

              stiripentol, phenytoin. Either increases effects of the other by sedation. Use Caution/Monitor. Concomitant use stiripentol with other CNS depressants, including alcohol, may increase the risk of sedation and somnolence.

            • streptomycin

              phenytoin will decrease the level or effect of streptomycin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • sufentanil SL

              phenytoin decreases effects of sufentanil SL by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Coadministration of CYP3A4 inducers may decrease sufentanil levels and efficacy, possibly precipitating withdrawal syndrome in patients who have developed physical dependence to sufentanil. Discontinuation of concomitantly used CYP3A4 inducers may increase sufentanil plasma concentration.

            • sulfamethoxazole

              sulfamethoxazole will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            • sunitinib

              phenytoin will decrease the level or effect of sunitinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • suvorexant

              phenytoin will decrease the level or effect of suvorexant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Strong CYP3A4 inducers may decrease suvorexant efficacy; if increased suvorexant dose required, do not exceed 20 mg/day

            • tacrolimus

              phenytoin will decrease the level or effect of tacrolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              phenytoin will decrease the level or effect of tacrolimus by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Tacrolimus dosage requirements may be greater when administered concurrently with phenytoin.

            • tadalafil

              phenytoin will decrease the level or effect of tadalafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Avoid combination in pulmonary HTN patients. For patients with ED, monitor response to tadalafil carefully because of potential for decreased effectiveness.

            • tamoxifen

              phenytoin will decrease the level or effect of tamoxifen by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • tasimelteon

              phenytoin will decrease the level or effect of tasimelteon by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Avoid coadministration of tasimelteon with strong CYP3A4 inducers

            • tecovirimat

              tecovirimat will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C19 metabolism. Use Caution/Monitor. Tecovirimat is a weak inhibitor of CYP2C8 and CYP2C19. Monitor for adverse effects if coadministered with sensitive substrates of these enzymes.

            • teduglutide

              teduglutide increases levels of phenytoin by Other (see comment). Use Caution/Monitor. Comment: Teduglutide may increase absorption of concomitant PO medications; caution with with drugs requiring titration or those with a narrow therapeutic index; dose adjustment may be necessary.

            • temsirolimus

              phenytoin will decrease the level or effect of temsirolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • teniposide

              phenytoin will decrease the level or effect of teniposide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • terbinafine

              phenytoin will decrease the level or effect of terbinafine by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

              phenytoin will decrease the level or effect of terbinafine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • tesamorelin

              tesamorelin will decrease the level or effect of phenytoin by altering metabolism. Modify Therapy/Monitor Closely. Monitor levels

            • tetracaine

              tetracaine, phenytoin. Other (see comment). Use Caution/Monitor. Comment: Monitor for signs of methemoglobinemia when methemoglobin-inducing drugs are coadministered.

            • theophylline

              phenytoin will decrease the level or effect of theophylline by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • tiagabine

              phenytoin will decrease the level or effect of tiagabine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • ticagrelor

              phenytoin decreases levels of ticagrelor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Avoid use of ticagrelor with potent CYP3A inducers.

            • ticlopidine

              ticlopidine will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            • tinidazole

              tinidazole will increase the level or effect of phenytoin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. During concurrent therapy, consider monitoring clinical response to tinidazole and signs/symptoms of phentyoin toxicity (eg, nystagmus, ataxis, dysarthria, and lethargy)

              phenytoin will decrease the level or effect of tinidazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • tipranavir

              phenytoin will decrease the level or effect of tipranavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • tobramycin

              phenytoin will decrease the level or effect of tobramycin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • tofacitinib

              phenytoin will decrease the level or effect of tofacitinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Loss of, or decreased response to tofacitinib may occur when coadministered with potent CYP3A4 inducers

            • tolterodine

              phenytoin will decrease the level or effect of tolterodine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • tolvaptan

              phenytoin will decrease the level or effect of tolvaptan by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • topiramate

              phenytoin decreases levels of topiramate by increasing metabolism. Use Caution/Monitor.

            • toremifene

              phenytoin decreases levels of toremifene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. CYP3A4 inducers increase rate of toremifene metabolism, lowering the steady-state concentration in serum.

            • tramadol

              phenytoin will decrease the level or effect of tramadol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Decreased AUC of tramadol and the active metabolite (O-desmethyltramadol) when coadministered with strong CYP3A4 and CYP2B6 inducers

            • treosulfan

              treosulfan decreases levels of phenytoin by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              treosulfan decreases levels of phenytoin by increasing metabolism. Use Caution/Monitor.

            • triamcinolone acetonide injectable suspension

              phenytoin will decrease the level or effect of triamcinolone acetonide injectable suspension by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • triazolam

              phenytoin will decrease the level or effect of triazolam by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • triclabendazole

              triclabendazole will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C19 metabolism. Use Caution/Monitor. If plasma concentrations of the CYP2C19 substrates are elevated during triclabendazole, recheck plasma concentration of the CYP2C19 substrates after discontinuation of triclabendazole.

            • ustekinumab

              ustekinumab, phenytoin. Other (see comment). Use Caution/Monitor. Comment: Formation of CYP450 enzymes can be altered by increased levels of certain cytokines during chronic inflammation; thus, normalizing the formation of CYP450 enzymes. Upon initiation or discontinuation of ustekinumab in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for therapeutic effect.

            • valproic acid

              valproic acid will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            • vardenafil

              phenytoin will decrease the level or effect of vardenafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • vecuronium

              phenytoin decreases effects of vecuronium by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Monitor closely for more rapid recovery from neuromuscular blockade than expected; infusion rate requirements may be higher.

            • vemurafenib

              phenytoin decreases levels of vemurafenib by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • verapamil

              phenytoin will decrease the level or effect of verapamil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • vilanterol/fluticasone furoate inhaled

              phenytoin will decrease the level or effect of vilanterol/fluticasone furoate inhaled by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • vilazodone

              phenytoin decreases levels of vilazodone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Consider increasing vilazodone dose up to 2-fold (not to exceed 80 mg/day) when coadministered with strong CYP3A4 inducers for >14 days.

            • vinblastine

              vinblastine decreases levels of phenytoin by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              vinblastine decreases levels of phenytoin by increasing metabolism. Use Caution/Monitor.

              vinblastine will decrease the level or effect of phenytoin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Concurrent use of vinblastine and phenytoin may reduce phenytoin plasma levels and increase seizure activity.

            • vincristine

              vincristine decreases levels of phenytoin by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              vincristine decreases levels of phenytoin by increasing metabolism. Use Caution/Monitor.

            • vincristine liposomal

              vincristine liposomal decreases levels of phenytoin by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              vincristine liposomal decreases levels of phenytoin by increasing metabolism. Use Caution/Monitor.

            • vindesine

              vindesine decreases levels of phenytoin by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              vindesine decreases levels of phenytoin by increasing metabolism. Use Caution/Monitor.

            • vinorelbine

              vinorelbine decreases levels of phenytoin by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

              vinorelbine decreases levels of phenytoin by increasing metabolism. Use Caution/Monitor.

            • vitamin D

              phenytoin decreases effects of vitamin D by Other (see comment). Use Caution/Monitor. Comment: Vitamin D supplementation or dosage adjustments may be required in patients who are receiving chronic treatment with anticonvulsants.

            • voriconazole

              voriconazole will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

              phenytoin decreases levels of voriconazole by increasing metabolism. Modify Therapy/Monitor Closely.

            • vortioxetine

              phenytoin increases levels of vortioxetine by increasing metabolism. Modify Therapy/Monitor Closely. Consider increasing the vortioxetine dose when coadministered with strong CYP inducers for >14 days; not to exceed 3 times original vortioxetine dose.

            • warfarin

              phenytoin will decrease the level or effect of warfarin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              warfarin increases levels of phenytoin by unknown mechanism. Use Caution/Monitor.

              phenytoin, warfarin. Other (see comment). Use Caution/Monitor. Comment: Hydantoin anticonvulsants increase anticoagulant effects at first, then decrease those effects with continued use (2+ wks). There are multiple mechanisms involved, including enzyme induction, plasma protein binding site competition, and additive effects on prothrombin time.

            • zafirlukast

              zafirlukast will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            Minor (109)

            • acetaminophen

              phenytoin decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • acetaminophen IV

              phenytoin decreases levels of acetaminophen IV by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • acetaminophen rectal

              phenytoin decreases levels of acetaminophen rectal by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

            • acetazolamide

              acetazolamide, phenytoin. Mechanism: pharmacodynamic synergism. Minor/Significance Unknown. Increased risk of anticonvulsant induced osteomalacia.

            • alfentanil

              phenytoin will decrease the level or effect of alfentanil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • alfuzosin

              phenytoin will decrease the level or effect of alfuzosin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • alosetron

              phenytoin will decrease the level or effect of alosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • alvimopan

              phenytoin will decrease the level or effect of alvimopan by P-glycoprotein (MDR1) efflux transporter. Minor/Significance Unknown.

            • ambrisentan

              phenytoin will decrease the level or effect of ambrisentan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • armodafinil

              phenytoin will decrease the level or effect of armodafinil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              phenytoin will decrease the level or effect of armodafinil by P-glycoprotein (MDR1) efflux transporter. Minor/Significance Unknown.

            • atracurium

              phenytoin decreases effects of atracurium by pharmacodynamic antagonism. Minor/Significance Unknown.

            • auranofin

              auranofin increases levels of phenytoin by unspecified interaction mechanism. Minor/Significance Unknown.

            • biotin

              phenytoin decreases levels of biotin by unspecified interaction mechanism. Minor/Significance Unknown. Biotin supplementation may be necessary.

            • bosentan

              phenytoin will decrease the level or effect of bosentan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • brinzolamide

              brinzolamide, phenytoin. Mechanism: pharmacodynamic synergism. Minor/Significance Unknown. Increased risk of anticonvulsant induced osteomalacia.

            • carbamazepine

              carbamazepine, phenytoin. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Carbamazepine may increase or decrease phenytoin levels.

            • caspofungin

              phenytoin decreases levels of caspofungin by increasing metabolism. Minor/Significance Unknown.

            • cevimeline

              phenytoin will decrease the level or effect of cevimeline by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • clarithromycin

              phenytoin will decrease the level or effect of clarithromycin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • clopidogrel

              clopidogrel increases levels of phenytoin by decreasing metabolism. Minor/Significance Unknown.

            • cyanocobalamin

              phenytoin decreases levels of cyanocobalamin by inhibition of GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown.

            • dapsone

              phenytoin will decrease the level or effect of dapsone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • dexmethylphenidate

              dexmethylphenidate increases effects of phenytoin by decreasing metabolism. Minor/Significance Unknown.

            • diazoxide

              diazoxide decreases levels of phenytoin by increasing metabolism. Minor/Significance Unknown.

            • disulfiram

              disulfiram increases levels of phenytoin by decreasing metabolism. Minor/Significance Unknown.

            • docetaxel

              phenytoin will decrease the level or effect of docetaxel by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • donepezil

              phenytoin will decrease the level or effect of donepezil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • doxycycline

              phenytoin decreases levels of doxycycline by increasing metabolism. Minor/Significance Unknown.

            • dutasteride

              phenytoin will decrease the level or effect of dutasteride by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • eplerenone

              phenytoin will decrease the level or effect of eplerenone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • ethosuximide

              ethosuximide increases effects of phenytoin by pharmacodynamic synergism. Minor/Significance Unknown.

            • eucalyptus

              phenytoin will decrease the level or effect of eucalyptus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • ezogabine

              phenytoin decreases levels of ezogabine by Mechanism: unknown. Minor/Significance Unknown. Upon discontinuation of phenytoin, ezogabine clearance decreased by approximately 30%. Consider an increase in the ezogabine dose during concurrent use.

            • fexofenadine

              phenytoin will decrease the level or effect of fexofenadine by P-glycoprotein (MDR1) efflux transporter. Minor/Significance Unknown.

            • finasteride

              phenytoin will decrease the level or effect of finasteride by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • folic acid

              folic acid decreases levels of phenytoin by increasing metabolism. Minor/Significance Unknown. Large doses of folic acid (>10 mg/day).

            • furosemide

              phenytoin decreases levels of furosemide by inhibition of GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown.

            • galantamine

              phenytoin will decrease the level or effect of galantamine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • grapefruit

              grapefruit, phenytoin. Other (see comment). Minor/Significance Unknown. Comment: Grapefruit juice has been determined to have no effect on the pharmacokinetics of phenytoin.

            • immune globulin IM (IGIM)

              phenytoin, immune globulin IM (IGIM). Mechanism: unknown. Minor/Significance Unknown. Risk of hypersensitivity myocarditis.

            • immune globulin IV (IGIV)

              phenytoin, immune globulin IV (IGIV). Mechanism: unknown. Minor/Significance Unknown. Risk of hypersensitivity myocarditis.

            • immune globulin SC

              phenytoin, immune globulin SC. Mechanism: unknown. Minor/Significance Unknown. Risk of hypersensitivity myocarditis (theoretical interaction, based on IM and IV immune globulin).

            • influenza virus vaccine quadrivalent

              influenza virus vaccine quadrivalent, phenytoin. Mechanism: unknown. Minor/Significance Unknown. Vaccine administration may incr or decr phenytoin levels.

            • influenza virus vaccine quadrivalent, cell-cultured

              influenza virus vaccine quadrivalent, cell-cultured, phenytoin. Mechanism: unknown. Minor/Significance Unknown. Vaccine administration may incr or decr phenytoin levels.

            • influenza virus vaccine trivalent

              influenza virus vaccine trivalent, phenytoin. Mechanism: unknown. Minor/Significance Unknown. Vaccine administration may incr or decr phenytoin levels.

            • influenza virus vaccine trivalent, recombinant

              influenza virus vaccine trivalent, recombinant, phenytoin. Mechanism: unknown. Minor/Significance Unknown. Vaccine administration may incr or decr phenytoin levels.

            • isoniazid

              isoniazid increases levels of phenytoin by decreasing metabolism. Minor/Significance Unknown.

            • isradipine

              phenytoin will decrease the level or effect of isradipine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • itraconazole

              phenytoin will decrease the level or effect of itraconazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • ketoconazole

              phenytoin will decrease the level or effect of ketoconazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • L-methylfolate

              L-methylfolate decreases levels of phenytoin by increasing metabolism. Minor/Significance Unknown.

            • levocarnitine

              phenytoin decreases levels of levocarnitine by unspecified interaction mechanism. Minor/Significance Unknown.

            • levothyroxine

              phenytoin decreases levels of levothyroxine by increasing metabolism. Minor/Significance Unknown.

              phenytoin decreases levels of levothyroxine by plasma protein binding competition. Minor/Significance Unknown.

            • lily of the valley

              phenytoin, lily of the valley. Either increases toxicity of the other by pharmacodynamic synergism. Minor/Significance Unknown.

            • liothyronine

              phenytoin decreases levels of liothyronine by increasing metabolism. Minor/Significance Unknown.

              phenytoin decreases levels of liothyronine by plasma protein binding competition. Minor/Significance Unknown.

            • lithium

              phenytoin increases toxicity of lithium by unknown mechanism. Minor/Significance Unknown.

            • loratadine

              phenytoin will decrease the level or effect of loratadine by P-glycoprotein (MDR1) efflux transporter. Minor/Significance Unknown.

            • meperidine

              phenytoin decreases levels of meperidine by increasing metabolism. Minor/Significance Unknown.

            • methazolamide

              methazolamide, phenytoin. Mechanism: pharmacodynamic synergism. Minor/Significance Unknown. Increased risk of anticonvulsant induced osteomalacia.

            • methsuximide

              methsuximide increases effects of phenytoin by pharmacodynamic synergism. Minor/Significance Unknown.

            • montelukast

              phenytoin will decrease the level or effect of montelukast by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • mycophenolate

              mycophenolate increases effects of phenytoin by plasma protein binding competition. Minor/Significance Unknown. Mycophenolate decreased phenytoin protein binding from 90% to 87% in vitro. The clinical significance of this interaction is unknown. .

            • nimodipine

              phenytoin will decrease the level or effect of nimodipine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • nitrendipine

              phenytoin will decrease the level or effect of nitrendipine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • onabotulinumtoxinA

              phenytoin decreases effects of onabotulinumtoxinA by pharmacodynamic antagonism. Minor/Significance Unknown.

            • oxcarbazepine

              phenytoin decreases levels of oxcarbazepine by increasing metabolism. Minor/Significance Unknown.

            • oxybutynin

              phenytoin will decrease the level or effect of oxybutynin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • paclitaxel

              phenytoin will decrease the level or effect of paclitaxel by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • paclitaxel protein bound

              phenytoin will decrease the level or effect of paclitaxel protein bound by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • parecoxib

              phenytoin will decrease the level or effect of parecoxib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • phenobarbital

              phenobarbital decreases levels of phenytoin by increasing metabolism. Minor/Significance Unknown. Phenobarbital may occasionally not change or even increase (via competitive inhibition) phenytoin levels.

            • pimozide

              phenytoin will decrease the level or effect of pimozide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • pioglitazone

              phenytoin will decrease the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • propafenone

              phenytoin will decrease the level or effect of propafenone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • pyridoxine

              pyridoxine decreases levels of phenytoin by increasing metabolism. Minor/Significance Unknown. High dose of pyridoxine (vitamin B6), >=200 mg/day.

            • pyridoxine (Antidote)

              pyridoxine (Antidote) decreases levels of phenytoin by increasing metabolism. Minor/Significance Unknown. High dose of pyridoxine (vitamin B6), >=200 mg/day.

            • pyrimethamine

              pyrimethamine decreases effects of phenytoin by pharmacodynamic antagonism. Minor/Significance Unknown.

            • rabeprazole

              phenytoin will decrease the level or effect of rabeprazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown. Consider alternative for one of the interacting drugs

            • ramelteon

              phenytoin will decrease the level or effect of ramelteon by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • rapacuronium

              phenytoin decreases effects of rapacuronium by pharmacodynamic antagonism. Minor/Significance Unknown.

            • rifabutin

              rifabutin decreases levels of phenytoin by increasing metabolism. Minor/Significance Unknown.

            • sage

              sage decreases effects of phenytoin by pharmacodynamic antagonism. Minor/Significance Unknown. Theoretical interaction; some species of sage may cause convulsions.

            • saxagliptin

              phenytoin will decrease the level or effect of saxagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • succinylcholine

              phenytoin decreases effects of succinylcholine by pharmacodynamic antagonism. Minor/Significance Unknown.

            • sucralfate

              sucralfate decreases levels of phenytoin by inhibition of GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown.

            • sufentanil

              phenytoin will decrease the level or effect of sufentanil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • sulfadiazine

              sulfadiazine increases levels of phenytoin by decreasing metabolism. Minor/Significance Unknown.

            • sulfamethoxazole

              sulfamethoxazole increases levels of phenytoin by decreasing metabolism. Minor/Significance Unknown.

            • sulfisoxazole

              sulfisoxazole increases levels of phenytoin by decreasing metabolism. Minor/Significance Unknown.

            • thyroid desiccated

              phenytoin decreases levels of thyroid desiccated by increasing metabolism. Minor/Significance Unknown.

              phenytoin decreases levels of thyroid desiccated by plasma protein binding competition. Minor/Significance Unknown.

            • tiagabine

              phenytoin decreases levels of tiagabine by increasing metabolism. Minor/Significance Unknown.

            • tibolone

              phenytoin decreases levels of tibolone by increasing metabolism. Minor/Significance Unknown. Theoretical interaction.

            • tolazamide

              tolazamide increases levels of phenytoin by plasma protein binding competition. Minor/Significance Unknown.

            • tolbutamide

              tolbutamide increases levels of phenytoin by plasma protein binding competition. Minor/Significance Unknown.

              phenytoin decreases effects of tolbutamide by pharmacodynamic antagonism. Minor/Significance Unknown.

            • topiramate

              topiramate increases levels of phenytoin by decreasing metabolism. Minor/Significance Unknown.

            • toremifene

              phenytoin decreases levels of toremifene by increasing metabolism. Minor/Significance Unknown.

            • trazodone

              trazodone increases levels of phenytoin by unspecified interaction mechanism. Minor/Significance Unknown.

            • typhoid polysaccharide vaccine

              phenytoin decreases levels of typhoid polysaccharide vaccine by increasing metabolism. Minor/Significance Unknown.

            • typhoid vaccine live

              phenytoin decreases levels of typhoid vaccine live by increasing metabolism. Minor/Significance Unknown.

            • valproic acid

              valproic acid, phenytoin. Mechanism: plasma protein binding competition. Minor/Significance Unknown. Valproic acid may increase or decrease phenytoin levels.

              phenytoin decreases levels of valproic acid by increasing metabolism. Minor/Significance Unknown.

            • vigabatrin

              vigabatrin decreases levels of phenytoin by unknown mechanism. Minor/Significance Unknown.

            • vinblastine

              phenytoin will decrease the level or effect of vinblastine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              phenytoin will decrease the level or effect of vinblastine by P-glycoprotein (MDR1) efflux transporter. Minor/Significance Unknown. Phenytoin may be less likely to interact with vinblastine. Careful monitoring of patients for seizure activity is recommended, as is monitoring of plasma phenytoin levels.

            • vincristine

              phenytoin will decrease the level or effect of vincristine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              phenytoin will decrease the level or effect of vincristine by P-glycoprotein (MDR1) efflux transporter. Minor/Significance Unknown. Plasma concentrations and therapeutic effect of Phenytoin may be reduced by Vincristine. Frequency of seizures may be increased.

            • vincristine liposomal

              phenytoin will decrease the level or effect of vincristine liposomal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              phenytoin will decrease the level or effect of vincristine liposomal by P-glycoprotein (MDR1) efflux transporter. Minor/Significance Unknown. Plasma concentrations and therapeutic effect of Phenytoin may be reduced by Vincristine. Frequency of seizures may be increased.

            • vinorelbine

              phenytoin will decrease the level or effect of vinorelbine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • zaleplon

              phenytoin will decrease the level or effect of zaleplon by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • ziprasidone

              phenytoin will decrease the level or effect of ziprasidone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • zolpidem

              phenytoin will decrease the level or effect of zolpidem by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • zonisamide

              phenytoin will decrease the level or effect of zonisamide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

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            Adverse Effects

            Frequency Not Defined

            Drowsiness

            Fatigue

            Ataxia

            Irritability

            Headache

            Restlessness

            Slurred speech

            Nervousness

            Nystagmus

            Dizziness

            Vertigo

            Dysarthria

            Paresthesia

            Rash

            Pruritus

            Gingival hyperplasia (pediatric patients)

            Ataxia

            Paradoxical seizure

            Drug withdrawal seizure

            Diplopia

            Psychosis (high dose)

            Toxic amblyopia

            Encephalopathy

            AV conduction disorder

            Ventricular fibrillation

            Nausea

            Vomiting

            Constipation

            Diarrhea

            Megaloblastic (folate-deficiency) anemia

            Hypocalcemia

            Hepatotoxicity

            Hypertrichosis

            Lymphadenopathy

            Purple glove syndrome

            Rash

            Allergic reactions in the form of rash or, rarely, more serious forms (drug reaction with eosinophilia and systemic symptoms, or DRESS) or anaphylaxis

            Purpuric rash

            Toxic epidermal necrolysis

            Bullous, exfoliative, or purpuric dermatitis

            Coarsening of facial features

            Periarteritis nodosa

            Immunoglobulin abnormalities

            Altered taste sensation, including metallic taste

            Peyronie disease

            IV >50 mg/min

            • CNS depression
            • Cardiovascular collapse
            • Hypotension

            Rare

            • Dyskinesia
            • Ophthalmoplegia
            • Nephrotoxicity
            • Stevens-Johnson syndrome
            • Lupus erythematosus
            • Rickets
            • Osteomalacia

            Postmarketing Reports

            Cerebellar atrophy

            Angioedema

            Generalized exanthematous pustulosis

            Urticaria

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            Warnings

            Black Box Warnings

            Cardiovascular risk associated with rapid infusion rates

            • Risk of hypotension and arrhythmias with infusion rates that exceed 50 mg/min in adults and 1-3 mg/kg/min (or 50 mg/min, whichever is slower) for pediatric patients
            • Careful cardiac monitoring is needed during and after IV administration
            • These events have also been reported at or below 50 mg/min
            • Reduce infusion rate or discontinuation may be needed

            Contraindications

            Hypersensitivity

            Sinus bradycardia

            Sinoatrial block

            Second and third degree A-V block

            Adams-Stokes syndrome

            Concurrent use with delavirdine

            History of prior acute hepatotoxicity attributable to phenytoin

            Cautions

            Erratically absorbed when administered IM, so this route should be used as a last resort

            ONLY extended-release capsules should be used for once-daily dosing regimens

            Decreased bone mineral density reported with chronic use

            Rapid intravenous administration increases the risk of adverse cardiovascular reactions, including severe hypotension and cardiac arrhythmias; in pediatric patients, administer the drug at a rate not exceeding 1 to 3 mg/kg/min or 50 mg per minute, whichever is slower; although risk of cardiovascular toxicity increases with infusion rates above recommended infusion rate, these events have also been reported at or below recommended infusion rate

            May cause fetal harm when administered to a pregnant woman

            Phenytoin induces hepatic metabolizing enzymes, which may enhance metabolism of vitamin D and decrease vitamin D levels, leading to vitamin D deficiency, hypocalcemia, and hypophosphatemia; consideration should be given to screening with bone-related laboratory and radiological tests as appropriate and initiating treatment plans according to established guidelines

            Use caution in cardiovascular disease, hypoalbuminemia, hepatic impairment, hypothyroidism, or seizures; because fraction of unbound phenytoin is increased in patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of phenytoin serum levels should be based on the unbound fraction in those patients

            Associated with exacerbation of porphyria; exercise caution when used in patients with this disease

            Extensively bound to serum plasma proteins and is prone to competitive displacement

            Acute alcoholic intake may increase phenytoin serum levels, while chronic alcoholic use may decrease serum levels

            Risk of hypotension and arrhythmias with infusion rates that exceed 50 mg/min in adults and 1-3 mg/kg/min (or 50 mg/min, whichever is slower) for pediatric patients

            Hematologic effects reported with use including agranulocytosis, leukopenia, pancytopenia, neutropenia, thrombocytopenia, and anemias

            Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes

            Increased risk of suicidal thoughts or behavior reported

            May render OCPs ineffective because of induction of hepatic metabolism

            Risk of gingival hyperplasia

            Local toxicity (purple glove syndrome) that includes edema, discoloration, and pain distal to the site of injection has been reported following peripheral IV injection; may or may not be associated with extravasation; this syndrome may not develop for several days after injection

            IV infusion not recommended by many due to poor solubility and risk of crystal formation; others state it is doable with right solvent and concentration

            Good for automatic and reentrant arrhythmias, not PSVT's

            Phenytoin was listed by the FDA as one of the drugs to monitor after having identified potential signs of serious risks or new safety information in the agency's Adverse Event Reporting System (AERS) database during the last 3 months of 2011

            Drug interactions resulting in decreased effectiveness of nondepolarizing neuromuscular blocking agents have been reported

            The FDA has not suggested that clinicians stop prescribing any drugs on the watch list or that patients stop taking them; it has, however, advised that patients with questions about watch-list drugs discuss them with their clinician

            Antiepileptic drugs should not be abruptly discontinued because of the possibility of increased seizure frequency, including status epilepticus

            Hyperglycemia, resulting from drug's inhibitory effect on insulin release reported; phenytoin may also raise serum glucose level in patients diabetes mellitus; use caution

            Not indicated for seizures resulting from hypoglycemia or other metabolic causes; appropriate diagnostic procedures should be performed as indicated

            Not effective for absence seizures; if tonic-clonic and absence seizures present, combined drug therapy needed

            Sustained serum levels of phenytoin above optimal range may produce confusional states referred to as "delirium", "psychosis", or "encephalopathy", or rarely irreversible cerebellar dysfunction; accordingly, at the first sign of acute toxicity, plasma levels are recommended; dose reduction of phenytoin therapy is indicated if plasma levels are excessive; termination recommended if symptoms persist

            The lethal dose in pediatric patients is not known; in adults, the lethal dose is estimated to be 2- 5 g; initial symptoms include nystagmus, ataxia, and dysarthria; other signs are tremor, hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and vomiting; death is due to respiratory and circulatory depression

            Phenytoin may decrease serum concentrations of thyroid hormone (T4 and T3), sometimes with an accompanying increase in thyroid-stimulating hormone (TSH), but usually in absence of clinical hypothyroidism

            Cases of bradycardia and cardiac arrest reported, both at recommended phenytoin doses and levels, and in association with phenytoin toxicity; most reports of cardiac arrest occurred in patients with underlying cardiac disease

            Angioedema reported with phenytoin and fosphenytoin; discontinue immediately if symptoms of angioedema (eg, facial, perioral, or upper airway swelling) occur

            Metabolized by hepatic cytochrome P450 enzymes CYP2C9 and CYP2C19, and is particularly susceptible to inhibitory drug interactions because it is subject to saturable metabolism; if metabolism inhibited, may produce significant increases in circulating phenytoin concentrations and enhance the risk of drug toxicity

            Patients with decreased CYP2C9 function

            • Patients who are intermediate or poor metabolizers of CYP2C9 substrates (eg, *1/*3, *2/*2, *3/*3) may exhibit increased phenytoin serum concentrations compared to patients who are normal metabolizers (eg, *1/*1); patients who are known to be intermediate or poor metabolizers may ultimately require lower doses to maintain similar steady-state concentrations compared to normal metabolizers
            • In patients who are known to be carriers of the decreased function CYP2C9*2 or *3 alleles (intermediate and poor metabolizers), consider starting at the low end of the dosage range and monitor serum concentrations to maintain total phenytoin concentrations of 10 to 20 mcg/mL; if early signs of dose-related central nervous system (CNS) toxicity develop, serum concentrations should be checked immediately

            Severe cutaneous reactions

            • Can cause severe cutaneous adverse reactions (SCARs), which may be fatal
            • Reported reactions include toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), acute generalized exanthematous pustulosis (AGEP), and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
            • Onset is usually within 28 days, but can occur later
            • Discontinue at the first sign of a rash, unless the rash is clearly not drug-related
            • If signs or symptoms suggest a severe cutaneous adverse reaction, do not resume drug; consider alternant therapy
            • Studies in patients of Chinese ancestry have found a strong association between risk of developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA B gene in patients taking carbamazepine
            • Limited evidence suggests that HLA-B*1502 or CYP2C9*3 may also be a risk factor for the development of SJS/TEN in patients taking other antiepileptic drugs
            • DRESS
              • DRESS, also known as multiorgan hypersensitivity, reported in patients taking antiepileptic drugs, including phenytoin and fosphenytoin
              • Some of these events have been fatal or life-threatening
              • DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement (eg, hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection); eosinophilia is often present
              • Early manifestations of hypersensitivity (eg, fever or lymphadenopathy) may be present even though rash is not evident
              • If such signs or symptoms are present, evaluate patient immediately; discontinue drug if unable to confirm other etiology for the rash
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            Pregnancy & Lactation

            Pregnancy: Pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as phenytoin, during pregnancy is available; pregnant patients taking should enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling the toll free number 1-888-233-2334; it must be done by patients themselves; Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/

            An increased incidence of major malformations (such as orofacial clefts and cardiac defects) and abnormalities characteristic of fetal hydantoin syndrome (dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities [including microcephaly], and cognitive deficits) reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy

            An increase in seizure frequency may occur during pregnancy; periodic measurement of plasma phenytoin concentrations may be valuable to make appropriate dosage adjustments; postpartum restoration of original dosage will probably be indicated

            Consider vitamin K supplementation for 1 month before birth

            Lactation: Phenytoin is secreted in human milk; developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on breastfed infant from phenytoin or from underlying maternal condition

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Promotes Na+ efflux or decreases Na+ influx from membranes in motor cortex neurons; stabilizes neuronal membrane

            Slows conduction velocity

            Absorption

            Bioavailability: May vary between different manufacturers; dependent on formulation

            Onset: 1 week (PO); 2-24 hr (PO with loading dose); 0.5-1 hr (IV)

            Peak plasma time: 1.5-3 hr (immediate-release); 4-12 hr (extended-release)

            Distribution

            Protein bound: 95% (adults); 85% (infants); 80% (neonates)

            Vd: 0.6-0.7 L/kg (adults); 0.7 L/kg (children); 0.7-0.8 L/kg (infants); 0.8-0.9 L/kg (full-term neonate); 1-1.2 L/kg (premature neonate)

            Metabolism

            Metabolized by hepatic P450 enzyme CYP2C9

            Metabolites: Inactive

            Enzymes induced: CYP3A4

            Elimination

            Half-life: 22 hr (PO); 10-15 hr (IV)

            Excretion: Urine

            Pharmacogenomics

            HLA variants

            • Patients with HLA-B*1502 with are more likely to have a severe dermatologic reaction (eg, toxic epidermal necrolysis, Stevens-Johnson syndrome) when taking phenytoin
            • This allele occurs almost exclusively in patients with ancestry across broad areas of Asia, including Han Chinese, Filipinos, Malaysians, South Asian Indians, and Thais

            Epoxide genotypes

            • Maternal epoxide (EPHX1) genotypes 113*H and 139*R are associated with risk of fetal hydantoin syndrome among pregnant women taking phenytoin
            • Increased levels of the reactive epoxide metabolites by either inhibiting the detoxification of these metabolites by epoxide hydrolase or by increasing conversion to epoxide metabolites by inducing CYP3A4, 2C9, or 2C19

            Genetic testing laboratories (for HLA variants)

            • Kashi Clinical Laboratories (www.kashilab.com)
            • LabCorp (http://www.labcorp.com/)
            • Specialty Laboratories (http://www.specialtylabs.com)
            • Quest (http://www.questdiagnostics.com)
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            Administration

            IV Incompatibilities

            Solution

            • D5/NS
            • D5W
            • LR
            • 1/2NS
            • NS(?)

            Additive

            • Amikacin
            • Bretylium
            • Dobutamine
            • Hydroxyzine
            • Insulin (regular)
            • Levorphanol, lidocaine, lincomycin
            • Meperidine, metaraminol, morphine sulfate
            • Nitroglycerin, norepinephrine
            • Pentobarbital, procaine
            • Streptomycin

            Syringe

            • Hydromorphone
            • Sufentanil

            Y-site

            • Ampho B cholesteryl sulfate, ciprofloxacin, clarithromycin, diltiazem, enalaprilat, fenoldopam, fentanyl, gatifloxacin, heparin, heparin/hydrocortisone, hydromorphone, linezolid, methadone, morphine sulfate, KCl, propofol, sufentanil, theophylline, vitamins B/C

            IV Compatibilities

            Additive

            • Verapamil

            Y-site

            • Esmolol
            • Famotidine
            • Fluconazole
            • Foscarnet
            • Tacrolimus

            IV Preparation

            Load IV in 250 mL NS; monitor BP

            Further dilution of IV infusion solution is controversial, and no consensus exists as to optimal concentration and length of stability

            Stability is concentration and pH dependent

            Based on limited clinical consensus, NS and LR are recommended diluents; dilutions of 1-10 mg/mL have been used and should be administered ASAP after preparation

            IV/IM Administration

            Administer slowly; no more than 50 mg/min in adults and no more than 1-3 mg/kg/min in pediatric patients

            IM: Although approved for IM use, IM administration is not recommended, due to erratic absorption and pain on injection; fosphenytoin may be considered

            IV: IV infusion not recommended

            Storage

            Store intact vials at room temperature; protect from freezing

            If refrigerated, ppt forms, but dissolves on standing at room temp; OK for use

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            Images

            BRAND FORM. UNIT PRICE PILL IMAGE
            Dilantin-125 oral
            -
            125 mg/5 mL suspension
            Dilantin Infatabs oral
            -
            50 mg chewable tablet
            phenytoin oral
            -
            50 mg chewable tablet
            phenytoin oral
            -
            125 mg/5 mL suspension
            phenytoin oral
            -
            100 mg/4 mL suspension
            phenytoin oral
            -
            50 mg chewable tablet
            phenytoin oral
            -
            125 mg/5 mL suspension
            phenytoin oral
            -
            100 mg/4 mL suspension
            phenytoin oral
            -
            125 mg/5 mL suspension
            phenytoin oral
            -
            50 mg chewable tablet

            Copyright © 2010 First DataBank, Inc.

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            Patient Handout

            Patient Education
            phenytoin oral

            PHENYTOIN CHEWABLE TABLET - ORAL

            (FEN-i-toyn)

            COMMON BRAND NAME(S): Dilantin

            USES: Phenytoin is used to prevent and control seizures (also called an anticonvulsant or antiepileptic drug). It works by reducing the spread of seizure activity in the brain.

            HOW TO USE: Read the Medication Guide provided by your pharmacist before you start taking phenytoin and each time you get a refill. If you have any questions, ask your doctor or pharmacist.The tablets may be chewed thoroughly before swallowing or swallowed whole.Take this medication by mouth usually 2 or 3 times a day, or as directed by your doctor. This product is not recommended for use once a day. You may take it with food if stomach upset occurs. Take this medication with a full glass (8 ounces or 240 milliliters) of water unless your doctor directs you otherwise.Use this medication regularly in order to get the most benefit from it. It is important to take all doses on time to keep the amount of medicine in your body at a constant level. Remember to use it at the same times each day. Dosage is based on your medical condition and response to therapy.Antacids and nutritional tube-feeding (enteral) products may decrease the absorption of phenytoin. Do not take these products at the same time as your phenytoin dose. Separate liquid nutritional products at least 1 hour before and 1 hour after your phenytoin dose, or as directed by your doctor.Do not stop taking this medication without consulting your doctor. Seizures may become worse when the drug is suddenly stopped. Your dose may need to be gradually decreased.Inform your doctor if your condition does not improve or worsens.

            SIDE EFFECTS: Headache, nausea, vomiting, constipation, dizziness, feeling of spinning, drowsiness, trouble sleeping, or nervousness may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.Phenytoin may cause swelling and bleeding of the gums. Massage your gums and brush and floss your teeth regularly to minimize this problem. See your dentist regularly.Remember that this medication has been prescribed because your doctor has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.Tell your doctor right away if you have any serious side effects, including: slow heartbeat, unusual eye movements, loss of coordination, trouble speaking, confusion, muscle twitching, double or blurred vision, tingling of the hands/feet, facial changes (e.g., swollen lips, butterfly-shaped rash around the nose/cheeks), excessive hair growth, increased thirst or urination, unusual tiredness, bone or joint pain, easily broken bones.A small number of people who take anticonvulsants for any condition (such as seizure, bipolar disorder, pain) may experience depression, suicidal thoughts/attempts, or other mental/mood problems. Tell your doctor right away if you or your family/caregiver notice any unusual/sudden changes in your mood, thoughts, or behavior including signs of depression, suicidal thoughts/attempts, thoughts about harming yourself.For males, in the very unlikely event you have a painful or prolonged erection lasting 4 or more hours, stop using this drug and seek immediate medical attention, or permanent problems could occur.Get medical help right away if any of these rare but very serious side effects occur: uncontrolled muscle movements, signs of liver problems (such as nausea/vomiting that doesn't stop, stomach/abdominal pain, yellowing eyes/skin, dark urine), easy bruising/bleeding.A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: fever, swollen lymph nodes, rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.In the US -Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

            PRECAUTIONS: Before taking phenytoin, tell your doctor or pharmacist if you are allergic to it; or to other anti-seizure medications (such as carbamazepine, ethosuximide, ethotoin, fosphenytoin, oxcarbazepine, phenobarbital, primidone, trimethadione); or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.Before using this medication, tell your doctor or pharmacist your medical history, especially of: alcohol use, certain blood conditions (porphyria), diabetes, liver disease (including liver disease caused by past phenytoin use), lupus, folate or vitamin B-12 deficiency (megaloblastic anemia).This drug may make you dizzy or drowsy. Alcohol or marijuana (cannabis) can make you more dizzy or drowsy. Do not drive, use machinery, or do anything that needs alertness until you can do it safely. Limit alcoholic beverages. Talk to your doctor if you are using marijuana (cannabis). Alcohol may also affect your blood levels of this drug.Tell your doctor you are using phenytoin prior to surgery or any procedure that makes you unable to take it by mouth.If you have diabetes, this drug may increase your blood sugar levels. Check your blood (or urine) glucose level frequently, as directed by your doctor. Promptly report any abnormal results as directed. Your medicine, exercise plan, or diet may need to be adjusted.Vitamin D supplements may be necessary to prevent weakening of the bones (osteomalacia). Discuss this with your doctor.During pregnancy, this medication should be used only when clearly needed. It may harm an unborn baby. However, since untreated seizures are a serious condition that can harm both a pregnant woman and her unborn baby, do not stop taking this medication unless directed by your doctor. If you are planning pregnancy, become pregnant, or think you may be pregnant, immediately talk to your doctor about the benefits and risks of using this medication during pregnancy. Since birth control pills, patches, implants, and injections may not work if taken with this medication (see also Drug Interactions section), discuss reliable forms of birth control with your doctor.Phenytoin passes into breast milk. Consult your doctor before breast-feeding.

            DRUG INTERACTIONS: See also How to Use section.Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.Some products that may interact with this drug include: azapropazone, colesevelam, darunavir, delavirdine, dofetilide, etravirine, molindone, nisoldipine, orlistat, pyridoxine (vitamin B6), rilpivirine, sucralfate, telithromycin.Other medications can affect the removal of phenytoin from your body, which may affect how phenytoin works. Examples include amiodarone, azole antifungals (such as itraconazole), macrolide antibiotics (such as erythromycin), estrogens, isoniazid, rifamycins (such as rifabutin), St. John's wort, other anti-seizure medicines (such as valproic acid), among others.Phenytoin can speed up the removal of other medications from your body, which may affect how they work. Examples of affected drugs include atazanavir, some drugs to treat cancer (such as imatinib, irinotecan), cobicistat, corticosteroids (such as prednisone), doravirine, felodipine, quetiapine, quinidine, suvorexant, theophylline, vitamin D, among others.This medication may decrease the effectiveness of hormonal birth control such as pills, patch, or ring. This could cause pregnancy. Discuss with your doctor or pharmacist if you should use additional reliable birth control methods while using this medication. Also tell your doctor if you have any new spotting or breakthrough bleeding, because these may be signs that your birth control is not working well.This product can affect the results of certain lab tests. Make sure laboratory personnel and your doctors know you use this drug.

            OVERDOSE: If someone has overdosed and has serious symptoms such as passing out or trouble breathing, call 911. Otherwise, call a poison control center right away. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: severe mental/mood changes, severe drowsiness, loss of consciousness, slowed breathing.

            NOTES: Do not share this medication with others.Laboratory and/or medical tests (e.g., phenytoin blood levels, liver function tests) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.Do not change from one brand of this product to another, or to another dose form of this drug (e.g., capsules) without consulting your doctor or pharmacist. Your dosage may have to be adjusted.

            MISSED DOSE: If you miss a dose, take it as soon as you remember unless it is within 4 hours of the next dose. In that case, skip the missed dose. Take your next dose at the regular time. Check with your doctor if you miss doses for more than 2 days in a row. Do not double the dose to catch up.

            STORAGE: Store at room temperature away from light and moisture. Do not store in the bathroom. Keep all medications away from children and pets.Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company.

            MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-888-633-4298 (US) or 1-800-668-1507 (Canada).

            Information last revised August 2021. Copyright(c) 2021 First Databank, Inc.

            IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

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            Formulary

            FormularyPatient Discounts

            Adding plans allows you to compare formulary status to other drugs in the same class.

            To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

            Adding plans allows you to:

            • View the formulary and any restrictions for each plan.
            • Manage and view all your plans together – even plans in different states.
            • Compare formulary status to other drugs in the same class.
            • Access your plan list on any device – mobile or desktop.

            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.