Phenytoin

Combined P-gp and strong CYP3A4 inducer that decreases apixaban exposure and increases risk of stroke and thromboembolic events. Avoid concomitant use.

Strong CYP3A4 inducer contraindicated with artemether and lumefantrine due to potential loss of antimalarial efficacy.

Strong UGT1A1 inducer that significantly decreases cabotegravir plasma concentrations. Coadministration is contraindicated.

Strong CYP3A4 inducer that decreases clozapine plasma concentration. Concomitant use is not recommended due to decreased clozapine effectiveness.

Co-administration decreases doravirine plasma concentrations. At least a 4-week cessation period is recommended prior to initiation of PIFELTRO.

Co-administration decreases doravirine plasma concentrations and is contraindicated. At least a 4-week cessation period is recommended prior to initiation of DELSTRIGO.

Strong CYP3A inducer expected to decrease elexacaftor, tezacaftor, and ivacaftor exposures, reducing TRIKAFTA efficacy.

Strong CYP3A4 inducer. Should not use Estradiol Valerate/Dienogest while taking or for 28 days after discontinuation due to risk of decreased contraceptive efficacy.

Phenytoin is incompatible with hyaluronidase.

Incompatible with hyaluronidase; physical or chemical incompatibility reported.

Strong CYP3A4 inducer substantially reduces exposure to irinotecan and SN-38. Do not administer unless no therapeutic alternatives exist.

Strong CYP3A4 inducer. Avoid concomitant use with istradefylline.

Strong CYP3A inducer. Avoid concomitant use with NINLARO (ixazomib).

Phenytoin decreases lenacapavir concentration, resulting in loss of therapeutic effect and development of resistance.

Strong CYP3A4 inducer that decreases lurasidone exposure; concomitant use is contraindicated.

Phenytoin reduces nisoldipine plasma concentrations to undetectable levels. Coadministration should be avoided and alternative antihypertensive therapy considered.

Avoid coadministration of phenytoin with posaconazole unless the benefit outweighs the risks.

CYP3A inducer. Do not use with ranolazine extended-release tablets.

Coadministration is contraindicated due to decreased rilpivirine plasma concentrations and loss of virologic response.

Coadministration is contraindicated. Induces CYP3A, resulting in decreased rilpivirine plasma concentrations and loss of virologic response.

Combined P-gp and strong CYP3A inducer that decreases rivaroxaban exposure and may increase thromboembolic risk. Avoid concomitant use.

Strong CYP3A inducer that substantially reduces ticagrelor exposure and decreases efficacy.

P-gp inducer that decreases tenofovir alafenamide concentrations. Coadministration is not recommended.

Strong CYP3A4 inducer substantially decreases aprepitant exposure, which may decrease efficacy. Avoid concomitant use.

Increased risk of methemoglobinemia when concurrently exposed to articaine.

Increased risk of developing methemoglobinemia when concurrently exposed to this anticonvulsant.

Folic acid may increase phenytoin metabolism, lowering serum concentration and increasing seizure activity risk.

Strong CYP3A4/5 inducer reduces axitinib plasma exposure. Co-administration should be avoided.

CYP3A4 inducer decreases hydrocodone plasma concentration, resulting in decreased efficacy and risk of withdrawal syndrome. Stopping inducer may cause serious respiratory depression.

Increased risk of methemoglobinemia when concurrently exposed to this anticonvulsant oxidizing agent with local anesthetics.

Increased risk of methemoglobinemia when local anesthetics are used concomitantly with anticonvulsants.

Increased risk of methemoglobinemia when concurrently exposed with bupivacaine.

CYP3A4 inducer decreases buprenorphine plasma concentration, potentially resulting in decreased efficacy or withdrawal syndrome. Upon discontinuation, buprenorphine levels increase with risk of serious respiratory depression.

CYP3A4 inducer decreases codeine levels and morphine formation, reducing efficacy or causing withdrawal. Discontinuation may increase morphine levels and cause respiratory depression.

CYP3A4 inducer decreases codeine levels and morphine formation, resulting in decreased efficacy or withdrawal syndrome. Upon discontinuation, may cause serious respiratory depression.

Capecitabine may increase phenytoin exposure, increasing risk of adverse reactions. Closely monitor phenytoin levels and adjust dose as appropriate.

The beneficial effects of levodopa in Parkinson's disease have been reported to be reversed by phenytoin.

Beneficial effects of levodopa may be reversed by phenytoin. Dose increase may be necessary and careful monitoring required.

Carboplatin decreases phenytoin serum levels, which may lead to exacerbation of seizures.

Carmustine may reduce phenytoin serum concentrations and efficacy. Consider alternative drugs to phenytoin.

XCOPRI increases phenytoin plasma concentrations approximately 2-fold, requiring gradual dosage reduction by up to 50% during titration.

Cimetidine reduces hepatic metabolism of phenytoin, delaying elimination and increasing blood levels. Adverse clinical effects have been reported.

Cimetidine reduces hepatic metabolism of phenytoin, delaying elimination and increasing blood levels with reported adverse clinical effects.

Altered serum levels of phenytoin (increased and decreased) requiring monitoring to avoid loss of seizure control or overdose-related adverse reactions.

Phenytoin induces clonazepam metabolism, causing approximately 30% decrease in plasma clonazepam levels.

Strong CYP3A inducer may decrease cobimetinib exposure by >80% and reduce efficacy. Avoid concurrent use.

Avoid concomitant use; may increase phenytoin levels and cause phenytoin toxicity. Chlorpheniramine may inhibit hepatic metabolism of phenytoin.

CYP3A4 inducer that decreases codeine and morphine levels, resulting in reduced efficacy or withdrawal syndrome in dependent patients.

Colesevelam may decrease phenytoin levels. Postmarketing reports of increased seizure activity in patients receiving phenytoin with colesevelam.

Postmarketing reports of increased seizure activity or decreased phenytoin levels in patients receiving phenytoin with colesevelam.

Induces methemoglobinemia; concomitant use may increase risk for developing methemoglobinemia.

Concomitant use may increase risk of developing methemoglobinemia. Monitor closely.

Moderate CYP3A4 inducer may reduce deflazacort efficacy. Avoid concomitant use.

Anticonvulsant associated with increased methemoglobinemia risk when used with ropivacaine.

Methylphenidate may inhibit the metabolism of phenytoin. Downward dose adjustments may be required and plasma drug concentration should be monitored.

Concomitant administration may result in loss of seizure control.

Concomitant administration can lead to phenytoin intoxication due to decreased metabolism. Baseline and ongoing serum level monitoring required with possible dosage adjustment.

Enzyme-inducing drug that can double valproate clearance. Increased monitoring of valproate and phenytoin concentrations and dosage adjustment indicated.

Can double the clearance of valproate, resulting in lower valproate concentrations and potential loss of therapeutic effect.

Administration has been reported to lead to hypotension and bradycardia. Alternatives to phenytoin are suggested if anticonvulsant therapy is needed.

CYP3A4 inducer that may decrease doxorubicin concentration and clinical effect.

CYP3A4 inducer and moderate CYP1A2 inducer decreases erlotinib exposure. Increase erlotinib dosage if co-administration is unavoidable.

CYP3A4 and moderate CYP1A2 inducer decreases erlotinib exposure. Increase erlotinib dosage if co-administration is unavoidable.

Strong CYP 3A4 inducer that significantly decreases exemestane exposure. Dose increase to 50 mg recommended.

Felbamate increases steady-state phenytoin plasma concentrations, requiring approximately 20-40% dose reduction of phenytoin to maintain therapeutic levels and avoid adverse effects.

Anticonvulsant that considerably reduces felodipine plasma concentrations to approximately 6% of levels in healthy volunteers; alternative antihypertensive therapy should be considered.

CYP3A4 inducer that decreases fentanyl plasma concentration, resulting in decreased efficacy and withdrawal syndrome. Discontinuation may cause serious respiratory depression.

CYP3A4 inducer that decreases fentanyl plasma concentration, resulting in decreased efficacy, withdrawal syndrome, and upon discontinuation, potential serious respiratory depression.

CYP3A4 inducer; concomitant use can decrease plasma concentration of fentanyl, resulting in decreased efficacy or withdrawal syndrome. Stopping inducer may increase fentanyl levels causing serious respiratory depression.

Fluoxetine may elevate phenytoin levels and cause clinical anticonvulsant toxicity.

Fluoxetine may elevate phenytoin levels and cause clinical anticonvulsant toxicity.

Folic acid antagonizes the anticonvulsant action of phenytoin, potentially requiring increased phenytoin doses to maintain seizure control.

Significantly decreases temsavir plasma concentrations, which may lead to loss of virologic response.

May significantly decrease plasma concentrations of glecaprevir and pibrentasvir, leading to reduced therapeutic effect. Use is not recommended.

CYP3A4 inducer that decreases hydrocodone plasma concentration, resulting in decreased efficacy or withdrawal syndrome. Discontinuation may cause serious respiratory depression.

CYP3A4 inducer that decreases hydrocodone plasma concentration, resulting in decreased efficacy and potential withdrawal syndrome. Upon discontinuation, may cause serious respiratory depression.

CYP3A4 inducer that can decrease hydrocodone plasma concentration, resulting in decreased efficacy or withdrawal syndrome.

CYP3A4 inducer that decreases hydrocodone plasma concentration, resulting in decreased opioid efficacy or withdrawal syndrome. Discontinuation may cause serious respiratory depression.

Avoid concomitant use; may increase phenytoin levels.

Enzyme-inducing anti-epileptic drug that decreases imatinib AUC by 73%, significantly reducing imatinib exposure.

Isoniazid may increase serum levels of phenytoin, requiring dosage adjustment to avoid phenytoin intoxication.

Potent CYP3A4 enzyme inducer that may decrease itraconazole bioavailability and efficacy. Avoid use 2 weeks before and during itraconazole treatment.

CYP3A4 inducer that decreases ivabradine plasma concentrations; avoid concomitant use.

Strong CYP3A inducer. Co-administration not recommended.

Potent CYP3A4 enzyme inducer that may decrease ketoconazole bioavailability and reduce antifungal efficacy. Coadministration not recommended.

Phenytoin decreases lamotrigine concentrations by approximately 40%, requiring dose adjustment.

Increases metabolism of contraceptive steroids, reducing contraceptive effectiveness and potentially resulting in unintended pregnancy or unscheduled bleeding.

Increased risk of methemoglobinemia when used concurrently with lidocaine.

Anticonvulsant that may cause methemoglobinemia when used concomitantly with lidocaine patch 5%.

Anticonvulsant that increases risk of methemoglobinemia when used concurrently with lidocaine and capsaicin patch.

Anticonvulsant; increased risk of methemoglobinemia when concurrently exposed.

Increased risk of methemoglobinemia when used concurrently with lidocaine hydrochloride.

Anticonvulsant associated with increased methemoglobinemia risk when used concurrently.

Increased risk of methemoglobinemia when local anesthetic is concurrently exposed to anticonvulsants.

Concurrent exposure increases risk of methemoglobinemia in patients administered local anesthetics.

Increased risk of methemoglobinemia; anticonvulsants associated with methemoglobinemia when used with local anesthetics.

Increased risk of methemoglobinemia when used with lidocaine.

Increased risk of methemoglobinemia when lidocaine is concurrently exposed to anticonvulsants.

Increased risk of methemoglobinemia when local anesthetics are concurrently exposed to anticonvulsants.

Concomitant use may increase risk of adverse reactions with phenytoin.

Strong CYP3A4 inducer may reduce plasma macimorelin concentrations and lead to false positive test results. Discontinue prior to use.

Increased risk of methemoglobinemia when concurrently exposed to anticonvulsants.

Strong CYP3A4 inducer that decreases maribavir concentrations. Dose adjustment is recommended when coadministered.

Strong CYP3A inducer may decrease medroxyprogesterone acetate concentrations and reduce contraceptive efficacy. Avoid concomitant use or use backup contraception.

Concurrent exposure increases risk of methemoglobinemia in patients administered mepivacaine.

CYP inducer that decreases methadone plasma concentration, resulting in decreased efficacy or withdrawal symptoms.

CYP3A4 and CYP2C19 inducer that decreases methadone plasma concentration, reducing efficacy and causing withdrawal symptoms, with risk of serious respiratory depression and death upon discontinuation.

May increase methotrexate toxicity by displacing the drug from serum albumin binding.

Highly protein-bound drug that may increase methotrexate plasma concentrations, increasing risk of severe adverse reactions and potentially reducing clinical effectiveness.

Folic acid may increase phenytoin metabolism, lowering serum concentration and increasing seizure activity risk.

Strong CYP3A inducer causing significant decrease in plasma naldemedine concentrations, which may reduce efficacy.

Co-administration lowers systemic exposure to nifedipine by approximately 70%. Avoid co-administration or consider alternative antihypertensive therapy.

Nilutamide inhibits cytochrome P-450 isoenzymes, reducing metabolism of phenytoin and increasing serum half-life, potentially leading to toxic levels. Dosage may need modification.

P-gp and CYP3A4 inducer that may decrease nintedanib exposure. Should be avoided due to risk of reduced efficacy.

Nitisinone inhibits CYP2C9, significantly increasing phenytoin exposure. Reduce dosage by half and adjust to maintain therapeutic drug concentrations due to narrow therapeutic index.

May reduce contraceptive effectiveness and result in unintended pregnancy or breakthrough bleeding by increasing metabolism of contraceptive steroids.

Phenytoin increases metabolism of ethinyl estradiol and/or norethindrone, which could result in reduced contraceptive effectiveness.

Phenytoin increases metabolism of ethinyl estradiol and/or norethindrone, potentially reducing contraceptive effectiveness.

May decrease plasma concentrations of COCs and potentially diminish effectiveness or increase breakthrough bleeding.

Potential for elevated phenytoin levels and clinical anticonvulsant toxicity.

CYP3A4 inducer that decreases oxycodone plasma concentration, resulting in decreased efficacy or withdrawal syndrome; discontinuation may cause serious respiratory depression.

CYP3A4 inducer that decreases plasma concentration of oxycodone, resulting in decreased efficacy or withdrawal syndrome; discontinuation may cause respiratory depression.

CYP450 inducer may increase clearance of oxycodone; salicylate can also displace protein-bound phenytoin, decreasing its concentration.

CYP3A4 inducer that decreases oxycodone plasma concentration, resulting in decreased efficacy or withdrawal syndrome. Upon discontinuation, oxycodone levels increase risking serious respiratory depression.

CYP3A4 inducer that decreases oxycodone plasma concentration, resulting in decreased efficacy and withdrawal syndrome risk. Stopping phenytoin increases oxycodone levels and serious respiratory depression risk.

CYP3A4 inducer that decreases oxycodone plasma concentration, resulting in decreased efficacy or withdrawal syndrome. Upon discontinuation, increased oxycodone levels may cause serious respiratory depression.

Strong CYP3A inducer. Avoid concomitant use with palbociclib.

Concomitant use decreased perampanel plasma levels by 50-67%. Dose adjustment of FYCOMPA necessary; close monitoring required when introduced or withdrawn.

Avoid coadministration unless benefit outweighs risks. Phenytoin may decrease posaconazole plasma concentrations.

CYP 3A4 inducer enhances metabolism of prednisolone, requiring increased dosage of corticosteroid.

Folic acid enhances phenytoin metabolism, lowering AED blood levels and allowing breakthrough seizures. Phenytoin impairs folate absorption and increases folate metabolism.

Increased risk of methemoglobinemia when prilocaine is concurrently exposed to phenytoin.

Increased risk of methemoglobinemia when used concurrently with prilocaine.

CYP3A4 inducer reduces codeine levels and morphine formation, decreasing efficacy or causing withdrawal syndrome. Avoid use; if necessary, monitor for reduced efficacy.

CYP3A4 inducer can result in lower codeine and morphine levels, causing decreased efficacy or withdrawal syndrome.

Potent CYP3A4 inducer increases quetiapine clearance 5-fold; increase quetiapine dose up to 5-fold during chronic use and reduce by 5-fold within 7-14 days of discontinuation.

Strong CYP3A4 inducer that increases quetiapine clearance 5-fold; quetiapine dose may need to be increased up to 5 fold.

Strong CYP3A4 inducer that decreases regorafenib plasma concentrations and may lead to decreased efficacy.

Strong CYP3A inducer may significantly reduce riociguat exposure. Data are not available to guide dosing.

Chronic use causes resistance to rocuronium effects with diminished neuromuscular block magnitude or shortened duration.

Strong CYP450 enzyme inducer that decreases roflumilast systemic exposure and may reduce therapeutic effectiveness. Use not recommended.

Increased risk of developing methemoglobinemia when concurrently exposed to phenytoin.

Strong CYP3A4 inducer that decreases midostaurin concentrations and may reduce efficacy. Avoid coadministration.

CYP3A4 inducer that decreases sufentanil plasma concentration, resulting in decreased efficacy or withdrawal syndrome. Upon discontinuation, can cause increased sufentanil levels and serious respiratory depression.

CYP3A4 inducer that decreases sufentanil plasma concentration, resulting in decreased efficacy or withdrawal syndrome. Discontinuation may cause increased sufentanil levels and serious respiratory depression.

BACTRIM inhibits hepatic metabolism of phenytoin, increasing phenytoin half-life by 39% and decreasing clearance by 27%.

Strong CYP3A inducer; substantially decreases suvorexant exposure and may reduce efficacy.

May decrease tacrolimus whole blood trough concentrations and increase risk of rejection. Increase tacrolimus dose and monitor concentrations.

Strong CYP3A inducer may decrease tacrolimus concentrations and increase risk of rejection. Increase tacrolimus dose and monitor concentrations.

Strong CYP3A inducer. Co-administration not recommended due to reduced SYMDEKO efficacy.

Strong CYP3A4 inducer; avoid co-administration due to potential effects on efficacy and toxicity of thiotepa.

Concomitant administration results in clinically significant decrease in plasma concentrations of topiramate. Dosage adjustment may be needed.

Strong CYP3A4 inducer that decreases toremifene exposure; also a CYP2C9 substrate requiring careful monitoring.

Torsemide may affect phenytoin efficacy and safety as a CYP2C9 substrate with narrow therapeutic range; requires monitoring and possible dose adjustment.

Increased risk of methemoglobinemia when concurrently exposed.

Increased risk of methemoglobinemia when used concurrently with triethanolamine salicylate.

Increased risk of methemoglobinemia when used with Trubrexa Transdermal Patch.

Strong CYP3A4 inducer expected to cause loss of ubrogepant efficacy. Concomitant use should be avoided.

Concomitant administration has been associated with increased risk of valproate-associated hyperammonemia. Patients should be monitored for signs and symptoms of hyperammonemia.

Strong CYP3A4 inducer that decreases vemurafenib plasma concentrations and may result in decreased efficacy. Avoid coadministration; replace with alternative drugs when possible.

Simultaneous administration may reduce blood levels of phenytoin and increase seizure activity. Interaction may result from reduced absorption or increased metabolism of phenytoin.

Simultaneous administration may reduce blood levels of phenytoin and increase seizure activity. Interaction may result from reduced absorption and increased metabolism/elimination of phenytoin.

CYP450 inducer significantly reduces voriconazole plasma exposure. Voriconazole maintenance dose should be increased.

CYP1A2 and CYP3A4 inducer that decreases warfarin effect and INR; requires close monitoring.

Phenytoin produces hyperglycemia and may lead to loss of blood glucose control in patients receiving Acarbose. Close observation for loss of glucose control is recommended.

Induces hepatic microsomal enzymes, increasing potential for acetaminophen hepatotoxicity.

Acetazolamide modifies phenytoin metabolism increasing serum levels, which may increase osteomalacia occurrence in patients on chronic therapy.

Acetazolamide modifies phenytoin metabolism with increased serum levels, which may increase or enhance osteomalacia occurrence in patients on chronic phenytoin therapy.

Acetazolamide modifies phenytoin metabolism with increased serum levels, which may increase osteomalacia occurrence in chronic therapy.

Concurrent administration of acitretin with phenytoin may reduce the protein binding of phenytoin.

P-glycoprotein inducer that decreases afatinib exposure. Increase GILOTRIF dose by 10 mg per day as tolerated.

Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir Calcium channel blockers Nifedipine, nimodipine, nisoldipine, verapamil Other Albendazole (decreases active metabolite), chlorpropamide, clozapine, cyclosporine, digoxin, disopyramide, folic acid, methadone, mexiletine, praziquantel, quetiapine 7.3 Hyperammonemia with Concomitant Use of Valproate Concomitant administration of phenytoin and valproate has been associated with an increased risk of valproate-associated hyperammonemia.

May increase phenytoin serum levels; monitoring of phenytoin levels recommended.

May produce hyperglycemia and lead to loss of glycemic control.

CYP3A inducer. Can increase alprazolam metabolism and decrease plasma levels. Caution recommended during coadministration.

CYP3A inducer can increase alprazolam metabolism and decrease plasma levels. Caution is recommended during coadministration.

May decrease phenytoin serum levels by affecting absorption; should not be taken at same time.

May increase phenytoin serum levels; monitoring of phenytoin levels recommended.

Amiodarone increases steady-state levels of phenytoin. Monitor phenytoin levels.

Calcium carbonate, aluminum hydroxide, magnesium hydroxide Prevention or Management: Phenytoin and antacids should not be taken at the same time of day Antineoplastic agents usually in combination Bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate Antiviral agents Fosamprenavir, nelfinavir, ritonavir Antiepileptic drugs Carbamazepine, vigabatrin Other Chronic alcohol abuse, diazepam, diazoxide, folic acid, reserpine, rifampin, St. Warfarin Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin Other Corticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D Drugs whose level is decreased by phenytoin Anticoagulants Apixaban, dabigatran, edoxaban, rivaroxaban Antiepileptic drugs The effect of phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is unpredictable Carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine, lacosamide Antilipidemic agents Atorvastatin, fluvastatin, simvastatin Antiplatelets Ticagrelor Antiviral agents Efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir Fosamprenavir: phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir Calcium channel blockers Nifedipine, nimodipine, nisoldipine, verapamil Other Albendazole (decreases active metabolite), chlorpropamide, clozapine, cyclosporine, digoxin, disopyramide, folic acid, methadone, mexiletine, praziquantel, quetiapine 7.3 Hyperammonemia with Concomitant Use of Valproate Concomitant administration of phenytoin and valproate has been associated with an increased risk of valproate-associated hyperammonemia.

May decrease phenytoin serum levels by affecting absorption; should not be taken at same time.

Elimination of phenytoin may be prolonged by armodafinil via inhibition of metabolic enzymes, resulting in higher systemic exposure. Dose reduction may be required.

Salicylic acid can displace protein-bound phenytoin, leading to decreased total phenytoin concentration.

Salicylic acid can displace protein-bound phenytoin, leading to decreased total concentration of phenytoin.

Salicylic acid can displace protein-bound phenytoin, leading to decreased total phenytoin concentration.

Drug interactions have been observed with other macrolide products. Careful monitoring of patients is advised until further data are developed.

Hepatic enzyme induction may enhance corticosteroid metabolism, requiring increased corticosteroid dosage.

May decrease phenytoin serum levels; monitoring of phenytoin levels recommended.

Brivaracetam can increase plasma concentrations of phenytoin. Phenytoin levels should be monitored when brivaracetam is added or discontinued.

Brivaracetam can increase plasma concentrations of phenytoin; phenytoin levels should be monitored when brivaracetam is added or discontinued.

May increase risk of methemoglobinemia when concurrently exposed with bupivacaine.

Increased risk of methemoglobinemia when concurrently exposed.

Increased risk of developing methemoglobinemia when concurrently exposed.

CYP2B6 inducer that may decrease bupropion exposure; dose increase may be necessary but should not exceed maximum recommended dose.

May induce metabolism of bupropion and decrease bupropion exposure; dose increase may be necessary.

CYP2B6 inducer that may decrease bupropion exposure. Dose increase may be necessary but should not exceed maximum recommended dose.

CYP2B6 inducer that may decrease bupropion exposure. Dose increase of bupropion may be necessary but should not exceed maximum recommended dose.

CYP2B6 inducer that may decrease bupropion exposure. Dose increase may be necessary but should not exceed maximum recommended dose.

Increases busulfan clearance by 15% or more, potentially resulting in lower exposure in patients treated with phenytoin compared to recommended dosing studies.

Strong CYP3A4 inducer. Avoid chronic co-administration or increase COMETRIQ dosage if unavoidable.

Increases caffeine elimination; higher caffeine doses may be needed when coadministered.

May reduce endogenous plasma levels of 25(OH)D3 by accelerating metabolism, potentially requiring higher calcitriol doses.

May reduce endogenous plasma levels of 25(OH)D3 and calcitriol; higher calcitriol doses may be necessary.

UGT enzyme inducer decreases canagliflozin exposure which may reduce effectiveness of INVOKANA. Dosage adjustment may be required.

UGT enzyme inducer that decreases canagliflozin exposure and may reduce effectiveness. May require canagliflozin dose increase.

CYP3A4 inducer that decreases carbamazepine plasma levels. Carbamazepine levels and/or dosage adjustment may be necessary.

Beneficial effects of levodopa in Parkinson's disease reported to be reversed; patients should be carefully observed for loss of therapeutic response.

Beneficial effects of levodopa in Parkinson's disease may be reversed; patients should be carefully observed for loss of therapeutic response.

Phenytoin is a hepatic CYP enzyme inducer expected to reduce caspofungin acetate plasma concentrations. Increased caspofungin dosing should be considered.

May increase phenytoin serum levels; monitoring of phenytoin levels recommended.

May increase phenytoin serum levels; monitoring of phenytoin levels recommended.

Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir Calcium channel blockers Nifedipine, nimodipine, nisoldipine, verapamil Other Albendazole (decreases active metabolite), chlorpropamide, clozapine, cyclosporine, digoxin, disopyramide, folic acid, methadone, mexiletine, praziquantel, quetiapine 7.3 Hyperammonemia with Concomitant Use of Valproate Concomitant administration of phenytoin and valproate has been associated with an increased risk of valproate-associated hyperammonemia.

Ciprofloxacin may alter serum phenytoin levels (increased or decreased), risking seizure control loss or toxicity.

Altered serum levels of phenytoin (increased and decreased) may occur. Monitor phenytoin therapy and serum concentration during and after co-administration.

May shorten duration of neuromuscular blockade and increase infusion rate requirements. Use peripheral nerve stimulator and monitor.

May decrease phenytoin serum levels; monitoring of phenytoin levels recommended.

Phenytoin decreases plasma levels of clomipramine.

Phenytoin may decrease plasma levels of clomipramine; dosage adjustment may be needed.

UGT inducer may increase bazedoxifene metabolism, reducing exposure and increasing risk of endometrial hyperplasia.

Produces hyperglycemia and may lead to loss of glycemic control when used with XIGDUO XR.

Phenytoin induces CYP3A4 enzyme activity, enhancing corticosteroid metabolism and requiring dose increases.

Induces CYP3A4 and may decrease plasma concentrations of desogestrel and ethinyl estradiol, potentially diminishing contraceptive effectiveness and increasing breakthrough bleeding.

CYP 3A4 inducers may enhance metabolism of dexamethasone, requiring dosage increase.

Phenytoin induces CYP 3A4 enzyme activity, enhancing dexamethasone metabolism and requiring dosage increase.

Phenytoin induces CYP 3A4 and enhances dexamethasone metabolism, requiring dosage increase.

Amphetamines may reduce the effects of this drug. Monitor for reduced efficacy.

CYP3A4 inducer that increases diazepam elimination, potentially decreasing efficacy.

Diazoxide may displace diphenylhydantoin from protein binding. Monitor serum levels and adjust dosage as needed.

Decreases digoxin concentrations. Requires monitoring and dose adjustment.

Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir Calcium channel blockers Nifedipine, nimodipine, nisoldipine, verapamil Other Albendazole (decreases active metabolite), chlorpropamide, clozapine, cyclosporine, digoxin, disopyramide, folic acid, methadone, mexiletine, praziquantel, quetiapine 7.3 Hyperammonemia with Concomitant Use of Valproate Concomitant administration of phenytoin and valproate has been associated with an increased risk of valproate-associated hyperammonemia.

Hepatic enzyme induction may lower plasma levels of disopyramide, potentially reducing effectiveness. Monitoring of disopyramide plasma levels recommended.

High doses of folic acid may decrease serum levels of this anticonvulsant drug.

May decrease phenytoin serum levels; monitoring of phenytoin levels recommended.

Phenytoin shortens the half-life of doxycycline, thereby lowering doxycycline concentration in the body.

Phenytoin decreases the half-life of doxycycline.

May decrease systemic concentrations of hormonal contraceptives and diminish effectiveness or increase breakthrough bleeding.

Induces CYP3A4 enzyme, may decrease effectiveness of COCs or increase breakthrough bleeding.

May decrease the effectiveness of hormonal contraceptives or increase breakthrough bleeding through CYP3A4 enzyme induction.

Enzyme inducer that may decrease effectiveness of COCs or increase breakthrough bleeding. Use back-up contraception.

Can double the clearance of valproate, potentially decreasing valproate concentrations. Monitor valproate levels when introduced or withdrawn.

May produce hyperglycemia and lead to loss of glycemic control; monitor closely.

Decreases TAF concentration. Consider alternative anticonvulsant.

May produce hyperglycemia and lead to loss of glycemic control; close monitoring recommended.

Higher dosage of eslicarbazepine acetate may be necessary and dose adjustment may be needed for phenytoin. Eslicarbazepine acetate inhibits CYP2C19 causing increased phenytoin plasma concentrations.

Potent CYP3A inducer; expected to decrease estazolam concentrations and reduce efficacy.

CYP3A4 inducer that may reduce plasma concentrations of estrogens, possibly decreasing therapeutic effects and altering uterine bleeding profile.

May increase phenytoin serum levels; monitoring of phenytoin levels recommended.

Ethosuximide may elevate phenytoin serum levels. Periodic serum level determinations may be necessary.

May decrease plasma concentrations of etonogestrel and diminish contraceptive effectiveness or increase breakthrough bleeding.

CYP3A4 enzyme inducer that may decrease plasma concentrations of etonogestrel and ethinyl estradiol, potentially diminishing contraceptive effectiveness or increasing breakthrough bleeding.

Induces CYP3A4, may decrease plasma concentrations of CHCs and potentially diminish effectiveness or increase breakthrough bleeding.

Enzyme inducer; limited data indicate only 30% increase in flecainide elimination rate.

CYP3A4 inducer; concomitant use may decrease flibanserin exposure and therapeutic effect.

May increase phenytoin serum levels; monitoring of phenytoin levels recommended.

Increased metabolic clearance of fludrocortisone acetate due to hepatic enzyme induction. May require increased steroid dosage.

May increase phenytoin serum levels; monitoring of phenytoin levels recommended.

Fluvastatin increases phenytoin exposure. Monitor plasma phenytoin levels when fluvastatin treatment is initiated or dosage is changed.

Monitor plasma phenytoin levels when fluvastatin treatment is initiated.

May increase phenytoin serum levels; monitoring of phenytoin levels recommended.

Calcium carbonate, aluminum hydroxide, magnesium hydroxide Prevention or Management: Phenytoin and antacids should not be taken at the same time of day Antineoplastic agents usually in combination Bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate Antiviral agents Fosamprenavir, nelfinavir, ritonavir Antiepileptic drugs Carbamazepine, vigabatrin Other Chronic alcohol abuse, diazepam, diazoxide, folic acid, reserpine, rifampin, St. Warfarin Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin Other Corticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D Drugs whose level is decreased by phenytoin Anticoagulants Apixaban, dabigatran, edoxaban, rivaroxaban Antiepileptic drugs The effect of phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is unpredictable Carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine, lacosamide Antilipidemic agents Atorvastatin, fluvastatin, simvastatin Antiplatelets Ticagrelor Antiviral agents Efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir Fosamprenavir: phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir Calcium channel blockers Nifedipine, nimodipine, nisoldipine, verapamil Other Albendazole (decreases active metabolite), chlorpropamide, clozapine, cyclosporine, digoxin, disopyramide, folic acid, methadone, mexiletine, praziquantel, quetiapine 7.3 Hyperammonemia with Concomitant Use of Valproate Concomitant administration of phenytoin and valproate has been associated with an increased risk of valproate-associated hyperammonemia.

Phenytoin interferes with renal action of furosemide and decreases intestinal absorption, leading to lower peak furosemide concentrations.

Phenytoin interferes directly with renal action of furosemide and decreases intestinal absorption, leading to lower peak serum furosemide concentrations.

CYP3A4 inducer that decreases ganaxolone exposure and efficacy; ZTALMY dosage may need to be increased but should not exceed maximum daily dosage.

Strong CYP3A4 inducer increases gefitinib metabolism and decreases plasma concentrations. Increase gefitinib to 500 mg daily during concomitant use.

Phenytoin may produce hyperglycemia and lead to loss of control of glyburide. Patients should be closely observed for loss of control.

May reduce glucose-lowering effect of glimepiride, leading to worsening glycemic control.

Phenytoin may produce hyperglycemia and lead to loss of glycemic control. Patient should be observed closely for loss of control when initiated or withdrawn.

Phenytoin may produce hyperglycemia and lead to loss of blood glucose control. Patient should be closely observed for loss of blood glucose control.

Phenytoin tends to produce hyperglycemia and may lead to loss of blood glucose control. Close observation required.

Microsomal enzyme inducer that reduces guanfacine elimination half-life and plasma concentration, particularly in patients with renal impairment, requiring more frequent dosing.

Microsomal enzyme inducer that significantly reduces guanfacine elimination half-life and plasma concentration, particularly in renal impairment patients, requiring more frequent dosing.

CYP3A4 inducer that can decrease hydrocodone plasma concentration, resulting in decreased efficacy or withdrawal syndrome.

Induces hepatic enzymes and increases clearance of corticosteroids, may require increased corticosteroid dose to achieve desired response.

Phenytoin induces hepatic enzyme activity, enhancing corticosteroid metabolism and may require dosage increase.

Phenytoin induces cytochrome P450 3A4 enzyme activity, enhancing corticosteroid metabolism and requiring increased corticosteroid dosage.

CYP3A4 inducer may increase metabolism of ifosfamide to active metabolites and increase formation of neurotoxic/nephrotoxic chloroacetaldehyde. Monitor for toxicities and consider dose adjustment.

Hepatic enzyme inducer that decreases imipramine plasma concentration. Dose adjustment of imipramine may be necessary.

Hepatic enzyme inducer that decreases imipramine plasma concentrations. Dosage adjustment of imipramine may be necessary.

Caution should be exercised when using together due to potential additive effects on bone loss.

Hepatic enzyme inducer may increase corticosteroid metabolism and reduce efficacy.

Decreased lamotrigine concentration approximately 40%.

Decreases lamotrigine concentration approximately 40%.

Folic acid in large amounts may counteract the antiepileptic effect and increase seizure frequency in susceptible children.

Folic acid in large amounts may counteract antiepileptic effect and increase seizure frequency in susceptible children. Monitor patients taking levoleucovorin with this drug.

Folic acid in large amounts may counteract the antiepileptic effect and increase seizure frequency in susceptible children. Unclear if folinic acid has same effects, but they share metabolic pathways. Monitor patients.

Folic acid in large amounts may counteract antiepileptic effect and increase seizure frequency. Monitor patients taking folinic acid with antiepileptic drugs.

Phenytoin induces CYP3A4 and may decrease plasma concentrations of COCs, potentially diminishing contraceptive effectiveness or increasing breakthrough bleeding.

Phenytoin induces CYP3A4 enzymes, potentially decreasing contraceptive effectiveness and increasing breakthrough bleeding.

Reduces serum protein binding of levothyroxine; total and free T4 may be reduced 20-40%, though most patients remain euthyroid. Closely monitor thyroid parameters.

Anticonvulsant that increases risk of methemoglobinemia when used concomitantly with lidocaine and tetracaine.

When administered with lidocaine, cardiac effects may be additive or antagonistic and toxic effects may be additive. Phenytoin may stimulate hepatic metabolism of lidocaine.

Phenytoin may produce hyperglycemia and lead to loss of glycemic control. Close monitoring of glycemic control is recommended.

Reduces serum protein binding of thyroid hormones, with total and FT4 potentially reduced by 20-40%, requiring thyroid hormone monitoring.

Concomitant use may increase risk of adverse reactions of phenytoin.

Concomitant use may increase risk of adverse reactions of phenytoin. Monitor patients closely for adverse reactions.

May decrease phenytoin serum levels by affecting absorption; should not be taken at same time.

Increased risk of methemoglobinemia when concurrently exposed to anticonvulsants with bupivacaine.

Mefloquine may reduce seizure control by lowering plasma levels of anticonvulsant. Monitor blood levels and adjust dosage appropriately.

Phenytoin induces CYP3A4, potentially increasing the rate of elimination of donepezil.

Produces hyperglycemia and may lead to loss of glycemic control when used with metformin.

May produce hyperglycemia and lead to loss of glycemic control. Monitor patient closely for loss of blood glucose control.

Drugs that produce hyperglycemia and may lead to loss of glycemic control; monitor blood glucose.

May produce hyperglycemia and lead to loss of glycemic control during metformin therapy; monitor blood glucose.

May produce hyperglycemia and lead to loss of glycemic control when used with metformin.

Methylene blue inhibits CYP2C9 and CYP2C19 metabolism. Phenytoin has narrow therapeutic index; clinical relevance unknown but concurrent use requires caution.

Prior chronic administration of phenytoin may reduce the effectiveness of methohexital sodium. Methohexital may influence the metabolism of phenytoin.

Methsuximide may increase plasma concentrations of phenytoin; periodic serum level determinations may be necessary.

Methylphenidate may inhibit metabolism of this anticonvulsant. Downward dose adjustments may be required.

Methylphenidate may inhibit metabolism of phenytoin; downward dose adjustment may be required and plasma concentrations should be monitored.

May increase the clearance of methylprednisolone and require increases in methylprednisolone dose to achieve the desired response.

Phenytoin induces cytochrome P450 3A4 and may enhance corticosteroid metabolism, requiring dosage increase.

Phenytoin induces CYP3A4 enzyme activity, enhancing corticosteroid metabolism and may require dosage increase.

Hepatic enzyme inducer that enhances corticosteroid metabolism and may require increased corticosteroid dosage.

Phenytoin induces microsomal liver enzymes, accelerating elimination of metronidazole and reducing plasma levels. Impaired clearance of phenytoin has also been reported.

Hepatic enzyme inducer that lowers mexiletine plasma levels; monitoring recommended to ensure therapeutic efficacy.

Potential interaction with phenytoin metabolized through CYP2C9 and CYP3A4 cannot be ruled out due to miconazole's inhibition of these enzymes.

CYP3A4 inducer that markedly decreases midazolam C max and AUC, reducing its efficacy.

CYP3A4 inducer anticonvulsant that may lower mifepristone serum concentrations and reduce efficacy. Verify treatment success through follow-up assessment.

Strong CYP3A inducer decreases mirtazapine plasma concentration. May require dose increase.

Elimination may be prolonged by modafinil with resultant higher systemic exposure. Dose adjustment may be necessary when used concomitantly.

CYP2B6 inducer that may reduce CONTRAVE efficacy by reducing bupropion exposure. Avoid concomitant use.

CYP inducer that may reduce blood-glucose-lowering effect and increase susceptibility to hyperglycemia. Dose increases and increased glucose monitoring may be required.

May decrease phenytoin serum levels; monitoring of phenytoin levels recommended.

Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir Calcium channel blockers Nifedipine, nimodipine, nisoldipine, verapamil Other Albendazole (decreases active metabolite), chlorpropamide, clozapine, cyclosporine, digoxin, disopyramide, folic acid, methadone, mexiletine, praziquantel, quetiapine 7.3 Hyperammonemia with Concomitant Use of Valproate Concomitant administration of phenytoin and valproate has been associated with an increased risk of valproate-associated hyperammonemia.

Enzyme inducer that may decrease plasma concentrations of CHCs and potentially diminish effectiveness or increase breakthrough bleeding.

Enzyme inducer that may decrease plasma concentrations of norethindrone and ethinyl estradiol, potentially diminishing contraceptive effectiveness or increasing breakthrough bleeding.

May decrease plasma concentrations and efficacy of contraceptive; may increase breakthrough bleeding.

CYP2C19 substrate; concomitant use with omeprazole may alter phenytoin exposure.

CYP2C19 substrate; concomitant use with omeprazole may increase exposure due to inhibition of CYP2C19.

CYP2C19 substrate; concomitant use with omeprazole may alter phenytoin concentrations.

CYP2C19 substrate with increased plasma concentrations when combined with omeprazole.

Potent CYP3A4 inducer significantly increases ondansetron clearance and decreases blood concentrations. Monitor for reduced ondansetron efficacy.

Potent CYP3A4 inducer significantly increases ondansetron clearance and decreases blood concentrations. Monitor for reduced ondansetron efficacy.

Potent CYP3A4 inducer significantly increases ondansetron clearance and decreases blood concentrations. Monitor for potential decreased ondansetron efficacy.

Oxcarbazepine increases phenytoin levels at doses >1200 mg/day. Plasma level monitoring and dose reduction of phenytoin may be required.

Barbiturates have variable effects on phenytoin metabolism. Blood levels of both drugs should be monitored more frequently when given concurrently.

Barbiturates have variable effects on phenytoin metabolism. Blood levels of both drugs should be monitored frequently during concurrent use.

The effect of barbiturates on phenytoin metabolism is variable and unpredictable. Blood levels of both drugs should be monitored more frequently if given concurrently.

May increase phenytoin serum levels; monitoring of phenytoin levels recommended.

Concomitant administration decreased topiramate plasma concentrations by 48% in epilepsy patients, reducing topiramate efficacy.

CYP 3A4 enzyme inducer enhances metabolism of corticosteroids, requiring increased prednisone dosage.

High doses of folic acid may result in decreased serum levels of phenytoin.

Hepatic enzyme inducer that decreases blood levels of propranolol by increasing hepatic metabolism.

Phenytoin induces cytochrome P450 IIIA4 and accelerates hepatic elimination of quinidine.

Induces cytochrome P450 IIIA4, accelerating hepatic elimination and decreasing quinidine levels.

CYP3A4 inducer that may decrease quinine plasma concentrations. Patients should be monitored closely for adverse reactions associated with phenytoin.

CYP3A4 inducer that may decrease quinine plasma concentrations and reduce efficacy.

Strong inducer of drug metabolizing enzymes that may decrease raltegravir levels. Coadministration not recommended.

Weak/moderate CYP3A4/P-gp inducer that may decrease sirolimus concentrations. Monitor and adjust dosage as needed.

May decrease phenytoin serum levels; monitoring of phenytoin levels recommended.

May decrease phenytoin serum levels; monitoring of phenytoin levels recommended.

Rifapentine may increase metabolism and decrease activity. Dosage adjustment may be necessary.

Calcium carbonate, aluminum hydroxide, magnesium hydroxide Prevention or Management: Phenytoin and antacids should not be taken at the same time of day Antineoplastic agents usually in combination Bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate Antiviral agents Fosamprenavir, nelfinavir, ritonavir Antiepileptic drugs Carbamazepine, vigabatrin Other Chronic alcohol abuse, diazepam, diazoxide, folic acid, reserpine, rifampin, St. Warfarin Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin Other Corticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D Drugs whose level is decreased by phenytoin Anticoagulants Apixaban, dabigatran, edoxaban, rivaroxaban Antiepileptic drugs The effect of phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is unpredictable Carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine, lacosamide Antilipidemic agents Atorvastatin, fluvastatin, simvastatin Antiplatelets Ticagrelor Antiviral agents Efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir Fosamprenavir: phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir Calcium channel blockers Nifedipine, nimodipine, nisoldipine, verapamil Other Albendazole (decreases active metabolite), chlorpropamide, clozapine, cyclosporine, digoxin, disopyramide, folic acid, methadone, mexiletine, praziquantel, quetiapine 7.3 Hyperammonemia with Concomitant Use of Valproate Concomitant administration of phenytoin and valproate has been associated with an increased risk of valproate-associated hyperammonemia.

Chronic phenytoin therapy may cause resistance to rocuronium effects, resulting in shorter neuromuscular block duration and higher infusion rates needed.

Phenytoin decreases rufinamide concentration by 25-46% and rufinamide increases phenytoin by 7-21% with potential for greater exposure due to phenytoin's non-linear pharmacokinetics.

May increase phenytoin serum levels; monitoring of phenytoin levels recommended.

Salicylate competes with phenytoin for protein binding sites, potentially affecting drug levels.

Metabolic enzyme inducer that may decrease systemic concentrations of estrogen and/or progestin, potentially diminishing contraceptive effectiveness.

May increase phenytoin serum levels; monitoring of phenytoin levels recommended.

May produce hyperglycemia and lead to loss of glycemic control. Monitor blood glucose closely during concomitant use.

May decrease phenytoin serum levels; induction potency may vary based on preparation.

Phenytoin is a strong inducer of CYP1A2, CYP3A4, and CYP2C19 and may decrease DIACOMIT concentrations. Concomitant use should be avoided or dosage adjustment made.

Sucralfate reduces the bioavailability of phenytoin. Separate dosing administration is recommended.

May increase phenytoin serum levels; monitoring of phenytoin levels recommended.

May increase phenytoin serum levels; monitoring of phenytoin levels recommended.

May increase phenytoin serum levels; monitoring of phenytoin levels recommended.

Phenytoin causes peripheral neuropathy and concomitant use with thalidomide can cause additive effect; should be used with caution.

May decrease phenytoin serum levels; monitoring of phenytoin levels recommended.

Phenytoin increases tiagabine clearance by 60%, which may require dose adjustments to maintain therapeutic efficacy.

May increase phenytoin serum levels; monitoring of phenytoin levels recommended.

Concomitant administration may result in prolongation of phenytoin half-life and reduction in clearance. Adjustment of anticonvulsant and/or tinidazole doses may be needed.

May increase phenytoin serum levels; monitoring of phenytoin levels recommended.

May increase phenytoin serum levels; monitoring of phenytoin levels recommended.

Monitor for increased phenytoin serum levels when used concomitantly with trazodone.

CYP 3A4 inducer enhances metabolism of corticosteroids and may require dosage increase.

Trimethoprim inhibits hepatic metabolism of phenytoin, increasing phenytoin half-life by 51% and decreasing metabolic clearance by 30%. Monitor for excessive phenytoin effect.

CYP3A4 inducer decreases plasma concentrations of ulipristal acetate and may decrease its effectiveness as emergency contraception.

Phenytoin is an enzyme-inducing drug that can increase valproate clearance and may double it. Monitoring of valproate and phenytoin concentrations and dosage adjustment are indicated.

Enzyme-inducing drug that can increase valproate clearance and double clearance rate. Increased monitoring of valproate and concomitant drug concentrations and dosage adjustment indicated.

Vigabatrin may cause moderate reduction in total phenytoin plasma levels; dose adjustment of phenytoin should be considered if clinically indicated.

Strong CYP3A4 inducer that decreases vilazodone exposure; consider increasing dose by 2-fold up to 80 mg daily.

Strong CYP inducer decreases plasma concentrations of vortioxetine. Consider increasing TRINTELLIX dose; maximum dose not to exceed 3 times original dose.

May increase phenytoin serum levels; monitoring of phenytoin levels recommended.

Zafirlukast may interact with phenytoin as it is metabolized by CYP2C9. Care should be exercised when coadministered.

Enzyme-inducing AED that increases zonisamide metabolism and clearance, decreasing its half-life to 27-38 hours.

In vitro data indicate doxazosin has no effect on protein binding of phenytoin.

Gabapentin had no effect on steady-state phenytoin plasma concentrations, and phenytoin had no effect on gabapentin pharmacokinetics.

Steady-state plasma concentrations of phenytoin were not affected by concomitant lacosamide at any dose in clinical studies.

Levetiracetam had no effect on phenytoin pharmacokinetics, and phenytoin did not affect levetiracetam pharmacokinetics.

In vitro protein binding studies showed tolcapone did not displace phenytoin from binding sites at therapeutic concentrations.

Warfarin Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin Other Corticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D Drugs whose level is decreased by phenytoin Anticoagulants Apixaban, dabigatran, edoxaban, rivaroxaban Antiepileptic drugs The effect of phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is unpredictable Carbamazepine, felbamate, lacosamide, lamotrigine, topiramate, oxcarbazepine Antilipidemic agents Atorvastatin, fluvastatin, simvastatin Antiplatelets Ticagrelor Antiviral agents Efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir Fosamprenavir: phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite.

Concurrent administration may increase phenytoin blood levels based on a single patient report.

Interaction not reported in azithromycin clinical trials but observed with other macrolides. Careful monitoring is advised.

Drug interactions have been observed with other macrolide products. Careful monitoring of patients is advised until further data are developed.

Reciprocal interactions may occur through cytochrome P450 system effects, though not studied.

Warfarin Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin Other Corticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D Drugs whose level is decreased by phenytoin Anticoagulants Apixaban, dabigatran, edoxaban, rivaroxaban Antiepileptic drugs The effect of phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is unpredictable Carbamazepine, felbamate, lacosamide, lamotrigine, topiramate, oxcarbazepine Antilipidemic agents Atorvastatin, fluvastatin, simvastatin Antiplatelets Ticagrelor Antiviral agents Efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir Fosamprenavir: phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite.

Warfarin Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin Other Corticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D Drugs whose level is decreased by phenytoin Anticoagulants Apixaban, dabigatran, edoxaban, rivaroxaban Antiepileptic drugs The effect of phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is unpredictable Carbamazepine, felbamate, lacosamide, lamotrigine, topiramate, oxcarbazepine Antilipidemic agents Atorvastatin, fluvastatin, simvastatin Antiplatelets Ticagrelor Antiviral agents Efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir Fosamprenavir: phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite.

Warfarin Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin Other Corticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D Drugs whose level is decreased by phenytoin Anticoagulants Apixaban, dabigatran, edoxaban, rivaroxaban Antiepileptic drugs The effect of phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is unpredictable Carbamazepine, felbamate, lacosamide, lamotrigine, topiramate, oxcarbazepine Antilipidemic agents Atorvastatin, fluvastatin, simvastatin Antiplatelets Ticagrelor Antiviral agents Efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir Fosamprenavir: phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite.

Warfarin Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin Other Corticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D Drugs whose level is decreased by phenytoin Anticoagulants Apixaban, dabigatran, edoxaban, rivaroxaban Antiepileptic drugs The effect of phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is unpredictable Carbamazepine, felbamate, lacosamide, lamotrigine, topiramate, oxcarbazepine Antilipidemic agents Atorvastatin, fluvastatin, simvastatin Antiplatelets Ticagrelor Antiviral agents Efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir Fosamprenavir: phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite.

Table 2: Drugs That Affect Phenytoin Concentrations Interacting Agent Examples Drugs that may increase phenytoin serum levels Antiepileptic drugs Ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate Azoles Fluconazole, ketoconazole, itraconazole, miconazole, voriconazole Antineoplastic agents Capecitabine, fluorouracil Antidepressants Fluoxetine, fluvoxamine, sertraline Gastric acid reducing agents H 2 antagonists (cimetidine), omeprazole Sulfonamides Sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim Other Acute alcohol intake, amiodarone, chloramphenicol, chlordiazepoxide, disulfiram, estrogen, fluvastatin, isoniazid, methylphenidate, phenothiazines, salicylates, ticlopidine, tolbutamide, trazodone, warfarin Drugs that may decrease phenytoin serum levels Antacids Antacids may affect absorption of phenytoin.