phenytoin (Rx)

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

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

Contraindicated (31)

• 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.

• mavacamten

  phenytoin will decrease the level or effect of mavacamten by affecting hepatic enzyme CYP2C19 metabolism. Contraindicated.
  
  phenytoin will decrease the level or effect of mavacamten by affecting hepatic/intestinal enzyme CYP3A4 metabolism. 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

• nirmatrelvir

  phenytoin will decrease the level or effect of nirmatrelvir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir, a CYP3A4 substrate, is contraindicated with strong CYP3A4 inducers. Significantly reduced nirmatrelvir plasma concentrations may be associated with potential for loss of virologic response and possible resistance. Do not initiate nirmatrelvir/ritonavir immediately after discontinuing a strong 3A4 inducer owing to time needed for systemic clearance of the inducer.

• nirmatrelvir/ritonavir

  phenytoin will decrease the level or effect of nirmatrelvir/ritonavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir, a CYP3A4 substrate, is contraindicated with strong CYP3A4 inducers. Significantly reduced nirmatrelvir plasma concentrations may be associated with potential for loss of virologic response and possible resistance. Do not initiate nirmatrelvir/ritonavir immediately after discontinuing a strong 3A4 inducer owing to time needed for systemic clearance of the inducer.

• ombitasvir/paritaprevir/ritonavir & dasabuvir (DSC)

  phenytoin will decrease the level or effect of ombitasvir/paritaprevir/ritonavir & dasabuvir (DSC) 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 (DSC) 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 (165)

• 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.

• abrocitinib

  phenytoin will decrease the level or effect of abrocitinib by increasing metabolism. Avoid or Use Alternate Drug. Abrocitinib is a CYP2C9 and CYP2C19 substrate. Drugs that are strong inducers of CYP2C19 or CYP2C9 decreases the combined exposure of abrocitinib and its active metabolites, resulting in loss of or reduced clinical response.

• 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.

• daridorexant

  phenytoin will decrease the level or effect of daridorexant 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.

• ganaxolone

  phenytoin will decrease the level or effect of ganaxolone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of ganaxolone with moderate or strong CYP3A4 inducers. If coadministration unavoidable, consider increasing ganaxolone dose; however, do not exceed maximum daily dose for weight.

• 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.

• lumateperone

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

• 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.

• ropeginterferon alfa 2b

  ropeginterferon alfa 2b and phenytoin both increase Other (see comment). Avoid or Use Alternate Drug. Narcotics, hypnotics or sedatives can produce additive neuropsychiatric side effects. Avoid use and monitor patients receiving the combination for effects of excessive CNS toxicity.

• 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.

• vonoprazan

  phenytoin will decrease the level or effect of vonoprazan 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 (339)

• 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.

• 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.

• atogepant

  phenytoin will decrease the level or effect of atogepant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Recommended atogepant dosage with concomitant use of strong or moderate CYP3A4 inducers is 30 mg or 60 mg qDay.

• 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.

• belumosudil

  phenytoin will decrease the level or effect of belumosudil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Increase belumosudil dosage to 200 mg PO BID when coadministered with strong CYP3A inducers.

• 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.

• 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.

• daridorexant

  phenytoin and daridorexant both increase sedation. Modify Therapy/Monitor Closely. Coadministration increases risk of CNS depression, which can lead to additive impairment of psychomotor performance and cause daytime impairment.

• 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.

• difelikefalin

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

• 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.

• levoketoconazole

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

• 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.

• methylphenidate transdermal

  methylphenidate transdermal will increase the level or effect of phenytoin by decreasing metabolism. Modify Therapy/Monitor Closely. Consider decreasing the dose of these drugs when given coadministered with methylphenidate. Monitor for drug toxiticities when initiating or discontinuing methylphenidate.

• 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.

• ruxolitinib topical

  phenytoin will decrease the level or effect of ruxolitinib topical 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 enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.

• zafirlukast

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

Minor (111)

• 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.

• levoketoconazole

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

• serdexmethylphenidate/dexmethylphenidate

  serdexmethylphenidate/dexmethylphenidate increases effects of phenytoin by decreasing 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.

• abemaciclib

  Serious - Use Alternative (1)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.

• abiraterone

  Monitor Closely (1)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.

• abrocitinib

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of abrocitinib by increasing metabolism. Avoid or Use Alternate Drug. Abrocitinib is a CYP2C9 and CYP2C19 substrate. Drugs that are strong inducers of CYP2C19 or CYP2C9 decreases the combined exposure of abrocitinib and its active metabolites, resulting in loss of or reduced clinical response.

• acalabrutinib

  Serious - Use Alternative (1)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.

• acetaminophen

  Minor (1)phenytoin decreases levels of acetaminophen by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

• acetaminophen IV

  Minor (1)phenytoin decreases levels of acetaminophen IV by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

• acetaminophen rectal

  Minor (1)phenytoin decreases levels of acetaminophen rectal by increasing metabolism. Minor/Significance Unknown. Enhanced metabolism incr levels of hepatotoxic metabolites.

• acetazolamide

  Minor (1)acetazolamide, phenytoin. Mechanism: pharmacodynamic synergism. Minor/Significance Unknown. Increased risk of anticonvulsant induced osteomalacia.

• afatinib

  Serious - Use Alternative (1)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.

• albendazole

  Monitor Closely (1)phenytoin decreases levels of albendazole by increasing metabolism. Use Caution/Monitor. Phenytoin decreases levels of albendazole active metabolites; monitor for decreased efficacy.

• alfentanil

  Minor (1)phenytoin will decrease the level or effect of alfentanil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• alfuzosin

  Minor (1)phenytoin will decrease the level or effect of alfuzosin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• almotriptan

  Monitor Closely (1)phenytoin will decrease the level or effect of almotriptan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• alosetron

  Minor (1)phenytoin will decrease the level or effect of alosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• alpelisib

  Monitor Closely (1)alpelisib will decrease the level or effect of phenytoin by pharmacodynamic synergism. Modify Therapy/Monitor Closely.Serious - Use Alternative (2)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.

• alprazolam

  Monitor Closely (1)phenytoin will decrease the level or effect of alprazolam by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• alvimopan

  Minor (1)phenytoin will decrease the level or effect of alvimopan by P-glycoprotein (MDR1) efflux transporter. Minor/Significance Unknown.

• ambrisentan

  Minor (1)phenytoin will decrease the level or effect of ambrisentan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• amikacin

  Monitor Closely (1)phenytoin will decrease the level or effect of amikacin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

• amiodarone

  Monitor Closely (2)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

  Monitor Closely (2)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.
  
  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.

• amlodipine

  Monitor Closely (1)amlodipine will increase the level or effect of phenytoin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely.

• amobarbital

  Monitor Closely (1)amobarbital will decrease the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

• antithrombin alfa

  Monitor Closely (2)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

  Monitor Closely (2)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

  Monitor Closely (1)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.Serious - Use Alternative (1)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.

• apixaban

  Contraindicated (1)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

• apremilast

  Serious - Use Alternative (1)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

• aprepitant

  Monitor Closely (1)phenytoin will decrease the level or effect of aprepitant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• argatroban

  Monitor Closely (2)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

  Monitor Closely (1)phenytoin will decrease the level or effect of aripiprazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• armodafinil

  Minor (2)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.

• artemether/lumefantrine

  Contraindicated (1)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

• artesunate

  Monitor Closely (1)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.

• atazanavir

  Contraindicated (1)phenytoin will decrease the level or effect of atazanavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.

• atogepant

  Monitor Closely (1)phenytoin will decrease the level or effect of atogepant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Recommended atogepant dosage with concomitant use of strong or moderate CYP3A4 inducers is 30 mg or 60 mg qDay.

• atorvastatin

  Monitor Closely (1)phenytoin will decrease the level or effect of atorvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• atracurium

  Minor (1)phenytoin decreases effects of atracurium by pharmacodynamic antagonism. Minor/Significance Unknown.

• auranofin

  Minor (1)auranofin increases levels of phenytoin by unspecified interaction mechanism. Minor/Significance Unknown.

• avanafil

  Monitor Closely (1)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.

• avapritinib

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of avapritinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• avatrombopag

  Monitor Closely (1)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.

• axitinib

  Serious - Use Alternative (1)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.

• bazedoxifene/conjugated estrogens

  Monitor Closely (3)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.

• bedaquiline

  Serious - Use Alternative (1)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

• belumosudil

  Monitor Closely (1)phenytoin will decrease the level or effect of belumosudil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Increase belumosudil dosage to 200 mg PO BID when coadministered with strong CYP3A inducers.

• bemiparin

  Monitor Closely (2)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

  Monitor Closely (1)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.

• berotralstat

  Serious - Use Alternative (1)phenytoin decreases levels of berotralstat by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug.

• bexarotene

  Monitor Closely (1)phenytoin will decrease the level or effect of bexarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• bictegravir

  Serious - Use Alternative (1)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.

• biotin

  Minor (1)phenytoin decreases levels of biotin by unspecified interaction mechanism. Minor/Significance Unknown. Biotin supplementation may be necessary.

• bivalirudin

  Monitor Closely (2)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

  Monitor Closely (1)bleomycin decreases levels of phenytoin by increasing metabolism. Use Caution/Monitor.

• blinatumomab

  Monitor Closely (1)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

  Monitor Closely (1)phenytoin will decrease the level or effect of bortezomib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• bosentan

  Monitor Closely (1)bosentan will decrease the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.Minor (1)phenytoin will decrease the level or effect of bosentan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• bosutinib

  Serious - Use Alternative (1)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

  Serious - Use Alternative (1)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.

• brentuximab vedotin

  Monitor Closely (1)phenytoin decreases levels of brentuximab vedotin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• brexanolone

  Monitor Closely (1)brexanolone, phenytoin. Either increases toxicity of the other by sedation. Use Caution/Monitor.

• brexpiprazole

  Monitor Closely (1)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.

• brigatinib

  Serious - Use Alternative (1)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.

• brinzolamide

  Minor (1)brinzolamide, phenytoin. Mechanism: pharmacodynamic synergism. Minor/Significance Unknown. Increased risk of anticonvulsant induced osteomalacia.

• brivaracetam

  Monitor Closely (2)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

  Monitor Closely (1)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

  Monitor Closely (1)phenytoin will decrease the level or effect of bromocriptine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• budesonide

  Monitor Closely (2)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

  Monitor Closely (1)phenytoin will decrease the level or effect of buprenorphine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• buprenorphine buccal

  Monitor Closely (1)phenytoin will decrease the level or effect of buprenorphine buccal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• buprenorphine subdermal implant

  Monitor Closely (1)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

  Monitor Closely (1)phenytoin will decrease the level or effect of buprenorphine transdermal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• buprenorphine, long-acting injection

  Monitor Closely (1)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

  Monitor Closely (1)phenytoin will decrease the level or effect of buspirone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• busulfan

  Monitor Closely (2)phenytoin will decrease the level or effect of busulfan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  phenytoin decreases levels of busulfan by increasing hepatic clearance. Use Caution/Monitor.

• butabarbital

  Monitor Closely (1)butabarbital will decrease the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

• butalbital

  Monitor Closely (1)butalbital will decrease the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

• cabazitaxel

  Monitor Closely (1)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.

• cabotegravir

  Contraindicated (1)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.

• cabozantinib

  Serious - Use Alternative (1)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.

• calcifediol

  Monitor Closely (1)phenytoin, calcifediol. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Drugs that stimulate microsomal hydroxylation reduce the half-life of calcifediol.

• calcitriol

  Monitor Closely (1)phenytoin will decrease the level or effect of calcitriol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely.

• calcium/magnesium/potassium/sodium oxybates

  Serious - Use Alternative (1)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.

• canagliflozin

  Monitor Closely (1)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

  Monitor Closely (3)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

  Monitor Closely (1)capecitabine increases levels of phenytoin by unknown mechanism. Use Caution/Monitor. Based on case reports.

• capmatinib

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of capmatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• carbamazepine

  Monitor Closely (2)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.Minor (1)carbamazepine, phenytoin. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Carbamazepine may increase or decrease phenytoin levels.

• carboplatin

  Monitor Closely (1)carboplatin decreases levels of phenytoin by unknown mechanism. Use Caution/Monitor.

• cariprazine

  Contraindicated (1)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.

• carmustine

  Monitor Closely (1)carmustine decreases levels of phenytoin by unknown mechanism. Use Caution/Monitor.

• caspofungin

  Minor (1)phenytoin decreases levels of caspofungin by increasing metabolism. Minor/Significance Unknown.

• cenobamate

  Monitor Closely (3)cenobamate, phenytoin. Either increases effects of the other by sedation. Use Caution/Monitor.
  
  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.

• ceritinib

  Serious - Use Alternative (2)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.

• cevimeline

  Minor (1)phenytoin will decrease the level or effect of cevimeline by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• chloramphenicol

  Monitor Closely (1)chloramphenicol increases levels of phenytoin by decreasing metabolism. Use Caution/Monitor.

• chlordiazepoxide

  Monitor Closely (1)phenytoin will decrease the level or effect of chlordiazepoxide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely.

• chloroquine

  Monitor Closely (1)phenytoin will decrease the level or effect of chloroquine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• cilostazol

  Monitor Closely (1)phenytoin will decrease the level or effect of cilostazol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• cimetidine

  Monitor Closely (1)cimetidine will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

• cinacalcet

  Monitor Closely (1)phenytoin will decrease the level or effect of cinacalcet by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• ciprofloxacin

  Monitor Closely (1)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

  Monitor Closely (1)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

  Monitor Closely (1)cisplatin decreases levels of phenytoin by unknown mechanism. Use Caution/Monitor.

• citalopram

  Monitor Closely (1)phenytoin will decrease the level or effect of citalopram by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• clarithromycin

  Minor (1)phenytoin will decrease the level or effect of clarithromycin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• clomipramine

  Monitor Closely (1)phenytoin will decrease the level or effect of clomipramine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• clonazepam

  Monitor Closely (1)phenytoin will decrease the level or effect of clonazepam by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• clopidogrel

  Monitor Closely (1)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 clopidogrelMinor (1)clopidogrel increases levels of phenytoin by decreasing metabolism. Minor/Significance Unknown.

• clorazepate

  Monitor Closely (1)phenytoin will decrease the level or effect of clorazepate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• clozapine

  Monitor Closely (1)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.

• cobicistat

  Serious - Use Alternative (1)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

• cobimetinib

  Contraindicated (1)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.

• colchicine

  Monitor Closely (1)phenytoin will decrease the level or effect of colchicine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• colesevelam

  Monitor Closely (1)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

  Monitor Closely (1)phenytoin will decrease the level or effect of conivaptan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• conjugated estrogens

  Monitor Closely (2)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

  Monitor Closely (2)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.

• copanlisib

  Serious - Use Alternative (1)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.

• cortisone

  Monitor Closely (2)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

  Monitor Closely (2)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.

• cyanocobalamin

  Minor (1)phenytoin decreases levels of cyanocobalamin by inhibition of GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown.

• cyclosporine

  Monitor Closely (2)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.Serious - Use Alternative (1)phenytoin decreases levels of cyclosporine by increasing metabolism. Avoid or Use Alternate Drug.

• dabigatran

  Serious - Use Alternative (1)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

  Serious - Use Alternative (2)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.

• dalteparin

  Monitor Closely (2)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.

• dantrolene

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of dantrolene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• dapsone

  Minor (1)phenytoin will decrease the level or effect of dapsone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• dapsone topical

  Monitor Closely (1)phenytoin increases toxicity of dapsone topical by altering metabolism. Modify Therapy/Monitor Closely. May induce methemoglobinemia.

• daridorexant

  Monitor Closely (1)phenytoin and daridorexant both increase sedation. Modify Therapy/Monitor Closely. Coadministration increases risk of CNS depression, which can lead to additive impairment of psychomotor performance and cause daytime impairment. Serious - Use Alternative (1)phenytoin will decrease the level or effect of daridorexant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• darifenacin

  Monitor Closely (1)phenytoin will decrease the level or effect of darifenacin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• darolutamide

  Serious - Use Alternative (1)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.

• darunavir

  Contraindicated (1)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

• dasatinib

  Monitor Closely (1)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

  Monitor Closely (1)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

  Monitor Closely (1)phenytoin will decrease the level or effect of deflazacort by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.Serious - Use Alternative (1)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.

• desipramine

  Monitor Closely (1)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

  Monitor Closely (1)phenytoin and deutetrabenazine both increase sedation. Use Caution/Monitor.

• dexamethasone

  Monitor Closely (2)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

  Monitor Closely (1)phenytoin will decrease the level or effect of dexlansoprazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• dexmethylphenidate

  Minor (1)dexmethylphenidate increases effects of phenytoin by decreasing metabolism. Minor/Significance Unknown.

• diazepam

  Monitor Closely (1)phenytoin will decrease the level or effect of diazepam by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• diazepam intranasal

  Monitor Closely (2)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.

• diazoxide

  Minor (1)diazoxide decreases levels of phenytoin by increasing metabolism. Minor/Significance Unknown.

• dienogest/estradiol valerate

  Contraindicated (1)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.

• difelikefalin

  Monitor Closely (1)difelikefalin and phenytoin both increase sedation. Use Caution/Monitor.

• digoxin

  Monitor Closely (1)phenytoin will decrease the level or effect of digoxin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

• dihydroergotamine

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of dihydroergotamine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.

• dihydroergotamine intranasal

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of dihydroergotamine intranasal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.

• diltiazem

  Monitor Closely (1)phenytoin will decrease the level or effect of diltiazem by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• disopyramide

  Monitor Closely (2)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

  Monitor Closely (1)disulfiram will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.Minor (1)disulfiram increases levels of phenytoin by decreasing metabolism. Minor/Significance Unknown.

• docetaxel

  Monitor Closely (3)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.Minor (1)phenytoin will decrease the level or effect of docetaxel by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• dofetilide

  Contraindicated (1)phenytoin, dofetilide. Either increases effects of the other by pharmacodynamic synergism. Contraindicated. Additive cardiac effects.

• dolutegravir

  Serious - Use Alternative (1)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

• donepezil

  Minor (1)phenytoin will decrease the level or effect of donepezil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• dopamine

  Serious - Use Alternative (1)phenytoin, dopamine. Mechanism: pharmacodynamic synergism. Avoid or Use Alternate Drug. Increased risk of hypotension.

• doravirine

  Contraindicated (1)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.

• doxorubicin

  Monitor Closely (2)doxorubicin decreases levels of phenytoin by increasing metabolism. Use Caution/Monitor.
  
  phenytoin will decrease the level or effect of doxorubicin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• doxorubicin liposomal

  Monitor Closely (2)doxorubicin liposomal decreases levels of phenytoin by increasing metabolism. Use Caution/Monitor.
  
  phenytoin will decrease the level or effect of doxorubicin liposomal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• doxycycline

  Minor (1)phenytoin decreases levels of doxycycline by increasing metabolism. Minor/Significance Unknown.

• dronabinol

  Monitor Closely (3)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.

• dronedarone

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of dronedarone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.

• dulaglutide

  Monitor Closely (1)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

  Monitor Closely (1)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.

• dutasteride

  Minor (1)phenytoin will decrease the level or effect of dutasteride by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• duvelisib

  Monitor Closely (1)phenytoin will decrease the level or effect of duvelisib by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.Serious - Use Alternative (1)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

  Serious - Use Alternative (1)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

• efavirenz

  Monitor Closely (3)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

  Monitor Closely (2)phenytoin will decrease the level or effect of elagolix by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
  
  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.

• elbasvir/grazoprevir

  Contraindicated (1)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.

• eletriptan

  Monitor Closely (1)phenytoin will decrease the level or effect of eletriptan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• eliglustat

  Monitor Closely (1)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.Serious - Use Alternative (1)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

  Serious - Use Alternative (1)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

• elvitegravir/cobicistat/emtricitabine/tenofovir DF

  Contraindicated (1)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.Monitor Closely (1)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.

• encorafenib

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of encorafenib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• enfortumab vedotin

  Monitor Closely (1)phenytoin will decrease the level or effect of enfortumab vedotin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• enoxaparin

  Monitor Closely (2)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.

• entrectinib

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of entrectinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• enzalutamide

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of enzalutamide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• eplerenone

  Minor (1)phenytoin will decrease the level or effect of eplerenone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• erdafitinib

  Serious - Use Alternative (1)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

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of ergotamine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.

• erlotinib

  Monitor Closely (2)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.

• erythromycin base

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of erythromycin base by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.

• erythromycin ethylsuccinate

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of erythromycin ethylsuccinate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.

• erythromycin lactobionate

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of erythromycin lactobionate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.

• erythromycin stearate

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of erythromycin stearate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.

• escitalopram

  Monitor Closely (1)phenytoin will decrease the level or effect of escitalopram by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• esketamine intranasal

  Monitor Closely (1)esketamine intranasal, phenytoin. Either increases toxicity of the other by sedation. Modify Therapy/Monitor Closely.

• eslicarbazepine acetate

  Monitor Closely (2)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

  Monitor Closely (2)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

  Monitor Closely (2)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

  Monitor Closely (1)phenytoin will decrease the level or effect of estradiol vaginal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• estrogens conjugated synthetic

  Monitor Closely (2)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

  Monitor Closely (1)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

  Monitor Closely (2)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

  Monitor Closely (1)phenytoin will decrease the level or effect of eszopiclone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• ethanol

  Monitor Closely (2)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.

• ethinylestradiol

  Serious - Use Alternative (1)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.

• ethosuximide

  Monitor Closely (1)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.).Minor (1)ethosuximide increases effects of phenytoin by pharmacodynamic synergism. Minor/Significance Unknown.

• etonogestrel

  Monitor Closely (1)phenytoin will decrease the level or effect of etonogestrel by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• etoposide

  Monitor Closely (1)phenytoin will decrease the level or effect of etoposide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• etravirine

  Serious - Use Alternative (4)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.

• eucalyptus

  Minor (1)phenytoin will decrease the level or effect of eucalyptus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• everolimus

  Serious - Use Alternative (2)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.

• exemestane

  Monitor Closely (1)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.

• ezogabine

  Minor (1)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.

• fedratinib

  Serious - Use Alternative (1)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.

• felbamate

  Monitor Closely (2)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

  Monitor Closely (2)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

  Monitor Closely (1)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

  Monitor Closely (1)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

  Monitor Closely (1)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

  Monitor Closely (1)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

  Monitor Closely (1)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

  Monitor Closely (1)phenytoin will decrease the level or effect of fesoterodine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• fexinidazole

  Monitor Closely (1)fexinidazole will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C19 metabolism. Use Caution/Monitor.Serious - Use Alternative (1)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.

• fexofenadine

  Minor (1)phenytoin will decrease the level or effect of fexofenadine by P-glycoprotein (MDR1) efflux transporter. Minor/Significance Unknown.

• finasteride

  Minor (1)phenytoin will decrease the level or effect of finasteride by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• finerenone

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of finerenone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• fleroxacin

  Monitor Closely (1)fleroxacin decreases effects of phenytoin by unknown mechanism. Use Caution/Monitor. There are also case reports of quinolones increasing phenytoin levels.

• flibanserin

  Monitor Closely (1)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

  Monitor Closely (1)floxuridine increases levels of phenytoin by unknown mechanism. Use Caution/Monitor. Based on case reports.

• fluconazole

  Monitor Closely (1)fluconazole will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

• fludrocortisone

  Monitor Closely (2)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

  Monitor Closely (1)fluorouracil increases levels of phenytoin by unknown mechanism. Use Caution/Monitor. Based on case reports.

• fluoxetine

  Monitor Closely (1)fluoxetine will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

• flurazepam

  Monitor Closely (1)phenytoin will decrease the level or effect of flurazepam by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• fluticasone furoate

  Monitor Closely (1)phenytoin will decrease the level or effect of fluticasone furoate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• fluticasone inhaled

  Monitor Closely (1)phenytoin will decrease the level or effect of fluticasone inhaled by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• fluvastatin

  Monitor Closely (1)fluvastatin increases levels of phenytoin by decreasing metabolism. Use Caution/Monitor.

• fluvoxamine

  Monitor Closely (1)fluvoxamine will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

• folic acid

  Minor (1)folic acid decreases levels of phenytoin by increasing metabolism. Minor/Significance Unknown. Large doses of folic acid (>10 mg/day).

• fondaparinux

  Monitor Closely (2)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

  Monitor Closely (1)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.

• fostamatinib

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of fostamatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• fostemsavir

  Contraindicated (1)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.

• furosemide

  Minor (1)phenytoin decreases levels of furosemide by inhibition of GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown.

• galantamine

  Minor (1)phenytoin will decrease the level or effect of galantamine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• ganaxolone

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of ganaxolone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of ganaxolone with moderate or strong CYP3A4 inducers. If coadministration unavoidable, consider increasing ganaxolone dose; however, do not exceed maximum daily dose for weight.

• gefitinib

  Monitor Closely (1)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

  Monitor Closely (1)gemifloxacin decreases effects of phenytoin by unknown mechanism. Use Caution/Monitor. There are also case reports of quinolones increasing phenytoin levels.

• gentamicin

  Monitor Closely (1)phenytoin will decrease the level or effect of gentamicin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

• gilteritinib

  Serious - Use Alternative (1)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

  Serious - Use Alternative (1)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

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of glecaprevir/pibrentasvir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• glyburide

  Monitor Closely (1)phenytoin decreases levels of glyburide by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor. Strong CYP2C9 inducers may increase glyburide metabolism.

• grapefruit

  Minor (1)grapefruit, phenytoin. Other (see comment). Minor/Significance Unknown. Comment: Grapefruit juice has been determined to have no effect on the pharmacokinetics of phenytoin.

• green tea

  Monitor Closely (1)phenytoin decreases levels of green tea by increasing metabolism. Use Caution/Monitor. (Caffeine). Potential for decreased effects of caffeine in green tea. .

• guanfacine

  Monitor Closely (1)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

  Monitor Closely (1)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.

• haloperidol

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of haloperidol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• hawthorn

  Monitor Closely (1)hawthorn increases effects of phenytoin by pharmacodynamic synergism. Use Caution/Monitor.

• heparin

  Monitor Closely (2)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

  Monitor Closely (1)hyaluronidase, phenytoin. Other (see comment). Use Caution/Monitor. Comment: Drug combination has been found to be incompatible.

• hydrocodone

  Monitor Closely (1)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

  Monitor Closely (2)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

  Monitor Closely (1)phenytoin will decrease the level or effect of hydroxyprogesterone caproate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• ibrutinib

  Serious - Use Alternative (1)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

  Serious - Use Alternative (1)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

• ifosfamide

  Monitor Closely (2)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

  Monitor Closely (1)phenytoin will decrease the level or effect of iloperidone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• imatinib

  Monitor Closely (3)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

  Monitor Closely (1)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.

• immune globulin IM (IGIM)

  Minor (1)phenytoin, immune globulin IM (IGIM). Mechanism: unknown. Minor/Significance Unknown. Risk of hypersensitivity myocarditis.

• immune globulin IV (IGIV)

  Minor (1)phenytoin, immune globulin IV (IGIV). Mechanism: unknown. Minor/Significance Unknown. Risk of hypersensitivity myocarditis.

• immune globulin SC

  Minor (1)phenytoin, immune globulin SC. Mechanism: unknown. Minor/Significance Unknown. Risk of hypersensitivity myocarditis (theoretical interaction, based on IM and IV immune globulin).

• indinavir

  Monitor Closely (2)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.

• infigratinib

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of infigratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• influenza virus vaccine quadrivalent

  Minor (1)influenza virus vaccine quadrivalent, phenytoin. Mechanism: unknown. Minor/Significance Unknown. Vaccine administration may incr or decr phenytoin levels.

• influenza virus vaccine quadrivalent, cell-cultured

  Minor (1)influenza virus vaccine quadrivalent, cell-cultured, phenytoin. Mechanism: unknown. Minor/Significance Unknown. Vaccine administration may incr or decr phenytoin levels.

• influenza virus vaccine trivalent

  Minor (1)influenza virus vaccine trivalent, phenytoin. Mechanism: unknown. Minor/Significance Unknown. Vaccine administration may incr or decr phenytoin levels.

• influenza virus vaccine trivalent, recombinant

  Minor (1)influenza virus vaccine trivalent, recombinant, phenytoin. Mechanism: unknown. Minor/Significance Unknown. Vaccine administration may incr or decr phenytoin levels.

• irinotecan

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of irinotecan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• irinotecan liposomal

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of irinotecan liposomal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• isavuconazonium sulfate

  Contraindicated (1)phenytoin will decrease the level or effect of isavuconazonium sulfate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.

• isoniazid

  Minor (1)isoniazid increases levels of phenytoin by decreasing metabolism. Minor/Significance Unknown.

• isosorbide dinitrate

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of isosorbide dinitrate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• isosorbide mononitrate

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of isosorbide mononitrate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• isradipine

  Minor (1)phenytoin will decrease the level or effect of isradipine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• istradefylline

  Serious - Use Alternative (1)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

  Monitor Closely (1)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.Serious - Use Alternative (1)phenytoin decreases levels of itraconazole by increasing metabolism. Avoid or Use Alternate Drug.Minor (1)phenytoin will decrease the level or effect of itraconazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• ivabradine

  Serious - Use Alternative (1)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

  Serious - Use Alternative (1)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).

• ivermectin

  Monitor Closely (1)phenytoin will decrease the level or effect of ivermectin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

• ivosidenib

  Serious - Use Alternative (2)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.

• ixabepilone

  Monitor Closely (1)phenytoin will decrease the level or effect of ixabepilone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• ixazomib

  Serious - Use Alternative (1)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%.

• ixekizumab

  Monitor Closely (1)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

  Monitor Closely (1)ketoconazole will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.Minor (1)phenytoin will decrease the level or effect of ketoconazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• L-methylfolate

  Monitor Closely (1)L-methylfolate decreases levels of phenytoin by unspecified interaction mechanism. Use Caution/Monitor.Minor (1)L-methylfolate decreases levels of phenytoin by increasing metabolism. Minor/Significance Unknown.

• lamotrigine

  Monitor Closely (1)phenytoin decreases levels of lamotrigine by increasing metabolism. Use Caution/Monitor.

• lansoprazole

  Serious - Use Alternative (2)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

• lapatinib

  Monitor Closely (2)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.

• larotrectinib

  Serious - Use Alternative (1)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

• lasmiditan

  Monitor Closely (1)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.

• ledipasvir/sofosbuvir

  Contraindicated (1)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

• lefamulin

  Serious - Use Alternative (1)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.

• leflunomide

  Monitor Closely (1)leflunomide will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

• lemborexant

  Monitor Closely (1)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.Serious - Use Alternative (1)phenytoin will decrease the level or effect of lemborexant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• lesinurad

  Monitor Closely (1)phenytoin will decrease the level or effect of lesinurad by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.

• letermovir

  Monitor Closely (1)letermovir will decrease the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor. Monitor phenytoin levels.Serious - Use Alternative (2)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.

• levamlodipine

  Monitor Closely (1)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.

• levocarnitine

  Minor (1)phenytoin decreases levels of levocarnitine by unspecified interaction mechanism. Minor/Significance Unknown.

• levodopa

  Monitor Closely (1)phenytoin decreases effects of levodopa by unknown mechanism. Use Caution/Monitor.

• levofloxacin

  Monitor Closely (1)levofloxacin decreases effects of phenytoin by unknown mechanism. Use Caution/Monitor. There are also case reports of quinolones increasing phenytoin levels.

• levoketoconazole

  Monitor Closely (1)levoketoconazole will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.Minor (1)phenytoin will decrease the level or effect of levoketoconazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• levonorgestrel intrauterine

  Monitor Closely (1)phenytoin decreases levels of levonorgestrel intrauterine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• levonorgestrel oral

  Monitor Closely (1)phenytoin decreases levels of levonorgestrel oral by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• levonorgestrel oral/ethinylestradiol/ferrous bisglycinate

  Monitor Closely (1)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.

• levothyroxine

  Minor (2)phenytoin decreases levels of levothyroxine by increasing metabolism. Minor/Significance Unknown.
  
  phenytoin decreases levels of levothyroxine by plasma protein binding competition. Minor/Significance Unknown.

• lidocaine

  Serious - Use Alternative (1)phenytoin decreases levels of lidocaine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• lily of the valley

  Minor (1)phenytoin, lily of the valley. Either increases toxicity of the other by pharmacodynamic synergism. Minor/Significance Unknown.

• linagliptin

  Monitor Closely (1)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.

• liothyronine

  Minor (2)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

  Minor (1)phenytoin increases toxicity of lithium by unknown mechanism. Minor/Significance Unknown.

• lomitapide

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of lomitapide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• lomustine

  Monitor Closely (2)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.

• lonafarnib

  Contraindicated (1)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.

• loperamide

  Monitor Closely (1)phenytoin will decrease the level or effect of loperamide by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

• lopinavir

  Monitor Closely (1)phenytoin will decrease the level or effect of lopinavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• loratadine

  Monitor Closely (1)phenytoin will decrease the level or effect of loratadine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.Minor (1)phenytoin will decrease the level or effect of loratadine by P-glycoprotein (MDR1) efflux transporter. Minor/Significance Unknown.

• lorlatinib

  Contraindicated (1)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.

• losartan

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of losartan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• lovastatin

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of lovastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.

• lumacaftor/ivacaftor

  Contraindicated (1)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.Monitor Closely (2)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. .

• lumateperone

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of lumateperone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• lumefantrine

  Contraindicated (1)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

  Contraindicated (1)phenytoin decreases levels of lurasidone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Contraindicated.Monitor Closely (1)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.

• lurbinectedin

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of lurbinectedin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• macimorelin

  Serious - Use Alternative (1)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

  Serious - Use Alternative (1)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

• maraviroc

  Monitor Closely (2)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

  Monitor Closely (1)phenytoin will decrease the level or effect of marijuana by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• mavacamten

  Contraindicated (2)phenytoin will decrease the level or effect of mavacamten by affecting hepatic enzyme CYP2C19 metabolism. Contraindicated.
  
  phenytoin will decrease the level or effect of mavacamten by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.

• mebendazole

  Serious - Use Alternative (1)phenytoin decreases levels of mebendazole by increasing metabolism. Contraindicated.

• medroxyprogesterone

  Monitor Closely (1)phenytoin will decrease the level or effect of medroxyprogesterone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Contraceptirve failure possible

• mefloquine

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of mefloquine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• meperidine

  Minor (1)phenytoin decreases levels of meperidine by increasing metabolism. Minor/Significance Unknown.

• mestranol

  Monitor Closely (3)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.Serious - Use Alternative (1)phenytoin decreases levels of mestranol by increasing metabolism. Avoid or Use Alternate Drug. May result in contraceptive failure.

• metformin

  Monitor Closely (1)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

  Monitor Closely (1)phenytoin will decrease the level or effect of methadone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.Serious - Use Alternative (1)phenytoin decreases levels of methadone by increasing metabolism. Contraindicated.

• methazolamide

  Minor (1)methazolamide, phenytoin. Mechanism: pharmacodynamic synergism. Minor/Significance Unknown. Increased risk of anticonvulsant induced osteomalacia.

• methotrexate

  Monitor Closely (1)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.

• methsuximide

  Minor (1)methsuximide increases effects of phenytoin by pharmacodynamic synergism. Minor/Significance Unknown.

• methylphenidate

  Monitor Closely (1)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.

• methylphenidate transdermal

  Monitor Closely (1)methylphenidate transdermal will increase the level or effect of phenytoin by decreasing metabolism. Modify Therapy/Monitor Closely. Consider decreasing the dose of these drugs when given coadministered with methylphenidate. Monitor for drug toxiticities when initiating or discontinuing methylphenidate.

• methylprednisolone

  Monitor Closely (2)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.

• metoclopramide intranasal

  Serious - Use Alternative (1)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.

• metronidazole

  Monitor Closely (1)metronidazole will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

• metyrapone

  Monitor Closely (1)phenytoin decreases levels of metyrapone by increasing metabolism. Use Caution/Monitor.

• mexiletine

  Monitor Closely (1)phenytoin decreases levels of mexiletine by increasing metabolism. Use Caution/Monitor.

• miconazole vaginal

  Monitor Closely (1)miconazole vaginal will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

• midazolam

  Monitor Closely (1)phenytoin will decrease the level or effect of midazolam by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• midazolam intranasal

  Monitor Closely (1)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.

• midostaurin

  Serious - Use Alternative (1)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.

• mifepristone

  Monitor Closely (1)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

  Monitor Closely (1)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

  Monitor Closely (1)phenytoin will decrease the level or effect of mirtazapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• mitoxantrone

  Monitor Closely (1)mitoxantrone decreases levels of phenytoin by increasing metabolism. Use Caution/Monitor.

• mobocertinib

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of mobocertinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• modafinil

  Monitor Closely (1)phenytoin will decrease the level or effect of modafinil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• montelukast

  Minor (1)phenytoin will decrease the level or effect of montelukast by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• moxifloxacin

  Monitor Closely (1)moxifloxacin decreases effects of phenytoin by unknown mechanism. Use Caution/Monitor. There are also case reports of quinolones increasing phenytoin levels.

• mycophenolate

  Minor (1)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. .

• naldemedine

  Serious - Use Alternative (1)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.

• naloxegol

  Contraindicated (1)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

• nateglinide

  Monitor Closely (2)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

  Monitor Closely (1)phenytoin will decrease the level or effect of nefazodone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• nelfinavir

  Monitor Closely (2)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

  Monitor Closely (1)phenytoin will decrease the level or effect of neomycin PO by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

• neratinib

  Serious - Use Alternative (1)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

  Serious - Use Alternative (1)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

• nevirapine

  Monitor Closely (1)phenytoin will decrease the level or effect of nevirapine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• nicardipine

  Monitor Closely (1)phenytoin will decrease the level or effect of nicardipine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• nifedipine

  Serious - Use Alternative (1)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%

• nilotinib

  Monitor Closely (3)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

  Monitor Closely (1)nilutamide will increase the level or effect of phenytoin by decreasing metabolism. Use Caution/Monitor.

• nimodipine

  Minor (1)phenytoin will decrease the level or effect of nimodipine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• nintedanib

  Serious - Use Alternative (1)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.

• nirmatrelvir

  Contraindicated (1)phenytoin will decrease the level or effect of nirmatrelvir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir, a CYP3A4 substrate, is contraindicated with strong CYP3A4 inducers. Significantly reduced nirmatrelvir plasma concentrations may be associated with potential for loss of virologic response and possible resistance. Do not initiate nirmatrelvir/ritonavir immediately after discontinuing a strong 3A4 inducer owing to time needed for systemic clearance of the inducer.

• nirmatrelvir/ritonavir

  Contraindicated (1)phenytoin will decrease the level or effect of nirmatrelvir/ritonavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Nirmatrelvir, a CYP3A4 substrate, is contraindicated with strong CYP3A4 inducers. Significantly reduced nirmatrelvir plasma concentrations may be associated with potential for loss of virologic response and possible resistance. Do not initiate nirmatrelvir/ritonavir immediately after discontinuing a strong 3A4 inducer owing to time needed for systemic clearance of the inducer.

• nisoldipine

  Monitor Closely (1)phenytoin will decrease the level or effect of nisoldipine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• nitazoxanide

  Serious - Use Alternative (1)nitazoxanide, phenytoin. Either increases levels of the other by Mechanism: plasma protein binding competition. Avoid or Use Alternate Drug.

• nitisinone

  Monitor Closely (1)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.

• nitrendipine

  Minor (1)phenytoin will decrease the level or effect of nitrendipine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• norethindrone

  Serious - Use Alternative (1)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

  Serious - Use Alternative (1)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

  Serious - Use Alternative (1)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

  Serious - Use Alternative (1)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

• ofloxacin

  Monitor Closely (1)ofloxacin decreases effects of phenytoin by unknown mechanism. Use Caution/Monitor. There are also case reports of quinolones increasing phenytoin levels.

• olaparib

  Serious - Use Alternative (1)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.

• oliceridine

  Monitor Closely (1)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.

• ombitasvir/paritaprevir/ritonavir & dasabuvir (DSC)

  Contraindicated (2)phenytoin will decrease the level or effect of ombitasvir/paritaprevir/ritonavir & dasabuvir (DSC) 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 (DSC) by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Strong CYP3A4 inducers may reduce partiaprevir and ritonavir levels, and therefore decreased efficacy of Viekira Pak

• omeprazole

  Monitor Closely (2)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.

• onabotulinumtoxinA

  Minor (1)phenytoin decreases effects of onabotulinumtoxinA by pharmacodynamic antagonism. Minor/Significance Unknown.

• ondansetron

  Monitor Closely (1)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

  Monitor Closely (1)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

  Monitor Closely (1)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

  Monitor Closely (1)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.

• osimertinib

  Serious - Use Alternative (1)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.

• ospemifene

  Monitor Closely (4)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

  Monitor Closely (3)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

  Monitor Closely (1)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.Minor (1)phenytoin decreases levels of oxcarbazepine by increasing metabolism. Minor/Significance Unknown.

• oxybutynin

  Minor (1)phenytoin will decrease the level or effect of oxybutynin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• oxycodone

  Monitor Closely (1)phenytoin decreases levels of oxycodone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• ozanimod

  Serious - Use Alternative (1)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.

• paclitaxel

  Monitor Closely (4)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 Minor (1)phenytoin will decrease the level or effect of paclitaxel by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• paclitaxel protein bound

  Monitor Closely (4)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 Minor (1)phenytoin will decrease the level or effect of paclitaxel protein bound by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• palbociclib

  Serious - Use Alternative (1)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%.

• paliperidone

  Monitor Closely (1)phenytoin will decrease the level or effect of paliperidone by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

• pancuronium

  Monitor Closely (1)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.

• panobinostat

  Contraindicated (1)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.

• pantoprazole

  Monitor Closely (1)phenytoin will decrease the level or effect of pantoprazole by affecting hepatic enzyme CYP2C19 metabolism. Use Caution/Monitor.

• parecoxib

  Minor (1)phenytoin will decrease the level or effect of parecoxib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• paricalcitol

  Monitor Closely (1)phenytoin will decrease the level or effect of paricalcitol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• paromomycin

  Monitor Closely (1)phenytoin will decrease the level or effect of paromomycin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

• pazopanib

  Monitor Closely (1)phenytoin will decrease the level or effect of pazopanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• peginterferon alfa 2b

  Monitor Closely (1)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. .

• pemigatinib

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of pemigatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• pentobarbital

  Monitor Closely (1)pentobarbital will decrease the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

• perampanel

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of perampanel by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• pexidartinib

  Serious - Use Alternative (2)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.

• phenindione

  Monitor Closely (2)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

  Monitor Closely (1)phenobarbital will decrease the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.Minor (1)phenobarbital decreases levels of phenytoin by increasing metabolism. Minor/Significance Unknown. Phenobarbital may occasionally not change or even increase (via competitive inhibition) phenytoin levels.

• pimavanserin

  Monitor Closely (1)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.

• pimozide

  Minor (1)phenytoin will decrease the level or effect of pimozide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• pioglitazone

  Minor (1)phenytoin will decrease the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• pitolisant

  Monitor Closely (1)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

  Monitor Closely (1)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.

• pomalidomide

  Serious - Use Alternative (1)phenytoin decreases levels of pomalidomide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• ponatinib

  Serious - Use Alternative (1)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

  Serious - Use Alternative (1)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

  Monitor Closely (1)phenytoin decreases levels of posaconazole by increasing metabolism. Use Caution/Monitor.Serious - Use Alternative (1)phenytoin will decrease the level or effect of posaconazole by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug.

• pralsetinib

  Serious - Use Alternative (1)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.

• praziquantel

  Contraindicated (1)phenytoin decreases levels of praziquantel by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Strong CYP450 inducers significantly decrease praziquantel blood levels.

• prednisolone

  Monitor Closely (2)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

  Monitor Closely (2)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.

• pretomanid

  Serious - Use Alternative (2)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.

• primidone

  Monitor Closely (2)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.

• progesterone intravaginal gel

  Serious - Use Alternative (1)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

  Serious - Use Alternative (1)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

  Serious - Use Alternative (1)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

• propafenone

  Minor (1)phenytoin will decrease the level or effect of propafenone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• protamine

  Monitor Closely (2)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.

• pyridoxine

  Minor (1)pyridoxine decreases levels of phenytoin by increasing metabolism. Minor/Significance Unknown. High dose of pyridoxine (vitamin B6), >=200 mg/day.

• pyridoxine (Antidote)

  Minor (1)pyridoxine (Antidote) decreases levels of phenytoin by increasing metabolism. Minor/Significance Unknown. High dose of pyridoxine (vitamin B6), >=200 mg/day.

• pyrimethamine

  Minor (1)pyrimethamine decreases effects of phenytoin by pharmacodynamic antagonism. Minor/Significance Unknown.

• quazepam

  Monitor Closely (1)phenytoin will decrease the level or effect of quazepam by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• quetiapine

  Monitor Closely (1)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

  Monitor Closely (2)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

  Monitor Closely (1)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.

• rabeprazole

  Serious - Use Alternative (1)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 drugsMinor (1)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

  Minor (1)phenytoin will decrease the level or effect of ramelteon by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• ranolazine

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of ranolazine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.

• rapacuronium

  Minor (1)phenytoin decreases effects of rapacuronium by pharmacodynamic antagonism. Minor/Significance Unknown.

• regorafenib

  Contraindicated (1)phenytoin, regorafenib. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Strong CYP3A4 inducers decrease regorafenib levels and increase exposure of the active metabolite M-5.

• repaglinide

  Monitor Closely (1)phenytoin will decrease the level or effect of repaglinide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• ribociclib

  Serious - Use Alternative (1)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

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of rifabutin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.Minor (1)rifabutin decreases levels of phenytoin by increasing metabolism. Minor/Significance Unknown.

• rifampin

  Monitor Closely (1)rifampin will decrease the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

• rifapentine

  Monitor Closely (1)rifapentine will decrease the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

• rilpivirine

  Contraindicated (1)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.

• rimegepant

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of rimegepant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• riociguat

  Monitor Closely (1)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

• ripretinib

  Serious - Use Alternative (1)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.

• risperidone

  Monitor Closely (1)phenytoin will decrease the level or effect of risperidone by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

• ritonavir

  Monitor Closely (2)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

  Monitor Closely (1)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

  Monitor Closely (1)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.

• roflumilast

  Contraindicated (1)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

• rolapitant

  Serious - Use Alternative (1)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

  Serious - Use Alternative (1)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.

• ropeginterferon alfa 2b

  Serious - Use Alternative (1)ropeginterferon alfa 2b and phenytoin both increase Other (see comment). Avoid or Use Alternate Drug. Narcotics, hypnotics or sedatives can produce additive neuropsychiatric side effects. Avoid use and monitor patients receiving the combination for effects of excessive CNS toxicity.

• rufinamide

  Monitor Closely (2)rufinamide increases levels of phenytoin by decreasing renal clearance. Use Caution/Monitor.
  
  phenytoin decreases levels of rufinamide by increasing metabolism. Use Caution/Monitor.

• ruxolitinib

  Monitor Closely (1)phenytoin will decrease the level or effect of ruxolitinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• ruxolitinib topical

  Monitor Closely (1)phenytoin will decrease the level or effect of ruxolitinib topical by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• sage

  Minor (1)sage decreases effects of phenytoin by pharmacodynamic antagonism. Minor/Significance Unknown. Theoretical interaction; some species of sage may cause convulsions.

• saquinavir

  Monitor Closely (2)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

  Monitor Closely (1)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.

• saxagliptin

  Minor (1)phenytoin will decrease the level or effect of saxagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• secobarbital

  Monitor Closely (1)secobarbital will decrease the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

• secukinumab

  Monitor Closely (1)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

  Monitor Closely (1)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.

• selpercatinib

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of selpercatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• selumetinib

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• serdexmethylphenidate/dexmethylphenidate

  Minor (1)serdexmethylphenidate/dexmethylphenidate increases effects of phenytoin by decreasing metabolism. Minor/Significance Unknown.

• sertraline

  Monitor Closely (1)sertraline increases levels of phenytoin by decreasing metabolism. Use Caution/Monitor.

• sevelamer

  Monitor Closely (1)sevelamer decreases levels of phenytoin by increasing elimination. Use Caution/Monitor.

• sildenafil

  Serious - Use Alternative (1)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

  Monitor Closely (1)phenytoin will decrease the level or effect of silodosin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.Serious - Use Alternative (1)phenytoin will decrease the level or effect of silodosin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.

• simvastatin

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of simvastatin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.

• siponimod

  Serious - Use Alternative (1)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

  Monitor Closely (1)phenytoin will decrease the level or effect of sirolimus by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.Serious - Use Alternative (1)phenytoin will decrease the level or effect of sirolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.

• sodium oxybate

  Serious - Use Alternative (1)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.

• sodium sulfate/?magnesium sulfate/potassium chloride

  Monitor Closely (1)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

  Monitor Closely (1)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.

• sofosbuvir

  Serious - Use Alternative (1)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

  Serious - Use Alternative (3)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.

• solifenacin

  Monitor Closely (1)phenytoin will decrease the level or effect of solifenacin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• sonidegib

  Serious - Use Alternative (1)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

  Monitor Closely (1)phenytoin decreases levels of sorafenib by increasing metabolism. Use Caution/Monitor.Serious - Use Alternative (1)phenytoin will decrease the level or effect of sorafenib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• sotorasib

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of sotorasib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• stiripentol

  Monitor Closely (2)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.
  
  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.Serious - Use Alternative (2)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.

• streptomycin

  Monitor Closely (1)phenytoin will decrease the level or effect of streptomycin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

• succinylcholine

  Minor (1)phenytoin decreases effects of succinylcholine by pharmacodynamic antagonism. Minor/Significance Unknown.

• sucralfate

  Minor (1)sucralfate decreases levels of phenytoin by inhibition of GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown.

• sufentanil

  Minor (1)phenytoin will decrease the level or effect of sufentanil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• sufentanil SL

  Monitor Closely (1)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.

• sulfadiazine

  Minor (1)sulfadiazine increases levels of phenytoin by decreasing metabolism. Minor/Significance Unknown.

• sulfamethoxazole

  Monitor Closely (1)sulfamethoxazole will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.Minor (1)sulfamethoxazole increases levels of phenytoin by decreasing metabolism. Minor/Significance Unknown.

• sulfisoxazole

  Minor (1)sulfisoxazole increases levels of phenytoin by decreasing metabolism. Minor/Significance Unknown.

• sunitinib

  Monitor Closely (1)phenytoin will decrease the level or effect of sunitinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• suvorexant

  Monitor Closely (1)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

  Monitor Closely (2)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

  Monitor Closely (1)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

  Monitor Closely (1)phenytoin will decrease the level or effect of tamoxifen by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• tamsulosin

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of tamsulosin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• tasimelteon

  Monitor Closely (1)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

• tazemetostat

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of tazemetostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• tecovirimat

  Monitor Closely (1)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

  Monitor Closely (1)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

  Monitor Closely (1)phenytoin will decrease the level or effect of temsirolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• teniposide

  Monitor Closely (1)phenytoin will decrease the level or effect of teniposide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• tepotinib

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of tepotinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• terbinafine

  Monitor Closely (2)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

  Monitor Closely (1)tesamorelin will decrease the level or effect of phenytoin by altering metabolism. Modify Therapy/Monitor Closely. Monitor levels

• tetracaine

  Monitor Closely (1)tetracaine, phenytoin. Other (see comment). Use Caution/Monitor. Comment: Monitor for signs of methemoglobinemia when methemoglobin-inducing drugs are coadministered.

• tetracycline

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of tetracycline by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• tezacaftor

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of tezacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• theophylline

  Monitor Closely (1)phenytoin will decrease the level or effect of theophylline by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• thyroid desiccated

  Minor (2)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

  Monitor Closely (1)phenytoin will decrease the level or effect of tiagabine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.Minor (1)phenytoin decreases levels of tiagabine by increasing metabolism. Minor/Significance Unknown.

• tibolone

  Minor (1)phenytoin decreases levels of tibolone by increasing metabolism. Minor/Significance Unknown. Theoretical interaction.

• ticagrelor

  Monitor Closely (1)phenytoin decreases levels of ticagrelor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Avoid use of ticagrelor with potent CYP3A inducers.

• ticlopidine

  Monitor Closely (1)ticlopidine will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

• tinidazole

  Monitor Closely (2)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

  Monitor Closely (1)phenytoin will decrease the level or effect of tipranavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• tivozanib

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of tivozanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• tobramycin

  Monitor Closely (1)phenytoin will decrease the level or effect of tobramycin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

• tofacitinib

  Monitor Closely (1)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

• tolazamide

  Minor (1)tolazamide increases levels of phenytoin by plasma protein binding competition. Minor/Significance Unknown.

• tolbutamide

  Minor (2)tolbutamide increases levels of phenytoin by plasma protein binding competition. Minor/Significance Unknown.
  
  phenytoin decreases effects of tolbutamide by pharmacodynamic antagonism. Minor/Significance Unknown.

• tolterodine

  Monitor Closely (1)phenytoin will decrease the level or effect of tolterodine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• tolvaptan

  Monitor Closely (1)phenytoin will decrease the level or effect of tolvaptan by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.Serious - Use Alternative (1)phenytoin will decrease the level or effect of tolvaptan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.

• topiramate

  Monitor Closely (1)phenytoin decreases levels of topiramate by increasing metabolism. Use Caution/Monitor.Minor (1)topiramate increases levels of phenytoin by decreasing metabolism. Minor/Significance Unknown.

• toremifene

  Monitor Closely (1)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.Minor (1)phenytoin decreases levels of toremifene by increasing metabolism. Minor/Significance Unknown.

• trabectedin

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of trabectedin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• tramadol

  Monitor Closely (1)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

• trazodone

  Minor (1)trazodone increases levels of phenytoin by unspecified interaction mechanism. Minor/Significance Unknown.

• treosulfan

  Monitor Closely (2)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

  Monitor Closely (1)phenytoin will decrease the level or effect of triamcinolone acetonide injectable suspension by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• triazolam

  Monitor Closely (1)phenytoin will decrease the level or effect of triazolam by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• triclabendazole

  Monitor Closely (1)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.

• trimipramine

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of trimipramine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• tucatinib

  Serious - Use Alternative (2)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.

• typhoid polysaccharide vaccine

  Minor (1)phenytoin decreases levels of typhoid polysaccharide vaccine by increasing metabolism. Minor/Significance Unknown.

• typhoid vaccine live

  Minor (1)phenytoin decreases levels of typhoid vaccine live by increasing metabolism. Minor/Significance Unknown.

• ubrogepant

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of ubrogepant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• ulipristal

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of ulipristal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• upadacitinib

  Serious - Use Alternative (1)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.

• ustekinumab

  Monitor Closely (1)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.

• valbenazine

  Serious - Use Alternative (1)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.

• valproic acid

  Monitor Closely (1)valproic acid will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.Minor (2)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.

• vandetanib

  Contraindicated (1)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%.

• vardenafil

  Monitor Closely (1)phenytoin will decrease the level or effect of vardenafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• vecuronium

  Monitor Closely (1)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.

• velpatasvir

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of velpatasvir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.

• vemurafenib

  Monitor Closely (1)phenytoin decreases levels of vemurafenib by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.Serious - Use Alternative (1)phenytoin decreases levels of vemurafenib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• venetoclax

  Serious - Use Alternative (1)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.

• verapamil

  Monitor Closely (1)phenytoin will decrease the level or effect of verapamil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• vigabatrin

  Minor (1)vigabatrin decreases levels of phenytoin by unknown mechanism. Minor/Significance Unknown.

• vilanterol/fluticasone furoate inhaled

  Monitor Closely (1)phenytoin will decrease the level or effect of vilanterol/fluticasone furoate inhaled by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

• vilazodone

  Monitor Closely (1)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

  Monitor Closely (3)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.Minor (2)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

  Monitor Closely (2)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.Minor (2)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

  Monitor Closely (2)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.Minor (2)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.

• vindesine

  Monitor Closely (2)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

  Monitor Closely (2)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.Minor (1)phenytoin will decrease the level or effect of vinorelbine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• vitamin D

  Monitor Closely (1)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.

• voclosporin

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of voclosporin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• vonoprazan

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of vonoprazan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• vorapaxar

  Serious - Use Alternative (1)phenytoin decreases levels of vorapaxar by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• voriconazole

  Monitor Closely (2)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.Serious - Use Alternative (1)phenytoin will decrease the level or effect of voriconazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• vortioxetine

  Monitor Closely (1)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.Serious - Use Alternative (1)phenytoin will decrease the level or effect of vortioxetine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• voxelotor

  Serious - Use Alternative (1)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

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of voxilaprevir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.

• warfarin

  Monitor Closely (1)phenytoin will decrease the level or effect of warfarin by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.

• zafirlukast

  Monitor Closely (1)zafirlukast will increase the level or effect of phenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

• zaleplon

  Minor (1)phenytoin will decrease the level or effect of zaleplon by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• zanubrutinib

  Serious - Use Alternative (1)phenytoin will decrease the level or effect of zanubrutinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

• ziprasidone

  Minor (1)phenytoin will decrease the level or effect of ziprasidone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• zolpidem

  Minor (1)phenytoin will decrease the level or effect of zolpidem by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

• zonisamide

  Minor (1)phenytoin will decrease the level or effect of zonisamide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.