Phenytoin is a medicine used to control epileptic seizures (tonic-clonic and partial) and to prevent seizures after brain surgery. It requires regular blood tests (blood level) and dental care, because it can make the gums grow.
Also known as: Dilantin, Epanutin
Corticosteroid + phenytoin: enzyme induction reduces the effect of both.
Phenytoin is a potent inducer of hepatic enzymes (the label states that "phenytoin is a potent inducer of hepatic drug-metabolising enzymes" and that it induces hepatic enzymes, increasing the metabolism of several drugs), and dexamethasone is metabolised by CYP3A4: the combination increases corticosteroid clearance and reduces its therapeutic effect — clinically relevant in epileptic patients treated with phenytoin who need corticosteroids (e.g. severe asthma, autoimmune disease, cerebral oedema). The phenytoin label also mentions interference with dexamethasone suppression tests. Monitor the clinical response to the corticosteroid and consider increasing the dexamethasone dose; if phenytoin is discontinued, reassess (the corticosteroid dose may need to be reduced to avoid excess).
Dexamethasone + phenytoin: phenytoin induces CYP3A4 and reduces dexamethasone efficacy. Monitor response and consider raising the corticosteroid dose.
Phenytoin induces CYP3A4 (dexamethasone metabolism) and dexamethasone alters phenytoin metabolism.
Clinical response and serum phenytoin levels.
Seizures, lack of allergic/inflammatory control.
Monitor response and, if feasible, phenytoin levels.
DailyMed (FDA) — approved Dexamethasone label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7cbd9005-7df2-47ee-adb3-7244c1c69bc3 ; approved Phenytoin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ef4e97a7-cd18-47a9-a016-2eca5481a87e — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
CYP1A2 inducer + CYP1A2 substrate: phenytoin reduces theophylline levels 20-30%.
Phenytoin moderately induces CYP1A2, reducing theophylline levels 20-30%. The effect is less than with carbamazepine. Adjust theophylline dose based on levels.
Phenytoin induces CYP1A2, reducing theophylline 20-30%. Adjust dose based on levels.
Phenytoin induces CYP1A2, reducing theophylline levels. The effect is moderate.
Theophylline levels.
Adjust theophylline dose based on levels.
DailyMed/FDA; EMC-UK
Antimalarial + UGT inducer: phenytoin reduces DHA levels.
Phenytoin induces UGT, decreasing DHA AUC. Effect similar to rifampicin but less pronounced.
Parasite count, phenytoin levels.
Antimalarial treatment failure.
Monitor parasitaemia. Consider dose adjustment.
drugs.com; MedScape
Combining Phenytoin with Isoniazid raises Phenytoin serum levels, with a risk of toxicity, especially in slow acetylators.
Isoniazid interferes with phenytoin metabolism (inhibition of the enzymes that metabolise it, namely CYP2C19), and the isoniazid label explicitly states that "isoniazid may increase serum levels of phenytoin" and that "to avoid phenytoin intoxication, appropriate adjustment of the anticonvulsant should be made"; the label repeats the caution in the overdosage section ("phenytoin should be used cautiously, because isoniazid interferes with the metabolism of phenytoin"). Phenytoin has non-linear kinetics and a narrow therapeutic window: raised levels can cause nystagmus, ataxia, dysarthria, drowsiness and, in severe cases, seizures or coma. When the combination is needed (e.g. tuberculosis in an epileptic patient), monitor phenytoin serum levels and clinical signs of toxicity at initiation and whenever the isoniazid dose changes, adjusting the anticonvulsant dose; consider transaminase monitoring, since both drugs are hepatotoxic.
Isoniazid + phenytoin: isoniazid inhibits phenytoin metabolism and raises its levels. Monitor and adjust the anticonvulsant dose.
Isoniazid inhibits Phenytoin metabolism, raising its concentrations; the risk is higher in patients who slowly acetylate Isoniazid.
Nystagmus, ataxia, diplopia or sedation after starting Isoniazid require level testing and adjustment.
Nystagmus, ataxia, diplopia or sedation require level testing and dose adjustment.
Monitor Phenytoin levels and signs of toxicity; consider reducing the Phenytoin dose when Isoniazid is started.
DailyMed/FDA (NIH/NLM) — approved Phenytoin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ef4e97a7-cd18-47a9-a016-2eca5481a87e ; approved Isoniazid label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=93252cc8-c8d4-401b-bde5-ca8a3b57651e — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Combining Phenytoin with Phenobarbital may increase or decrease Phenytoin concentrations, requiring monitoring.
Phenobarbital is a potent inducer of hepatic enzymes (CYP2C9/2C19 — the same ones that metabolise phenytoin) and may reduce phenytoin levels, but competition for the same pathways and the saturable kinetics of phenytoin make the net effect variable: the phenytoin label includes phenobarbital among the "antiepileptics that may either increase or decrease phenytoin serum levels" and states that "the effect of phenytoin on phenobarbital serum levels... is unpredictable". Conversely, phenytoin may raise or lower phenobarbital levels. Both drugs have narrow therapeutic windows and additive CNS-depressant effects. Monitor serum levels of both during initiation/withdrawal, adjust doses based on levels and clinical symptoms, and watch for sedation, nystagmus and ataxia.
Phenytoin + phenobarbital: unpredictable bidirectional interaction (enzyme induction and competition for shared pathways). Monitor serum levels of both.
Phenobarbital, an enzyme inducer, and Phenytoin compete and induce shared metabolic pathways; the net effect is variable (increase or decrease in Phenytoin levels).
Monitor serum Phenytoin levels and clinical signs of toxicity.
Toxicity or loss of seizure control require dose reassessment.
Monitor serum Phenytoin and, if possible, Phenobarbital levels at start and dose adjustments.
DailyMed/FDA (NIH/NLM) — approved Phenytoin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ef4e97a7-cd18-47a9-a016-2eca5481a87e ; approved Phenobarbital label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fa09b4f2-edb0-4594-a2d2-b16f7b9686b4 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Combining Phenytoin with Omeprazole may increase Phenytoin concentrations and cause toxicity.
Phenytoin is metabolised in the liver, partly by CYP2C19, the same enzyme inhibited by omeprazole. Co-administration can raise phenytoin concentrations and precipitate toxicity (nystagmus, ataxia, sedation, dysarthria), especially at PPI start or at high doses. Monitor serum phenytoin levels and signs of toxicity when starting or stopping omeprazole, adjusting the dose as needed. In epileptic patients with stable control, prefer, if possible, a PPI with lower interaction potential.
Phenytoin + omeprazole: the PPI can raise phenytoin levels (CYP2C19 inhibition). Monitor levels and signs of toxicity.
Omeprazole is a CYP2C19 inhibitor, a pathway involved in Phenytoin metabolism, and may raise its levels.
Watch for nystagmus, ataxia and sedation after starting Omeprazole.
Nystagmus, ataxia or sedation after starting Omeprazole require level testing and adjustment.
Monitor signs of Phenytoin toxicity and serum levels, adjusting the dose if needed.
DailyMed/FDA (NIH/NLM) — approved Phenytoin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ef4e97a7-cd18-47a9-a016-2eca5481a87e ; approved Omeprazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=37291cab-e350-d8e3-e063-6294a90a9cb1 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Phenytoin can reduce the effectiveness of levonorgestrel. If you take both, consider an additional or alternative contraceptive method.
Phenytoin is an enzyme inducer that accelerates the metabolism of levonorgestrel and other progestogens, compromising contraceptive effectiveness. The Prontuário lists phenytoin among the inducers that reduce progestogen effectiveness, and the levonorgestrel OTC label warns that seizure medicines can reduce effectiveness. In women with epilepsy on hormonal contraception, a non-hormonal method or high-oestrogen hormonal contraception is recommended according to clinical guidance.
Enzyme inducers (phenytoin) reduce progestogen effectiveness. Recommend a non-hormonal method (copper IUD) or an additional barrier method; for emergency contraception, the copper IUD.
Enzyme induction, accelerating levonorgestrel metabolism.
Contraceptive effectiveness and cycle regularity.
Unplanned pregnancy.
Use a copper IUD or an additional barrier method; reassess contraception with the doctor.
DailyMed/FDA (NIH/NLM) — approved Levonorgestrel label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=07567b80-d8a1-41c0-95e4-33afa584bbc4 ; approved Phenytoin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ef4e97a7-cd18-47a9-a016-2eca5481a87e ; Prontuário Terapêutico do INFARMED (11th ed., 2012)
Combining Phenytoin with Warfarin reduces the anticoagulant effect of Warfarin, posing a risk of thrombotic events.
The phenytoin-warfarin interaction is one of the most complex in clinical pharmacology: phenytoin induces CYP2C9 and CYP2C19 (which can reduce warfarin's effect) but also competes with warfarin for plasma protein binding, and warfarin itself inhibits phenytoin metabolism, raising its levels and the risk of neurological toxicity (nystagmus, ataxia, sedation). The net effect on the INR is unpredictable and can oscillate in the first weeks. The INR and serum phenytoin levels should be monitored at initiation and whenever either drug is adjusted, with gradual dose changes.
Complex bidirectional interaction: phenytoin induces and inhibits CYP2C9, and warfarin raises phenytoin levels. Monitor INR and phenytoin levels when starting, adjusting and stopping.
As an enzyme inducer, Phenytoin accelerates Warfarin metabolism, lowering its concentrations and its anticoagulant effect.
Frequent INR at start and dose changes; signs of thromboembolism.
A suboptimal INR or thrombotic events require Warfarin dose adjustment.
Monitor the INR and adjust the Warfarin dose during co-administration.
DailyMed/FDA (NIH/NLM) — approved Phenytoin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ef4e97a7-cd18-47a9-a016-2eca5481a87e ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Combining Phenytoin with Amiodarone increases Phenytoin concentrations and may cause signs of toxicity.
The interaction is bidirectional: phenytoin induces CYP3A4 and lowers amiodarone (and active metabolite) concentrations, potentially reducing the antiarrhythmic effect; conversely, amiodarone inhibits CYP2C9 and epoxide hydrolase, potentially doubling phenytoin levels and causing toxicity (nystagmus, ataxia, lethargy). Changes develop over weeks because of the very long amiodarone half-life. Monitor phenytoin plasma levels, adjust the dose and watch for amiodarone efficacy.
Phenytoin + amiodarone: phenytoin lowers amiodarone levels (CYP3A4 induction) and amiodarone raises phenytoin levels (CYP2C9 inhibition). Monitor both.
Amiodarone inhibits Phenytoin metabolism, raising its serum levels; Phenytoin may in turn lower Amiodarone levels.
Watch for signs of Phenytoin toxicity: nystagmus, ataxia, diplopia, sedation.
Nystagmus, ataxia or signs of Phenytoin toxicity require level testing and adjustment.
Monitor serum Phenytoin concentrations and adjust the dose; watch the cardiac effects of Amiodarone.
DailyMed/FDA (NIH/NLM) — approved Phenytoin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ef4e97a7-cd18-47a9-a016-2eca5481a87e ; approved Amiodarone label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=51a88e8e-da02-4b97-9e7e-442fbffd908d — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Phenytoin + metronidazole: metronidazole inhibits phenytoin metabolism, increasing its serum levels and the toxicity risk (QUADRO 2).
Metronidazole inhibits CYP2C9, the enzyme that metabolises phenytoin, potentially increasing its plasma concentrations and the risk of toxicity. QUADRO 2 of Annex 7 records this interaction in the phenytoin section. Early toxicity signs include nystagmus, ataxia, dysarthria, drowsiness and, in severe cases, paradoxical seizures. The risk is higher in patients on near-maximum phenytoin doses, the elderly or those with hypoalbuminaemia (more free drug). Monitor phenytoin levels and neurological signs during metronidazole treatment; consider reducing the phenytoin dose and using an alternative antibiotic when possible.
Metronidazole + phenytoin: metronidazole inhibits phenytoin metabolism — toxicity risk (nystagmus, ataxia); monitor levels and clinical signs.
Metronidazole inhibits the enzymes that metabolise phenytoin — increased phenytoin serum level (QUADRO 2, Phenytoin: "Drugs that inhibit phenytoin metabolism... Metronidazole").
Watch for signs of phenytoin toxicity (nystagmus, ataxia, diplopia, somnolence).
Nystagmus, ataxia, diplopia (phenytoin toxicity) during metronidazole.
Monitor phenytoin levels during metronidazole; consider dose reduction.
Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 7, QUADRO 2 (Phenytoin)
Phenytoin + fluconazole: fluconazole inhibits phenytoin metabolism (CYP2C9), increasing its levels and the toxicity risk (QUADRO 2).
Fluconazole (and other azoles) inhibits CYP2C9, reducing phenytoin metabolism and increasing its plasma concentrations. QUADRO 2 of Annex 7 records this interaction in the azole antifungal and phenytoin sections. The phenytoin rise can be clinically significant within the first days, with nystagmus, ataxia and sedation. The risk is higher with high fluconazole doses, the elderly or hepatic impairment. Monitor phenytoin levels and reduce the phenytoin dose if needed; consider azoles with less inhibition (e.g. amphotericin) and reinforce clinical surveillance.
Fluconazole + phenytoin: fluconazole inhibits CYP2C9 — increased phenytoin and toxicity risk; monitor levels and adjust dose.
Fluconazole inhibits CYP2C9 which metabolises phenytoin — reduced phenytoin metabolism with increased serum level (QUADRO 2, Azole antifungals/Phenytoin: "Phenytoin: reduced metabolism with fluconazole").
Watch for signs of phenytoin toxicity (nystagmus, ataxia, diplopia).
Phenytoin toxicity during fluconazole.
Monitor phenytoin levels during fluconazole; consider dose reduction.
Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 7, QUADRO 2 (Azole antifungals; Phenytoin)
Phenytoin + chloramphenicol: chloramphenicol inhibits phenytoin metabolism, increasing its serum levels (QUADRO 2).
Chloramphenicol inhibits hepatic microsomal enzymes (including CYP2C9) and can markedly increase phenytoin concentrations; conversely, phenytoin can induce chloramphenicol metabolism, reducing its antibiotic efficacy. QUADRO 2 of Annex 7 records this interaction in the chloramphenicol and phenytoin sections. Phenytoin toxicity (nystagmus, ataxia, drowsiness) is the most feared consequence, especially in patients on near-maximum doses or with hypoalbuminaemia. Monitor phenytoin levels and clinical signs; adjust the phenytoin dose when starting or stopping chloramphenicol and consider an alternative antibiotic when possible.
Chloramphenicol + phenytoin: chloramphenicol inhibits phenytoin metabolism — toxicity risk; monitor levels and neurological signs.
Chloramphenicol inhibits hepatic drug-metabolising enzymes — decreased phenytoin metabolism and increased serum level (QUADRO 2, Chloramphenicol/Phenytoin: "Phenytoin: decreased metabolism").
Watch for signs of phenytoin toxicity (nystagmus, ataxia, diplopia).
Phenytoin toxicity during chloramphenicol.
Monitor phenytoin levels during chloramphenicol (use restricted to serious infections).
Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 7, QUADRO 2 (Chloramphenicol; Phenytoin)
Phenytoin + rifampicin: rifampicin increases phenytoin metabolism, reducing its serum levels and anticonvulsant effect (QUADRO 2).
Rifampicin induces CYP2C9 and CYP3A4, accelerating phenytoin metabolism and reducing its plasma concentrations and antiepileptic effect. QUADRO 2 of Annex 7 records this interaction in the phenytoin section. The fall in levels can lead to loss of seizure control within days to weeks; when rifampicin is stopped, phenytoin levels rise and toxicity may appear. The risk is higher in patients with well-controlled epilepsy starting antituberculosis therapy. Monitor phenytoin levels and seizure control; adjust the phenytoin dose when starting, adjusting or stopping rifampicin.
Rifampicin + phenytoin: enzyme induction — reduced phenytoin concentrations and loss of seizure control; monitor and adjust dose.
Rifampicin (potent inducer) increases phenytoin metabolism — reduced phenytoin serum levels (QUADRO 2, Phenytoin: "Drugs that increase phenytoin metabolism: Rifampicin").
Watch seizure control during rifampicin.
Seizures (subtherapeutic phenytoin levels) with rifampicin.
Monitor phenytoin levels and adjust the dose when starting/stopping rifampicin.
Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 7, QUADRO 2 (Phenytoin)
Phenytoin + eslicarbazepine: eslicarbazepine inhibits CYP2C19 and increases phenytoin concentrations — QUADRO 2 records the need for phenytoin dose adjustment.
Eslicarbazepine induces CYP3A4 and may reduce phenytoin concentrations; conversely, phenytoin induces eslicarbazepine metabolism, reducing its exposure and efficacy. QUADRO 2 of Annex 7 records this interaction in the eslicarbazepine acetate section. The practical result is a bidirectional interaction with mutual reduction of levels, potentially compromising seizure control of both drugs. The risk is higher in polytherapy patients with difficult epilepsy. Monitor serum levels of both when available and clinical control; adjust doses when introducing or changing either drug.
Eslicarbazepine + phenytoin: mutual induction of metabolism and altered levels — risk of underdosing or toxicity; monitor levels.
Eslicarbazepine inhibits CYP2C19 (which metabolises phenytoin) — increased phenytoin concentrations requiring dose adjustment (QUADRO 2, Eslicarbazepine acetate: "Phenytoin (dose adjustment needed)").
Watch for signs of phenytoin toxicity (nystagmus, ataxia, diplopia).
Phenytoin toxicity after starting eslicarbazepine.
Monitor phenytoin levels when starting eslicarbazepine; adjust the dose as needed.
Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 7, QUADRO 2 (Eslicarbazepine acetate)
Isotretinoin + Phenytoin: caution due to the possible additive effect on bone loss (phenytoin-associated osteomalacia).
Phenytoin is known to cause osteomalacia and isotretinoin may also affect bone metabolism, especially in growing adolescents. The isotretinoin label found no change in phenytoin pharmacokinetics, but no formal studies assessed the interactive effect on bone loss and caution is recommended. The risk is higher in prolonged treatment, osteoporosis, anorexia nervosa or chronic therapy affecting vitamin D. Consider bone health monitoring and reassess the need for each drug during long-term treatment.
Isotretinoin + phenytoin: caution — possible additive effect on bone loss (phenytoin osteomalacia).
Phenytoin is known to cause osteomalacia; no formal studies assessed the interactive effect on bone loss with isotretinoin, but the label advises caution.
Monitor for signs of bone loss or fractures during prolonged therapy.
Bone pain, fractures or osteomalacia during prolonged treatment.
Use with caution; consider bone health monitoring during prolonged treatment.
DailyMed/FDA (NIH/NLM) — approved Isotretinoin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d5a26c5e-9c3e-4781-8c08-62b91d21a68d ; approved Phenytoin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3580e6a8-f7c3-44a0-a1eb-2a84ae589d21
Acitretin + Phenytoin: acitretin may reduce the protein binding of phenytoin, possibly increasing the free fraction.
When acitretin is given with phenytoin, the protein binding of phenytoin may be reduced, increasing the pharmacologically active free fraction and the potential for toxicity. Phenytoin has a narrow therapeutic index, so an increase in the free fraction may cause nystagmus, ataxia and drowsiness even with apparently normal total levels. Use with caution, consider monitoring free phenytoin and watch for clinical signs of toxicity, especially when starting the combination.
Acitretin + phenytoin: acitretin may reduce phenytoin protein binding, increasing the free fraction.
When acitretin is given with phenytoin, the protein binding of phenytoin may be reduced, increasing the pharmacologically active free fraction.
Monitor for signs of phenytoin toxicity (nystagmus, ataxia, drowsiness).
Nystagmus, ataxia, drowsiness or other signs of phenytoin toxicity.
Use with caution; consider monitoring phenytoin levels and signs of toxicity.
DailyMed/FDA (NIH/NLM) — approved Acitretin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a6546625-acb8-460e-b34e-f795bfb3680a ; approved Phenytoin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3580e6a8-f7c3-44a0-a1eb-2a84ae589d21
Methotrexate + phenytoin: risk of increased methotrexate toxicity (and possibly reduced phenytoin levels).
The Prontuário documents for methotrexate "phenytoin (increased toxicity)". Phenytoin is highly protein-bound and the combination involves protein displacement and metabolic changes that may increase methotrexate toxicity; conversely, methotrexate may alter phenytoin levels. The combination is relevant in oncology patients with concomitant epilepsy. Monitor signs of methotrexate toxicity (myelosuppression, mucositis) and, if applicable, serum phenytoin levels; any ataxia, nystagmus or neurological symptoms should prompt evaluation. Consider an alternative anticonvulsant when seizure control allows.
Methotrexate + phenytoin: monitor methotrexate toxicity and phenytoin levels — risk of increased toxicity.
The Prontuário documents "phenytoin (increased toxicity)" for methotrexate. Phenytoin is highly protein-bound and the interaction involves displacement and metabolic changes — the methotrexate label lists phenytoin among drugs requiring caution.
Blood count and clinical monitoring of adverse effects during the combination.
Fever, neutropenia, mucositis or signs of phenytoin intoxication (nystagmus, ataxia).
Monitor for signs of methotrexate toxicity (myelosuppression, mucositis) and, if applicable, phenytoin levels.
DailyMed/FDA (NIH/NLM) — approved Methotrexate label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=04a95db9-a124-4b97-bd71-1c37a6b3b0c8 ; approved Phenytoin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3580e6a8-f7c3-44a0-a1eb-2a84ae589d21 ; Prontuário Terapêutico do INFARMED (11th ed., 2012) — Methotrexate, 16.1.3
Calcium folinate + phenytoin: antiepileptics may reduce folinate effectiveness — monitor seizure activity.
The FDA leucovorin label documents in the interactions section that certain antiepileptics may reduce folinate effectiveness ("Certain Antiepileptic Drugs: Increase monitoring for seizure activity in leucovorin-treated patients... Certain antiepileptic drugs may reduce the effectiveness of leucovorin"), and the Prontuário Terapêutico records the interaction in the opposite direction — folinate "may reduce the therapeutic activity of phenytoin and phenobarbital". The interaction is therefore bidirectional and clinically relevant in the epileptic patient receiving folinate as methotrexate rescue or for the treatment of folic acid antagonist toxicity: phenytoin may compromise the expected haematological recovery, and folinate may destabilise seizure control. Clinical monitoring for seizures and, when applicable, serum phenytoin level monitoring are the practical guidance. This is not an interaction requiring discontinuation, but active monitoring during the combination.
Calcium folinate + phenytoin: monitor seizure activity — antiepileptics may reduce folinate effectiveness (and folinate may reduce phenytoin activity).
The FDA leucovorin label documents: "Certain Antiepileptic Drugs: Increase monitoring for seizure activity in leucovorin-treated patients... Certain antiepileptic drugs may reduce the effectiveness of leucovorin". The Prontuário records the same in the opposite direction: "May reduce the therapeutic activity of phenytoin and phenobarbital". The interaction is bidirectional and relevant when folinate is used as methotrexate rescue in epileptic patients.
Clinical monitoring for seizures and, when applicable, phenytoin levels.
New-onset seizure, subtherapeutic phenytoin levels or absence of expected haematological recovery.
Monitor seizure activity in patients taking folinate with antiepileptics; monitor response to folinate (e.g., haematological recovery after methotrexate).
DailyMed/FDA (NIH/NLM) — approved Calcium Leucovorin label (Leading Pharma): https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c8102043-79f2-421a-b849-94bac19007a6 ; approved Phenytoin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7cbd9005-7df2-47ee-adb3-7244c1c69bc3 ; Prontuário Terapêutico do INFARMED (11th ed., 2012) — Calcium folinate, 17
Montelukast + phenytoin: phenytoin may reduce montelukast efficacy — monitor asthma control.
The Prontuário Terapêutico documents the montelukast interaction with phenytoin (5.1.3.2). Phenytoin is a CYP3A4/2C9 inducer and accelerates montelukast metabolism, potentially reducing its serum concentrations and compromising the preventive effect in asthma. The combination is possible in patients with asthma and epilepsy on phenytoin. The practical guidance is to monitor asthma control (symptoms, reliever use, PEF) during the combination; if control is lost, consider montelukast dose adjustment or a therapeutic alternative. The interaction is moderate in severity and does not require prophylactic discontinuation, only clinical vigilance.
Montelukast + phenytoin: phenytoin may reduce montelukast efficacy — monitor asthma control.
The Prontuário Terapêutico documents the montelukast interaction with phenytoin (5.1.3.2). Phenytoin, a CYP3A4/2C9 inducer, accelerates montelukast metabolism and may reduce its serum concentrations.
Assess asthma symptoms and respiratory function in the combination.
Loss of asthma control with the combination.
Monitor asthma control during the combination.
Prontuário Terapêutico do INFARMED (11th ed., 2012) — Montelukast, 5.1.3.2 ; approved Phenytoin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7cbd9005-7df2-47ee-adb3-7244c1c69bc3
Phenytoin reduces hormonal contraceptive efficacy through enzyme induction, with risk of unintended pregnancy.
Phenytoin is a microsomal metabolism inducer; Annex 7 (Oestrogens): "Phenytoin" among drugs increasing oestrogen metabolism.
Intermenstrual bleeding, missed periods.
Intermenstrual bleeding, unintended pregnancy.
Recommend additional barrier contraception; consider non-hormonal methods; pregnancy in women with epilepsy also requires planning with the neurologist.
INFARMED Prontuário Terapêutico (11th ed., 2012), Annex 7 — Oestrogens: "Phenytoin"; DailyMed — Phenytoin Tablet label [RLD Dilantin]: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=46d5c0d1-a97b-46d9-8cf4-994780673337
Antiepileptic + antiepileptic: no clinically significant pharmacokinetic interaction.
Levetiracetam is not metabolised by CYP and does not significantly bind to plasma proteins. There is no pharmacokinetic interaction with phenytoin.
No specific monitoring required.
No dose adjustment required.
DailyMed/FDA; EMC-UK
CYP inducer + antiepileptic: phenytoin may reduce topiramate levels 30-40%.
Phenytoin induces CYP3A4 and CYP2C9, accelerating topiramate metabolism. Levels may decrease 30-40%. The effect is dose-dependent — higher phenytoin doses cause greater reduction. Monitor seizure control and adjust topiramate dose.
Phenytoin induces CYP3A4/2C9, reducing topiramate 30-40%. Adjust dose based on response.
Phenytoin induces CYP3A4 and CYP2C9, accelerating topiramate metabolism. The effect is dose-dependent.
Seizure control.
Loss of seizure control.
Adjust topiramate dose. Monitor levels.
DailyMed/FDA; EMC-UK
Antiepileptic + antiepileptic: oxcarbazepine reduces phenytoin levels 20-30%.
MHD (active metabolite of oxcarbazepine) may compete for plasma protein binding and weakly induce CYP, reducing phenytoin levels 20-30%. The effect is more pronounced at higher oxcarbazepine doses (>1200 mg/day). Monitor phenytoin levels (target: 10-20 μg/mL) and signs of toxicity.
Oxcarbazepine (MHD) reduces phenytoin 20-30%. Monitor phenytoin levels.
Oxcarbazepine (MHD) may compete for plasma protein binding and induce CYP, reducing phenytoin levels. The effect is more pronounced at higher oxcarbazepine doses.
Phenytoin levels, signs of toxicity.
Ataxia, nystagmus, toxicity.
Monitor phenytoin levels. Adjust dose as needed.
DailyMed/FDA; EMC-UK
Combining Phenytoin with Valproate may increase or decrease the free fraction of Phenytoin, with a risk of toxicity or loss of efficacy.
Valproate may displace phenytoin from plasma albumin, increasing the free fraction from 10% to 20-30%. The effect is complex: total phenytoin levels may decrease (first-order metabolism of the increased free fraction), but free (pharmacologically active) levels may increase. Measure FREE phenytoin levels, not just total. Adjust dose based on free levels (target: 1-2 μg/mL free).
Valproate displaces phenytoin from albumin, increasing free fraction. Monitor free levels.
Valproate displaces Phenytoin from plasma proteins and inhibits its metabolism; the effect on the free fraction is variable. Phenytoin may in turn lower Valproate levels.
Nystagmus, ataxia, sedation or worsening seizure control require reassessment.
Signs of Phenytoin toxicity or worsening seizures require level assessment.
Monitor Phenytoin levels (ideally the free fraction) and clinical signs of toxicity.
DailyMed/FDA (NIH/NLM) — approved Phenytoin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ef4e97a7-cd18-47a9-a016-2eca5481a87e ; approved Valproic acid label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a33f7657-ad0f-43e9-ba48-024746e6d08e — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Folic acid increases phenytoin metabolism, lowering serum concentrations of the antiepileptic and possibly increasing seizure frequency.
Increased phenytoin metabolism by folate: the Prontuário (Folic acid 4.1.2) states that "folic acid may increase phenytoin metabolism with reduced serum concentrations of the antiepileptic and a possible increase in seizure frequency".
Serum phenytoin levels, seizure frequency, full blood count and folate/B12.
Increased seizure frequency or severity, status epilepticus.
Maintain supplementation when indicated (for example in pregnancy) but monitor phenytoin levels and seizure control, adjusting the antiepileptic dose; do not change dosing without monitoring.
INFARMED Prontuário Terapêutico (11th ed., 2012), Folic acid 4.1.2 — phenytoin metabolism and seizure risk.
Phenytoin lowers mebendazole plasma concentrations through enzyme induction, risking treatment failure in parasitic infections requiring prolonged therapy.
Enzyme induction of mebendazole metabolism: the Prontuário (Mebendazole 1.4.1) groups carbamazepine and phenytoin as inducers that lower mebendazole concentrations; phenytoin is also a classic CYP3A4 inducer.
Clinical response of the parasitic infection, liver enzymes; phenytoin levels if dosing changes.
Persistence of the parasitic infection, seizures (if phenytoin is poorly adjusted).
In prolonged therapy, discuss with a specialist adjusting the mebendazole dose or using an alternative while maintaining the antiepileptic; monitor the clinical response.
INFARMED Prontuário Terapêutico (11th ed., 2012), Mebendazole 1.4.1 — carbamazepine and phenytoin reduce mebendazole concentrations.
Phenytoin accelerates norethisterone metabolism, potentially reducing the contraceptive efficacy of progestogen-only contraception.
Enzyme induction: the Prontuário (Phenytoin entry 2.6) states that phenytoin "increases the metabolism of corticosteroids, oral contraceptives and nisoldipine"; migration 267 created the homologous pair with the combined pill (moderate).
Intermenstrual spotting, withdrawal bleeding, pregnancy test if failure is suspected; phenytoin levels if dosing changes.
Absent withdrawal bleeding, persistent spotting, unintended pregnancy.
Add a barrier method during treatment and for the following 4 weeks; reassess hormonal contraception in the epilepsy setting.
INFARMED Prontuário Terapêutico (11th ed., 2012), Phenytoin entry 2.6 — increased metabolism of oral contraceptives; Annex 7 — Oestrogens/contraceptives.
Phenytoin + vitamin D3: phenytoin increases vitamin D metabolism.
Phenytoin (and other enzyme inducers such as carbamazepine and phenobarbital) induces hepatic cytochrome P450 enzymes (CYP3A4, CYP2C9) that hydroxylate vitamin D, accelerating its catabolism and reducing 25-hydroxyvitamin D levels. Long-term, this loss can cause hypocalcaemia, secondary hyperparathyroidism, reduced bone density and osteomalacia in epileptic patients on prolonged therapy. Monitor vitamin D levels and serum calcium, consider preventive vitamin D (and calcium) supplementation and assess bone density in patients on chronic phenytoin.
Phenytoin + vitamin D3: phenytoin accelerates vitamin D metabolism — risk of deficiency and osteomalacia.
Phenytoin enzyme induction (CYP450) accelerates vitamin D degradation.
25(OH)D and calcium.
Vitamin D deficiency and bone changes in chronic use.
Monitor 25(OH)D in at-risk patients; supplement if needed.
DailyMed (FDA) — approved Phenytoin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ef4e97a7-cd18-47a9-a016-2eca5481a87e ; approved Cholecalciferol (vitamin D3) label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3822c324-e22a-4ac4-ac1c-9b63983b516a — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Alcohol has a variable effect on phenytoin: acute intake can raise concentrations (inhibition) and chronic intake lower them (enzyme induction).
Avoid alcohol; if unavoidable, keep the pattern stable and monitor phenytoin levels.
DailyMed/FDA (NIH/NLM) — approved Phenytoin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ef4e97a7-cd18-47a9-a016-2eca5481a87e
Phenytoin can be administered with or without food, consistently; high-fat meals can slightly alter absorption.
Always take the same way, with or without food.
DailyMed/FDA (NIH/NLM) — approved Phenytoin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ef4e97a7-cd18-47a9-a016-2eca5481a87e
Risk of fetal hydantoin syndrome (vertebral dysraphia, digital/facial hypoplasia, intrauterine growth restriction). Levels may decrease during pregnancy.
Supplement folic acid. Monitor levels trimestrally. Adjust dose as needed.
DailyMed/FDA; EMC-UK
Phenytoin is extensively metabolised in the liver; hepatic impairment alters levels and increases the risk of toxicity.
Monitor phenytoin levels and adjust the dose; watch for signs of toxicity.
DailyMed/FDA (NIH/NLM) — approved Phenytoin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ef4e97a7-cd18-47a9-a016-2eca5481a87e
Phenytoin can precipitate acute porphyria attacks in susceptible patients.
Avoid or use with great caution in patients with porphyria.
DailyMed/FDA (NIH/NLM) — approved Phenytoin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ef4e97a7-cd18-47a9-a016-2eca5481a87e
Phenytoin is teratogenic (cleft palate, cardiac defects, fetal hydantoin syndrome); the risk increases with polytherapy.
Avoid in the first trimester; do not stop abruptly in epileptic patients — reassess therapy before pregnancy.
Present in breast milk in small amounts; generally compatible, monitoring the infant.
Use effective contraception during treatment; phenytoin can reduce the efficacy of hormonal contraceptives.
DailyMed/FDA (NIH/NLM) — approved Phenytoin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ef4e97a7-cd18-47a9-a016-2eca5481a87e ; Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 1, Drugs and Pregnancy: Avoid; use only if the potential benefit outweighs the possible risks to the fetus. ; Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 2, Drugs and Breastfeeding: Present in small amounts in milk; avoiding is recommended.
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
Anticonvulsant. Stable therapeutic serum levels are reached 7 to 10 days after starting treatment with 300 mg/day (5 to 7 half-lives). Because of saturable kinetics, a dose increase of 10% or more can produce disproportionate increases in serum level, with risk of toxicity.
The precise mechanism has not been established but is thought to involve voltage-dependent blockade of membrane sodium channels, reducing sustained high-frequency neuronal discharges.
With extended-release capsules, peak serum levels occur 4 to 12 hours after administration. Phenytoin is extensively bound to plasma proteins; the free fraction may increase in renal or hepatic disease and in hypoalbuminaemia.
Mainly metabolised in the liver by CYP2C9 and, to a lesser extent, CYP2C19, by hydroxylation that is saturable at high serum levels. It is a potent inducer of hepatic drug-metabolising enzymes. Most is excreted in bile as inactive metabolites, reabsorbed and eliminated in urine; renal excretion occurs by glomerular filtration and mainly by tubular secretion.
The mean plasma half-life after oral administration is about 22 hours (range 7 to 42 hours), increasing at doses in the upper range because of saturable kinetics.
Medicines from the same therapeutic group (ATC classification) or the same pharmacological class.
