Antiepileptic, hydantoin derivative (sodium channel blocker)
Brand names: Dilantin, Phenytek
Updated · Methodology
Second line
Phenytoin is a second-line antiepileptic for focal and generalised tonic-clonic seizures in adults when levetiracetam, lamotrigine or oxcarbazepine fail. The narrow therapeutic window (10–20 mcg/mL) and non-linear kinetics require blood level monitoring. ILAE 2017 and SEN moved phenytoin off first-line because of gingival hyperplasia, hirsutism, long-term osteopenia and drug hypersensitivity syndrome.
Sources
ICD-10: G40 · ICD-11: 8A6Z
Blocks fast sodium channels in cardiomyocytes and neurons in the activated state, stabilising the membrane and preventing repetitive firing. Metabolised by hepatic CYP2C9 and CYP2C19 with non-linear (saturable) kinetics: a 30% dose increase can double the blood level. Phenytoin itself is a strong inducer of CYP3A4, CYP2C9, CYP2C19, UGT and P-glycoprotein, accelerating metabolism of most co-administered drugs.
Teratogen: raises the risk of facial malformations (fetal hydantoin syndrome), cleft palate and cardiac defects. EMA recommends pre-conception planning and, when possible, switching to levetiracetam or lamotrigine. While on therapy, folic acid 5 mg/day is required.
Passes into breast milk in small amounts. AEMPS allows breastfeeding with infant monitoring for drowsiness and poor sucking.
Reference information, not a clinical decision. Discuss feeding pauses or changes with your physician or an IBCLC.
9 pairs found. Sorted from critical to minor.
Mechanism
Strong CYP3A4 induction.
Symptoms
Mycosis progression.
Management
Combination contraindicated.
Mechanism
Phenytoin is a strong inducer of the CYP3A4 enzyme and the P-glycoprotein transporter (rivaroxaban label of the US Food and Drug Administration, ), and rivaroxaban is cleared through both routes. Rivaroxaban blood levels fall and protection against clots weakens. For rifampicin, another strong inducer, the SmPC of the European Medicines Agency () reports about a 50% fall in rivaroxaban area under the curve (AUC) with a parallel loss of effect. There are no figures for phenytoin; the SmPC states that it can also lower rivaroxaban levels (rivaroxaban SmPC, EMA).
Symptoms
Stroke or recurrent venous thrombosis.
Management
The combination is contraindicated in the 2021 practical guide of the European Heart Rhythm Association (EHRA): its antiepileptic drug table marks this pair as contraindicated because of reduced rivaroxaban levels (EHRA 2021). The rivaroxaban labels require avoiding it: the European Medicines Agency () allows it only if the patient is closely monitored for signs of thrombosis (rivaroxaban SmPC, EMA), and the US Food and Drug Administration () advises avoiding it (FDA rivaroxaban label). The European Society of Cardiology () advises avoiding the combination where possible (ESC 2024). If it cannot be avoided, monitor the patient closely for signs of thrombosis (rivaroxaban SmPC, EMA): leg swelling and pain, sudden breathlessness and chest pain, sudden weakness or numbness of an arm, a leg or one side of the face, speech problems.
Sources
Mechanism
Phenytoin is a strong inducer of the CYP3A4 enzyme and the P-glycoprotein transporter, and apixaban is cleared through both routes. Strong inducers can lower the apixaban area under the curve (AUC) by about 50%; with rifampicin the fall was 54% (apixaban SmPC of the European Medicines Agency, ). Protection against stroke and thrombosis weakens. In a study of patients with atrial fibrillation, apixaban given with strong inducers showed lower efficacy and a higher bleeding risk (apixaban SmPC, EMA).
Symptoms
Signs of thrombosis from weaker anticoagulation: sudden weakness or numbness of an arm, a leg or one side of the face, speech problems (stroke), leg swelling and pain (deep vein thrombosis), sudden breathlessness and chest pain (pulmonary embolism). Bleeding can also occur: bruising without trauma, nosebleeds, blood in the urine, black stools.
Management
The US Food and Drug Administration () advises avoiding the combination (FDA apixaban label), and the European Society of Cardiology () advises avoiding it where possible (ESC 2024). Do not use apixaban to treat deep vein thrombosis or pulmonary embolism in a patient on phenytoin, because efficacy may be reduced (apixaban SmPC of the European Medicines Agency, ). For stroke prevention in atrial fibrillation, prevention of thrombosis after elective hip or knee surgery and prevention of recurrent thrombosis, the EMA SmPC allows the combination with caution and without changing the apixaban dose (apixaban SmPC, EMA). The European Heart Rhythm Association (EHRA) also asks for caution, especially when the patient takes several drugs that lower anticoagulant levels (EHRA 2021). If the combination continues, watch for signs of thrombosis, stroke and bleeding: these are the outcomes the SmPC describes in atrial fibrillation patients on strong inducers (apixaban SmPC, EMA).
Sources
Mechanism
Disulfiram inhibits CYP2C9 and CYP2C19. Phenytoin rises 2-3 fold – toxicity (nystagmus, ataxia).
Symptoms
Nystagmus, ataxia, dizziness within 5-7 days.
Management
Check phenytoin level at 5 and 14 days. Reduce dose 30-50%.
Mechanism
5-FU inhibits CYP2C9 – phenytoin rises 2-fold. Toxicity with ataxia, nystagmus.
Symptoms
Nystagmus, ataxia, drowsiness after 7-14 days.
Management
Check phenytoin level on day 7. Reduce dose 25-50%.
Mechanism
Phenytoin induces UGT1A4. Lamotrigine falls 50%.
Symptoms
Seizure breakthrough.
Management
Double lamotrigine dose.
Sources
Mechanism
Phenytoin induces CYP3A4. Simvastatin level falls 60%, lipid-lowering effect is lost. cholesterol returns to baseline, cardiovascular risk rises.
Symptoms
returns to baseline over 4–6 weeks.
Management
Alternative statin: pravastatin or rosuvastatin (not CYP3A4-metabolised). Alternative anticonvulsant: levetiracetam.
Mechanism
Phenytoin induces CYP3A4. Tacrolimus level falls 2–3 fold with transplant rejection risk.
Symptoms
Tacrolimus trough below target, laboratory signs of rejection.
Management
For post-transplant epilepsy: levetiracetam or lacosamide as alternative. If phenytoin is needed, increase tacrolimus 2–3 fold with frequent monitoring.
Sources
Mechanism
Phenytoin induces CYP1A2. Theophylline falls 30-50%.
Symptoms
Return of obstructive symptoms.
Management
Theophylline level monitoring with dose adjustment.
Sources
Verbatim lines from the interaction sections, in the language of the label
«Drugs that Affect Phenytoin Concentrations: Antacids Antacids may affect absorption of phenytoin. Calcium carbonate, aluminum hydroxide, magnesium hydroxide Prevention or Management: Phenytoin and…»FDA, section 7 · Open on DailyMed
«Drugs that Affect Phenytoin Concentrations: Antacids Antacids may affect absorption of phenytoin. Calcium carbonate, aluminum hydroxide, magnesium hydroxide Prevention or Management: Phenytoin and…»FDA, section 7 · Open on DailyMed
«CONTRAINDICATIONS: Anticonvulsants Carbamazepine, phenobarbital, phenytoin»FDA, section 4 · Open on DailyMed
«CONTRAINDICATIONS: Anticonvulsants: carbamazepine, phenobarbital, phenytoin»FDA, section 4 · Open on DailyMed
«Effects of Other Drugs on Ranolazine: CYP3A Inducers Do not use ranolazine extended-release tablets with CYP3A inducers such as rifampin, rifabutin, rifapentine, phenobarbital, phenytoin…»FDA, section 7 · Open on DailyMed
«Fenitoína: La combinación de fenitoína con amiodarona puede conducir a una sobredosis de fenitoína, dando lugar a signos neurológicos. Debe realizarse una monitorización clínica y se debe reducir la…»AEMPS, section 4.5 · Open on CIMA
«Inductores del CYP3A4 y de la P ‑ gp: La administración concomitante de apixabán con rifampicina, un potente inductor del CYP3A4 y de la P ‑ gp, produjo disminuciones aproximadas del 54 % y 42 % en…»AEMPS, section 4.5 · Open on CIMA
«Combined P-gp and Strong CYP3A4 Inducers: Avoid concomitant use of ELIQUIS with combined P-gp and strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, St. John’s wort) because such drugs…»FDA, section 7 · Open on DailyMed
«Antiarrítmicos de Clase-I (ej. quinidina, disopiramida; lidocaína, fenitoína; flecainida, propafenona): Pueden potenciar los efectos sobre el tiempo de conducción auriculoventricular y aumentar el…»AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: • CYP2B6 inducers: Dose increase may be necessary if coadministered with CYP2B6 inducers (e.g., ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, and phenytoin) based…»FDA, section 7 · Open on DailyMed
«DRUG INTERACTIONS: • Allopurinol: Avoid concomitant use of allopurinol with capecitabine. ( 7.1 ) • Leucovorin: Closely monitor for toxicities when capecitabine is coadministered with leucovorin. (…»FDA, section 7 · Open on DailyMed
«DRUG INTERACTIONS: Phenytoin Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to…»FDA, section 7 · Open on DailyMed
«Precauciones que incluyen ajuste de dosis: La administración concomitante de sustancias conocidas como inductoras de los enzimas del citocromo P450 puede disminuir los niveles plasmáticos de…»AEMPS, section 4.5 · Open on CIMA
«Potential for Other Drugs to Affect Clozapine: Concomitant treatment with drugs that induce CYP1A2 or CYP3A4 can decrease the plasma concentration of clozapine, resulting in decreased effectiveness…»FDA, section 7 · Open on DailyMed
«Darunavir potenciado con cobicistat es más sensible a la inducción del CYP3A que darunavir potenciado con ritonavir. El uso concomitante con inductores potentes de CYP3A está contraindicado, dado que…»AEMPS, section 4.3 · Open on CIMA
«CYP3A4 Inhibitors and Inducers: Co-administration of deflazacort with rifampin, a strong CYP3A4 inducer, significantly decreased the exposure of 21-desDFZ. Avoid concomitant use of strong (e.g…»FDA, section 7 · Open on DailyMed
«Tratamiento de larga duración: Sustancias que aumentan el aclaramiento de las hormonas anticonceptivas (disminución de la eficacia anticonceptiva por inducción enzimática), por ejemplo: Barbitúricos…»AEMPS, section 4.5 · Open on CIMA
«La administración de dexametasona con inductores de CYP3A4, como efedrina, barbitúricos, rifabutina, rifampicina, fenitoína, y carbamazepina puede conducir a una reducción de las concentraciones…»AEMPS, section 4.5 · Open on CIMA
«Inductores del CYP 3A4: Rifampicina (600 mg una vez al día) disminuye los niveles de dronedarona en un 80% sin cambios importantes en los niveles de su metabolito activo. Por lo tanto, la…»AEMPS, section 4.5 · Open on CIMA
«Effects of Other Drugs on Dronedarone: Avoid rifampin or other CYP3A inducers such as phenobarbital, carbamazepine, phenytoin, and St. John's wort because they decrease exposure to dronedarone…»FDA, section 7 · Open on DailyMed
«No se ha estudiado el efecto de la inducción de la UGT (p. ej., inducción por rifampicina o por fenitoína) sobre empagliflozina. No se recomienda el tratamiento concomitante con inductores de las…»AEMPS, section 4.5 · Open on CIMA
«Inductores CYP3A4: Debido al riesgo de descenso de la eficacia de eplerenona, no se recomienda el uso concomitante de inductores CYP3A4 (rifampicina, carbamazepina, fenitoína, fenobarbital, hierba de…»AEMPS, section 4.5 · Open on CIMA
«Tratamiento de larga duración: Barbitúricos, bosentán, carbamazepina, fenitoína, primidona, rifampicina y los medicamentos para el VIH ritonavir, nevirapina y efavirenz y, también posiblemente…»AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: Co-medications that induce CYP 3A4 (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital, or St. John's wort) may significantly decrease exposure to EXEMESTANE. Dose…»FDA, section 7 · Open on DailyMed
«Inductores del CYP3A4: La inducción del CYP3A4 puede llevar a niveles plasmáticos subterapéuticos. No se recomienda el uso concomitante con inductores del CYP3A4 (por ejemplo, carbamazepina…»AEMPS, section 4.5 · Open on CIMA
«Drug Interactions: The pharmacokinetic interactions listed below are potentially clinically important. Drugs that induce hepatic enzymes such as phenobarbital, phenytoin and rifampin may increase the…»FDA, section 7 · Open on DailyMed
«Potencial de interacción: No se debe usar itraconazol hasta 2 semanas después de la suspensión del tratamiento con medicamentos inductores del CYP3A4 (rifampicina, rifabutina, fenobarbital…»AEMPS, section 4.4 · Open on CIMA
«Cytochrome P450-Based Interactions: Ivabradine is primarily metabolized by CYP3A4. Concomitant use of CYP3A4 inhibitors increases ivabradine plasma concentrations and use of CYP3A4 inducers decreases…»FDA, section 7 · Open on DailyMed
«Drug Interactions: The pharmacokinetic interactions listed below are potentially clinically important. Mutual inhibition of metabolism occurs with concurrent use of cyclosporine and…»FDA, section 7 · Open on DailyMed
«Drug Interactions:: Nifedipine is metabolized by CYP3A4. Co-administration of nifedipine with phenytoin, an inducer of CYP3A4, lowers the systemic exposure to nifedipine by approximately 70%. Avoid…»FDA, section 7 · Open on DailyMed
«P-glycoprotein (P-gp) and CYP3A4 Inhibitors and Inducers: Nintedanib is a substrate of P-gp and, to a minor extent, CYP3A4 [see Clinical Pharmacology (12.3) ] . Coadministration with oral doses of a…»FDA, section 7 · Open on DailyMed
«Los inductores de la CYP3A4 como la rifampicina, la carbamacepina, la fenitoína y el hipérico (hierba de San Juan) pueden inducir el metabolismo de la oxicodona y provocar un aumento del aclaramiento…»AEMPS, section 4.5 · Open on CIMA
«Fenitoína: Fenitoína (200 mg una vez al día) disminuyó la C máx y el AUC de posaconazol en un 41 % y un 50 %, respectivamente. Se debe evitar el uso concomitante de posaconazol con fenitoína e…»AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: Rifabutin, phenytoin, efavirenz Avoid coadministration unless the benefit outweighs the risks ( 7.1 , 7.2 )»FDA, section 7 · Open on DailyMed
«Inductores del CYP3A4: La rifampicina (600 mg una vez al día) disminuye las concentraciones de ranolazina en el estado estacionario en aproximadamente un 95%. Se debe evitar iniciar un tratamiento…»AEMPS, section 4.5 · Open on CIMA
«Inductores del CYP3A4: La administración concomitante de rivaroxabán con rifampicina, un potente inductor del CYP3A4, produjo una disminución aproximada del 50% del AUC media de rivaroxabán, con…»AEMPS, section 4.5 · Open on CIMA
«Drugs that Induce Cytochrome P450 3A Enzymes and Drug Transport Systems: Avoid concomitant use of rivaroxaban with drugs that are combined P-gp and strong CYP3A inducers (e.g., carbamazepine…»FDA, section 7 · Open on DailyMed
«La administración de rifampicina, inductora de enzimas del citocromo P450, resultó en una reducción de aproximadamente un 60% de la actividad inhibidora total de la PDE4. Por lo tanto, el uso de…»AEMPS, section 4.5 · Open on CIMA
«Drugs that Induce Cytochrome P450 (CYP) Enzymes: Strong cytochrome P450 enzyme inducers decrease systemic exposure to roflumilast and may reduce the therapeutic effectiveness of roflumilast tablets…»FDA, section 7 · Open on DailyMed
«La administración de sunitinib con inductores potentes del CYP3A4 (por ejemplo, dexametasona, fenitoína, carbamazepina, rifampicina, fenobarbital o plantas medicinales que contienen Hierba de San…»AEMPS, section 4.5 · Open on CIMA
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Phenytoin is evaluated for the following indications with varying evidence strength: Epilepsy (evidence tier B). See the full indication matrix with dosing and citations above on this page.
Common side effects of Phenytoin (≥ 1 in 100): Nystagmus, ataxia, dizziness with supratherapeutic levels, Gingival hyperplasia, Hirsutism and coarsening of facial features on long-term use, Drowsiness, Rash, Laboratory liver enzyme rise. See the Safety section for uncommon and serious reactions.
Teratogen: raises the risk of facial malformations (fetal hydantoin syndrome), cleft palate and cardiac defects. EMA recommends pre-conception planning and, when possible, switching to levetiracetam or lamotrigine. While on therapy, folic acid 5 mg/day is required.
Passes into breast milk in small amounts. AEMPS allows breastfeeding with infant monitoring for drowsiness and poor sucking.
Phenytoin is contraindicated in: Second- or third-degree AV block and sinus bradycardia (for IV use); Combination with delavirdine – risk of ARV resistance; Known hydantoin hypersensitivity or prior DRESS; Acute porphyria. Full list in the Safety section.
Direct links to regulator labels. Open in a new tab.
Pregabalin, Topiramate, Valproic acid, Zonisamide, Gabapentin, Lamotrigine, Carbamazepine, Eslicarbazepine acetate