fosphenytoin (Rx)

Brand and Other Names:Cerebyx, Sesquient
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

injectable solution

  • Cerebyx, Sesquient, generic
    • 100mg PE/2mL
    • 500mg PE/10mL

Status Epilepticus

Cerebyx, Sesquient, generic

Indicated for treatment of generalized tonic-clonic status epilepticus

Loading dose: 15-20 mg PE/kg IV at a rate of 100-150 mg PE/min, not to exceed 150 mg PE/min  

Owing to full antiepileptic effect of phenytoin is not immediate, other measures, including coadministration of an IV benzodiazepine, may be necessary for the control of status epilepticus

If seizures continues after administration, consider using other anticonvulsants and other appropriate measures

If IV access is unavailable, loading doses have been given by IM route

Nonemergent Seizures

Cerebyx, Sesquient, generic

Indicated for prevention and treatment of seizures occurring during neurosurgery

Also, indicated for short-term substitution for oral phenytoin; only when oral phenytoin administration is not possible

Loading dose: 10-20 mg PE/kg IV; not to exceed 150 mg PE/min

Maintenance dose: 4-6 mg PE/kg/day IV in divided doses IV, not to exceed 150 mg PE/min

Individualize subsequent maintenance doses by monitoring serum concentrations to achieve a target therapeutic concentration

Owing to risks of cardiac and local toxicity associated with IV administration, oral phenytoin should be used whenever possible

Dosage Modifications

Renal or renal impairment

  • Patients with renal or hepatic disease, or in those with hypoalbuminemia may have an increase amount of unbound phenytoin (active metabolite); monitor phenytoin serum levels based on the unbound fraction
  • After IV administration to patients with renal and/or hepatic disease, or hypoalbuminemia, fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance; may potentiate the frequency and severity of adverse events

Dosing Considerations

Use caution when administering owing to the risk of dosing errors

Phenytoin sodium equivalents (PE)

  • Express dose, concentration, and infusion rate of fosphenytoin as phenytoin sodium equivalents (PE) when prescribing
  • No need to perform molecular weight-based adjustments when converting between fosphenytoin and phenytoin sodium doses

Concentration of 50 mg PE/mL

  • Do not confuse the concentration of fosphenytoin with the total amount of drug in the vial
  • Errors, including fatal overdoses, have occurred when vial concentration (50 mg PE/mL) was misinterpreted to mean that the total content of the vial was 50 mg PE
  • These errors have resulted in 2-10 fold overdoses since each of the vials actually contains a total of 100 mg PE (2-mL vial) or 500 mg PE (10-mL vial)
  • Ensure appropriate volume is withdrawn from vial when preparing dose

Monitoring parameters

  • Continually monitor electrocardiogram, blood pressure, and respiratory function
  • Observe patient throughout period where maximal serum phenytoin concentrations occur (~10-20 min after infusion ended)

Dosage Forms & Strengths

injectable solution

  • Cerebyx, Sesquient, generic
    • 100mg PE/2mL
    • 500mg PE/10mL

Status Epilepticus

Cerebyx, generic

Indicated for treatment of generalized tonic-clonic status epilepticus

Owing to full antiepileptic effect of phenytoin is not immediate, other measures, including coadministration of an IV benzodiazepine, may be necessary for the control of status epilepticus

If seizures continues after administration, consider using other anticonvulsants and other appropriate measures

If IV access is unavailable, loading doses have been given by IM route

Birth to <17 years

  • Loading dose: 15-20 mg PE/kg IV at a rate of 2 mg PE/kg/min (or 150 mg PE/min, whichever is slower)  

≥17 years

  • Loading dose: 15-20 mg PE/kg IV at a rate of 100-150 mg PE/min, not to exceed 150 mg PE/min  

Nonemergent Seizures

Cerebyx: Indicated for prevention and treatment of seizures occurring during neurosurgery

Cerebyx, Sesquient: Also, indicated for short-term substitution for oral phenytoin; only when oral phenytoin administration is not possible

Individualize subsequent maintenance doses by monitoring serum concentrations to achieve a target therapeutic concentration

Owing to risks of cardiac and local toxicity associated with IV administration, oral phenytoin should be used whenever possible

Birth to <17 years (Cerebyx, generic)

  • Loading dose: 10-15 mg PE/kg IV; 1-2 PE/kg/min, or 150 mg PE/min, whichever is slower
  • Maintenance dose
    • 2-4 mg PE/kg/day IV in q12hr divided doses initially, THEN
    • 4-8 mg PE/kg/day IV in q12hr divided doses
    • At a rate of 1-2 mg PE/kg/min (or 100 mg PE/min, whichever is slower)

≥17 years (Cerebyx)

  • Loading dose: 10-15 mg PE/kg IV; not to exceed 150 mg PE/min
  • Maintenance dose: 4-6 mg PE/kg/day IV in divided doses, not to exceed 150 mg PE/min

2-17 years (Sesquient)

  • <2 years: Safety and efficacy not established
  • >2 years
    • Loading dose: 10-15 mg PE/kg IV; not to exceed 0.4 mg PE/kg/min
    • 2-4 mg PE/kg IV in q12hr divided doses initially, THEN
    • 4-8 PE/kg/day IV in q12hr divided doses
    • Because of the betadex sulfobutyl ether sodium ingredient in Sesquient, do not exceed administration rate in pediatric patients of 0.4 mg PE/kg/min

Dosage Modifications

Renal or renal impairment

  • Patients with renal or hepatic disease, or in those with hypoalbuminemia may have an increase amount of unbound phenytoin (active metabolite); monitor phenytoin serum levels based on the unbound fraction
  • After IV administration to patients with renal and/or hepatic disease, or hypoalbuminemia, fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance; may potentiate the frequency and severity of adverse events

Dosing Considerations

Use caution when administering owing to the risk of dosing errors

Phenytoin sodium equivalents (PE)

  • Express dose, concentration, and infusion rate of fosphenytoin should always be expressed as phenytoin sodium equivalents (PE) when prescribing
  • No need to perform molecular weight-based adjustments when converting between fosphenytoin and phenytoin sodium doses

Concentration of 50 mg PE/mL

  • Do not confuse the concentration of fosphenytoin with the total amount of drug in the vial
  • Errors, including fatal overdoses, have occurred when vial concentration (50 mg PE/mL) was misinterpreted to mean that the total content of the vial was 50 mg PE
  • These errors have resulted in 2-10 fold overdoses since each of the vials actually contains a total of 100 mg PE (2-mL vial) or 500 mg PE (10-mL vial)
  • Ensure appropriate volume is withdrawn from vial when preparing dose

Monitoring parameters

  • Continually monitor electrocardiogram, blood pressure, and respiratory function
  • Observe patient throughout period where maximal serum phenytoin concentrations occur (~10-20 min after infusion ended)
  • Usual therapeutic serum total phenytoin concentration 10-20 mcg/mL (unbound phenytoin concentration [1-2 mcg/mL])
  • Recommended to not monitor until conversion to phenytoin is complete (~2 hr after end of IV infusion and ~4 hr after IM administration)
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Interactions

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            Contraindicated (25)

            • apixaban

              fosphenytoin 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

              fosphenytoin 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

            • cariprazine

              fosphenytoin 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

              fosphenytoin 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.

            • dienogest/estradiol valerate

              fosphenytoin 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

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

            • doravirine

              fosphenytoin 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

              fosphenytoin 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

              fosphenytoin 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

              fosphenytoin 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

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

            • ledipasvir/sofosbuvir

              fosphenytoin 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

              fosphenytoin 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

              fosphenytoin 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

              fosphenytoin 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

              fosphenytoin 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

              fosphenytoin decreases levels of lurasidone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Contraindicated; decreases lurasidone Cmax by ~85%.

            • naloxegol

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

            • ombitasvir/paritaprevir/ritonavir & dasabuvir

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

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

            • panobinostat

              fosphenytoin 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

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

            • regorafenib

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

            • rilpivirine

              fosphenytoin 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

              fosphenytoin 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

              fosphenytoin 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 (150)

            • abemaciclib

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

            • acalabrutinib

              fosphenytoin 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

              fosphenytoin 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

              fosphenytoin will decrease the level or effect of alpelisib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of alpelisib (CYP3A4 substrate) with strong CYP3A4 inducers.

            • apalutamide

              apalutamide will decrease the level or effect of fosphenytoin 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

              fosphenytoin 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

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

            • axitinib

              fosphenytoin 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

              fosphenytoin 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

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

            • bosutinib

              fosphenytoin 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%.

            • brigatinib

              fosphenytoin 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

              fosphenytoin 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.

            • capmatinib

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

            • ceritinib

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

              ceritinib increases levels of fosphenytoin 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

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

            • copanlisib

              fosphenytoin 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.

            • dabigatran

              fosphenytoin 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

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

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

            • dantrolene

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

            • darolutamide

              fosphenytoin 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

              fosphenytoin 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

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

            • dihydroergotamine intranasal

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

            • dolutegravir

              fosphenytoin 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

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

            • doxepin cream

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

            • dronedarone

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

            • duvelisib

              fosphenytoin 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

              fosphenytoin 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

              efavirenz will increase the level or effect of fosphenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Avoid or Use Alternate Drug.

            • eliglustat

              fosphenytoin 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

              fosphenytoin 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

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

            • entrectinib

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

            • enzalutamide

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

            • erdafitinib

              fosphenytoin 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

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

            • erythromycin base

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

            • erythromycin ethylsuccinate

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

            • erythromycin lactobionate

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

            • erythromycin stearate

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

            • everolimus

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

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

            • fedratinib

              fosphenytoin 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.

            • fentanyl

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

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

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

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

            • fexinidazole

              fosphenytoin 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

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

            • fostamatinib

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

            • gilteritinib

              fosphenytoin 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

              fosphenytoin 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.

            • haloperidol

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

            • ibrutinib

              fosphenytoin 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

              fosphenytoin 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

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

            • irinotecan

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

            • irinotecan liposomal

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

            • isosorbide dinitrate

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

            • isosorbide mononitrate

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

            • istradefylline

              fosphenytoin 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.

            • ivabradine

              fosphenytoin 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

              fosphenytoin 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

              fosphenytoin 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 fosphenytoin 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

              fosphenytoin 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%.

            • larotrectinib

              fosphenytoin 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

              fosphenytoin 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

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

            • letermovir

              fosphenytoin 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.

            • lomitapide

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

            • lovastatin

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

            • lurbinectedin

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

            • macimorelin

              fosphenytoin 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

              fosphenytoin 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

              fosphenytoin decreases levels of mebendazole by increasing metabolism. Contraindicated.

            • mefloquine

              mefloquine increases toxicity of fosphenytoin by QTc interval. Avoid or Use Alternate Drug. Mefloquine may enhance the QTc prolonging effect of high risk QTc prolonging agents.

            • mestranol

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

            • methadone

              fosphenytoin decreases levels of methadone by increasing metabolism. Contraindicated.

            • metoclopramide intranasal

              fosphenytoin, 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

              fosphenytoin 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

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

            • naldemedine

              fosphenytoin 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

              fosphenytoin 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

              fosphenytoin 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

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

            • nintedanib

              fosphenytoin 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.

            • norethindrone

              fosphenytoin 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

              fosphenytoin 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

              fosphenytoin 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

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

            • olaparib

              fosphenytoin 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.

            • osilodrostat

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

            • osimertinib

              fosphenytoin 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

              fosphenytoin 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

              fosphenytoin 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

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

            • perampanel

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

            • pexidartinib

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

            • pomalidomide

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

            • ponatinib

              fosphenytoin 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.

            • pralsetinib

              fosphenytoin 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

              fosphenytoin 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.

            • primaquine

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

            • progesterone intravaginal gel

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

            • progesterone micronized

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

            • progesterone, natural

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

            • ranolazine

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

            • ribociclib

              fosphenytoin 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

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

            • rimegepant

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

            • ripretinib

              fosphenytoin 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.

            • rivaroxaban

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

            • rolapitant

              fosphenytoin 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

              fosphenytoin will decrease the level or effect of romidepsin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration with strong 3A4 inducers should be avoided if possible.

            • selpercatinib

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

            • selumetinib

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

            • silodosin

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

            • simvastatin

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

            • siponimod

              fosphenytoin 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

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

            • sofosbuvir

              fosphenytoin 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

              fosphenytoin 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.

              fosphenytoin 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.

              fosphenytoin 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

              fosphenytoin 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

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

            • sotorasib

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

            • stiripentol

              fosphenytoin 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.

              fosphenytoin 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

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

            • tazemetostat

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

            • tepotinib

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

            • tetracycline

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

            • tezacaftor

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

            • tivozanib

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

            • tolvaptan

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

            • trabectedin

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

            • trimipramine

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

            • tucatinib

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

              fosphenytoin 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

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

            • ulipristal

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

            • upadacitinib

              fosphenytoin 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

              fosphenytoin 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

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

            • vemurafenib

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

            • venetoclax

              fosphenytoin 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.

            • vorapaxar

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

            • voriconazole

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

            • vortioxetine

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

            • voxelotor

              fosphenytoin 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

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

            • zanubrutinib

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

            Monitor Closely (322)

            • abiraterone

              fosphenytoin 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

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

            • alitretinoin

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

            • almotriptan

              fosphenytoin 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 fosphenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.

            • alprazolam

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

            • amikacin

              fosphenytoin 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 fosphenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

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

            • amitriptyline

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

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

            • amlodipine

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

            • amobarbital

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

            • antithrombin alfa

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

              fosphenytoin, 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 fosphenytoin by unknown mechanism. Use Caution/Monitor.

              fosphenytoin, 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 fosphenytoin 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.

              fosphenytoin will decrease the level or effect of apalutamide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. No initial dose adjustment

            • aprepitant

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

            • argatroban

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

              fosphenytoin, 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

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

            • atogepant

              fosphenytoin 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

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

            • avanafil

              fosphenytoin 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

              fosphenytoin 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

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

              fosphenytoin will decrease the level or effect of bazedoxifene/conjugated estrogens by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • belumosudil

              fosphenytoin 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 fosphenytoin by unknown mechanism. Use Caution/Monitor.

              fosphenytoin, 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

              fosphenytoin 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.

            • bivalirudin

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

              fosphenytoin, 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 fosphenytoin by increasing metabolism. Use Caution/Monitor.

            • blinatumomab

              blinatumomab increases levels of fosphenytoin 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

              fosphenytoin 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 fosphenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            • brentuximab vedotin

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

            • brexanolone

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

            • brexpiprazole

              fosphenytoin 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.

            • brodalumab

              brodalumab, fosphenytoin. 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

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

            • budesonide

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

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

            • buprenorphine

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

            • buprenorphine buccal

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

            • buprenorphine subdermal implant

              fosphenytoin 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

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

            • buprenorphine, long-acting injection

              fosphenytoin 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

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

            • busulfan

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

              fosphenytoin 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 fosphenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            • butalbital

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

            • cabazitaxel

              fosphenytoin 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

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

            • calcitriol

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

            • cannabidiol

              fosphenytoin 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 fosphenytoin 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 fosphenytoin by decreasing metabolism. Modify Therapy/Monitor Closely. Cannabidiol may potentially inhibit CYP2C9 activity. Consider reducing the dose when concomitantly using CYP2C9 substrates.

            • capecitabine

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

            • carbamazepine

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

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

            • carboplatin

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

            • carmustine

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

            • cenobamate

              cenobamate will increase the level or effect of fosphenytoin 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.

            • chloramphenicol

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

            • chlordiazepoxide

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

            • chlorpheniramine

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

            • cilostazol

              fosphenytoin 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 fosphenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            • cinacalcet

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

            • cisatracurium

              fosphenytoin 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 fosphenytoin by unknown mechanism. Use Caution/Monitor.

            • citalopram

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

            • clobetasone

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

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

            • clomipramine

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

            • clonazepam

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

            • clopidogrel

              fosphenytoin 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

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

            • clozapine

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

            • colesevelam

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

            • conivaptan

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

            • conjugated estrogens

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

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

            • conjugated estrogens, vaginal

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

              fosphenytoin will decrease the level or effect of conjugated estrogens, vaginal by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • cortisone

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

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

            • crizotinib

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

            • cyclosporine

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

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

            • dalteparin

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

              fosphenytoin, 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.

            • darifenacin

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

            • darunavir

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

            • dasatinib

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

            • deferasirox

              fosphenytoin 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

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

            • desipramine

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

            • deutetrabenazine

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

            • dexamethasone

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

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

            • dexlansoprazole

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

            • diazepam

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

            • diazepam intranasal

              fosphenytoin 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.

              fosphenytoin 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.

            • dichlorphenamide

              dichlorphenamide and fosphenytoin both decrease serum potassium. Use Caution/Monitor.

            • digoxin

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

            • diltiazem

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

              diltiazem will increase the level or effect of fosphenytoin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor for phenytoin toxicity if diltiazem is initiated/dose increased, or decreased phenytoin effects if diltiazem is discontinued/dose decreased. Monitor for reduced diltiazem therapeutic effects with concomitant fosphenytoin.

            • disopyramide

              fosphenytoin 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 fosphenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            • docetaxel

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

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

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

            • doxorubicin

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

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

            • doxorubicin liposomal

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

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

            • dronabinol

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

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

            • dulaglutide

              dulaglutide, fosphenytoin. 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, fosphenytoin. 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

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

            • elagolix

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

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

            • eletriptan

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

            • elvitegravir/cobicistat/emtricitabine/tenofovir DF

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

            • enfortumab vedotin

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

            • enoxaparin

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

              fosphenytoin, 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

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

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

            • escitalopram

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

            • esketamine intranasal

              esketamine intranasal, fosphenytoin. Either increases toxicity of the other by sedation. Use Caution/Monitor.

            • eslicarbazepine acetate

              fosphenytoin decreases levels of eslicarbazepine acetate by increasing metabolism. Modify Therapy/Monitor Closely. Higher doses of eslicarbazepine may be required.

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

            • esomeprazole

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

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

            • estradiol

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

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

            • estradiol vaginal

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

            • estrogens conjugated synthetic

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

              fosphenytoin will decrease the level or effect of estrogens conjugated synthetic by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • estrogens esterified

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

            • estropipate

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

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

            • eszopiclone

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

            • ethanol

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

              ethanol will increase the level or effect of fosphenytoin by decreasing metabolism. Use Caution/Monitor. Increased phenytoin levels may be seen with acute alcohol ingestion

            • ethosuximide

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

            • etonogestrel

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

            • etoposide

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

            • etravirine

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

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

            • exemestane

              fosphenytoin 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.

            • fedratinib

              fedratinib will increase the level or effect of fosphenytoin by affecting hepatic enzyme CYP2C19 metabolism. Use Caution/Monitor. Adjust dose of drugs that are CYP2C19 substrates as necessary.

            • felbamate

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

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

            • felodipine

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

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

            • fenofibrate

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

            • fenofibrate micronized

              fosphenytoin will decrease the level or effect of fenofibrate micronized by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • fenofibric acid

              fosphenytoin will decrease the level or effect of fenofibric acid by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • ferric maltol

              ferric maltol, fosphenytoin. 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

              fosphenytoin 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 fosphenytoin by affecting hepatic enzyme CYP2C19 metabolism. Use Caution/Monitor.

            • fleroxacin

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

            • flibanserin

              fosphenytoin 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 fosphenytoin by unknown mechanism. Use Caution/Monitor. Based on case reports.

            • fluconazole

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

            • fludrocortisone

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

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

            • fluorouracil

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

            • fluoxetine

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

            • flurazepam

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

            • fluticasone furoate

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

            • fluticasone inhaled

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

            • fluvastatin

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

            • fluvoxamine

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

            • fondaparinux

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

              fosphenytoin, 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

              fosphenytoin, fosamprenavir. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration of fosphenytoin 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

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

            • gentamicin

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

            • glecaprevir/pibrentasvir

              fosphenytoin will decrease the level or effect of glecaprevir/pibrentasvir by increasing metabolism. Use Caution/Monitor. Coadministration of drugs that induce CYP3A4 and P-gp with glecaprevir/pibrentasvir may decrease glecaprevir/pibrentasvir plasma concentrations. Potential for loss of therapeutic effect.

              fosphenytoin will decrease the level or effect of glecaprevir/pibrentasvir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • glyburide

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

            • green tea

              fosphenytoin decreases levels of green tea by increasing metabolism. Use Caution/Monitor. Potential for decreased effects of caffeine in green tea. .

            • guanfacine

              fosphenytoin 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, fosphenytoin. 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.

            • heparin

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

              fosphenytoin, 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.

            • hydrocodone

              fosphenytoin 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

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

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

            • hydroxyprogesterone caproate

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

            • ifosfamide

              fosphenytoin increases toxicity of ifosfamide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. CYP3A4/CYP2B6 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

              fosphenytoin 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 fosphenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

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

            • imipramine

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

            • indinavir

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

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

            • ivermectin

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

            • ixabepilone

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

            • ixekizumab

              ixekizumab, fosphenytoin. 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 fosphenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            • lacosamide

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

            • lamotrigine

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

            • lapatinib

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

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

            • lasmiditan

              lasmiditan, fosphenytoin. 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 fosphenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            • lemborexant

              lemborexant, fosphenytoin. 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

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

            • levamlodipine

              fosphenytoin 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

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

            • levofloxacin

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

            • levonorgestrel intrauterine

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

            • levonorgestrel oral

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

            • levonorgestrel oral/ethinylestradiol/ferrous bisglycinate

              fosphenytoin 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

              fosphenytoin 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

              fosphenytoin 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.

            • loperamide

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

            • lopinavir

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

            • loratadine

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

            • losartan

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

            • lumacaftor/ivacaftor

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

              lumacaftor/ivacaftor, fosphenytoin. 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, fosphenytoin. 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

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

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

            • marijuana

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

            • medroxyprogesterone

              fosphenytoin will decrease the level or effect of medroxyprogesterone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Contraceptirve failure possible. Use alternative if available.

            • mestranol

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

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

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

            • metformin

              fosphenytoin 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

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

            • methotrexate

              fosphenytoin 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.

            • methylphenidate

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

            • methylprednisolone

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

              fosphenytoin 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 fosphenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            • metyrapone

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

            • mexiletine

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

            • miconazole oral

              fosphenytoin will decrease the level or effect of miconazole oral by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • miconazole vaginal

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

            • midazolam

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

            • midazolam intranasal

              midazolam intranasal, fosphenytoin. 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

              fosphenytoin 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, fosphenytoin. 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

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

            • mitoxantrone

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

            • modafinil

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

            • moxifloxacin

              moxifloxacin decreases effects of fosphenytoin 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 fosphenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

              fosphenytoin 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

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

            • nelfinavir

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

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

            • neomycin PO

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

            • nevirapine

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

            • nicardipine

              fosphenytoin 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 fosphenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

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

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

            • nisoldipine

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

            • oliceridine

              fosphenytoin 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 fosphenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

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

            • oritavancin

              oritavancin will increase the level or effect of fosphenytoin 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 fosphenytoin by inhibition of GI absorption. Applies only to oral form of both agents. Modify Therapy/Monitor Closely. Risk of convulsions.

            • osilodrostat

              fosphenytoin 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

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

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

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

            • oxaliplatin

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

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

              oxaliplatin will decrease the level or effect of fosphenytoin 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 will increase the level or effect of fosphenytoin by affecting hepatic enzyme CYP2C19 metabolism. Use Caution/Monitor.

            • oxycodone

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

            • paclitaxel

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

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

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

              fosphenytoin 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 fosphenytoin by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

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

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

              fosphenytoin 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

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

            • pancuronium

              fosphenytoin 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.

            • paricalcitol

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

            • paromomycin

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

            • pazopanib

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

            • pentobarbital

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

            • phenindione

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

              fosphenytoin, 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 fosphenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            • pimavanserin

              fosphenytoin 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

              fosphenytoin 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

              fosphenytoin 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

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

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

            • prednisolone

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

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

            • prednisone

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

              fosphenytoin 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 fosphenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

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

            • protamine

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

              fosphenytoin, 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

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

            • quetiapine

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

            • quinidine

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

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

            • repaglinide

              fosphenytoin 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 fosphenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            • rifapentine

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

            • riociguat

              fosphenytoin 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

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

            • ritonavir

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

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

            • rocuronium

              fosphenytoin 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.

            • ruxolitinib

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

            • saquinavir

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

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

            • sarilumab

              sarilumab, fosphenytoin. 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 fosphenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            • secukinumab

              secukinumab, fosphenytoin. 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

              fosphenytoin 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 fosphenytoin by decreasing metabolism. Use Caution/Monitor.

            • sevelamer

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

            • sildenafil

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

            • silodosin

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

            • sirolimus

              fosphenytoin 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 fosphenytoin 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 fosphenytoin 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

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

            • sorafenib

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

            • stiripentol

              stiripentol will increase the level or effect of fosphenytoin 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, fosphenytoin. 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

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

            • sufentanil SL

              fosphenytoin 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 fosphenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            • sunitinib

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

            • suvorexant

              fosphenytoin 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

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

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

            • tadalafil

              fosphenytoin 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

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

            • tasimelteon

              fosphenytoin 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 fosphenytoin 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.

            • temsirolimus

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

            • teniposide

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

            • terbinafine

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

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

            • theophylline

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

            • tiagabine

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

            • ticagrelor

              fosphenytoin 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 fosphenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

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

            • tinidazole

              tinidazole will increase the level or effect of fosphenytoin 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)

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

            • tipranavir

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

            • tobramycin

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

            • tofacitinib

              fosphenytoin 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

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

            • tolvaptan

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

            • topiramate

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

            • toremifene

              fosphenytoin 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

              fosphenytoin 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

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

            • treosulfan

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

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

            • triamcinolone acetonide injectable suspension

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

            • triazolam

              fosphenytoin 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 fosphenytoin 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.

            • trimethoprim

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

            • ustekinumab

              ustekinumab, fosphenytoin. 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 fosphenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

            • vardenafil

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

            • vecuronium

              fosphenytoin 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

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

            • verapamil

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

            • vilanterol/fluticasone furoate inhaled

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

            • vilazodone

              fosphenytoin 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

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

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

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

            • vincristine

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

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

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

            • vincristine liposomal

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

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

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

            • vindesine

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

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

            • vinorelbine

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

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

            • vitamin D

              fosphenytoin 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 fosphenytoin by affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor.

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

            • vortioxetine

              fosphenytoin decreases 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

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

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

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

            • zafirlukast

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

            Minor (113)

            • acetaminophen

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

            • acetaminophen IV

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

            • acetaminophen rectal

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

            • acetazolamide

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

            • alfentanil

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

            • alfuzosin

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

            • alosetron

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

            • alvimopan

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

            • ambrisentan

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

            • armodafinil

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

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

            • atazanavir

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

            • atracurium

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

            • auranofin

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

            • bexarotene

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

            • biotin

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

            • bosentan

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

            • brinzolamide

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

            • carbamazepine

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

            • caspofungin

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

            • cevimeline

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

            • clarithromycin

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

            • clopidogrel

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

            • cyanocobalamin

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

            • dapsone

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

            • dexmethylphenidate

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

            • diazoxide

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

            • disopyramide

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

            • disulfiram

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

            • docetaxel

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

            • donepezil

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

            • doxycycline

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

            • dutasteride

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

            • efavirenz

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

            • eplerenone

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

            • ethosuximide

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

            • eucalyptus

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

            • felbamate

              fosphenytoin decreases levels of felbamate by increasing metabolism. Minor/Significance Unknown. Toxicity increased with combination.

            • fexofenadine

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

            • finasteride

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

            • furosemide

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

            • galantamine

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

            • imatinib

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

            • immune globulin IM (IGIM)

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

            • immune globulin IV (IGIV)

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

            • immune globulin SC

              fosphenytoin, 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, fosphenytoin. 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, fosphenytoin. Mechanism: unknown. Minor/Significance Unknown. Vaccine administration may incr or decr phenytoin levels.

            • influenza virus vaccine trivalent

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

            • influenza virus vaccine trivalent, recombinant

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

            • isoniazid

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

            • isradipine

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

            • ketoconazole

              fosphenytoin 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 fosphenytoin by increasing metabolism. Minor/Significance Unknown.

            • lansoprazole

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

            • levocarnitine

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

            • levothyroxine

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

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

            • liothyronine

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

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

            • lithium

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

            • loratadine

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

            • meperidine

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

            • methazolamide

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

            • methsuximide

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

            • montelukast

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

            • nimodipine

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

            • nitrendipine

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

            • onabotulinumtoxinA

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

            • ondansetron

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

            • oxcarbazepine

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

            • oxybutynin

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

            • paclitaxel

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

            • paclitaxel protein bound

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

            • pantoprazole

              fosphenytoin will decrease the level or effect of pantoprazole by affecting hepatic enzyme CYP2C19 metabolism. Minor/Significance Unknown.

            • parecoxib

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

            • phenobarbital

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

            • pimozide

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

            • pioglitazone

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

            • propafenone

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

            • pyridoxine

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

            • pyridoxine (Antidote)

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

            • pyrimethamine

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

            • quinine

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

            • rabeprazole

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

            • ramelteon

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

            • rapacuronium

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

            • rifabutin

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

            • sage

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

            • saxagliptin

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

            • succinylcholine

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

            • sucralfate

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

            • sufentanil

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

            • sulfadiazine

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

            • sulfamethoxazole

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

            • sulfisoxazole

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

            • thyroid desiccated

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

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

            • tiagabine

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

            • tibolone

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

            • tolazamide

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

            • tolbutamide

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

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

            • topiramate

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

            • trazodone

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

            • typhoid polysaccharide vaccine

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

            • typhoid vaccine live

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

            • valproic acid

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

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

            • vigabatrin

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

            • vinblastine

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

            • vincristine

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

            • vincristine liposomal

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

            • vinorelbine

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

            • zaleplon

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

            • ziprasidone

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

            • zolpidem

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

            • zonisamide

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

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            Adverse Effects

            >10%

            Adults and children

            • Body as a whole: Fever, injection-site reaction, infection, chills, face edema, injection-site pain
            • Cardiovascular: Hypertension
            • Digestive: Constipation
            • Metabolic and nutritional: Hypokalemia
            • Musculoskeletal: Myasthenia; Infrequent: myopathy, leg cramps, arthralgia, myalgia
            • Nervous: Reflexes increased, speech disorder, dysarthria, intracranial hypertension, thinking abnormal, nervousness
            • Respiratory: Pneumonia
            • Skin and appendages: Rash

            IV, adults

            • Pruritus (49%)
            • Nystagmus (44%)
            • Dizziness (31%)
            • Somnolence (20%)
            • Ataxia (11%)

            IV, children and adolescents

            • Vomiting (21%)
            • Nystagmus (18%)

            IM

            • Nystagmus (15%)

            1-10%

            Adults and children

            • Body as a whole: Sepsis, injection-site inflammation, injection-site edema, injection-site hemorrhage, flu syndrome, malaise, generalized edema, shock, photosensitivity reaction, cachexia, cryptococcosis
            • Endocrine: Diabetes insipidus
            • Hematologic and lymphatic: Thrombocytopenia, anemia, leukocytosis, cyanosis, hypochromic anemia, leukopenia, lymphadenopathy, petechia
            • Metabolic and nutritional: Hyperglycemia, hypophosphatemia, alkalosis, acidosis, dehydration, hyperkalemia, ketosis
            • Musculoskeletal: Myopathy, leg cramps, arthralgia, myalgia
            • Nervous: Confusion, twitching, Babinski sign positive, circumoral paresthesia, hemiplegia, hypotonia, convulsion, extrapyramidal syndrome, insomnia, meningitis, depersonalization, CNS depression, depression, hypokinesia, hyperkinesia, paralysis, psychosis, aphasia, emotional lability, coma, hyperesthesia, myoclonus, personality disorder, acute brain syndrome, encephalitis, subdural hematoma, encephalopathy, hostility, akathisia, amnesia, neurosis
            • Skin and appendages: Maculopapular rash, urticaria, sweating, skin discoloration, contact dermatitis, pustular rash, skin nodule
            • Special senses: Visual field defect, eye pain, conjunctivitis, photophobia, hyperacusis, mydriasis, parosmia, ear pain, taste loss
            • Urogenital: Urinary retention, oliguria, dysuria, vaginitis, albuminuria, genital edema, kidney failure, polyuria, urethral pain, urinary incontinence, vaginal moniliasis

            IV, adults

            • Nausea (9%)
            • Tinnitus (9%)
            • Hypotension (8%)
            • Stupor (8%)
            • Vasodilatation (6%)
            • Pelvic pain (4%)
            • Tongue disorder (4%)
            • Dry mouth (4%)
            • Incoordination (4%)
            • Paresthesia (4%)
            • Extrapyramidal syndrome (4%)
            • Tremor (3%)
            • Agitation (3%)
            • Diplopia (3%)
            • Taste perversion (3%)
            • Amblyopia (2%)
            • Deafness (2%)
            • Hypesthesia (2%)
            • Dysarthria (2%)
            • Vertigo (2%)
            • Brain edema (2%)
            • Vomiting (2%)
            • Asthenia (2%)
            • Back pain (2%)
            • Headache (2%)

            IV, children and adolescents

            • Ataxia (10%)
            • Fever (8%)
            • Nervousness (7%)
            • Pruritus (6%)
            • Somnolence (6%)
            • Hypotension (5%)
            • Rash (5%)

            IM

            • Tremor (10%)
            • Headache (9%)
            • Asthenia (9%)
            • Ataxia (8%)
            • Incoordination (8%)
            • Somnolence (7%)
            • Dizziness (5%)
            • Nausea (5%)
            • Paresthesia (4%)
            • Reflexes decreased (3%)
            • Pruritus (3%)
            • Vomiting (3%)

            Postmarketing Reports

            Body as a whole: Anaphylaxis, angioedema

            Laboratory test abnormality: Decrease serum concentrations of T4; may also produce lower than normal values for dexamethasone or metyrapone tests; increase serum levels of gamma glutamyl transpeptidase

            Nervous system disorders: Dyskinesia

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            Warnings

            Black Box Warnings

            Cardiovascular risk associated with rapid infusion rates

            • Risk of hypotension and arrhythmias with infusion rates that exceed 150 mg/minute of phenytoin sodium equivalents (PE)
            • Careful cardiac monitoring is needed during and after administering IV administration; these events have also been reported at or below 150 mg PE/minute
            • Recommended doses should not be changed when substituting fosphenytoin for phenytoin or vice versa; they are not equivalent on mg to mg basis
            • Reduce infusion rate or discontinuation may be needed

            Contraindications

            Hypersensitivity to or its inactive ingredients, or to phenytoin or other hydantoins

            Sinus bradycardia, sinoatrial block, 2nd or 3rd degree AV block, Adams-Stokes syndrome

            Prior history of acute hepatotoxicity attributable to fosphenytoin or phenytoin

            Coadministration with delavirdine

            Cautions

            Do NOT give IM for status epilepticus initial dose

            Renal, hepatic or other hypoalbuminemic disease: monitor unbound phenytoin concentration

            Do not abruptly discontinue antiepileptic drugs because of the possibility of increased seizure frequency, including status epilepticus; in the event of an allergic or hypersensitivity reaction, rapid substitution of alternative therapy may be necessary

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

            Hyperglycemia, resulting from phenytoin’s inhibitory effect on insulin release, reported; phenytoin may also raise serum glucose concentrations in diabetic patients

            Do not discontinue antiepileptic drugs abruptly because of possibility of increased seizure frequency, including status epilepticus; reduce dose gradually when necessary; in the event of allergic or hypersensitivity reaction, rapid substitution of alternative therapy, not belonging to hydantoin chemical class is necessary

            Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, reported with phenytoin; discontinue and do not readminister if acute hepatotoxicity occurs

            Hematopoietic complications (eg, thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, pancytopenia with or without bone marrow suppression), some fatal, have occasionally been reported; in cases of lymphadenopathy, follow-up observation for an extended period is indicated

            Consider phosphate load (0.0037 mmol phosphate/mg PE fosphenytoin) when treating patients who require phosphate restriction, such as those with severe renal impairment

            Safety/efficacy not evaluated for administration > 5 days

            Consider alternatives to structurally similar drugs such as carboxamides (eg, carbamazepine), barbiturates, succinimides, and oxazolidinediones (eg, trimethadione) in patients who experienced phenytoin hypersensitivity

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

            Severe burning, itching, and/or paresthesia were reported; IV fosphenytoin at doses of 20 mg PE/kg at 150 mg PE/min are expected to experience discomfort of some degree; occurrence and intensity of discomfort can be lessened by slowing or temporarily stopping the infusion

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

            May cause fetal harm when administered to pregnant females

            Hyperglycemia, resulting from inhibitory effect of phenytoin on insulin release, has been reported; phenytoin may also raise serum glucose concentrations in diabetic patients

            Serum levels of phenytoin (the active metabolite of fosphenytoin) sustained above therapeutic range may produce confusional states referred to as “delirium,” “psychosis,” or “encephalopathy,” or rarely, irreversible cerebellar dysfunction and/or cerebellar atrophy; at first sign of acute toxicity, check serum levels immediately; reduce dose if serum levels are excessive; discontinue therapy if symptoms persist

            Patients with decreased CYP2C9 function

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

            Cardiovascular risk associated with rapid infusion

            • Rapid IV administration increases the risk of adverse cardiovascular reactions, including severe hypotension and cardiac arrhythmias (eg, bradycardia, heart block, QT prolongation, ventricular tachycardia, ventricular fibrillation); use oral phenytoin whenever possible
            • Carefully monitor cardiac and respiratory function and after IV administration; consider reducing rate or discontinuing dose

            Severe cutaneous reactions

            • Can cause severe cutaneous adverse reactions (SCARs), which may be fatal
            • Reported reactions include toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), acute generalized exanthematous pustulosis (AGEP), and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
            • Onset is usually within 28 days, but can occur later
            • Discontinue at the first sign of a rash, unless the rash is clearly not drug-related
            • If signs or symptoms suggest a severe cutaneous adverse reaction, do not resume drug; consider alternant therapy
            • Studies in patients of Chinese ancestry have found a strong association between risk of developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA B gene in patients taking carbamazepine
            • Limited evidence suggests that HLA-B*1502 or CYP2C9*3 may also be a risk factor for the development of SJS/TEN in patients taking other antiepileptic drugs

            DRESS

            • DRESS, also known as multiorgan hypersensitivity, reported in patients taking antiepileptic drugs, including phenytoin and fosphenytoin
            • Some of these events have been fatal or life-threatening
            • DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement (eg, hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection); eosinophilia is often present
            • Early manifestations of hypersensitivity (eg, fever or lymphadenopathy) may be present even though rash is not evident
            • If such signs or symptoms are present, evaluate patient immediately; discontinue drug if unable to confirm other etiology for the rash

            Dosing errors

            • Do not confuse amount of drug to be given in PE with concentration of drug in vial
            • Medication errors associated with fosphenytoin have resulted in wrong dose being administer

            Drug interaction overview

            • CYP2C9 and CYP2C19 substrate; potent inducer of hepatic drug-metabolizing enzymes
            • Extensively bound to human plasma proteins
            • Addition or withdrawal of these agents in patients on phenytoin therapy may require an dosage adjustment of the phenytoin to achieve optimal clinical outcome
            • Drugs that may increase phenytoin concentration
              • Antiepileptic drugs (ie, ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate)
              • Azoles (ie, fluconazole, ketoconazole, itraconazole, miconazole, voriconazole)
              • Antineoplastic agents (eg, capecitabine, fluorouracil)
              • Antidepressants (ie, fluoxetine, fluvoxamine, sertraline)
              • Gastric acid reducing agents (eg, H2 antagonists, omeprazole)
              • Sulfonamides (eg, sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole/trimethoprim)
              • Acute alcohol intake, amiodarone, chloramphenicol, chlordiazepoxide, disulfiram, estrogen, fluvastatin, isoniazid, methylphenidate, phenothiazines, salicylates, ticlopidine, tolbutamide, trazodone, warfarin
              • Drugs highly bound to albumin could increase the unbound fraction of fosphenytoin
            • Drug that may decrease phenytoin serum levels
              • Antineoplastic agents, usually in combination (eg, bleomycin, carboplatin, cisplatin, methotrexate
              • Antiviral agents (eg, fosamprenavir, nelfinavir, ritonavir)
              • Antiepileptic drugs (eg, carbamazepine, vigabatrin)
              • Chronic alcohol abuse, diazepam, diazoxide, folic acid, reserpine, rifampin, St. John wort, theophylline
              • Drugs that may either increase or decrease phenytoin serum levels H5
              • Antiepileptic drugs (eg, phenobarbital, valproate sodium, valproic acid)
            • Drugs that decrease efficacy by phenytoin
              • Azoles (eg, fluconazole, ketoconazole, itraconazole, posaconazole, voriconazole)
              • Antineoplastic agents (eg, irinotecan, paclitaxel, teniposide)
              • Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin
              • Coadministration with NNRTIs may cause loss of virologic response and possible resistance to NNRTIs (eg, delavirdine)
              • Cisatracurium, pancuronium, rocuronium and vecuronium: resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents has occurred in patients chronically administered phenytoin; closely monitor for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher
              • Others: Corticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D
            • Drugs whose level is decreased by phenytoin
              • Antiepileptic drugs (eg, carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine)
              • Antilipidemic agents (eg, atorvastatin, fluvastatin, simvastatin)
              • Antiviral agents (eg, efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir)
              • Fosamprenavir: Phenytoin is coadministered with fosamprenavir alone may decrease the concentration of amprenavir (active metabolite); when phenytoin is coadministered with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir
              • Calcium channel blockers (eg, nifedipine, nimodipine, nisoldipine, verapamil)
              • Others: Albendazole (decreases active metabolite), chlorpropamide, clozapine, cyclosporine, digoxin, disopyramide, folic acid, methadone, mexiletine, praziquantel, quetiapine
            • Drug/laboratory test interactions
              • Exercise caution when using immunoanalytical methods to measure serum phenytoin concentrations following administration
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            Pregnancy & Lactation

            Pregnancy

            Exposure of phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes

            Prenatal phenytoin exposure is associated with an increased incidence of major malformations, including orofacial clefts and cardiac defects

            In addition, the fetal hydantoin syndrome, a pattern of abnormalities including dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits has been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy

            There have been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy

            Pregnancy exposure registry

            • Monitors pregnancy outcomes in women exposed to antiepileptic drugs during pregnancy
            • Advised to pregnant females to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling the toll free number 1-888-233-2334, and must be done by patients themselves
            • Information on the registry can also be found at http://www.aedpregnancyregistry.org/

            Animal data

            • Administration to pregnant animals resulted in an increased incidence of fetal malformations and other manifestations of developmental toxicity (including embryofetal death, growth impairment, and behavioral abnormalities) in multiple species at clinically relevant doses

            Clinical considerations

            • An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics
            • Consider periodic measurement of serum phenytoin concentrations to provide the appropriate dosage adjustment; postpartum restoration of original dosage may be necessary
            • A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero; may be prevented with vitamin K administration to mother before delivery and to neonate after birth

            Lactation

            It is not known whether fosphenytoin is secreted in human milk

            Following administration of phenytoin, phenytoin is secreted in human milk

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Converted to phenytoin after injection; stabilizes neuronal membranes and decrease seizure activity by increasing efflux or decreasin influx of sodium ions across cell membranes in the motor cortex during generation of nerve impulses

            Absorption

            Bioavailability (IM): Completely bioavailable

            Peak plasma concentration

            • IV: When administered by IV infusion, maximum plasma fosphenytoin concentrations are achieved at the end of the infusion
            • IM: Following IM administration, plasma concentration are lower but more sustained than IV due to time required for absorption of fosphenytoin from the injection site

            Peak plasma time

            • IM: ~30 minutes postdose

            Distribution

            Protein bound: ~95-99% to human plasma proteins, primarily albumin

            Vd: 4.3-10.8 L

            Metabolism

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

            Elimination

            Half-life: ~ 15 min (conversion of fosphenytoin to phenytoin)

            Excretion: Not in urine

            Pharmacogenomics

            Patients with HLA-B*1502 with are more likely to have a severe dermatologic reaction (eg, TEN, Stevens-Johnson syndrome) when taking phenytoin

            This allele occurs almost exclusively in patients with ancestry across broad areas of Asia, including Han Chinese, Filipinos, Malaysians, South Asian Indians, and Thais

            Maternal epoxide (EPHX1) genotypes 113*H and 139*R are associated with risk of fetal hydantoin syndrome among pregnant women taking phenytoin

            Increased levels of the reactive epoxide metabolites by either inhibiting the detoxification of these metabolites by epoxide hydrolase or by increasing conversion to epoxide metabolites by inducing CYP3A4, 2C9, or 2C19

            Genetic testing laboratories

            • The following companies provide genetic testing for HLA variants
            • Kashi Clinical Laboratories (www.kashilab.com)
            • LabCorp (http://www.labcorp.com/)
            • Specialty Laboratories (http://www.specialtylabs.com)
            • Quest (http://www.questdialgnotics.com)
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            Administration

            IV Incompatibilities

            Y-site: fenoldopam, midazolam

            IV Preparation

            Dilute in D5W or NS to concentration of 1.5-25 mg PE/mL

            IV Administration

            Express all dosing in mg "phenytoin equivalents" (PE); 1 mg PE is equivalent to 1 mg phenytoin sodium

            Do not confuse the concentration with the total amount of drug in the vial

            IV infusion preferred route for emergent use and for pediatrics because of delayed absorption

            Maximum IV infusion rate

            • Adults (≥17 years): Not to exceed 150 mg PE/min
            • Birth to <17 years: 2 mg PE/kg/min (or 100 mg PE/min, whichever is slower)

            Monitor

            • Continuous monitoring of ECG, BP, and respiratory function essential; observe patient throughout the period where maximal serum phenytoin concentrations occur, ~10-20 min after the end of infusions
            • Phenytoin levels: Obtain 2 hr after IV or 4 hr after IM

            Storage

            Unused vials

            • Cerebyx, generic: Refrigerate at 2-8ºC (36-46ºF); do not store at room temperature for more than 48 hr
            • Sesquient: Store at room temperature 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86∫F)
            • Vials that develop particulate matter should not be used
            • After opening, discard any unused solution in vials

            Diluted infusions

            • Stable at 1, 8, and 20 mg PE/mL in normal saline or D5W at 25ºC (77ºF) for 30 days in glass container and at 4-20ºC (39-68ºF) for 30 days in PVC bag
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            Images

            BRAND FORM. UNIT PRICE PILL IMAGE
            fosphenytoin injection
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            100 mg PE/2 mL vial
            fosphenytoin injection
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            500 mg PE/10 mL vial
            fosphenytoin injection
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            100 mg PE/2 mL vial
            fosphenytoin injection
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            500 mg PE/10 mL vial
            fosphenytoin injection
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            500 mg PE/10 mL vial
            fosphenytoin injection
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            100 mg PE/2 mL vial
            fosphenytoin injection
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            100 mg PE/2 mL vial
            fosphenytoin injection
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            100 mg PE/2 mL vial
            fosphenytoin injection
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            500 mg PE/10 mL vial
            fosphenytoin injection
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            100 mg PE/2 mL vial
            fosphenytoin injection
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            500 mg PE/10 mL vial
            fosphenytoin injection
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            500 mg PE/10 mL vial
            fosphenytoin injection
            -
            500 mg PE/10 mL vial
            fosphenytoin injection
            -
            100 mg PE/2 mL vial
            fosphenytoin injection
            -
            500 mg PE/10 mL vial
            Cerebyx injection
            -
            100 mg PE/2 mL vial
            Cerebyx injection
            -
            500 mg PE/10 mL vial
            Cerebyx injection
            -
            100 mg PE/2 mL vial
            Cerebyx injection
            -
            500 mg PE/10 mL vial
            Cerebyx injection
            -
            100 mg PE/2 mL vial
            Cerebyx injection
            -
            500 mg PE/10 mL vial
            Cerebyx injection
            -
            500 mg PE/10 mL vial
            Cerebyx injection
            -
            100 mg PE/2 mL vial

            Copyright © 2010 First DataBank, Inc.

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            Patient Handout

            Patient Education
            fosphenytoin injection

            NO MONOGRAPH AVAILABLE AT THIS TIME

            USES: Consult your pharmacist.

            HOW TO USE: Consult your pharmacist.

            SIDE EFFECTS: Consult your pharmacist.In the US -Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

            PRECAUTIONS: Consult your pharmacist.

            DRUG INTERACTIONS: Consult your pharmacist.Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

            OVERDOSE: If someone has overdosed and has serious symptoms such as passing out or trouble breathing, call 911. Otherwise, call a poison control center right away. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center.

            NOTES: No monograph available at this time.

            MISSED DOSE: Consult your pharmacist.

            STORAGE: Consult your pharmacist.Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

            Information last revised July 2016. Copyright(c) 2021 First Databank, Inc.

            IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

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            Formulary

            FormularyPatient Discounts

            Adding plans allows you to compare formulary status to other drugs in the same class.

            To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

            Adding plans allows you to:

            • View the formulary and any restrictions for each plan.
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            • Compare formulary status to other drugs in the same class.
            • Access your plan list on any device – mobile or desktop.

            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
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            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.