Antiepileptic (sodium channel blocker)
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)
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 Valproate may increase or decrease the free fraction of Phenytoin, with a risk of toxicity or loss of efficacy.
Valproate displaces phenytoin from plasma protein binding and inhibits its metabolism, potentially raising the free fraction of phenytoin even with apparently normal total levels — the valproate label states that "phenobarbital and/or phenytoin concentrations may be affected" and recommends "periodic plasma concentration determinations of concomitant antiepileptics during the early course of therapy"; phenytoin, in turn, is an enzyme inducer and "may lower valproate levels" (the phenytoin label classifies its effect on valproate as unpredictable). A raised phenytoin free fraction increases the risk of toxicity (nystagmus, ataxia, confusion) with total levels in the therapeutic range. Monitor free phenytoin (or clinical symptoms), toxicity signs and adjust doses; do not interpret total levels in isolation in patients with hypoalbuminaemia or renal impairment.
Phenytoin + valproate: valproate displaces phenytoin from protein binding and inhibits its metabolism (free fraction up); phenytoin may lower valproate levels. Monitor levels and toxicity signs.
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)
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)
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)
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
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
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.
