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Dilantin
Classes
Anticonvulsants, Hydantoins
Administration
Hazardous Drugs Classification
NIOSH 2016 List: Group 2
NIOSH (Draft) 2020 List: Table 2
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
INJECTABLES: Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
ORAL TABLETS/CAPSULES/ORAL LIQUID: Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Eye/face and respiratory protection may be needed during preparation and administration.
Different oral dosage forms are not directly interchangeable. Phenytoin capsules contain phenytoin sodium, which is 92% phenytoin. Chewable tablets and suspensions contain 100% phenytoin. Dosage adjustments may be needed when switching products, as small changes in dosage may lead to significant changes in serum phenytoin concentrations.
In general, phenytoin should be administered at the same time with regard to meals to ensure consistent absorption.
Chewable tablets: Administer at a consistent time with an adequate amount of fluid. Crush or chew tablet well before swallowing; tablets may be swallowed whole if preferable.
Immediate-release capsules: Administer at a consistent time with an adequate amount of fluid. For patients with difficulty swallowing, the capsules may be opened and the contents mixed with food or fluids.
Extended-release capsules: Administer intact; do not crush, cut, or chew. Administer at a consistent time with an adequate amount of fluid. While food does not affect the absorption of Dilantin Kapseals, some generic products exhibit reduced absorption in the presence of a high-fat meal. Administer in a consistent manner in relation to food.
Oral suspension: Shake well prior to each dose. Administer with an oral syringe or calibrated measuring device. Enteral nutrition through feeding tubes may decrease the absorption of phenytoin suspension by up to 80%. Hold enteral nutrition at least 1 hour before and 1 hour after administration of phenytoin; flush the tubing with 0.9% Sodium Chloride or Sterile Water before and after drug administration. It may be preferable to divide total daily dose into 2 doses to minimize enteral nutrition interruption; however, this may not be possible for young children with fast phenytoin metabolism. Monitor therapeutic concentrations and clinical response as dosage may need to be adjusted with feeding status changes.
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Parenteral phenytoin is generally for intravenous (IV) administration only. Although intramuscular (IM) is a labeled route of administration, it is generally avoided due to injection site pain, tissue damage, and erratic absorption. If IM administration is needed, fosphenytoin is preferred over phenytoin.
Storage: Vials are for single-dose only. Discard any unused product.
Intermittent IV Infusion
May be given undiluted or diluted with 0.9% Sodium Chloride Injection to a concentration of no less than 5 mg/mL. Do not dilute with a dextrose-containing solution; precipitation can occur.
Administer immediately after preparation and complete the infusion within 1 to 4 hours. Do not refrigerate the diluted infusion mixture.
If undiluted parenteral phenytoin is refrigerated or frozen, precipitation is possible; however, this will dissolve during exposure to room temperature and the product is still suitable for use. A faint yellow coloration may develop, but this does not affect the potency of the solution.[46974]
Intermittent IV Administration
Phenytoin is irritating to the veins and can result in local tissue damage; good IV access is recommended prior to administration. Acceptable access includes a) peripheral vein that is at least as large as the antecubital fossa vein, preferably accessed with a catheter size 20 gauge or larger; or b) pre-existing central venous access. The vein utilized should be free from injury or thrombophlebitis. Avoid the use of scalp veins for infusion in neonates and infants. In emergency situations, the treatment of the emergency dictates the importance of these IV access recommendations.[26240] [46974]
Administer phenytoin through a free-flowing IV of 0.9% Sodium Chloride Injection or other non-dextrose containing saline solution. Prior to administration, test the patency of the IV catheter with a flush of sterile saline. Follow each dose by a flush of sterile saline through the same catheter to reduce the risk of local vein irritation.
Use an in-line filter of 0.22 to 0.55 microns.[46974]
Avoid extravasation; phenytoin is irritating to tissues and may cause injury.
The rate of administration is critically important. Do not exceed the following infusion rates:
Adults: Infuse at a rate not to exceed 50 mg/minute. Slower infusion rates are recommended to reduce the risk of adverse cardiovascular events.
Elderly or debilitated adults: Infuse at a rate not to exceed 25 to 50 mg/minute. Slower infusion rates are recommended to reduce the risk of adverse cardiovascular events.
Children and Adolescents: Infuse at a rate of 0.5 to 1 mg/kg/minute. Max rate: 50 mg/minute. While rates of administration of up to 3 mg/kg/minute are recommended in the product labeling, they are associated with an increased frequency of infusion-related adverse events and generally not recommended in pediatric patients. [46974] [64934]
Neonates and Infants: Infuse at a rate of 0.5 to 1 mg/kg/minute. Max rate: 50 mg/minute. Due to their small veins, infants may be more at risk of thrombophlebitis or other tissue injury from IV phenytoin; do not infuse via scalp veins. While rates of administration of up to 3 mg/kg/minute are recommended in the product labeling, they are associated with an increased frequency of infusion-related adverse events and generally not recommended in pediatric patients. [46974] [64934]
Continuously monitor electrocardiogram (ECG), blood pressure, and respiratory function throughout infusion until 1-hour post-infusion.[26240] [46974]
Do not use IM phenytoin for the treatment of status epilepticus or other emergent conditions; absorption is erratic and peak plasma concentrations may not be achieved for up to 24 hours.
Avoid IM administration if possible. IM administration is painful and may cause tissue injury, necrosis, or abscess formation at the injection site.
If IM administration is the only available option and the patient is currently stable on an oral regimen with plasma concentrations within the therapeutic range, an intramuscular dose of 50% greater than the oral dose is necessary to maintain these plasma concentrations. Experience for periods greater than 1 week is lacking and plasma concentration monitoring is recommended. When returning to oral administration, the dose should be reduced by 50% of the original oral dose for 1 week to prevent excessive plasma concentrations caused by sustained release from muscle tissue sites.
Inject deeply into a large muscle (e.g., lateral part of the thigh). Aspirate prior to injection to avoid injection into a blood vessel.
Adverse Reactions
cerebral edema / Early / 4.5-4.5
suicidal ideation / Delayed / Incidence not known
seizures / Delayed / Incidence not known
coma / Early / Incidence not known
toxic epidermal necrolysis / Delayed / Incidence not known
angioedema / Rapid / Incidence not known
exfoliative dermatitis / Delayed / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
erythema multiforme / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
lupus-like symptoms / Delayed / Incidence not known
acute generalized exanthematous pustulosis (AGEP) / Delayed / Incidence not known
scarlatiniform exanthema / Rapid / Incidence not known
diabetic ketoacidosis / Delayed / Incidence not known
hepatic failure / Delayed / Incidence not known
hepatic necrosis / Delayed / Incidence not known
agranulocytosis / Delayed / Incidence not known
pancytopenia / Delayed / Incidence not known
aplastic anemia / Delayed / Incidence not known
hemolytic anemia / Delayed / Incidence not known
methemoglobinemia / Early / Incidence not known
megaloblastic anemia / Delayed / Incidence not known
porphyria / Delayed / Incidence not known
red cell aplasia / Delayed / Incidence not known
bone fractures / Delayed / Incidence not known
nephrotic syndrome / Delayed / Incidence not known
interstitial nephritis / Delayed / Incidence not known
glomerulonephritis / Delayed / Incidence not known
renal failure (unspecified) / Delayed / Incidence not known
cardiac arrest / Early / Incidence not known
ventricular tachycardia / Early / Incidence not known
AV block / Early / Incidence not known
bradycardia / Rapid / Incidence not known
ventricular fibrillation / Early / Incidence not known
teratogenesis / Delayed / Incidence not known
new primary malignancy / Delayed / Incidence not known
skin necrosis / Early / Incidence not known
vasculitis / Delayed / Incidence not known
ataxia / Delayed / 1.0-10.0
nystagmus / Delayed / 1.0-10.0
constipation / Delayed / 1.0-10.0
hypotension / Rapid / 0-9.1
amblyopia / Delayed / 0-9.1
peripheral vasodilation / Rapid / 0-4.5
gingival hyperplasia / Delayed / 10.0
depression / Delayed / Incidence not known
peripheral neuropathy / Delayed / Incidence not known
confusion / Early / Incidence not known
respiratory depression / Rapid / Incidence not known
dysarthria / Delayed / Incidence not known
bullous rash / Early / Incidence not known
eosinophilia / Delayed / Incidence not known
lymphadenopathy / Delayed / Incidence not known
hyperglycemia / Delayed / Incidence not known
hepatomegaly / Delayed / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known
hepatitis / Delayed / Incidence not known
cholestasis / Delayed / Incidence not known
jaundice / Delayed / Incidence not known
neutropenia / Delayed / Incidence not known
thrombocytopenia / Delayed / Incidence not known
leukopenia / Delayed / Incidence not known
osteoporosis / Delayed / Incidence not known
hypocalcemia / Delayed / Incidence not known
hypophosphatemia / Delayed / Incidence not known
osteomalacia / Delayed / Incidence not known
osteopenia / Delayed / Incidence not known
impotence (erectile dysfunction) / Delayed / Incidence not known
nephrolithiasis / Delayed / Incidence not known
priapism / Early / Incidence not known
infusion-related reactions / Rapid / Incidence not known
hypothyroidism / Delayed / Incidence not known
dystonic reaction / Delayed / Incidence not known
choreoathetosis / Delayed / Incidence not known
dyskinesia / Delayed / Incidence not known
cataracts / Delayed / Incidence not known
vitamin D deficiency / Delayed / Incidence not known
folate deficiency / Delayed / Incidence not known
paresthesias / Delayed / 1.0-10.0
insomnia / Early / 1.0-10.0
vertigo / Early / 1.0-10.0
headache / Early / 1.0-10.0
asthenia / Delayed / 1.0-10.0
dizziness / Early / 1.0-10.0
drowsiness / Early / 1.0-10.0
hyporeflexia / Delayed / 1.0-10.0
vomiting / Early / 1.0-10.0
abdominal pain / Early / 1.0-10.0
nausea / Early / 1.0-10.0
dysgeusia / Early / 1.0-10.0
tinnitus / Delayed / 0-9.1
tremor / Early / 10.0
maculopapular rash / Early / Incidence not known
hypertrichosis / Delayed / Incidence not known
purpura / Delayed / Incidence not known
skin hyperpigmentation / Delayed / Incidence not known
hirsutism / Delayed / Incidence not known
macrocytosis / Delayed / Incidence not known
libido decrease / Delayed / Incidence not known
asterixis / Delayed / Incidence not known
metallic taste / Early / Incidence not known
injection site reaction / Rapid / Incidence not known
Boxed Warning
Phenytoin injection is contraindicated in patients with sinus bradycardia, sino-atrial block, second or third degree AV block, and Adams-Stokes syndrome because of the effects of the drug on ventricular automaticity. Intravenous phenytoin should not be used in patients with other cardiac conduction abnormalities (e.g., bundle-branch block) and should be used with caution in any patient with cardiac disease, such as cardiac arrhythmias, congestive heart failure, or coronary artery disease, because symptoms may be potentiated or exacerbated.[46974] Cases of bradycardia and cardiac arrest have been reported in patients treated with enteral phenytoin, at recommended doses and concentrations and in association with toxicity. Most cases of cardiac arrest occurred in patients with underlying cardiac disease.[52351] FDA-approved labeling for parenteral phenytoin contains a boxed warning that highlights infusion-related reactions, specifically cardiovascular risks, associated with rapid intravenous administration rates. Severe cardiovascular reactions have occurred, including bradycardia, heart block, ventricular tachycardia, and ventricular fibrillation, which have resulted in asystole, cardiac arrest, and death in some cases. The rate of intravenous administration is critically important to avoid or limit adverse reactions; do not exceed recommended infusion rates. In elderly or debilitated patients, some experts suggest infusing IV no faster than 25 mg/minute; consider slower infusion rates if concurrent cardiac disease is present.[46974] Though the FDA-approved labeling recommends a pediatric infusion rate of 1 to 3 mg/kg/minute (not to exceed 50 mg/minute), most experts recommend not exceeding a rate of 1 mg/kg/minute in any pediatric patient.[46974] [44772] Hypotension may occur, especially after high doses are given at high rates of administration. Although the risk of cardiovascular toxicity is increased with rapid intravenous administration, cardiac events have also been reported at or below the recommended infusion rates. Reactions to parenteral phenytoin occur more often in elderly or debilitated patients, children (particularly infants), those who are critically ill, or those with preexisting hypotension or severe myocardial insufficiency. Careful cardiac and respiratory monitoring is required during and after intravenous phenytoin administration. A reduction in the rate of administration or discontinuation of the drug may be necessary if cardiac reactions occur.[46974] Some cardiac effects are thought to be secondary to the propylene glycol (PEG) diluent of the parenteral product.[61542]
Common Brand Names
Dilantin, Dilantin Infatabs, Dilantin-125, Phenytek
Dea Class
Rx
Description
Oral and parenteral hydantoin anticonvulsant
Used for tonic-clonic seizures and complex partial seizures
Switching dosage forms may produce significant changes in serum concentrations
Dosage And Indications
20 mg/kg/dose (Max: 1,500 mg/dose) IV as a single dose; may administer additional 5 to 10 mg/kg/dose IV as single dose after 10 minutes if needed. Persons who are intermediate or poor metabolizers of CYP2C9 should receive a standard loading dose.[59510] [59511]
15 to 20 mg/kg/dose (Max: 1,500 mg/dose) IV as a single dose; may administer additional 5 to 10 mg/kg/dose IV as a single dose after 10 minutes if needed.[26240] [46974] [52093] [61569] Persons who are intermediate or poor metabolizers of CYP2C9 should receive a standard loading dose.[59510] [59511]
15 to 20 mg/kg/dose IV as a single dose.[26240] [46974] [52093] [52135] [52139] Persons who are intermediate or poor metabolizers of CYP2C9 should receive a standard loading dose.[59510] [59511]
125 mg PO 3 times daily, initially. Adjust dose every 7 to 10 days as needed based on clinical status and/or serum concentrations. Max: 625 mg/day in divided doses.
5 mg/kg/day PO in 2 or 3 divided doses, initially. Adjust dose every 7 to 10 days as needed based on clinical status and/or serum concentrations. Usual dose: 4 to 8 mg/kg/day in equally divided doses. Usual Max: 300 mg/day in divided doses. Infants may require larger maintenance doses due to enhanced hepatic clearance seen until 1 year of age. Pharmacokinetic data suggest the following maintenance doses are often required: children younger than 3 years, 10 mg/kg/day; children 4 to 6 years, 7.5 mg/kg/day; children 7 to 9 years, 7 mg/kg/day; children and adolescents 10 to 16 years, 6 mg/kg/day.
5 mg/kg/day PO in 2 or 3 divided doses, initially. Adjust dose every 7 to 10 days as needed based on clinical status and/or serum concentrations. Usual dose: 4 to 8 mg/kg/day in equally divided doses. Some neonates, particularly after the first week of life, may have difficulty maintaining therapeutic concentrations within this dosage range and require higher maintenance doses (e.g., 10 mg/kg/day).
100 mg PO 3 times daily, initially. Adjust dose every 7 to 10 days as needed based on clinical status and/or serum concentrations. Usual dose: 100 mg PO 3 to 4 times daily. Max: 200 mg PO 3 times daily.
5 mg/kg/day PO in 2 or 3 divided doses, initially. Adjust dose every 7 to 10 days as needed based on clinical status and/or serum concentrations. Usual dose: 4 to 8 mg/kg/day in equally divided doses. Usual Max: 300 mg/day in divided doses. If the daily dosage cannot be divided equally, give the larger dose before bedtime. Pharmacokinetic data suggest the following maintenance doses are often required: children younger than 3 years, 10 mg/kg/day; children 4 to 6 years, 7.5 mg/kg/day; children 7 to 9 years, 7 mg/kg/day; children and adolescents 10 to 16 years, 6 mg/kg/day.
100 mg PO 3 times daily, initially. Adjust dose every 7 to 10 days as needed based on clinical status and/or serum concentrations. Usual dose: 100 mg PO 3 to 4 times daily. Max: 200 mg PO 3 times daily. May consider a dose of 300 mg PO once daily if seizure control is established with 100 mg PO 3 times daily. Studies comparing divided doses of 300 mg with a single daily dose indicated absorption, peak serum concentrations, biologic half-life, difference between peak and minimum values, and urinary recovery were equivalent. Once-daily dosing offers a convenience and is intended to be used only for persons requiring this amount of drug daily. An oral loading dose of 400 mg PO as a single dose, followed by 300 mg PO every 2 hours for 2 doses may be given when rapid steady-state serum concentrations are required and intravenous administration is not desirable with the maintenance dose started 24 hours after the loading dose.
5 mg/kg/day PO in 2 or 3 divided doses, initially. Adjust dose every 7 to 10 days as needed based on clinical status and/or serum concentrations. Usual dose: 4 to 8 mg/kg/day in equally divided doses. Usual Max: 300 mg/day in divided doses. Pharmacokinetic data suggest the following maintenance doses are often required: children younger than 3 years, 10 mg/kg/day; children 4 to 6 years, 7.5 mg/kg/day; children 7 to 9 years, 7 mg/kg/day; children and adolescents 10 to 16 years, 6 mg/kg/day.
10 to 15 mg/kg/dose IV loading dose, then 100 mg IV 3 to 4 times daily, initially. Adjust dose every 7 to 10 days as needed based on clinical status and/or serum concentrations. Usual dose: 100 mg IV 3 to 4 times daily. Max: 200 mg IV 3 times daily.
15 to 20 mg/kg/dose IV loading dose, then 5 mg/kg/day IV in 3 or 4 divided doses, initially. Adjust dose every 7 to 10 days as needed based on clinical status and/or serum concentrations. Usual dose: 4 to 8 mg/kg/day in equally divided doses. Usual Max: 300 mg/day in divided doses. Pharmacokinetic data suggest the following maintenance doses are often required: children younger than 3 years, 10 mg/kg/day; children 4 to 6 years, 7.5 mg/kg/day; children 7 to 9 years, 7 mg/kg/day; children and adolescents 10 to 16 years, 6 mg/kg/day.
15 to 20 mg/kg/dose IV loading dose, then 5 mg/kg/day IV in 3 or 4 divided doses, initially. Adjust dose every 7 to 10 days as needed based on clinical status and/or serum concentrations. Usual dose: 4 to 8 mg/kg/day in equally divided doses. Some neonates, particularly after the first week of life, may have difficulty maintaining therapeutic concentrations within this dosage range and require higher maintenance doses (e.g., 10 mg/kg/day).
Typically not given IM due to the risk of necrosis, abscess formation, and erratic absorption. If IM administration is required, compensating dosage adjustments are necessary to maintain therapeutic serum concentrations. An IM dose 50% more than the oral dose is necessary to maintain these concentrations. When return to oral administration, reduce the dose by 50% of the original oral dose for 1 week to prevent excessive serum concentrations due to sustained release from intramuscular tissue sites.
The loading dose is 10 to 20 mg/kg IV (Usual Max: 1,000 mg). Patients who are intermediate or poor metabolizers of CYP2C9 should receive a standard loading dose. Continuously monitor electrocardiogram (ECG), blood pressure, and respiratory function throughout infusion until 1 hour post-infusion. The maintenance dose is 4 to 6 mg/kg/day IV, divided into 2 or more doses. Do not exceed an IV administration rate of 50 mg/minute. Use IV route only when oral phenytoin administration is not possible. Consider at least a 25% reduction of the recommended starting maintenance dose in patients who are intermediate metabolizers of CYP2C9 and at least a 50% reduction of the recommended starting maintenance dose in patients who are poor metabolizers of CYP2C9. Adjust dose to therapeutic effect and phenytoin concentrations. Routine seizure prophylaxis beyond 1 week is not recommended by clinical practice guidelines for the treatment of traumatic brain injury.
The loading dose is 10 to 20 mg/kg IV. Max initial IV load: 1,000 mg IV. Patients who are intermediate or poor metabolizers of CYP2C9 should receive a standard loading dose. Continuously monitor electrocardiogram (ECG), blood pressure, and respiratory function throughout infusion until 1 hour post-infusion. The maintenance dose is 5 mg/kg/day IV (range: 4 to 8 mg/kg/day IV), divided into 2 or more doses per day. Max IV administration rate: 0.5 to 1 mg/kg/minute (Max: 50 mg/minute). Consider at least a 25% reduction of the recommended starting maintenance dose in patients who are intermediate metabolizers of CYP2C9 and at least a 50% reduction of the recommended starting maintenance dose in patients who are poor metabolizers of CYP2C9. Due to faster clearance, dosing frequencies of at least every 8 hours may provide more consistent concentrations. Pharmacokinetic data from oral formulations (chewable tablets and capsules) suggest higher maintenance doses are typically required to maintain therapeutic concentrations for pediatric patients. Limited studies are available for traumatic brain injury seizure prophylaxis; efficacy data are inconsistent. Clinical practice guidelines state that prophylactic phenytoin may be considered in pediatric patients with severe traumatic brain injury to reduce incidence of early post-traumatic seizures; however, the data do not suggest prophylaxis improves neurologic outcome or reduces the risk of seizures long-term. Monitor phenytoin concentrations.
The loading dose is 10 to 20 mg/kg IV. Patients who are intermediate or poor metabolizers of CYP2C9 should receive a standard loading dose. Continuously monitor electrocardiogram (ECG), blood pressure, and respiratory function throughout infusion until 1 hour post-infusion. The maintenance dose is 5 mg/kg/day IV (range: 4 to 8 mg/kg/day IV), divided into 2 or more doses per day. Max IV administration rate: 0.5 to 1 mg/kg/minute. Infants may require larger maintenance doses due to enhanced hepatic clearance seen until 1 year of age. Consider at least a 25% reduction of the recommended starting maintenance dose in patients who are intermediate metabolizers of CYP2C9 and at least a 50% reduction of the recommended starting maintenance dose in patients who are poor metabolizers of CYP2C9. Due to fast clearance, a dosing frequency of at least every 8 hours may provide more consistent plasma concentrations. Limited studies are available for traumatic brain injury seizure prophylaxis; efficacy data are inconsistent. Clinical practice guidelines state that prophylactic phenytoin may be considered in pediatric patients with severe traumatic brain injury to reduce incidence of early post-traumatic seizures; however, the data do not suggest prophylaxis improves neurologic outcome or reduces the risk of seizures long-term. Monitor phenytoin concentrations.
100 mg IV every 5 minutes as needed until desired effect obtained to control the arrhythmia or adverse events limit tolerance, or up to a maximum total dose of 1,000 mg IV. Oral therapy may follow use of IV dosing. Monitor serum concentrations. Phenytoin exhibits class IB anti-arrhythmic activity but is not commonly used due to limited utility.
Dosage not established. 300 mg/day and 5 to 6 mg/kg/day PO have been reported. Consider at least a 25% reduction of the recommended starting maintenance dose in patients who are intermediate metabolizers of CYP2C9 and at least a 50% reduction of the recommended starting maintenance dose in patients who are poor metabolizers of CYP2C9. Phenytoin is not considered a primary or secondary treatment option in guidelines and should not be used.
100 mg PO 3 to 4 times daily.
Not recommended by clinical practice guidelines; phenytoin has been inferior to magnesium sulfate in clinical trials. 10 mg/kg IV initially, then 5 mg/kg IV 2 hours later is a traditionally administered phenytoin regimen for eclampsia (Ryan regimen) in the obstetric setting. A 1,000 mg IV loading dose followed by 100 mg IV every 6 hours for 24 hours has also been used. Patients who are intermediate or poor metabolizers of CYP2C9 should receive a standard loading dose. Due to the increased risk of cardiovascular toxicity associated with rapid IV administration, do not exceed an infusion rate of 50 mg/minute in adults. Magnesium sulfate is the preferred agent for use and is initiated in patients with preeclampsia who are showing signs of progression to severe preeclampsia or to eclampsia and in all women with diagnosed eclampsia. In the Eclampsia Trial Collaborative Group multicenter trial, phenytoin was inferior to magnesium sulfate IV. Women who received magnesium sulfate IV had a 67% lower risk of recurrent seizures than those who received phenytoin. Also, maternal and neonatal morbidity were lower in the magnesium group.
†Indicates off-label use
Dosing Considerations
Dosage adjustments may be required based on serum phenytoin concentrations and clinical response. Phenytoin is primarily metabolized in the liver. Patients with hepatic disease may have an increased fraction of unbound ('free') phenytoin.
Renal ImpairmentDosage adjustments may be required based on serum phenytoin concentrations and clinical response. Patients with renal disease may have an increased fraction of unbound ('free') phenytoin.
Intermittent hemodialysis
Phenytoin is not significantly removed during a standard hemodialysis session; therefore, supplemental dosing after hemodialysis is not necessary.
Drug Interactions
Abacavir; Dolutegravir; Lamivudine: (Major) Avoid concurrent use of dolutegravir with phenytoin, as coadministration may result in decreased dolutegravir plasma concentrations. Currently, there are insufficient data to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Phenytoin is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Minor) Coadministration with zidovudine has resulted in altered phenytoin concentrations. Reports have varied, with increased and decreased phenytoin concentrations being reported. Use combination with caution.
Abemaciclib: (Major) Avoid coadministration of phenytoin with abemaciclib due to decreased exposure to abemaciclib and its active metabolites, which may lead to reduced efficacy. Consider alternative treatments. Abemaciclib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by approximately 70% in healthy subjects.
Abiraterone: (Major) Avoid coadministration of abiraterone with phenytoin if possible due to decreased plasma concentrations of abiraterone. If concomitant use is unavoidable, increase the dosing frequency of abiraterone to twice daily. Reduce the dose back to the previous dose and frequency if phenytoin is discontinued. Abiraterone is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased abiraterone exposure by 55%.
Acalabrutinib: (Major) Avoid the concomitant use of acalabrutinib and phenytoin. If coadministration cannot be avoided, increase the acalabrutinib dose to 200 mg PO twice daily. Decreased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer. In healthy subjects, the Cmax and AUC values of acalabrutinib were decreased by 68% and 77%, respectively, when acalabrutinib was coadministered with another strong CYP3A4 inducer for 9 days.
Acetaminophen: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Higher caffeine doses may be needed after hydantoin administration; hydantoins increase caffeine elimination. (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Aspirin: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Aspirin; Diphenhydramine: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Caffeine: (Moderate) Higher caffeine doses may be needed after hydantoin administration; hydantoins increase caffeine elimination. (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with phenytoin can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If phenytoin is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Phenytoin is a strong inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. (Moderate) Higher caffeine doses may be needed after hydantoin administration; hydantoins increase caffeine elimination. (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Caffeine; Pyrilamine: (Moderate) Higher caffeine doses may be needed after hydantoin administration; hydantoins increase caffeine elimination. (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Chlorpheniramine: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with phenytoin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If phenytoin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Phenytoin is a strong CYP3A4 inducer. (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Dextromethorphan: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Dextromethorphan; Doxylamine: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Dextromethorphan; Phenylephrine: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Dextromethorphan; Pseudoephedrine: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) Phenytoin theoretically can add to the CNS-depressant effects of other CNS depressants. (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Diphenhydramine: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Guaifenesin; Phenylephrine: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with phenytoin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If phenytoin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Ibuprofen: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with phenytoin is necessary; consider increasing the dose of oxycodone as needed. If phenytoin is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Pamabrom; Pyrilamine: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Phenylephrine: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acetaminophen; Pseudoephedrine: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Acitretin: (Moderate) Acitretin reduces the protein binding of phenytoin. Free phenytoin concentrations may be useful for therapeutic monitoring if both acitretin and phenytoin are administered concurrently.
Acyclovir: (Minor) In a single case report, the addition of acyclovir to a regimen of phenytoin and valproate led to a clinically significant decrease in phenytoin serum concentrations and loss of seizure control. Acyclovir did not appear to affect valproate concentrations in this report. Until more data are known, clinicians should be prepared to make adjustments in hydantoin dosing if acyclovir therapy is added or discontinued.
Adagrasib: (Major) Avoid concurrent use of adagrasib and phenytoin due to the risk of decreased adagrasib exposure which may reduce its efficacy. The exposure of phenytoin may also be increased. Adagrasib is a CYP3A substrate and moderate CYP2C9 inhibitor and phenytoin is a CYP2C9 substrate and strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced adagrasib exposure by more than 66%.
Afatinib: (Major) Increase the daily dose of afatinib by 10 mg as tolerated if the concomitant use with phenytoin is necessary; resume the previous dose of afatinib 2 to 3 days after discontinuation of phenytoin. Afatinib is a P-glycoprotein (P-gp) substrate and phenytoin is a P-gp inducer; coadministration may decrease plasma concentrations of afatinib. Pre-treatment with another strong P-gp inducer decreased afatinib exposure by 34%.
Albendazole: (Minor) Antiepileptic drugs (AEDs) are often administered concomitantly with albendazole for the treatment of neurocysticercosis. Hydantoins appear to induce the oxidative metabolism of albendazole. Notably, a significant reduction in the plasma concentration of the active albendazole sulfoxide metabolite may occur. Monitor patient clinical response closely during treatment.
Alendronate; Cholecalciferol: (Moderate) Phenytoin and fosphenytoin can decrease the activity of vitamin D (e.g., cholecalciferol) by increasing its metabolism. In rare cases, this has caused anticonvulsant-induced rickets and osteomalacia. Vitamin D supplementation or dosage adjustments may be required in patients who are receiving chronic treatment with anticonvulsants.
Alfentanil: (Moderate) Drugs that induce CYP3A4, including phenytoin or fosphenytoin (and possibly ethotoin), may decrease the effectiveness of alfentanil. Alfentanil is a substrate for the cytochrome (CYP) 3A4 isoenzyme. Induction of alfentanil metabolism may take several days. In addition, additive CNS depression could be seen with the combined use of the hydantoin and opiate agonists.
Alogliptin: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Alogliptin; Metformin: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients. (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Alogliptin; Pioglitazone: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Alosetron: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of aolsetron, leading to reduced efficacy of alosetron.
Alpelisib: (Major) Avoid coadministration of alpelisib with phenytoin due to decreased exposure to alpelisib which could decrease efficacy; phenytoin exposure may also decrease. Alpelisib is a CYP3A4 substrate and may induce CYP2C9; phenytoin is a strong CYP3A4 inducer and a CYP2C9 substrate.
Alpha-glucosidase Inhibitors: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Alprazolam: (Moderate) Monitor for reduced efficacy of alprazolam and signs of benzodiazepine withdrawal if coadministration with hydantoins is necessary. Alprazolam is a CYP3A4 substrate and hydantoins are strong CYP3A4 inducers. Concomitant use with CYP3A4 inducers can decrease alprazolam concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Altretamine: (Minor) Altretamine undergoes significant metabolism by the cytochrome P450 system. Phenytoin is known to induce CYP450 enzymes. In theory, co-administration may increase the rate of altretamine metabolism thus decreasing altretamine effect; one study in mice has suggested that hepatic enzyme induction antagonizes antitumor activity of altretamine.
Amiodarone: (Moderate) Monitor phenytoin concentrations during concomitant therapy with amiodarone due to increased phenytoin steady-state concentrations. Concomitant use may also reduce amiodarone exposure and efficacy. Phenytoin is a CYP2C9 substrate and a strong CYP3A inducer; amiodarone is a CYP3A substrate and a CYP2C9 inhibitor.
Amitriptyline: (Moderate) Tricyclic antidepressants (TCA), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently. In addition, hydantoins may increase TCA metabolism.
Amlodipine: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with hydantoins is necessary. Amlodipine is a CYP3A4 substrate and hydantoins are strong CYP3A4 inducers. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amlodipine; Atorvastatin: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with hydantoins is necessary. Amlodipine is a CYP3A4 substrate and hydantoins are strong CYP3A4 inducers. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine. (Moderate) Monitor for a decrease in atorvastatin efficacy if concomitant use with phenytoin is necessary. Concomitant use may decrease atorvastatin exposure. Atorvastatin is a CYP3A substrate and phenytoin is a strong CYP3A inducer.
Amlodipine; Benazepril: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with hydantoins is necessary. Amlodipine is a CYP3A4 substrate and hydantoins are strong CYP3A4 inducers. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amlodipine; Celecoxib: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with hydantoins is necessary. Amlodipine is a CYP3A4 substrate and hydantoins are strong CYP3A4 inducers. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amlodipine; Olmesartan: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with hydantoins is necessary. Amlodipine is a CYP3A4 substrate and hydantoins are strong CYP3A4 inducers. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amlodipine; Valsartan: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with hydantoins is necessary. Amlodipine is a CYP3A4 substrate and hydantoins are strong CYP3A4 inducers. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with hydantoins is necessary. Amlodipine is a CYP3A4 substrate and hydantoins are strong CYP3A4 inducers. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amobarbital: (Moderate) Barbiturates can stimulate the hydroxylating enzyme that metabolizes phenytoin or, conversely, may inhibit phenytoin (or fosphenytoin) metabolism. In general, therapeutic doses of phenobarbital induce the hepatic metabolism of phenytoin, producing lower phenytoin serum concentrations. Large doses of phenobarbital, however, tend to increase phenytoin serum concentrations due to competition for hepatic pathways. Thus, phenytoin serum concentrations can increase, decrease, or not change during concomitant therapy with barbiturates. Conversely, phenytoin can increase serum concentrations of the barbiturate, however this has not been as well studied. Similar interactions may occur with ethotoin, although specific data are lacking.
Amoxapine: (Moderate) Amoxapine, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Pharmacokinetic interactions may occur, since hydantoins may induce hepatic metabolism of certain antidepressants. Monitor patients on anticonvulsants carefully when amoxapine is used concurrently.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid concomitant use of omeprazole and phenytoin as omeprazole exposure may be decreased, reducing its efficacy. Concomitant use may also increase phenytoin concentrations. Omeprazole is a CYP2C19 inhibitor and CYP3A substrate and phenytoin is a CYP2C19 substrate and strong CYP3A inducer. (Major) Coadministration of phenytoin and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking potent CYP3A4 inducers. Additionally, there have been postmarketing reports of interactions of clarithromycin and phenytoin. The clarithromycin manufacturer recommends caution if coadministered.
Amphetamine; Dextroamphetamine Salts: (Moderate) Monitor for decreased efficacy of phenytoin during coadministration with amphetamine; dextroamphetamine salts. Amphetamines may delay the intestinal absorption of phenytoin.
Antacids: (Moderate) Because the absorption of phenytoin suspension can be reduced by antacids containing magnesium, aluminum, or calcium, administration at the same time of day should be avoided when possible. Ingestion times of phenytoin capsules and calcium antacids should be staggered in patients with low serum phenytoin levels to prevent absorption difficulties. Studies evaluating the effects of magnesium-aluminium antacids on the absorption of phenytoin capsules or tablets have yielded conflicting results. Nevertheless, serum phenytoin levels and clinical response should be closely monitored if these agents are co-administered. The mechanisms by which antacids reduce phenytoin absorption may involve increased gastric transit time, chelation, adsorption, and/or altered solubility. The oral absorption of phenytoin may be reduced by calcium carbonate (e.g., as found in antacids) or other calcium salts. Calcium products may form complexes with phenytoin that are nonabsorbable. Although the magnitude of the interaction is not great, an occasional patient may be affected and the interaction may lead to subtherapeutic phenytoin concentrations. Separating the administration of phenytoin and antacids or calcium salts by at least 2 hours will help minimize the possibility of interaction.
Apixaban: (Major) Avoid the concomitant administration of apixaban and phenytoin. Coadministration results in decreased exposure to apixaban and an increase in the risk of stroke. Apixaban is a P-gp and CYP3A4 substrate; phenytoin is a P-gp and strong CYP3A4 inducer. Coadministration of another combined P-gp/strong CYP3A4 inducer reduced the apixaban AUC by more than 0.5-fold.
Apremilast: (Major) The coadministration of apremilast and phenytoin is not recommended. Apremilast is metabolized primarily by CYP3A4; phenytoin is a strong CYP3A4 inducer. Coadministration of rifampin, another strong CYP3A4 inducer, with a single dose of apremilast resulted in a decrease in apremilast AUC and Cmax by 72% and 43%, respectively. A similar reduction in systemic exposure may be seen with coadministration of apremilast and phenytoin which may result in a loss of efficacy of apremilast.
Aprepitant, Fosaprepitant: (Major) Avoid the concurrent use of phenytoin with aprepitant, fosaprepitant due to substantially decreased exposure of aprepitant. If these drugs must be coadministered, monitor for a decrease in the efficacy of aprepitant as well as an increase in phenytoin-related adverse effects for several days after administration of a multi-day aprepitant regimen. Phenytoin is a strong CYP3A4 inducer and aprepitant is a CYP3A4 substrate. When a single dose of aprepitant (375 mg, or 3 times the maximum recommended dose) was administered on day 9 of a 14-day rifampin regimen (a strong CYP3A4 inducer), the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased by 3-fold. Additionally, phenytoin is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may also increase plasma concentrations of phenytoin. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. Finally, aprepitant is a CYP2C9 inducer and phenytoin is a CYP2C9 substrate. Administration of a CYP2C9 substrate, tolbutamide, on days 1, 4, 8, and 15 with a 3-day regimen of oral aprepitant (125 mg/80 mg/80 mg) decreased the tolbutamide AUC by 23% on day 4, 28% on day 8, and 15% on day 15. The AUC of tolbutamide was decreased by 8% on day 2, 16% on day 4, 15% on day 8, and 10% on day 15 when given prior to oral administration of aprepitant 40 mg on day 1, and on days 2, 4, 8, and 15. The effects of aprepitant on tolbutamide were not considered significant.
Aripiprazole: (Major) Recommendations for managing aripiprazole and phenytoin/fosphenytoin vary by aripiprazole dosage form. For aripiprazole oral dosage forms, double the usual dose over 1 to 2 weeks. For extended-release aripiprazole injections administered monthly (Abilify Maintena) and every 2 months (Abilify Asimtufii), avoid concomitant use. Concomitant use may decrease aripiprazole exposure and reduce efficacy. Aripiprazole is CYP3A substrate; phenytoin/fosphenytoin is a strong CYP3A inducer. (Major) Recommendations for managing aripiprazole and phenytoin/fosphenytoin vary by aripiprazole dosage form. For extended-release aripiprazole lauroxil injections (Aristada), increase the 441 mg dose to 662 mg; no adjustments are necessary for other dosages. For fixed dose extended-release aripiprazole lauroxil injections (Aristada Initio), avoid concomitant use because the dose cannot be modified. Concomitant use may decrease aripiprazole exposure and reduce efficacy. Aripiprazole is CYP3A substrate; phenytoin/fosphenytoin are strong CYP3A inducers.
Armodafinil: (Moderate) Since armodafinil is metabolized by the CYP3A4 isoenzyme, and hydantoins (e.g., phenytoin, fosphenytoin) are CYP3A4 inducers. Decreased armodafinil efficacy may result from increased armodafinil metabolism. In addition, armodafinil is an inhibitor of the CYP2C19 and CYP2C9 isoenzymes. Hydantoins are substrates of CYP2C19, and phenytoin is a substrate of CYP2C9. Hydantoin concentrations may increase. Monitor carefully for signs of toxicity; phenytoin concentration monitoring may be helpful.
Artemether; Lumefantrine: (Contraindicated) Concomitant use of phenytoin and artemether; lumefantrine is contraindicated. Phenytoin is an inducer of CYP3A4 and both components of artemether; lumefantrine are substrates of this isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations and possible reduction in antimalarial activity.
Artesunate: (Moderate) Monitor for a decrease in antimalarial efficacy if artesunate is coadministered with phenytoin. Coadministration may decrease the exposure of the active metabolite of artesunate, dihydroartemisinin (DHA). DHA is a UGT substrate, and phenytoin is a strong UGT inducer.
Articaine; Epinephrine: (Moderate) Coadministration of articaine with oxidizing agents, such as phenytoin, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue articaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Barbiturates can stimulate the hydroxylating enzyme that metabolizes phenytoin or, conversely, may inhibit phenytoin (or fosphenytoin) metabolism. In general, therapeutic doses of phenobarbital induce the hepatic metabolism of phenytoin, producing lower phenytoin serum concentrations. Large doses of phenobarbital, however, tend to increase phenytoin serum concentrations due to competition for hepatic pathways. Thus, phenytoin serum concentrations can increase, decrease, or not change during concomitant therapy with barbiturates. Conversely, phenytoin can increase serum concentrations of the barbiturate, however this has not been as well studied. Similar interactions may occur with ethotoin, although specific data are lacking. (Moderate) Higher caffeine doses may be needed after hydantoin administration; hydantoins increase caffeine elimination.
Aspirin, ASA; Caffeine: (Moderate) Higher caffeine doses may be needed after hydantoin administration; hydantoins increase caffeine elimination.
Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Higher caffeine doses may be needed after hydantoin administration; hydantoins increase caffeine elimination.
Aspirin, ASA; Carisoprodol: (Minor) Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. If carisoprodol is combined with an inducer of hepatic enzymes, such as phenytoin, the potential exists for increased metabolism of carisoprodol and meprobamate, the active metabolite, plasma concentrations could be increased.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with phenytoin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If phenytoin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Phenytoin is a strong CYP3A4 inducer. (Minor) Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. If carisoprodol is combined with an inducer of hepatic enzymes, such as phenytoin, the potential exists for increased metabolism of carisoprodol and meprobamate, the active metabolite, plasma concentrations could be increased.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Because the absorption of phenytoin suspension can be reduced by antacids containing magnesium, aluminum, or calcium, administration at the same time of day should be avoided when possible. Ingestion times of phenytoin capsules and calcium antacids should be staggered in patients with low serum phenytoin levels to prevent absorption difficulties. Studies evaluating the effects of magnesium-aluminium antacids on the absorption of phenytoin capsules or tablets have yielded conflicting results. Nevertheless, serum phenytoin levels and clinical response should be closely monitored if these agents are co-administered. The mechanisms by which antacids reduce phenytoin absorption may involve increased gastric transit time, chelation, adsorption, and/or altered solubility. The oral absorption of phenytoin may be reduced by calcium carbonate (e.g., as found in antacids) or other calcium salts. Calcium products may form complexes with phenytoin that are nonabsorbable. Although the magnitude of the interaction is not great, an occasional patient may be affected and the interaction may lead to subtherapeutic phenytoin concentrations. Separating the administration of phenytoin and antacids or calcium salts by at least 2 hours will help minimize the possibility of interaction.
Aspirin, ASA; Omeprazole: (Major) Avoid concomitant use of omeprazole and phenytoin as omeprazole exposure may be decreased, reducing its efficacy. Concomitant use may also increase phenytoin concentrations. Omeprazole is a CYP2C19 inhibitor and CYP3A substrate and phenytoin is a CYP2C19 substrate and strong CYP3A inducer.
Aspirin, ASA; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with phenytoin is necessary; consider increasing the dose of oxycodone as needed. If phenytoin is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Atazanavir: (Major) Coadministration of phenytoin and atazanavir may increase the metabolism of atazanavir and lead to decreased atazanavir concentrations resulting in reduction of antiretroviral efficacy and development of viral resistance. Avoid coadministration of atazanavir with phenytoin unless atazanavir is boosted with ritonavir. Coadministration may also result in decreased phenytoin concentrations. If atazanavir and phenytoin are used together, the patient must be closely monitored for antiviral efficacy and decreased phenytoin efficacy; clinical monitoring of phenytoin concentrations with dosage titration if necessary is also warranted.
Atazanavir; Cobicistat: (Contraindicated) Coadministration of phenytoin with cobicistat-containing regimens is contraindicated. If these drugs are used together, significant decreases in the plasma concentrations of the antiretrovirals may occur, resulting in reduction of antiretroviral efficacy and development of viral resistance. Consider use of an alternative anticonvulsant or antiretroviral therapy. (Major) Coadministration of phenytoin and atazanavir may increase the metabolism of atazanavir and lead to decreased atazanavir concentrations resulting in reduction of antiretroviral efficacy and development of viral resistance. Avoid coadministration of atazanavir with phenytoin unless atazanavir is boosted with ritonavir. Coadministration may also result in decreased phenytoin concentrations. If atazanavir and phenytoin are used together, the patient must be closely monitored for antiviral efficacy and decreased phenytoin efficacy; clinical monitoring of phenytoin concentrations with dosage titration if necessary is also warranted.
Atogepant: (Major) Avoid use of atogepant and phenytoin/fosphenytoin when atogepant is used for chronic migraine. Use an atogepant dose of 30 or 60 mg PO once daily for episodic migraine if coadministered with phenytoin/fosphenytoin. Concurrent use may decrease atogepant exposure and reduce efficacy. Atogepant is a CYP3A substrate and phenytoin/fosphenytoin is a strong CYP3A inducer. Coadministration with a strong CYP3A inducer resulted in a 60% reduction in atogepant overall exposure and a 30% reduction in atogepant peak concentration.
Atorvastatin: (Moderate) Monitor for a decrease in atorvastatin efficacy if concomitant use with phenytoin is necessary. Concomitant use may decrease atorvastatin exposure. Atorvastatin is a CYP3A substrate and phenytoin is a strong CYP3A inducer.
Atorvastatin; Ezetimibe: (Moderate) Monitor for a decrease in atorvastatin efficacy if concomitant use with phenytoin is necessary. Concomitant use may decrease atorvastatin exposure. Atorvastatin is a CYP3A substrate and phenytoin is a strong CYP3A inducer.
Atracurium: (Moderate) Concomitant use of neuromuscular blockers and phenytoin may increase resistance to the neuromuscular blockade action of neuromuscular blockers, resulting in shorter durations of neuromuscular blockade and higher infusion rate requirements. The use of a peripheral nerve stimulator is strongly recommended to evaluate the level of neuromuscular blockade, to assess the need for additional doses of neuromuscular blocker, and to determine whether adjustments need to be made to the dose with subsequent administration.
Atropine; Difenoxin: (Moderate) Concurrent administration of diphenoxylate/difenoxin with hydantoins can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
Auranofin: (Minor) One patient receiving concomitant phenytoin and auranofin therapy developed an increased blood concentration of phenytoin. Further studies of this potential interaction are warranted.
Avacopan: (Major) Avoid concomitant use of avacopan and phenytoin/fosphenytoin due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and phenytoin is a strong CYP3A inducer. Concomitant use of another strong CYP3A inducer decreased avacopan overall exposure by 93%.
Avanafil: (Major) Coadministration of avanafil with phenytoin is not recommended due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A substrate and phenytoin is a strong CYP3A inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil has not been evaluated, plasma concentrations may decrease.
Avapritinib: (Major) Avoid coadministration of avapritinib with phenytoin due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of avapritinib by 92% and 74%, respectively.
Avatrombopag: (Major) In patients with chronic immune thrombocytopenia (ITP), increase the starting dose of avatrombopag to 40 mg PO once daily when used concomitantly with phenytoin. In patients starting phenytoin while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A4 substrate, and dual moderate or strong inducers such as phenytoin decrease avatrombopag exposure, which may reduce efficacy.
Axitinib: (Major) Avoid coadministration of axitinib with phenytoin due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
Azelastine; Fluticasone: (Moderate) Monitor for decreased corticosteroid efficacy if fluticasone is used with phenytoin; a dosage increase may be necessary. Concurrent use may decrease the exposure of fluticasone.
Azithromycin: (Minor) Until more data are available, the manufacturer of azithromycin recommends caution and careful monitoring of patients who receive azithromycin with phenytoin. Azithromycin was not implicated in clinical trials with drug interactions with phenytoin. However, specific drug interaction studies have not been performed with the combination of azithromycin and phenytoin.
Barbiturates: (Moderate) Barbiturates can stimulate the hydroxylating enzyme that metabolizes phenytoin or, conversely, may inhibit phenytoin (or fosphenytoin) metabolism. In general, therapeutic doses of phenobarbital induce the hepatic metabolism of phenytoin, producing lower phenytoin serum concentrations. Large doses of phenobarbital, however, tend to increase phenytoin serum concentrations due to competition for hepatic pathways. Thus, phenytoin serum concentrations can increase, decrease, or not change during concomitant therapy with barbiturates. Conversely, phenytoin can increase serum concentrations of the barbiturate, however this has not been as well studied. Similar interactions may occur with ethotoin, although specific data are lacking.
Bedaquiline: (Major) Avoid concurrent use of phenytoin with bedaquiline. Phenytoin may induce CYP3A4 metabolism resulting in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
Belladonna; Opium: (Moderate) Additive CNS depression could be seen with the combined use of the hydantoin and opiate agonists. Methadone is a primary substrate for the CYP3A4 isoenzyme. Serum concentrations of methadone may decrease due to CYP3A4 induction by phenytoin; withdrawal symptoms may occur.
Belumosudil: (Major) Increase the dosage of belumosudil to 200 mg PO twice daily when coadministered with phenytoin. Belumosudil is a CYP3A4 substrate and phenytoin is a strong CYP3A inducer; concomitant use may result in decreased belumosudil exposure and reduced belumosudil efficacy. Coadministration with another strong CYP3A inducer decreased belumosudil exposure by 72% in healthy subjects.
Bendamustine: (Major) Consider the use of an alternative therapy if phenytoin treatment is needed in patients receiving bendamustine. Phenytoin may decrease bendamustine exposure, which may result in decreased efficacy. Bendamustine is a CYP1A2 substrate and phenytoin is a CYP1A2 inducer.
Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with phenytoin may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If concomitant use is necessary, consider increasing the benzhydrocodone dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Discontinuation of phenytoin may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. If phenytoin is discontinued, consider a benzhydrocodone dosage reduction and monitor patients for respiratory depression and sedation at frequent intervals. Benzhydrocodone is a prodrug of hydrocodone. Phenytoin is a strong inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of hydrocodone. (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Benzphetamine: (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use benzphetamine with caution. Amphetamines may decrease the seizure threshold and increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary. Additionally, the amphetamines may delay the intestinal absorption of phenytoin; the extent of absorption of these seizure medications is not known to be affected.
Berotralstat: (Major) Avoid coadministration of berotralstat with phenytoin. Concurrent use may decrease berotralstat exposure, leading to reduced efficacy. Berotralstat is a P-gp substrate and phenytoin is a P-gp inducer.
Betrixaban: (Major) Avoid the concomitant administration of betrixaban and phenytoin. Concomitant administration of betrixaban and phenytoin results in decreased plasma concentrations of betrixaban that may be insufficient to achieve the intended therapeutic effect. Betrixaban is a P-glycoprotein (P-gp) substrate and phenytoin is a P-gp inducer.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Consider an alternative anticonvulsant during treatment with bictegravir. Concomitant use of bictegravir and phenytoin may result in decreased bictegravir plasma concentrations, which may result in the loss of therapeutic efficacy and development of resistance. Bictegravir is a substrate of CYP3A4; phenytoin is a strong inducer of CYP3A4.
Biotin: (Moderate) Phenytoin use for greater than one year while taking biotin can lead to decreased concentrations of biotin. Anticonvulsants that are potent CYP3A4 inducers, like phenytoin, are thought to increase biotin metabolism, leading to reduced biotin status and inhibition of intestinal biotin absorption. This can result in decreased efficacy of biotin. Discuss biotin status with patients taking these medications concomitantly.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Monitor phenytoin concentrations and for loss of metronidazole efficacy during concomitant therapy. Phenytoin may accelerate the elimination of metronidazole, resulting in reduced plasma concentrations; impaired clearance of phenytoin has also been reported.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Monitor phenytoin concentrations and for loss of metronidazole efficacy during concomitant therapy. Phenytoin may accelerate the elimination of metronidazole, resulting in reduced plasma concentrations; impaired clearance of phenytoin has also been reported.
Bleomycin: (Major) Patients receiving antineoplastic agents concurrently with hydantoins may be at risk for toxicity or loss of clinical efficacy and seizures; anticonvulsant therapy should be monitored closely during and after administration of antineoplastic agents. Concurrent therapy with phenytoin and bleomycin has been associated with subtherapeutic phenytoin serum concentrations and seizure activity. Phenytoin dosage increases of 20 to 100% have been required in some patients, depending on the chemotherapy administered.
Blinatumomab: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as phenytoin. The dose of the concomitant drug may need to be adjusted.
Bortezomib: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, including bortezomib, leading to reduced efficacy of the concomitant medication.
Bosentan: (Moderate) Bosentan is a significant inducer of CYP2C9 hepatic enzymes. Theoretically, bosentan can increase phenytoin clearance via hepatic induction. Monitor phenytoin levels.
Bosutinib: (Major) Avoid concomitant use of bosutinib, a CYP3A4 substrate, with a strong CYP3A4 inducer such as phenytoin, as a large decrease in bosutinib plasma exposure may occur.
Brentuximab vedotin: (Moderate) Concomitant administration of brentuximab vedotin with phenytoin or fosphenytoin may decrease the exposure of monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin. MMAE is a CYP3A4 substrate and phenytoin is a potent CYP3A4 inducer; therefore, the efficacy of brentuximab may be reduced.
Brexpiprazole: (Major) Because brexpiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the brexpiprazole dose be doubled over 1 to 2 weeks when a strong CYP3A4 inducer, such as ethotoin, phenytoin, or fosphenytoin, is added to brexpiprazole therapy. If these agents are used in combination, the patient should be carefully monitored for a decrease in brexpiprazole efficacy. When the CYP3A4 inducer is withdrawn from the combination therapy, the brexpiprazole dose should be reduced to the original level over 1 to 2 weeks.
Brigatinib: (Major) Avoid coadministration of brigatinib with phenytoin due to decreased plasma exposure to brigatinib, which may result in decreased efficacy. Brigatinib is a CYP3A4 su
Brivaracetam: (Major) Phenytoin plasma concentrations may increase up to 20% during concomitant treatment with brivaracetam. Monitoring of phenytoin concentrations is recommended when brivaracetam is added to or discontinued from ongoing phenytoin treatment. A 21% decrease in the plasma concentration of brivaracetam has also been observed during co-administration with phenytoin. No dose adjustment is recommended for brivaracetam during concomitant phenytoin therapy.
Brodalumab: (Moderate) If brodalumab is initiated or discontinued in a patient taking phenytoin, monitor phenytoin concentrations; phenytoin dose adjustments may be needed. The formation of CYP450 enzymes may be altered by increased concentrations of cytokines during chronic inflammation. Thus, the formation of CYP450 enzymes could be normalized during brodalumab administration. In theory, clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as phenytoin.
Bromocriptine: (Moderate) Caution and close monitoring are advised if bromocriptine and phenytoin are used together. Concurrent use may decrease the plasma concentrations of bromocriptine resulting in loss of efficacy. Bromocriptine is extensively metabolized by the liver via CYP3A4; phenytoin is a strong inducer of CYP3A4.
Bupivacaine Liposomal: (Minor) Bupivacaine is metabolized by CYP3A4. Hydantoins induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
Bupivacaine: (Minor) Bupivacaine is metabolized by CYP3A4. Hydantoins induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
Bupivacaine; Epinephrine: (Minor) Bupivacaine is metabolized by CYP3A4. Hydantoins induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
Bupivacaine; Lidocaine: (Moderate) Concomitant use of systemic lidocaine and phenytoin may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; phenytoin induces both hepatic isoenzymes. Additionally, coadministration of lidocaine with oxidizing agents, such as phenytoin, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Minor) Bupivacaine is metabolized by CYP3A4. Hydantoins induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
Bupivacaine; Meloxicam: (Minor) Bupivacaine is metabolized by CYP3A4. Hydantoins induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
Buprenorphine: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with phenytoin is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If phenytoin is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A4 substrate and phenytoin is a CYP3A4 inducer.
Buprenorphine; Naloxone: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with phenytoin is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If phenytoin is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A4 substrate and phenytoin is a CYP3A4 inducer.
Bupropion: (Moderate) Monitor for loss of efficacy of bupropion during coadministration of phenytoin as concurrent use may decrease bupropion exposure. A bupropion dose adjustment may be necessary; do not exceed maximum dose.
Bupropion; Naltrexone: (Moderate) Monitor for loss of efficacy of bupropion during coadministration of phenytoin as concurrent use may decrease bupropion exposure. A bupropion dose adjustment may be necessary; do not exceed maximum dose.
Buspirone: (Moderate) Monitor for decreased efficacy of buspirone if phenytoin is added to a patient on a stable dosage of buspirone; a dose increase of buspirone may be needed to maintain anxiolytic activity. Buspirone is a sensitive CYP3A substrate and phenytoin is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased buspirone exposure by 89.6%.
Busulfan: (Moderate) Phenytoin may increase the metabolism of some antineoplastic drugs, which could potentially affect chemotherapy efficacy. Increased antineoplastic clearance has been reported with busulfan when phenytoin was administered concurrently.
Butabarbital: (Moderate) Barbiturates can stimulate the hydroxylating enzyme that metabolizes phenytoin or, conversely, may inhibit phenytoin (or fosphenytoin) metabolism. In general, therapeutic doses of phenobarbital induce the hepatic metabolism of phenytoin, producing lower phenytoin serum concentrations. Large doses of phenobarbital, however, tend to increase phenytoin serum concentrations due to competition for hepatic pathways. Thus, phenytoin serum concentrations can increase, decrease, or not change during concomitant therapy with barbiturates. Conversely, phenytoin can increase serum concentrations of the barbiturate, however this has not been as well studied. Similar interactions may occur with ethotoin, although specific data are lacking.
Butalbital; Acetaminophen: (Moderate) Barbiturates can stimulate the hydroxylating enzyme that metabolizes phenytoin or, conversely, may inhibit phenytoin (or fosphenytoin) metabolism. In general, therapeutic doses of phenobarbital induce the hepatic metabolism of phenytoin, producing lower phenytoin serum concentrations. Large doses of phenobarbital, however, tend to increase phenytoin serum concentrations due to competition for hepatic pathways. Thus, phenytoin serum concentrations can increase, decrease, or not change during concomitant therapy with barbiturates. Conversely, phenytoin can increase serum concentrations of the barbiturate, however this has not been as well studied. Similar interactions may occur with ethotoin, although specific data are lacking. (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Butalbital; Acetaminophen; Caffeine: (Moderate) Barbiturates can stimulate the hydroxylating enzyme that metabolizes phenytoin or, conversely, may inhibit phenytoin (or fosphenytoin) metabolism. In general, therapeutic doses of phenobarbital induce the hepatic metabolism of phenytoin, producing lower phenytoin serum concentrations. Large doses of phenobarbital, however, tend to increase phenytoin serum concentrations due to competition for hepatic pathways. Thus, phenytoin serum concentrations can increase, decrease, or not change during concomitant therapy with barbiturates. Conversely, phenytoin can increase serum concentrations of the barbiturate, however this has not been as well studied. Similar interactions may occur with ethotoin, although specific data are lacking. (Moderate) Higher caffeine doses may be needed after hydantoin administration; hydantoins increase caffeine elimination. (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Barbiturates can stimulate the hydroxylating enzyme that metabolizes phenytoin or, conversely, may inhibit phenytoin (or fosphenytoin) metabolism. In general, therapeutic doses of phenobarbital induce the hepatic metabolism of phenytoin, producing lower phenytoin serum concentrations. Large doses of phenobarbital, however, tend to increase phenytoin serum concentrations due to competition for hepatic pathways. Thus, phenytoin serum concentrations can increase, decrease, or not change during concomitant therapy with barbiturates. Conversely, phenytoin can increase serum concentrations of the barbiturate, however this has not been as well studied. Similar interactions may occur with ethotoin, although specific data are lacking. (Moderate) Concomitant use of codeine with phenytoin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If phenytoin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Phenytoin is a strong CYP3A4 inducer. (Moderate) Higher caffeine doses may be needed after hydantoin administration; hydantoins increase caffeine elimination. (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Barbiturates can stimulate the hydroxylating enzyme that metabolizes phenytoin or, conversely, may inhibit phenytoin (or fosphenytoin) metabolism. In general, therapeutic doses of phenobarbital induce the hepatic metabolism of phenytoin, producing lower phenytoin serum concentrations. Large doses of phenobarbital, however, tend to increase phenytoin serum concentrations due to competition for hepatic pathways. Thus, phenytoin serum concentrations can increase, decrease, or not change during concomitant therapy with barbiturates. Conversely, phenytoin can increase serum concentrations of the barbiturate, however this has not been as well studied. Similar interactions may occur with ethotoin, although specific data are lacking. (Moderate) Concomitant use of codeine with phenytoin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If phenytoin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Phenytoin is a strong CYP3A4 inducer. (Moderate) Higher caffeine doses may be needed after hydantoin administration; hydantoins increase caffeine elimination.
Cabotegravir: (Contraindicated) Coadministration of cabotegravir and phenytoin is contraindicated due to the potential for significant decreases in the plasma concentrations of cabotegravir, which may result in potential loss of virologic response and development of resistance. Cabotegravir is a substrate for UGT1A1 and UGT1A9; phenytoin is an inducer of UGT. Coadministration with another UGT inducer decreased cabotegravir exposure by 59%.
Cabotegravir; Rilpivirine: (Contraindicated) Coadministration of cabotegravir and phenytoin is contraindicated due to the potential for significant decreases in the plasma concentrations of cabotegravir, which may result in potential loss of virologic response and development of resistance. Cabotegravir is a substrate for UGT1A1 and UGT1A9; phenytoin is an inducer of UGT. Coadministration with another UGT inducer decreased cabotegravir exposure by 59%. (Contraindicated) Concurrent use of phenytoin or fosphenytoin and rilpivirine is contraindicated. When these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Phenytoin is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
Cabozantinib: (Major) Avoid coadministration of cabozantinib with phenytoin due to the risk of decreased cabozantinib exposure which could affect efficacy. If concomitant use is unavoidable, increase the dose of cabozantinib. For patients taking cabozantinib tablets, increase the dose of cabozantinib by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day); the daily dose should not exceed 80 mg. For patients taking cabozantinib capsules, increase the dose of cabozantinib by 40 mg (e.g., 140 mg/day to 180 mg/day or 100 mg/day to 140 mg/day); the daily dose should not exceed 180 mg. Resume the cabozantinib dose that was used prior to initiating treatment with phenytoin 2 to 3 days after discontinuation of phenytoin. Cabozantinib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased single-dose cabozantinib exposure by 77%.
Caffeine: (Moderate) Higher caffeine doses may be needed after hydantoin administration; hydantoins increase caffeine elimination.
Caffeine; Sodium Benzoate: (Moderate) Higher caffeine doses may be needed after hydantoin administration; hydantoins increase caffeine elimination.
Calcifediol: (Moderate) Dose adjustment of calcifediol may be necessary during coadministration with phenytoin. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with phenytoin. Phenytoin stimulates microsomal hydroxylation and reduces the half-life of calcifediol. In rare cases, this has caused anticonvulsant-induced rickets and osteomalacia.
Calcitriol: (Moderate) Dosage adjustments of vitamin D analogs may be required during coadministration with phenytoin and fosphenytoin (which is metabolized to phenytoin). Phenytoin can increase the metabolism of endogenous vitamin D, thereby lowering serum concentrations and decreasing its activity. In rare cases, this has caused antiepileptic drug-induced rickets and osteomalacia.
Calcium Acetate: (Moderate) Oral absorption of phenytoin can be reduced by calcium salts. Calcium salts can form complexes that are nonabsorbable. Separating the administration of phenytoin and calcium salts by at least 2 hours will help avoid this interaction. A similar interaction may occur with ethotoin.
Calcium Carbonate: (Moderate) Calcium carbonate can significantly decrease the oral bioavailability of phenytoin. Calcium carbonate should not affect the pharmacokinetics of parenteral phenytoin. Separating the administration of phenytoin and calcium carbonate by at least 2 hours will help minimize the possibility of an interaction.
Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Moderate) Calcium carbonate can significantly decrease the oral bioavailability of phenytoin. Calcium carbonate should not affect the pharmacokinetics of parenteral phenytoin. Separating the administration of phenytoin and calcium carbonate by at least 2 hours will help minimize the possibility of an interaction.
Calcium Carbonate; Magnesium Hydroxide: (Moderate) Calcium carbonate can significantly decrease the oral bioavailability of phenytoin. Calcium carbonate should not affect the pharmacokinetics of parenteral phenytoin. Separating the administration of phenytoin and calcium carbonate by at least 2 hours will help minimize the possibility of an interaction.
Calcium Carbonate; Magnesium Hydroxide; Simethicone: (Moderate) Calcium carbonate can significantly decrease the oral bioavailability of phenytoin. Calcium carbonate should not affect the pharmacokinetics of parenteral phenytoin. Separating the administration of phenytoin and calcium carbonate by at least 2 hours will help minimize the possibility of an interaction.
Calcium Carbonate; Simethicone: (Moderate) Calcium carbonate can significantly decrease the oral bioavailability of phenytoin. Calcium carbonate should not affect the pharmacokinetics of parenteral phenytoin. Separating the administration of phenytoin and calcium carbonate by at least 2 hours will help minimize the possibility of an interaction.
Calcium Chloride: (Moderate) Oral absorption of phenytoin can be reduced by calcium salts. Calcium salts can form complexes that are nonabsorbable. Separating the administration of phenytoin and calcium salts by at least 2 hours will help avoid this interaction.
Calcium Gluconate: (Moderate) Oral absorption of phenytoin can be reduced by calcium salts. Calcium salts can form complexes that are nonabsorbable. Separating the administration of phenytoin and calcium salts by at least 2 hours will help avoid this interaction. A similar interaction may occur with ethotoin.
Calcium, Magnesium, Potassium, Sodium Oxybates: (Moderate) In primates, sodium oxybate blood levels were elevated with phenytoin pretreatment. The clinical relevance of these pharmacokinetic changes have not been evaluated.
Calcium; Vitamin D: (Moderate) Calcium carbonate can significantly decrease the oral bioavailability of phenytoin. Calcium carbonate should not affect the pharmacokinetics of parenteral phenytoin. Separating the administration of phenytoin and calcium carbonate by at least 2 hours will help minimize the possibility of an interaction. (Moderate) Phenytoin and fosphenytoin can decrease the activity of vitamin D (e.g., cholecalciferol) by increasing its metabolism. In rare cases, this has caused anticonvulsant-induced rickets and osteomalacia. Vitamin D supplementation or dosage adjustments may be required in patients who are receiving chronic treatment with anticonvulsants.
Canagliflozin: (Major) Increase the canagliflozin dose to 200 mg/day in persons who are tolerating canagliflozin 100 mg/day and receiving concomitant phenytoin. The canagliflozin dose may be further increased to 300 mg/day for persons with an eGFR of 60 mL/minute/1.73 m2 or more who require additional glycemic control; consider adding another antihyperglycemic agent for persons with an eGFR less than 60 mL/minute/1.73 m2 who require additional glycemic control. Canagliflozin is an UGT1A9 and UGT2B4 substrate, and phenytoin is an UGT inducer. Coadministration with a nonselective inducer of several UGT enzymes decreased canagliflozin exposure by 51%. This decrease in exposure may decrease canagliflozin efficacy.
Canagliflozin; Metformin: (Major) Increase the canagliflozin dose to 200 mg/day in persons who are tolerating canagliflozin 100 mg/day and receiving concomitant phenytoin. The canagliflozin dose may be further increased to 300 mg/day for persons with an eGFR of 60 mL/minute/1.73 m2 or more who require additional glycemic control; consider adding another antihyperglycemic agent for persons with an eGFR less than 60 mL/minute/1.73 m2 who require additional glycemic control. Canagliflozin is an UGT1A9 and UGT2B4 substrate, and phenytoin is an UGT inducer. Coadministration with a nonselective inducer of several UGT enzymes decreased canagliflozin exposure by 51%. This decrease in exposure may decrease canagliflozin efficacy. (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Cannabidiol: (Moderate) Consider a dose increase of cannabidiol and monitor serum phenytoin concentrations if coadministered. Consider a dose reduction of phenytoin if phenytoin adverse reactions occur. Coadministration may decrease cannabidiol plasma concentrations resulting in a decrease in efficacy and increase phenytoin exposure resulting in increased adverse effects. Cannabidiol is metabolized by CYP3A4; in vitro data predicts inhibition of CYP2C9 by cannabidiol. Phenytoin is a strong inducer of CYP3A4 and is a CYP2C9 substrate.
Capecitabine: (Moderate) Carefully monitor phenytoin levels if coadministration with capecitabine is necessary; a dose reduction of phenytoin may be necessary. Phenytoin is a CYP2C9 substrate and capecitabine is a weak CYP2C9 inhibitor. Postmarketing reports indicate that some patients receiving capecitabine and phenytoin had toxicity associated with elevated phenytoin levels. Formal drug interaction studies of capecitabine with phenytoin have not been conducted.
Capmatinib: (Major) Avoid coadministration of capmatinib and phenytoin due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased capmatinib exposure by 67%.
Carbamazepine: (Moderate) Monitor carbamazepine and phenytoin concentrations closely during coadministration; dose adjustments may be needed. Concomitant use may decrease carbamazepine or phenytoin concentrations. Carbamazepine is a CYP3A4 substrate and hydantoins are strong CYP3A4 inducers. Hydantoins are CYP2C9 and CYP2C19 substrates and carbamazepine is a moderate CYP2C9 and CYP2C19 inducer.
Carbidopa; Levodopa: (Moderate) Monitor for loss of efficacy in during concomitant use of levodopa and phenytoin. The beneficial effects of levodopa in Parkinson disease have been reported to be revered by phenytoin.
Carbidopa; Levodopa; Entacapone: (Moderate) Monitor for loss of efficacy in during concomitant use of levodopa and phenytoin. The beneficial effects of levodopa in Parkinson disease have been reported to be revered by phenytoin.
Carbonic anhydrase inhibitors: (Minor) Acetazolamide or methazolamide can induce osteomalacia in patients being concomitantly treated with hydantoin anticonvulsants. The carbonic anhydrase inhibitors increase the rate of urinary calcium excretion; phenytoin increases the metabolism of the D vitamins. When combined, the effects on bone catabolism can be additive.
Carboplatin: (Major) Patients receiving antineoplastic agents concurrently with hydantoins may be at risk for toxicity or loss of clinical efficacy and seizures; anticonvulsant therapy should be monitored closely during and after administration of antineoplastic agents. Concurrent therapy with phenytoin and carboplatin has been associated with subtherapeutic phenytoin serum concentrations and seizure activity. Phenytoin dosage increases of 20 to 100% have been required in some patients, depending on the chemotherapy administered.
Cariprazine: (Major) Cariprazine and its active metabolites are extensively metabolized by CYP3A4. Concurrent use of cariprazine with CYP3A4 inducers, such as phenytoin or fosphenytoin, has not been evaluated and is not recommended because the net effect on active drug and metabolites is unclear.
Carisoprodol: (Minor) Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. If carisoprodol is combined with an inducer of hepatic enzymes, such as phenytoin, the potential exists for increased metabolism of carisoprodol and meprobamate, the active metabolite, plasma concentrations could be increased.
Carmustine, BCNU: (Moderate) Use phenytoin and carmustine together with caution; phenytoin serum concentration may be reduced resulting in decreased phenytoin efficacy. Consider using an alternative agent in place of phenytoin. If these drugs are used together, anticonvulsant therapy should be monitored closely during and after administration of carmustine. Phenytoin dosage increases of 20 to 100% have been required in some patients, depending on the chemotherapy administered.
Caspofungin: (Major) Consider dosing caspofungin as 70 mg IV once daily in adult patients and 70 mg/m2 IV once daily (Max: 70 mg/day) in pediatric patients receiving phenytoin. Administering inducers of hepatic cytochrome P450, such as phenytoin, concurrently with caspofungin may reduce the plasma concentrations of caspofungin.
Celecoxib; Tramadol: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with hydantoins is necessary; consider increasing the dose of tramadol as needed. If hydantoins are discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A substrate and hydantoins are strong CYP3A inducers. Concomitant use with CYP3A inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Cenobamate: (Major) Decrease phenytoin dosage by up to 50% as cenobamate is being titrated due to the potential for increased phenytoin exposure. Multiple doses of cenobamate increased phenytoin exposure by 84%.
Ceritinib: (Major) Avoid concomitant use of ceritinib with phenytoin as ceritinib exposure may be decreased, which may reduce its efficacy. Ceritinib is a CYP3A substrate and phenytoin is a strong CYP3A inducer. Coadministration with a strong CYP3A inducer decreased ceritinib exposure by 70%.
Charcoal: (Major) Charcoal exerts a nonspecific effect, and many medications can be adsorbed by activated charcoal. In some drug overdoses (e.g., fosphenytoin or phenytoin), multiple-doses of charcoal slurries may be an effective therapeutic adjunct. Patients who ingest activated charcoal in non-overdose situations for flatulence or other purposes should be aware that the effectiveness of other regularly taken medications (e.g., oral phenytoin) might be decreased.
Chlordiazepoxide: (Moderate) Phenytoin is a hepatic inducer and can theoretically increase the clearance of chlordiazepoxide oxidative metabolism, leading to lower benzodiazepine concentrations. In addition, chlordiazepoxide has been reported to have an unpredictable effect on phenytoin serum concentrations (e.g., to increase, decrease, or cause no change in phenytoin serum concentrations). Conflicting results may have been observed due to saturable phenytoin metabolism and/or other conditions associated with the reported data. Since definitive controlled trial data are lacking, phenytoin concentrations should be monitored more closely when chlordiazepoxide is added or discontinued.
Chlordiazepoxide; Amitriptyline: (Moderate) Phenytoin is a hepatic inducer and can theoretically increase the clearance of chlordiazepoxide oxidative metabolism, leading to lower benzodiazepine concentrations. In addition, chlordiazepoxide has been reported to have an unpredictable effect on phenytoin serum concentrations (e.g., to increase, decrease, or cause no change in phenytoin serum concentrations). Conflicting results may have been observed due to saturable phenytoin metabolism and/or other conditions associated with the reported data. Since definitive controlled trial data are lacking, phenytoin concentrations should be monitored more closely when chlordiazepoxide is added or discontinued. (Moderate) Tricyclic antidepressants (TCA), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently. In addition, hydantoins may increase TCA metabolism.
Chlordiazepoxide; Clidinium: (Moderate) Phenytoin is a hepatic inducer and can theoretically increase the clearance of chlordiazepoxide oxidative metabolism, leading to lower benzodiazepine concentrations. In addition, chlordiazepoxide has been reported to have an unpredictable effect on phenytoin serum concentrations (e.g., to increase, decrease, or cause no change in phenytoin serum concentrations). Conflicting results may have been observed due to saturable phenytoin metabolism and/or other conditions associated with the reported data. Since definitive controlled trial data are lacking, phenytoin concentrations should be monitored more closely when chlordiazepoxide is added or discontinued.
Chloroprocaine: (Moderate) Coadministration of chloroprocaine with oxidizing agents, such as phenytoin, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue chloroprocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Chloroquine: (Moderate) Coadministration of chloroquine and phenytoin may decrease exposure of chloroquine which may reduce its efficacy. Chloroquine may be an in vitro CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with phenytoin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If phenytoin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Phenytoin is a strong CYP3A4 inducer.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with phenytoin can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If phenytoin is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Phenytoin is a strong inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with phenytoin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If phenytoin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer.
Chlorpromazine: (Moderate) Monitor phenytoin concentrations during concomitant therapy with phenytoin and phenothiazines; a phenytoin dosage decrease may be necessary. Phenothiazines may inhibit the metabolism of phenytoin.
Cimetidine: (Moderate) Monitor phenytoin concentrations during concomitant therapy with cimetidine due to risk for phenytoin toxicity. Concomitant use may increase phenytoin concentrations. Phenytoin is a CYP2C19 substrate and cimetidine is a CYP2C19 inhibitor.
Ciprofloxacin: (Moderate) Monitor phenytoin concentration and for phenytoin toxicity during and shortly after concomitant ciprofloxacin use. Concurrent use may result in altered phenytoin concentrations (increased or decreased).
Cisapride: (Moderate) Cisapride is metabolized by the hepatic cytochrome P450 enzyme system, specifically the CYP3A4 isoenzyme. Inducers of CYP3A4, such as phenytoin may increase the clearance of cisapride.
Cisatracurium: (Moderate) Concomitant use of neuromuscular blockers and phenytoin may increase resistance to the neuromuscular blockade action of neuromuscular blockers, resulting in shorter durations of neuromuscular blockade and higher infusion rate requirements. The use of a peripheral nerve stimulator is strongly recommended to evaluate the level of neuromuscular blockade, to assess the need for additional doses of neuromuscular blocker, and to determine whether adjustments need to be made to the dose with subsequent administration.
Cisplatin: (Moderate) Closely monitor phenytoin concentrations if coadministration with cisplatin is necessary, as cisplatin may decrease phenytoin levels. The addition or withdrawal of cisplatin in patients already on phenytoin therapy may require an adjustment of the phenytoin dose to achieve optimal clinical outcome.
Clarithromycin: (Major) Coadministration of phenytoin and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking potent CYP3A4 inducers. Additionally, there have been postmarketing reports of interactions of clarithromycin and phenytoin. The clarithromycin manufacturer recommends caution if coadministered.
Clindamycin: (Moderate) Monitor for loss of clindamycin efficacy with coadministration of phenytoin as concurrent use may decrease clindamycin exposure. Clindamycin is a CYP3A substrate; phenytoin is a strong inducer of CYP3A.
Clobazam: (Moderate) Concomitant administration of clobazam with other CNS-depressant drugs including phenytoin can potentiate the CNS effects (i.e., increased sedation or respiratory depression) of either agent.
Clomipramine: (Moderate) Tricyclic antidepressants (TCA), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently. In addition, hydantoins may increase TCA metabolism.
Clonazepam: (Moderate) Monitor phenytoin concentration and for decreased efficacy and a change in clonazepam dosage requirements when coadministered with phenytoin. Clonazepam has the potential to influence concentrations of phenytoin. In a case report, an epileptic patient experienced a decrease in phenytoin concentrations by approximately 28%, which coincided with an increase in seizures. In a study that assessed the effect of clonazepam on phenytoin plasma concentrations, 9 patients experienced increased phenytoin concentrations when clonazepam was introduced. Phenytoin concentrations decreased in 1 patient and remained unchanged in 3 patients when clonazepam was introduced. It is unclear if the concentration increases were due to a drug interaction or increased compliance with phenytoin therapy. Clonazepam is a CYP3A substrate and phenytoin is a strong CYP3A inducer. Clonazepam concentration decreases of approximately 38% have been reported when clonazepam is used with other strong CYP3A inducers.
Clorazepate: (Moderate) Phenytoin is a hepatic inducer and can theoretically increase the clearance of benzodiazpines metabolized by oxidative metabolism, leading to lower benzodiazepine concentrations.
Clozapine: (Major) Coadministration of clozapine, a CYP3A4 substrate, with a potent inducer of CYP3A4, such as phenytoin, is not recommended. If coadministration is necessary, monitor for decreased effectiveness of clozapine and consider increasing the clozapine dose if necessary. If the inducer is discontinued, reduce the clozapine dose based on clinical response. Phenytoin may also increase the metabolism of clozapine through induction of CYP1A2. Close monitoring is recommended when clozapine is administered to patients with a seizure disorder because clozapine lowers the seizure threshold. The effectiveness of phenytoin in treating seizures may be reduced. Dosage adjustments may be necessary, and close monitoring of clinical and/or adverse effects is warranted when phenobarbital is used with clozapine.
Cobicistat: (Contraindicated) Coadministration of phenytoin with cobicistat-containing regimens is contraindicated. If these drugs are used together, significant decreases in the plasma concentrations of the antiretrovirals may occur, resulting in reduction of antiretroviral efficacy and development of viral resistance. Consider use of an alternative anticonvulsant or antiretroviral therapy.
Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with phenytoin due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro; phenytoin is a strong inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 83% when coadministered with a strong CYP3A inducer.
Codeine: (Moderate) Concomitant use of codeine with phenytoin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If phenytoin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Phenytoin is a strong CYP3A4 inducer.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with phenytoin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If phenytoin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Phenytoin is a strong CYP3A4 inducer.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with phenytoin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If phenytoin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Phenytoin is a strong CYP3A4 inducer.
Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with phenytoin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If phenytoin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Phenytoin is a strong CYP3A4 inducer. (Moderate) Monitor phenytoin concentrations during concomitant therapy with phenytoin and phenothiazines; a phenytoin dosage decrease may be necessary. Phenothiazines may inhibit the metabolism of phenytoin.
Codeine; Promethazine: (Moderate) Concomitant use of codeine with phenytoin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If phenytoin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Phenytoin is a strong CYP3A4 inducer. (Moderate) Monitor phenytoin concentrations during concomitant therapy with phenytoin and phenothiazines; a phenytoin dosage decrease may be necessary. Phenothiazines may inhibit the metabolism of phenytoin.
Colesevelam: (Moderate) Colesevelam may decrease the bioavailability of the hydantoin anticonvulsants. To minimize potential for interactions, consider administering oral anticonvulsants at least 1 hour before or at least 4 hours after colesevelam. Although colesevelam was found to have no significant effect on the bioavailability of phenytoin in an in vivo pharmacokinetic study, there have been post-marketing reports of increased seizure activity or decreased phenytoin concentrations in patients receiving concomitant colesevelam therapy. Hydantoins should be administered at least 4 hours before colesevelam. The manufacturer recommends that when administering other drugs with a narrow therapeutic index, consideration should be given to separating the administration of the drug with colesevelam. Although not specifically studied, it may be prudent to administer other anticonvulsants at least 4 hours before colesevelam. Additionally, drug response and/or serum concentrations should also be monitored.
Conjugated Estrogens; Bazedoxifene: (Moderate) Bazedoxifene undergoes metabolism by UGT enzymes in the intestinal tract and liver. The metabolism of bazedoxifene may be increased by concomitant use of substances known to induce UGTs, such as phenytoin. A reduction in bazedoxifene exposure may be associated with an increase risk of endometrial hyperplasia. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.
Conjugated Estrogens; Medroxyprogesterone: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Copanlisib: (Major) Avoid the concomitant use of copanlisib and phenytoin; decreased copanlisib exposure and loss of efficacy may occur. Copanlisib is a CYP3A substrate; phenytoin is a strong CYP3A inducer. The AUC and Cmax values of copanlisib decreased by 60% and 12%, respectively, when a single IV dose of copanlisib 60 mg was administered following 12 days of another strong CYP3A4 inducer in a drug interaction study in patients with cancer.
Crizotinib: (Major) Avoid coadministration of crizotinib with phenytoin due to decreased plasma concentrations of crizotinib, which may result in decreased efficacy. Crizotinib is primarily metabolized by CYP3A and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the crizotinib AUC and Cmax at steady state by 84% and 79%, respectively.
Cyclosporine: (Moderate) Hydantoin anticonvulsants (i.e, phenytoin, fosphenytoin, and ethotoin) can induce the hepatic cytochrome P-450 enzyme system, thus decreasing plasma concentrations of cyclosporine. If a hydantoin anticonvulsant is added to a cyclosporine-containing regimens, cyclosporine concentrations should be closely monitored and adjusted as needed until a new steady-state is achieved. Conversely, if the anticonvulsant is discontinued, cyclosporine concentrations could increase and result in toxicity.
Dabigatran: (Major) Coadministration of dabigatran with phenytoin should generally be avoided due to the risk of deceased dabigatran exposure which may reduce its efficacy. Dabigatran is a P-glycoprotein (P-gp) substrate and phenytoin is a P-gp inducer.
Dabrafenib: (Major) Use dabrafenib and phenytoin together with caution; concentrations of either agent may be decreased. Use an alternate agent in place of phenytoin if possible. If concomitant use cannot be avoided, monitor patients for loss of phenytoin efficacy. Phenytoin is a strong CYP3A4 inducer and a substrate of CYP2C9 and CYP2C19; dabrafenib is a CYP3A4 substrate and a CYP2C9 and CYP2C19 inducer.
Dacarbazine, DTIC: (Moderate) Subtherapeutic phenytoin concentrations may occur during the use of selected concurrent chemotherapy treatments. Because case reports of this interaction often include chemotherapy regimens of several different agents, it is not always clearly known which agent may be involved in the interaction, or the precise mechanism of interaction.
Daclatasvir: (Contraindicated) Concomitant use of daclatasvir with phenytoin or fosphenytoin is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to daclatasvir. Phenytoin is a potent inducer of the hepatic isoenzyme CYP3A4; daclatasvir is a substrate of this isoenzyme.
Dapagliflozin: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Dapagliflozin; Metformin: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients. (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Dapagliflozin; Saxagliptin: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients. (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Dapsone: (Moderate) Monitor for an increase in hemolysis if coadministration of dapsone with phenytoin is necessary; dapsone efficacy may also be compromised. Dapsone is a CYP3A4 metabolite and phenytoin is a strong CYP3A4 inducer. Strong CYP3A4 inducers may increase the formation of dapsone hydroxylamine, a metabolite associated with hemolysis. Coadministration with another strong CYP3A4 inducer decreased dapsone levels by 7-fold to 10-fold; in leprosy, this reduction has not required a change in dosage. Also, coadministration of dapsone with phenytoin may increase the risk of developing methemoglobinemia. Advise patients to discontinue treatment and seek immediate medical attention with any signs or symptoms of methemoglobinemia.
Daridorexant: (Major) Avoid concomitant use of daridorexant and phenytoin. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and phenytoin is a strong CYP3A inducer. Concomitant use of another strong CYP3A inducer decreased daridorexant overall exposure by over 50%.
Darifenacin: (Minor) Phenytoin may induce the CYP3A4 metabolism of darifenacin and thereby reduce its oral bioavailability. The dosage requirements of darifenacin may be increased in patients receiving concurrent enzyme inducers.
Darolutamide: (Major) Avoid coadministration of darolutamide with phenytoin due to the risk of decreased darolutamide plasma concentrations which may decrease efficacy. Phenytoin is a P-glycoprotein (P-gp) inducer and a strong inducer of CYP3A4; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp and strong CYP3A4 inducer decreased the mean AUC and Cmax of darolutamide by 72% and 52%, respectively.
Darunavir: (Major) Closely monitor for decreased phenytoin efficacy during coadministration; clinical monitoring of phenytoin concentrations with dosage titration if necessary is also warranted. Coadministration of darunavir and phenytoin may result in decreased phenytoin concentrations. In drug interaction studies, the concentration of darunavir was unaffected during coadministration with phenytoin.
Darunavir; Cobicistat: (Contraindicated) Coadministration of phenytoin with cobicistat-containing regimens is contraindicated. If these drugs are used together, significant decreases in the plasma concentrations of the antiretrovirals may occur, resulting in reduction of antiretroviral efficacy and development of viral resistance. Consider use of an alternative anticonvulsant or antiretroviral therapy. (Major) Closely monitor for decreased phenytoin efficacy during coadministration; clinical monitoring of phenytoin concentrations with dosage titration if necessary is also warranted. Coadministration of darunavir and phenytoin may result in decreased phenytoin concentrations. In drug interaction studies, the concentration of darunavir was unaffected during coadministration with phenytoin.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Contraindicated) Coadministration of phenytoin with cobicistat-containing regimens is contraindicated. If these drugs are used together, significant decreases in the plasma concentrations of the antiretrovirals may occur, resulting in reduction of antiretroviral efficacy and development of viral resistance. Consider use of an alternative anticonvulsant or antiretroviral therapy. (Major) Closely monitor for decreased phenytoin efficacy during coadministration; clinical monitoring of phenytoin concentrations with dosage titration if necessary is also warranted. Coadministration of darunavir and phenytoin may result in decreased phenytoin concentrations. In drug interaction studies, the concentration of darunavir was unaffected during coadministration with phenytoin.
Dasatinib: (Major) Avoid coadministration of dasatinib and phenytoin due to the potential for decreased dasatinib exposure and reduced efficacy. Consider an alternative to phenytoin with less potential for enzyme induction. If coadministration cannot be avoided, consider an increased dose of dasatinib and monitor for toxicity. Dasatinib is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer. Concurrent use of another strong CYP3A4 inducer decreased the mean Cmax and AUC of dasatinib by 81% and 82%, respectively.
Deferasirox: (Major) Deferasirox undergoes UGT metabolism, and phenytoin is a potent inducer of this enzyme system. The concomitant administration of deferasirox (single dose of 30 mg/kg) and the potent UGT inducer rifampin (i.e., rifampicin 600 mg/day for 9 days) resulted in a decrease in deferasirox AUC by 44%. Although specific drug interaction studies of deferasirox and phenytoin are not available, a similar interaction may occur. Avoid the concomitant use of phenytoin and deferasirox if possible. If phenytoin and deferasirox coadministration is necessary, consider increasing the initial dose of deferasirox. Monitor serum ferritin concentrations and clinical response for further modifications.
Deflazacort: (Major) Avoid concomitant use of deflazacort and phenytoin. Concurrent use may significantly decrease concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in loss of efficacy. Deflazacort is a CYP3A4 substrate; phenytoin is a strong inducer of CYP3A4. Administration of deflazacort with multiple doses of rifampin (a strong CYP3A4 inducer) resulted in geometric mean exposures that were approximately 95% lower compared to administration alone.
Delavirdine: (Contraindicated) Concurrent use of phenytoin and delavirdine is contraindicated due to the potential for subtherapeutic antiretroviral activity and development of resistant mutations of HIV. In addition, delavirdine may inhibit the CYP metabolism of phenytoin, resulting in increased phenytoin concentrations and possible side effects.
Desipramine: (Moderate) Tricyclic antidepressants (TCA), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently. In addition, hydantoins may increase TCA metabolism.
Desogestrel; Ethinyl Estradiol: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Dexamethasone: (Moderate) Monitor for decreased efficacy of dexamethasone if coadministration with phenytoin/fosphenytoin is necessary; consider increasing the dose of dexamethasone if clinically appropriate. Dexamethasone is a CYP3A substrate and phenytoin is a strong CYP3A inducer.
Dexlansoprazole: (Moderate) Some manufacturers recommend avoiding the coadministration of hepatic cytochrome P-450 enzyme inducers and proton pump inhibitors (PPIs). Fosphenytoin induces hepatic cytochrome P-450 enzymes, including those responsible for the metabolism of PPIs (e.g., CYP3A4, CYP2C19). A reduction in PPI concentrations may increase the risk of gastrointestinal (GI) adverse events such as GI bleeding. If fosphenytoin and PPIs must be used together, monitor the patient closely for signs and symptoms of GI bleeding or other signs and symptoms of reduced PPI efficacy.
Dextromethorphan; Bupropion: (Moderate) Monitor for loss of efficacy of bupropion during coadministration of phenytoin as concurrent use may decrease bupropion exposure. A bupropion dose adjustment may be necessary; do not exceed maximum dose.
Dextromethorphan; Quinidine: (Major) Quinidine is eliminated primarily via hepatic metabolism, primarily by the CYP3A4 isoenzyme. Inducers of CYP3A4, such as fosphenytoin or phenytoin, may increase hepatic elimination of quinidine and decrease its serum concentrations. Quinidine concentrations should be monitored closely after the anticonvulsant is added to the treatment regimen. No special precautions appear necessary if these agents are begun several weeks before quinidine is added but quinidine doses may require adjustment if one of these agents is added or discontinued during quinidine therapy.
Diazepam: (Moderate) Monitor for decreased efficacy of diazepam and/or phenytoin and phenytoin toxicity if coadministration is necessary; dosage adjustments may be required. Concurrent use may decrease diazepam exposure and decrease or increase phenytoin exposure. Diazepam is a CYP3A substrate and phenytoin is a CYP3A inducer. There have also been reports that the metabolic elimination of phenytoin is decreased by diazepam.
Diazoxide: (Moderate) Diazoxide may increase the hepatic metabolism of phenytoin, but the mechanism and incidence of the interaction is not certain. Subtherapeutic phenytoin concentrations have been documented in three children when coadministered with diazoxide; in two cases, the phenytoin serum concentrations were undetectable. In addition, the risk of developing hyperglycemia is increased when diazoxide is given concomitantly with phenytoin. Until further data are available, use caution when hydantoins such as phenytoin, fosphenytoin, or ethotoin are prescribed with diazoxide. It is prudent to monitor serum drug concentrations and clinical response during concomitant therapy.
Dienogest; Estradiol valerate: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Digoxin: (Moderate) Measure serum digoxin concentrations before starting and during concomitant phenytoin therapy; increase the digoxin dose by approximately 20% to 40% as necessary. Concomitant administration may result in decreased digoxin concentrations.
Diltiazem: (Major) Avoid coadministration of diltiazem and phenytoin due to decreased plasma concentrations of diltiazem. Diltiazem is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. C oadministration with another strong CYP3A4 inducer lowered diltiazem plasma concentrations to undetectable.
Diphenhydramine; Naproxen: (Minor) Naproxen is 99% bound to albumin. Thus, naproxen may displace other highly protein bound drugs from albumin or vice versa. If naproxen is used concurrently with hydantoins, monitor patients for toxicity from either drug.
Diphenoxylate; Atropine: (Moderate) Concurrent administration of diphenoxylate/difenoxin with hydantoins can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
Disopyramide: (Moderate) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, including disopyramide, leading to reduced efficacy of the concomitant medication. Patients should be monitored for loss of disopyramide activity if a hydantoin is added. In addition, disopyramide doses may need to be reduced if a hydantoin is stopped and disopyramide therapy is continued. Serum disopyramide concentrations should be monitored closely if hepatic enzyme inducers are either added or discontinued during disopyramide therapy.
Disulfiram: (Major) Disulfiram can interfere with the metabolism of hydantoin anticonvulsants, particularly phenytoin, resulting in increased serum concentrations and possible phenytoin toxicity (i.e., ataxia, hyperreflexia, nystagmus, tremor). The mechanism is most likely due to inhibition of CYP2C9 by disulfiram. Phenytoin serum concentrations should be performed prior to and during disulfiram administration, and dosages of either agent should be adjusted accordingly. This interaction may not occur if disulfiram therapy is initiated prior to beginning phenytoin, but, in this scenario, if disulfiram therapy is discontinued, subtherapeutic phenytoin concentrations can ensue. A similar interaction may occur with fosphenytoin or ethotoin.
Docetaxel: (Major) Avoid coadministration of docetaxel with phenytoin due to decreased plasma concentrations of docetaxel. Docetaxel is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Concomitant use with other strong CYP3A4 inducers increased docetaxel metabolism by 2.6-fold to 32-fold.
Dolutegravir: (Major) Avoid concurrent use of dolutegravir with phenytoin, as coadministration may result in decreased dolutegravir plasma concentrations. Currently, there are insufficient data to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Phenytoin is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Dolutegravir; Lamivudine: (Major) Avoid concurrent use of dolutegravir with phenytoin, as coadministration may result in decreased dolutegravir plasma concentrations. Currently, there are insufficient data to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Phenytoin is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Dolutegravir; Rilpivirine: (Contraindicated) Concurrent use of phenytoin or fosphenytoin and rilpivirine is contraindicated. When these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Phenytoin is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine. (Major) Avoid concurrent use of dolutegravir with phenytoin, as coadministration may result in decreased dolutegravir plasma concentrations. Currently, there are insufficient data to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Phenytoin is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Donepezil: (Moderate) Phenytoin induces hepatic microsomal enzymes and may increase the metabolism of other drugs, including donepezil, leading to reduced efficacy of the concomitant medication.
Donepezil; Memantine: (Moderate) Phenytoin induces hepatic microsomal enzymes and may increase the metabolism of other drugs, including donepezil, leading to reduced efficacy of the concomitant medication.
Dopamine: (Major) An interaction between dopamine and intravenous phenytoin is not clear. In one case series report, critically-ill patients stablized on dopamine and with adequate volume status who were given IV phenytoin for seizures developed hypotension; some patients developed cardiac arrest. Phenytoin IV is known to cause these particular side effects, so the contribution of dopamine to these events is uncertain. Other reports have not corroborated the combination as having additional risks to patients. Intravenous administration should not exceed 50 mg per minute in adults. In pediatric patients, administer the drug at a rate not exceeding 1 to 3 mg/kg/min or 50 mg per minute, whichever is slower. Although the risk of cardiovascular toxicity increases with infusion rates above the recommended infusion rate, these events have also been reported at or below the recommended infusion rate. Monitor blood pressure, heart rate, and be alert for evidence of hypotension or cardiac effects.
Doravirine: (Contraindicated) Concurrent administration of doravirine and phenytoin is contraindicated due to decreased doravirine exposure, resulting in potential loss of virologic control. At least a 4-week cessation period is recommended before initiating treatment with doravirine. Doravirine is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Contraindicated) Concurrent administration of doravirine and phenytoin is contraindicated due to decreased doravirine exposure, resulting in potential loss of virologic control. At least a 4-week cessation period is recommended before initiating treatment with doravirine. Doravirine is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer.
Doxepin: (Moderate) Tricyclic antidepressants (TCA), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently. In addition, hydantoins may increase TCA metabolism.
Doxercalciferol: (Moderate) Although these interactions have not been specifically studied, hepatic enzyme inducers such as phenytoin and fosphenytoin may affect the 25-hydroxylation of doxercalciferol and may necessitate dosage adjustments of doxercalciferol. Phenytoin can decrease the activity of vitamin D by increasing its metabolism. In rare cases, this has caused anticonvulsant-induced rickets and osteomalacia. Vitamin D supplementation or dosage adjustments may be required in patients who are receiving chronic treatment with anticonvulsants.
Doxorubicin Liposomal: (Major) Patients receiving antineoplastic agents concurrently with hydantoins may be at risk for toxicity or loss of clinical efficacy and seizures; anticonvulsant therapy should be monitored closely during and after administration of antineoplastic agents. Phenytoin concentrations may be decreased by doxorubicin. Fosphenytoin, a prodrug of phenytoin, may also be susceptible to this interaction with doxorubicin; as well as ethotoin, another anticonvulsant hydantoin. Additionally, phenytoin and fosphenytoin are potent inducers of CYP3A4; doxorubicin is a major CYP3A4 substrate. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of doxorubicin with phenytoin or fosphenytoin if possible. If not possible, monitor doxorubicin closely for efficacy.
Doxorubicin: (Major) Patients receiving antineoplastic agents concurrently with hydantoins may be at risk for toxicity or loss of clinical efficacy and seizures; anticonvulsant therapy should be monitored closely during and after administration of antineoplastic agents. Phenytoin concentrations may be decreased by doxorubicin. Fosphenytoin, a prodrug of phenytoin, may also be susceptible to this interaction with doxorubicin; as well as ethotoin, another anticonvulsant hydantoin. Additionally, phenytoin and fosphenytoin are potent inducers of CYP3A4; doxorubicin is a major CYP3A4 substrate. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of doxorubicin with phenytoin or fosphenytoin if possible. If not possible, monitor doxorubicin closely for efficacy.
Doxycycline: (Moderate) Monitor for decreased efficacy of doxycycline if coadministered with hydantoins. Hydantoins decrease the half-life of doxycycline.
Dronabinol: (Major) Use caution if coadministration of dronabinol with phenytoin is necessary, and monitor for an increase in phenytoin levels and phenytoin-related adverse effects, as well as a decrease in the efficacy of dronabinol. Dronabinol is a CYP2C9 and 3A4 substrate; phenytoin is a strong inducer of CYP3A4 and a moderate CYP2C9 inducer. Concomitant use may result in decreased plasma concentrations of dronabinol. Additionally, dronabinol is highly bound to plasma proteins, and may displace and increase the free fraction of other concomitantly administered protein-bound drugs; caution is recommended with other drugs with a narrow therapeutic index.
Dronedarone: (Major) The concomitant use of dronedarone and CYP3A4 inducers should be avoided. Dronedarone is metabolized by CYP3A. Phenytoin induces CYP3A4. Coadministration of CYP3A4 inducers, such as phenytoin, with dronedarone may result in reduced plasma concentration and subsequent reduced effectiveness of dronedarone therapy.
Droperidol: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the droperidol.
Drospirenone: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Drospirenone; Estetrol: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Drospirenone; Estradiol: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Drospirenone; Ethinyl Estradiol: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). (Moderate) Numerous studies indicate that folate status is impaired with the chronic use of diphenylhydantoin (phenytoin or fosphenytoin). Prolonged administration of phenytoin reportedly has resulted in a folate deficiency. In addition, folic acid replacement has resulted in an increase in metabolism of phenytoin and a decrease in phenytoin concentration in some patients, apparently through increased metabolism and/or redistribution of phenytoin in the brain and CSF. Although no decrease in effectiveness of anticonvulsants has been reported with the concurrent use of L-methylfolate, caution still should be exercised with the coadministration of these agents, and patients should be monitored closely for seizure activity.
Dulaglutide: (Minor) Phenytoin can decrease the hypoglycemic effects of dulaglutide by producing an increase in blood glucose levels. Monitor for signs indicating loss of diabetic control when therapy with a hydantoin is instituted. Conversely, patients should be closely monitored for signs of hypoglycemia when therapy with a hydantoin is discontinued.
Dupilumab: (Moderate) Coadministration of dupilumab may result in altered exposure to phenytoin. During chronic inflammation, increased levels of certain cytokines can alter the formation of CYP450 enzymes. Thus, the formation of CYP450 enzymes could be normalized during dupilumab administration. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as phenytoin. Monitor phenytoin concentrations if dupilumab is initiated or discontinued in a patient taking phenytoin; phenytoin dose adjustments may be needed.
Duvelisib: (Major) Avoid coadministration of duvelisib with phenytoin. Coadministration may decrease the exposure of duvelisib, which may reduce the efficacy of duvelisib. Duvelisib is a CYP3A substrate; phenytoin is a strong CYP3A inducer. In drug interaction studies, coadministration of duvelisib with another strong CYP3A inducer for 7 days decreased duvelisib Cmax and AUC by 66% and 82%, respectively.
Edoxaban: (Moderate) Monitor for decreased efficacy of edoxaban if coadministration with phenytoin is necessary; decreased concentrations of edoxaban may occur with concomitant use. Edoxaban is a P-glycoprotein (P-gp) substrate and phenytoin is a P-gp inducer.
Efavirenz: (Major) Complex interactions may occur when hydantoins (phenytoin, fosphenytoin, and possibly ethotoin) are administered to patients receiving treatment for HIV infection; if possible, a different anticonvulsant should be used. The combination regimens used to treat HIV often include substrates, inducers, and inhibitors of several CYP isoenzymes. If phenytoin is used in patients being treated for HIV, the patient must be closely monitored for antiviral efficacy and seizure control; appropriate dose adjustments for phenytoin or the antiretroviral medications are unknown. Efavirenz is a substrate and inducer of CYP3A4 and an inhibitor of CYP2C9 and CYP2C19. Phenytoin is a substrate and inducer of CYP3A4, CYP2C9, and CYP2C19. Use of these drugs in combination may decrease the serum concentrations of both phenytoin and efavirenz.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Complex interactions may occur when hydantoins (phenytoin, fosphenytoin, and possibly ethotoin) are administered to patients receiving treatment for HIV infection; if possible, a different anticonvulsant should be used. The combination regimens used to treat HIV often include substrates, inducers, and inhibitors of several CYP isoenzymes. If phenytoin is used in patients being treated for HIV, the patient must be closely monitored for antiviral efficacy and seizure control; appropriate dose adjustments for phenytoin or the antiretroviral medications are unknown. Efavirenz is a substrate and inducer of CYP3A4 and an inhibitor of CYP2C9 and CYP2C19. Phenytoin is a substrate and inducer of CYP3A4, CYP2C9, and CYP2C19. Use of these drugs in combination may decrease the serum concentrations of both phenytoin and efavirenz.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Complex interactions may occur when hydantoins (phenytoin, fosphenytoin, and possibly ethotoin) are administered to patients receiving treatment for HIV infection; if possible, a different anticonvulsant should be used. The combination regimens used to treat HIV often include substrates, inducers, and inhibitors of several CYP isoenzymes. If phenytoin is used in patients being treated for HIV, the patient must be closely monitored for antiviral efficacy and seizure control; appropriate dose adjustments for phenytoin or the antiretroviral medications are unknown. Efavirenz is a substrate and inducer of CYP3A4 and an inhibitor of CYP2C9 and CYP2C19. Phenytoin is a substrate and inducer of CYP3A4, CYP2C9, and CYP2C19. Use of these drugs in combination may decrease the serum concentrations of both phenytoin and efavirenz.
Elacestrant: (Major) Avoid concurrent use of elacestrant and phenytoin due to the risk of decreased elacestrant exposure which may reduce its efficacy. Elacestrant is a CYP3A substrate and phenytoin/fosphenytoin is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced elacestrant overall exposure by 86%.
Elagolix: (Moderate) Concomitant use of elagolix and phenytoin may result in decreased concentrations of elagolix; monitor for decreased efficacy with coadministration. Elagolix is a CYP3A substrate; phenytoin is a strong inducer of CYP3A.
Elagolix; Estradiol; Norethindrone acetate: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). (Moderate) Concomitant use of elagolix and phenytoin may result in decreased concentrations of elagolix; monitor for decreased efficacy with coadministration. Elagolix is a CYP3A substrate; phenytoin is a strong inducer of CYP3A.
Elbasvir; Grazoprevir: (Contraindicated) Concurrent administration of elbasvir; grazoprevir with phenytoin is contraindicated. Phenytoin is a strong CYP3A inducer, while both elbasvir and grazoprevir are substrates of CYP3A. Use of these drugs together is expected to significantly decrease the plasma concentrations of both elbasvir and grazoprevir, and may result in decreased virologic response.
Elexacaftor; tezacaftor; ivacaftor: (Major) Coadministration of elexacaftor; tezacaftor; ivacaftor with phenytoin is not recommended as concurrent use may decrease exposure of elexacaftor; tezacaftor; ivacaftor. Elexacaftor, tezacaftor, and ivacaftor are CYP3A4 substrates (ivacaftor is a sensitive CYP3A4 substrate). Phenytoin is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer significantly decreased ivacaftor exposure by 89%; elexacaftor and tezacaftor exposures are expected to also decrease during coadministration of strong CYP3A4 inducers. (Major) Coadministration of ivacaftor with phenytoin is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold. (Major) Do not administer tezacaftor; ivacaftor and phenytoin together; coadministration may reduce the efficacy of tezacaftor; ivacaftor. Exposure to ivacaftor is significantly decreased and exposure to tezacaftor may be reduced by the concomitant use of phenytoin, a strong CYP3A inducer; both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate). Coadministration of ivacaftor with a strong CYP3A inducer decreased ivacaftor exposure 89%.
Eliglustat: (Major) Coadministration of phenytoin or fosphenytoin and eliglustat may result in increased phenytoin concentrations and decreased eliglustat concentrations. Concomitant use is not recommended in extensive, intermediate, or poor metabolizers of CYP2D6. If concomitant use is necessary, monitor therapeutic phenytoin concentrations as indicated; the dosage of phenytoin may need to be reduced. Monitor patients closely for therapeutic effect of eliglustat. Eliglustat is a P-glycoprotein (P-gp) inhibitor and CYP3A substrate; phenytoin is a P-gp substrate and strong CYP3A inducer.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Contraindicated) Coadministration of phenytoin with cobicistat-containing regimens is contraindicated. If these drugs are used together, significant decreases in the plasma concentrations of the antiretrovirals may occur, resulting in reduction of antiretroviral efficacy and development of viral resistance. Consider use of an alternative anticonvulsant or antiretroviral therapy. (Major) Coadministration may result in significant decreases in the plasma concentrations of elvitegravir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Phenytoin induces the CYP3A4 metabolism of elvitegravir. Consider an alternative anticonvulsant when using elvitegravir. The combination product cobicistat; elvitegravir; emtricitabine; tenofovir is contraindicated in combination with phenytoin as the concentrations of both elvitegravir and cobicistat may be significantly decreased.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Contraindicated) Coadministration of phenytoin with cobicistat-containing regimens is contraindicated. If these drugs are used together, significant decreases in the plasma concentrations of the antiretrovirals may occur, resulting in reduction of antiretroviral efficacy and development of viral resistance. Consider use of an alternative anticonvulsant or antiretroviral therapy. (Major) Coadministration may result in significant decreases in the plasma concentrations of elvitegravir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Phenytoin induces the CYP3A4 metabolism of elvitegravir. Consider an alternative anticonvulsant when using elvitegravir. The combination product cobicistat; elvitegravir; emtricitabine; tenofovir is contraindicated in combination with phenytoin as the concentrations of both elvitegravir and cobicistat may be significantly decreased.
Emapalumab: (Moderate) Monitor for decreased efficacy of phenytoin and adjust the dose as needed during coadministration with emapalumab. Phenytoin is a CYP2C9 and CYP2C19 substrate with a narrow therapeutic index. Emapalumab may normalize CYP450 activity, which may decrease the efficacy of drugs that are CYP450 substrates due to increased metabolism.
Empagliflozin: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Empagliflozin; Linagliptin: (Moderate) Monitor for a decrease in linagliptin efficacy during concomitant use of linagliptin and phenytoin/fosphenytoin if coadministration is required. Concomitant use may decrease linagliptin exposure. Linagliptin is a CYP3A and P-gp substrate and phenytoin/fosphenytoin is a strong CYP3A and P-gp inducer. Concomitant use with a strong CYP3A and P-gp inducer reduced linagliptin overall exposure by 0.6-fold. (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Empagliflozin; Linagliptin; Metformin: (Moderate) Monitor for a decrease in linagliptin efficacy during concomitant use of linagliptin and phenytoin/fosphenytoin if coadministration is required. Concomitant use may decrease linagliptin exposure. Linagliptin is a CYP3A and P-gp substrate and phenytoin/fosphenytoin is a strong CYP3A and P-gp inducer. Concomitant use with a strong CYP3A and P-gp inducer reduced linagliptin overall exposure by 0.6-fold. (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients. (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Empagliflozin; Metformin: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients. (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Contraindicated) Concurrent use of phenytoin or fosphenytoin and rilpivirine is contraindicated. When these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Phenytoin is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Contraindicated) Concurrent use of phenytoin or fosphenytoin and rilpivirine is contraindicated. When these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Phenytoin is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
Encorafenib: (Major) Avoid coadministration of encorafenib and phenytoin due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
Enteral Feedings: (Major) The oral absorption of phenytoin suspension can be substantially reduced (up to 70%) by the concurrent administration of enteral feedings. Conversely, when enteral feedings are halted, phenytoin concentrations may markedly rise. Other oral dosage forms of phenytoin (e.g., phenytoin sodium) do not interact with enteral feedings to the same extent as the oral suspension. There are several ways to manage patients receiving enteral feedings and phenytoin. If the patient is on intermittent feedings, time phenytoin administration 1 to 2 hours after the feeding, flush the tubing with water or normal saline, and delay subsequent feedings for another 1 to 2 hours. If practical, continuous feedings may be held for 1 to 2 hours before and after each phenytoin dose (again, flushing the tubing after drug administration); to minimize the amount of time feedings are held, give phenytoin suspension twice daily rather than more often. If enteral feeding cannot be held, increase the dose of phenytoin suspension to account for the interaction or consider the use of parenteral phenytoin/fosphenytoin. If larger enteral doses are used, phenytoin dosage reduction may be required when enteral nutrition is stopped, and an oral diet resumed. Regardless of the approach, monitor serum phenytoin concentrations and clinical status, adjusting the dosage to achieve desired therapeutic outcomes.
Entrectinib: (Major) Avoid coadministration of entrectinib with phenytoin due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the entrectinib AUC by 77% in a drug interaction study.
Enzalutamide: (Major) Avoid coadministration of phenytoin with enzalutamide if possible due to decreased enzalutamide exposure which may compromise efficacy; phenytoin plasma concentrations may also be reduced. If concomitant use is unavoidable, increase the dose of enzalutamide from 160 mg to 240 mg once daily; the original dose of enzalutamide may be resumed when phenytoin is discontinued. Monitor phenytoin serum concentrations and adjust phenytoin doses as needed. Enzalutamide is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Enzalutamide is also a moderate CYP2C9 and CYP2C19 inducer and phenytoin is a CYP2C9 and CYP2C19 substrate. Coadministration with another strong CYP3A4 inducer decreased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 37%.
Eravacycline: (Major) Increase the dose of eravacycline to 1.5 mg/kg IV every 12 hours when coadministered with a strong CYP3A4 inducer, such as phenytoin. Concomitant use of strong CYP3A4 inducers decreases the exposure of eravacycline, which may reduce its efficacy. When eravacycline was administered with a strong CYP3A4/3A5 inducer, the eravacycline AUC was decreased by 35% and its clearance was increased by 54%.
Erdafitinib: (Major) Avoid coadministration of erdafitinib and phenytoin due to the risk of decreased plasma concentrations of erdafitinib resulting in decreased efficacy. Erdafitinib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer.
Ergotamine; Caffeine: (Moderate) Higher caffeine doses may be needed after hydantoin administration; hydantoins increase caffeine elimination.
Erlotinib: (Major) Avoid coadministration of erlotinib with phenytoin if possible due to the risk of decreased erlotinib efficacy. If concomitant use is unavoidable, increase the dose of erlotinib in 50 mg increments at 2-week intervals as tolerated (maximum dose, 450 mg). Erlotinib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased erlotinib exposure by 58% to 80%.
Ertugliflozin; Metformin: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Ertugliflozin; Sitagliptin: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Eslicarbazepine: (Moderate) An increased dose of eslicarbazepine may be necessary if these drugs are coadministered. Phenytoin may induce the metabolism of eslicarbazepine resulting in decreased plasma concentrations of and potentially reduced efficacy of eslicarbazepine. In addition, eslicarbazepine may inhibit the CYP2C19-mediated metabolism of phenytoin resulting in increased concentrations of phenytoin. Monitor phenytoin plasma concentrations if coadministered with eslicarbazepine and adjust the dose of phenytoin based on clinical response and serum concentration.
Esomeprazole: (Moderate) Monitor phenytoin concentrations during concomitant therapy with esomeprazole due to risk for phenytoin toxicity. Concomitant use may increase phenytoin concentrations. Phenytoin is a CYP2C19 substrate and esomeprazole is a CYP2C19 inhibitor.
Estazolam: (Moderate) Hydantoin anticonvulsants are hepatic inducers and can theoretically increase the clearance of benzodiazepines metabolized by oxidative metabolism, possibly leading to reduced benzodiazepine concentrations.
Estradiol; Levonorgestrel: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Estradiol; Norethindrone: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Estradiol; Norgestimate: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Estradiol; Progesterone: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Estramustine: (Moderate) Estrogens are metabolized by CYP3A4. Concurrent administration of hepatic enzyme inducers with estrogens, including hydantoin anticonvulsants, may increase the elimination of estrogen.
Estrogens affected by CYP3A inducers: (Major) Women taking both estrogens and phenytoin/fosphenytoin should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed phenytoin/fosphenytoin. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of phenytoin/fosphenytoin. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on phenytoin/fosphenytoin, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and phenytoin/fosphenytoin is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination. Additionally, epileptic women taking both anticonvulsants and hormonal contraceptives may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; if oral contraceptive failure occurs, the additive effects could potentially heighten the risk of neural tube defects in pregnancy.
Eszopiclone: (Moderate) Potent inducers of CYP3A4, such as hydantoins, may increase the rate of eszopiclone metabolism. The serum concentration and clinical effect of eszopiclone may be reduced. An alternative hypnotic agent may be more prudent in patients taking CYP3A4 inducers.
Ethanol: (Major) Phenytoin theoretically can add to the CNS-depressant effects of alcohol. Chronic ingestion of alcohol induces hepatic microsomal isozymes and increases the clearance of phenytoin. Alcohol also exhibits epileptogenic potential. Alcohol should generally be avoided in patients on fosphenytoin or phenytoin. Acute ingestion of small amounts of ethanol in non-alcoholic patients does not appear to affect the hepatic metabolism of phenytoin to a clinically significant degree.
Ethinyl Estradiol; Norelgestromin: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Ethinyl Estradiol; Norethindrone Acetate: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Ethinyl Estradiol; Norgestrel: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Ethosuximide: (Moderate) Phenytoin induces hepatic microsomal enzymes. Increased hepatic metabolism of ethosuximide leads to a decrease in its plasma concentration and a reduction in its half-life. To maintain a therapeutic dosage, serum concentrations of ethosuximide should be measured, especially if additional anticonvulsant therapy is added to or withdrawn from ethosuximide therapy.
Ethynodiol Diacetate; Ethinyl Estradiol: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Etonogestrel: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Etonogestrel; Ethinyl Estradiol: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Etravirine: (Major) Etravirine should not be coadministered with phenytoin due to the potential for subtherapeutic antiretroviral activity and the subsequent possibility for the development of resistant mutations of HIV; substantial reductions in etravirine concentrations may occur.
Everolimus: (Major) Avoid coadministration of everolimus with phenytoin due to the risk of decreased efficacy of everolimus. If concomitant use is unavoidable, coadministration requires a dose increase for some indications and close monitoring for others. For oncology indications and tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, double the daily dose using increments of 5 mg or less; multiple increments may be required. For patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures, assess the everolimus whole blood trough concentration 2 weeks after initiation of phenytoin and adjust the dose as necessary to remain in the recommended therapeutic range. Also closely monitor everolimus whole blood trough concentrations in patients receiving everolimus for either kidney or liver transplant and adjust the dose as necessary to remain in the recommended therapeutic range. Everolimus is a sensitive CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of everolimus by 63%. For indications where everolimus trough concentrations are monitored, the addition of a second strong CYP3A4 inducer in a patient already receiving treatment with a strong CYP3A4 inducer may not require additional dose modification.
Exemestane: (Major) If coadministration of exemestane with phenytoin is necessary, increase the dose of exemestane to 50 mg once daily after a meal. Exemestane is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased exemestane exposure by 54%.
Exenatide: (Minor) Phenytoin can decrease the hypoglycemic effects of exenatide by producing an increase in blood glucose levels. Monitor for signs indicating loss of diabetic control when therapy with a hydantoin is instituted. Conversely, patients should be closely monitored for signs of hypoglycemia when therapy with a hydantoin is discontinued.
Ezetimibe; Simvastatin: (Moderate) Monitor for a decrease in simvastatin efficacy if concomitant use with phenytoin is necessary. Concomitant use may decrease simvastatin exposure. Simvastatin is a CYP3A substrate and phenytoin is a strong CYP3A inducer.
Fedratinib: (Major) Avoid coadministration of fedratinib with phenytoin as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response; phenytoin exposure may also increase. Monitoring of serum phenytoin concentrations is advised. Fedratinib is a CYP3A4 substrate and moderate CYP2C19 inhibitor; phenytoin is a strong CYP3A4 inducer and CYP2C19 substrate. Coadministration of fedratinib with another strong CYP3A4 inducer decreased the overall exposure of fedratinib by 81%.
Felbamate: (Moderate) Hydantoins are hepatic enzyme inducers and thus may accelerate the metabolism of several other anticonvulsants, including felbamate.
Felodipine: (Moderate) Hydantoin anticonvulsants (i.e., phenytoin, fosphenytoin, or ethotoin) induce CYP3A4 and may significantly enhance the hepatic metabolism of felodipine. Higher doses of felodipine may be necessary in epileptic patients receiving any of these anticonvulsants.
Fenfluramine: (Major) Avoid concurrent use of fenfluramine and phenytoin due to the risk of decreased fenfluramine plasma concentrations, which may reduce its efficacy. If concomitant use is necessary, monitor for decreased efficacy and consider increasing fenfluramine dose as needed. If phenytoin is discontinued during fenfluramine maintenance treatment, consider gradual reduction in the fenfluramine dosage to the dose administered prior to phenytoin initiation. Fenfluramine is a CYP3A substrate and phenytoin is a strong CYP3A inducer.
Fenofibric Acid: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19 and a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C19 and CYP2C9 substrates, such as phenytoin, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 and CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of phenytoin during coadministration with fenofibric acid.
Fenoprofen: (Minor) As fenoprofen is 99% bound to albumin, an interaction may occur between fenoprofen and hydantoins. Fenoprofen may displace other highly protein bound drugs from albumin or vice versa. If fenoprofen is used concurrently with hydantoins, monitor patients for toxicity from any of the drugs.
Fentanyl: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of phenytoin is necessary. If phenytoin is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like phenytoin with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Finasteride; Tadalafil: (Major) Avoid coadministration of tadalafil with phenytoin in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of phenytoin due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
Finerenone: (Major) Avoid concurrent use of finerenone and phenytoin/fosphenytoin due to the risk for decreased finerenone exposure which may reduce its efficacy. Finerenone is a CYP3A substrate and phenytoin and fosphenytoin are strong CYP3A inducers. Coadministration with another strong CYP3A inducer decreased overall exposure to finerenone by 90%.
Flibanserin: (Major) The concomitant use of flibanserin with CYP3A4 inducers significantly decreases flibanserin exposure compared to the use of flibanserin alone. Therefore, concurrent use of flibanserin and phenytoin or fosphenytoin, which are strong CYP3A4 inducers, is not recommended.
Floxuridine: (Major) Alterations in phenytoin serum concentrations (increases and decreases) have been reported in patients previously stabilized on phenytoin who receive systemic fluorouracil, 5-FU, chemotherapy. The possibility exists for similar interactions with floxuridine, which is metabolized to 5-FU. Most commonly, decreased phenytoin serum concentrations are reported in the literature, usually associated with decreased phenytoin absorption due to 5-FU induced GI toxicity. However, increased levels of phenytoin have been reported in a small number of patients possibly due to 5-FU inhibition of cytochrome P450 isoenzyme 2C9, which is responsible for phenytoin metabolism.
Fluconazole: (Moderate) Monitor phenytoin concentrations during concomitant therapy with fluconazole due to risk for phenytoin toxicity. Concomitant use may increase phenytoin concentrations. The incidence of abnormally elevated serum transaminases was higher in patients taking fluconazole concomitantly with phenytoin. A mean increase of 88% in phenytoin serum AUC has been seen in some healthy volunteers taking both fluconazole and phenytoin. Phenytoin is a CYP2C9 and CYP2C19 substrate and fluconazole is a CYP2C9 and CYP2C19 inhibitor.
Fluorouracil, 5-FU: (Major) Alterations in phenytoin serum concentrations have been reported in patients previously stabilized on phenytoin who receive systemic fluorouracil, 5-FU. Most commonly, decreased phenytoin serum concentrations are reported in the literature, however, increased levels of phenytoin have been reported in a small number of patients. Similar interactions may be expected between 5-FU and fosphenytoin or ethotoin.
Fluoxetine: (Moderate) Monitor phenytoin concentrations during concomitant therapy with fluoxetine due to risk for phenytoin toxicity. Concomitant use may increase phenytoin concentrations. Phenytoin is a CYP2C9 and CYP2C19 substrate and fluoxetine is a CYP2C9 and CYP2C19 inhibitor.
Fluphenazine: (Moderate) Monitor phenytoin concentrations during concomitant therapy with phenytoin and phenothiazines; a phenytoin dosage decrease may be necessary. Phenothiazines may inhibit the metabolism of phenytoin.
Flurazepam: (Moderate) Monitor patients for decreased efficacy of flurazepam if coadministration with phenytoin/fosphenytoin is necessary. Concurrent use may decrease flurazepam exposure. Flurazepam is a CYP3A substrate and phenytoin/fosphenytoin are strong CYP3A inducers.
Fluticasone: (Moderate) Monitor for decreased corticosteroid efficacy if fluticasone is used with phenytoin; a dosage increase may be necessary. Concurrent use may decrease the exposure of fluticasone.
Fluticasone; Salmeterol: (Moderate) Monitor for decreased corticosteroid efficacy if fluticasone is used with phenytoin; a dosage increase may be necessary. Concurrent use may decrease the exposure of fluticasone.
Fluticasone; Umeclidinium; Vilanterol: (Moderate) Monitor for decreased corticosteroid efficacy if fluticasone is used with phenytoin; a dosage increase may be necessary. Concurrent use may decrease the exposure of fluticasone.
Fluticasone; Vilanterol: (Moderate) Monitor for decreased corticosteroid efficacy if fluticasone is used with phenytoin; a dosage increase may be necessary. Concurrent use may decrease the exposure of fluticasone.
Fluvastatin: (Moderate) Monitor for a decrease in fluvastatin efficacy and for an increase in phenytoin-related adverse effects if concomitant use is necessary. Concomitant use may decrease fluvastatin exposure and may increase phenytoin concentrations.
Fluvoxamine: (Moderate) Phenytoin clearance can be decreased by drugs that inhibit hepatic microsomal enzymes, particularly those drugs that significantly inhibit the cytochrome P450 2C subset of isoenzymes including fluvoxamine. Phenytoin dosage adjustments may be necessary in some patients who receive any of these drugs concurrently; monitor for signs of phenytoin toxicity.
Folic Acid, Vitamin B9: (Minor) Concurrent use of folic acid, vitamin B9 and phenytoin may result in decreased folic acid serum concentrations and decreased anticonvulsant effect. It is important to maintain adequate folic acid concentrations in epileptic patients taking enzyme-inducing anticonvulsants, and maintenance doses may require upward adjustment. However, in large amounts, folic acid may counteract the anticonvulsant effect of some agents, including phenytoin. Therefore, it has been recommended that oral folic acid supplementation not exceed 1 mg/day in epileptic patients taking anticonvulsants. If large doses are used, monitor phenytoin concentrations upon folic acid initiation, dose titration, and discontinuation and adjust the anticonvulsant dosage as appropriate. Prolonged administration of phenytoin reportedly has resulted in a folate deficiency in 27% to 91% of patients. Megaloblastic anemia occurs in fewer than 1% of patients receiving phenytoin. The proposed mechanisms of this phenomenon include an increase in folate catabolism, folate malabsorption, or use of folic acid secondary to enzyme induction by phenytoin. Some evidence suggests that the anticonvulsant effect of phenytoin is partially the result of a reduction in folic acid concentrations. Folic acid replacement has resulted in an increase in metabolism of phenytoin and a decrease in phenytoin concentration in some patients, apparently through increased metabolism and/or redistribution of phenytoin in the brain and CSF. A clinically significant increase in seizure activity has occurred with this drug combination in rare instances, especially when doses of 4 mg/day or more were utilized.
Fomepizole: (Minor) In healthy volunteers, moderate oral doses of fomepizole significantly reduced the rate of elimination of ethanol by approximately 40%. Similarly, ethanol decreased the rate of elimination of fomepizole by approximately 50%. Both interactions occur via alcohol dehydrogenase inhibition. Although not studied, reciprocal interactions may occur with concomitant use of fomepizole and drugs that increase or inhibit the cytochrome P450 enzyme system like phenytoin.
Food: (Major) Advise patients to avoid cannabis use during phenytoin/fosphenytoin treatment. Concomitant use may decrease the concentration of some cannabinoids and alter their effects. The cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are CYP3A substrates and phenytoin/fosphenytoin are strong CYP3A inducers. Concomitant use of a cannabinoid product containing THC and CBD at an approximate 1:1 ratio with another strong CYP3A inducer decreased THC, 11-OH-THC, and CBD peak exposures by 36%, 87%, and 52% respectively.
Fosamprenavir: (Moderate) Monitor for decreased fosamprenavir efficacy if coadministered with phenytoin or fosphenytoin. Concurrent use may decrease the plasma concentrations of fosamprenavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Fosamprenavir is a CYP3A substrate and phenytoin/fosphenytoin is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the fosamprenavir overall exposure by 82%.
Fostamatinib: (Major) Avoid the concomitant use of fostamatinib with phenytoin. Concomitant use of fostamatinib with a strong CYP3A4 inducer decreases exposure to the major active metabolite, R406. R406 is extensively metabolized by CYP3A4; phenytoin is a strong CYP3A4 inducer. Concomitant use of fostamatinib with another strong CYP3A4 inducer decreased R406 AUC by 75% and Cmax by 59%.
Fostemsavir: (Contraindicated) Concomitant use of fostemsavir and phenytoin is contraindicated. Use of these drugs together may significantly decrease the plasma concentrations of temsavir, the active moiety of fostemsavir, thereby increasing the risk for HIV treatment failure or development of viral resistance. Temsavir is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer.
Furosemide: (Moderate) Monitor for loss of furosemide efficacy during concomitant phenytoin use. Phenytoin interferes directly with renal action of furosemide. There is evidence that treatment with phenytoin leads to decreased intestinal absorption of furosemide, and consequently to lower peak serum furosemide concentrations.
Futibatinib: (Major) Avoid concurrent use of futibatinib and phenytoin. Concomitant use may decrease futibatinib exposure, which may reduce its efficacy. Futibatinib is a substrate of CYP3A and P-gp; phenytoin is a dual P-gp and strong CYP3A inducer. Coadministration with another dual P-gp and strong CYP3A inducer decreased futibatinib exposure by 64%.
Ganaxolone: (Major) Avoid concurrent use of ganaxolone and phenytoin due to the risk of decreased ganaxolone efficacy. If concomitant use is unavoidable, consider increasing ganaxolone dose without exceeding the maximum daily dose. Ganaxolon e is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ganaxolone overall exposure by 68%.
Gefitinib: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with phenytoin is necessary. If phenytoin is discontinued, gefitinib at a dose of 250 mg once daily may be resumed 7 days later. Gefitinib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer reduced gefitinib exposure by 83%.
Gilteritinib: (Major) Avoid coadministration of gilteritinib and phenytoin due to the potential for decreased gilteritinib exposure and risk of decreased efficacy. Gilteritinib is a P-gp and CYP3A4 substrate; phenytoin is a combined P-gp and strong CYP3A4 inducer. Coadministration of another combined P-gp and strong CYP3A4 inducer decreased the gilteritinib AUC by 70% in a drug interaction study.
Glasdegib: (Major) Avoid coadministration of glasdegib and phenytoin due to the potential for decreased glasdegib exposure. Glasdegib is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the glasdegib AUC by 70% in a drug interaction study.
Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with coadministration of glecaprevir and phenytoin as decreased plasma concentrations of glecaprevir may occur resulting in the potential loss of efficacy of glecaprevir. Glecaprevir is a substrate of CYP3A4 and P-glycoprotein (P-gp); phenytoin is a CYP3A4/P-gp inducer. (Moderate) Caution is advised with coadministration of pibrentasvir and phenytoin as decreased plasma concentrations of pibrentasvir may occur resulting in the potential loss of efficacy of pibrentasvir. Pibrentasvir is a substrate of P-gp and phenytoin is a P-gp inducer.
Glipizide; Metformin: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Glyburide; Metformin: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Green Tea: (Minor) Some green tea products contain caffeine. The metabolism of caffeine can be increased by concurrent use with hydantoin anticonvulsants.
Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with phenytoin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If phenytoin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer.
Guanfacine: (Major) Monitor patients for guanfacine efficacy during phenytoin coadministration. Guanfacine plasma concentrations can be reduced by phenytoin, by induction of CYP3A4 metabolism. Immediate-release guanfacine may require more frequent dosing to achieve or maintain desired hypotensive response; if it is discontinued, carefully taper the dose to prevent rebound hypertension. The extended-release guanfacine dose for attention deficit hyperactivity disorder (ADHD) may need to be doubled, per FDA-approved labeling; any dose change should occur over 1 to 2 weeks (e.g., dose increase when adding, or decrease when discontinuing, an enzyme inducer). Guanfacine is primarily metabolized by CYP3A4. Phenytoin is a strong CYP3A4 inducer. Guanfacine plasma concentrations and elimination half-life were significantly reduced with coadministration of an enzyme inducer (e.g., phenobarbital, primidone, phenytoin, fosphenytoin) in two patients with renal impairment.
Haloperidol: (Major) Haloperidol is metabolized in the liver; hydantoin anticonvulsants are known to induce certain hepatic enzymes. Clinicians should monitor for reduced haloperidol effectiveness if a hydantoin is used concurrently. Conversely, the discontinuation of these drugs may produce an increase in haloperidol concentrations. Additionally, antipsychotic use may lower the seizure threshold in patients receiving anticonvulsants, although the risk is less with haloperidol than with the phenothiazines. Additional CNS depression may occur when haloperidol is given with anticonvulsant drugs.
Homatropine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with phenytoin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If phenytoin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer.
Hydrocodone: (Moderate) Concomitant use of hydrocodone with phenytoin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If phenytoin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer.
Hydrocodone; Ibuprofen: (Moderate) Concomitant use of hydrocodone with phenytoin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If phenytoin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer.
Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with phenytoin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If phenytoin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer.
Hydromorphone: (Moderate) Additive CNS depression could be seen with the combined use of the hydantoin and opiate agonists. Methadone is a primary substrate for the CYP3A4 isoenzyme. Serum concentrations of methadone may decrease due to CYP3A4 induction by phenytoin; withdrawal symptoms may occur.
Hydroxychloroquine: (Moderate) Monitor for a decrease in hydroxychloroquine and phenytoin efficacy if coadministration is necessary. Antiepileptic drug activity may be impaired if coadministered with hydroxychloroquine and concomitant use may decrease exposure of hydroxychloroquine. Hydroxychloroquine is a CYP3A substrate and phenytoin is a strong CYP3A inducer.
Ibrexafungerp: (Major) Avoid concurrent administration of ibrexafungerp with phenytoin/fosphenytoin. Use of these drugs together is expected to significantly decrease ibrexafungerp exposure, which may reduce its efficacy. Ibrexafungerp is a CYP3A substrate and phenytoin and fosphenytoin are strong CYP3A inducers.
Ibrutinib: (Major) Avoid the concomitant use of ibrutinib and phenytoin; ibrutinib plasma concentrations may decrease. Ibrutinib is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ibrutinib exposure by more than 10-fold.
Ibuprofen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with phenytoin is necessary; consider increasing the dose of oxycodone as needed. If phenytoin is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Idelalisib: (Contraindicated) Avoid concomitant use of idelalisib, a CYP3A4 substrate, with strong CYP3A4 inducer such as phenytoin, as idelalisib exposure may be significantly reduced and efficacy compromised. Additionally, idelalisib is a strong CYP3A inhibitor while phenytoin is a CYP3A substrate. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib. Avoid concomitant use of idelalisib and phenytoin.
Ifosfamide: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with phenytoin is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; phenytoin is a strong CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
Imatinib: (Major) Avoid coadministration of imatinib and phenytoin if possible due to decreased plasma concentrations of imatinib. If concomitant use is unavoidable, increase the dose of imatinib by at least 50%, carefully monitoring clinical response; imatinib doses up to 1,200 mg per day (600 mg twice daily) have been given to patients receiving concomitant strong CYP3A4 inducers. Imatinib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer increased imatinib clearance by 3.8-fold, which significantly decreased the mean Cmax and AUC of imatinib.
Imipramine: (Moderate) Tricyclic antidepressants (TCA), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently. In addition, hydantoins may increase TCA metabolism.
Indinavir: (Major) Hydantoins like phenytoin, ethotoin, fosphenytoin may increase the metabolism of indinavir and lead to decreased efficacy. In addition, indinavir may inhibit the CYP metabolism of hydantoins, resulting in increased hydantoin concentrations.
Infigratinib: (Major) Avoid concurrent use of infigratinib and phenytoin/fosphenytoin. Coadministration may decrease infigratinib exposure resulting in decreased efficacy. Infigratinib is a CYP3A4 substrate and phenytoin and fosphenytoin are strong CYP3A4 inducers. Coadministration with another strong CYP3A4 inducer decreased the AUC of infigratinib by 56%.
Insulin Degludec; Liraglutide: (Minor) Phenytoin can decrease the hypoglycemic effects of liraglutide by producing an increase in blood glucose levels. Monitor for signs indicating loss of diabetic control when therapy with a hydantoin is instituted. Conversely, patients should be closely monitored for signs of hypoglycemia when therapy with a hydantoin is discontinued.
Insulin Glargine; Lixisenatide: (Minor) Phenytoin can decrease the hypoglycemic effects of lixisenatide by producing an increase in blood glucose levels. Monitor for signs indicating loss of diabetic control when therapy with a hydantoin is instituted. Conversely, patients should be closely monitored for signs of hypoglycemia when therapy with a hydantoin is discontinued.
Insulins: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Irinotecan Liposomal: (Major) Avoid administration of phenytoin during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Phenytoin is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers substantially reduced exposure to irinotecan or SN-38 in both adult and pediatric patients. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
Irinotecan: (Major) Avoid administration of phenytoin during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Phenytoin is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers substantially reduced exposure to irinotecan or SN-38 in both adult and pediatric patients. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
Isavuconazonium: (Contraindicated) Concomitant use of isavuconazonium with phenytoin or fosphenytoin is contraindicated due to the potential for decreased isavuconazole serum concentrations and treatment failure. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate of hepatic isoenzyme CYP3A4; phenytoin is a strong inducer of this enzyme. According to the manufacturer, coadministration of isavuconazole with strong CYP3A4 inducers is contraindicated. There was a 97% decrease in isavuconazole serum concentrations when coadministered with rifampin, another strong CYP3A4 inducer. Elevated phenytoin concentrations would also be expected with coadministration, as phenytoin is a substrate and isavuconazole is moderate inhibitor of CYP3A4.
Isoflurane: (Moderate) Caution is advised with the concomitant use of isoflurane and phenytoin as concurrent use may increase the risk of hepatotoxicity.
Isoniazid, INH: (Moderate) The metabolism of phenytoin is inhibited by isoniazid, INH, resulting in possible phenytoin intoxication. Monitoring is recommended for signs of toxicity such as ataxia, nystagmus, mental impairment, involuntary muscular movements, and seizures. Conversely, a decrease in clinical response to phenytoin may occur following withdrawal of INH.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Rifampin is a potent inducer of the cytochrome P-450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of the phenytoin. (Moderate) The metabolism of phenytoin is inhibited by isoniazid, INH, resulting in possible phenytoin intoxication. Monitoring is recommended for signs of toxicity such as ataxia, nystagmus, mental impairment, involuntary muscular movements, and seizures. Conversely, a decrease in clinical response to phenytoin may occur following withdrawal of INH.
Isoniazid, INH; Rifampin: (Major) Rifampin is a potent inducer of the cytochrome P-450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of the phenytoin. (Moderate) The metabolism of phenytoin is inhibited by isoniazid, INH, resulting in possible phenytoin intoxication. Monitoring is recommended for signs of toxicity such as ataxia, nystagmus, mental impairment, involuntary muscular movements, and seizures. Conversely, a decrease in clinical response to phenytoin may occur following withdrawal of INH.
Isotretinoin: (Minor) Long-term use of phenytoin has been associated with osteomalacia. No formal clinical studies have been conducted to assess if there is an additive or interactive effect on bone loss between phenytoin and isotretinoin therapy. Patients receiving phenytoin or other anticonvulsants that may affect the bone should receive isotretinoin therapy with caution.
Isradipine: (Moderate) Because isradipine is a substrate of CYP3A4 , the concomitant use of drugs that induce CYP3A4, such as hydantoin anticonvulsants (i.e., phenytoin, fosphenytoin, or ethotoin), may cause a reduction in the bioavailability and thus decreased therapeutic effect of isradipine. Until more data are available, patients should be monitored for potential loss of therapeutic effect when hepatic enzyme inducers are added to isradipine therapy.
Istradefylline: (Major) Avoid coadministration of istradefylline with phenytoin as istradefylline exposure and efficacy may be reduced. Phenytoin is a strong inducer. Istradefylline exposure was decreased by 81% when administered with a strong inducer in a drug interaction study.
Itraconazole: (Major) Use of phenytoin is not recommended for 2 weeks before or during itraconazole therapy. Phenytoin has been shown to significantly reduce itraconazole AUC and half-life. Itraconazole, in turn, modestly increased phenytoin AUC.
Ivabradine: (Major) Avoid coadministration of ivabradine and phenytoin or fosphenytoin. Ivabradine is primarily metabolized by CYP3A4; phenytoin induces CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
Ivacaftor: (Major) Coadministration of ivacaftor with phenytoin is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with phenytoin due to decreased plasma concentrations of ivosidenib. Ivosidenib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer is predicted to decrease ivosidenib exposure at steady-state by 33%.
Ixabepilone: (Major) Avoid concurrent use of ixabepilone and phenytoin due to decreased plasma concentrations of ixabepilone, which may reduce its efficacy. If concomitant use is unavoidable, gradually increase the dose of ixabepilone as tolerated from 40 mg/m2 to 60 mg/m2 and infuse over 4 hours; monitor carefully for ixabepilone-related toxicities. Ixabepilone is a CYP3A substrate and phenytoin is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased ixabepilone exposure by 43%.
Ixazomib: (Major) Avoid the concomitant use of ixazomib and phenytoin or fosphenytoin; ixazomib levels may be significantly decreased and its efficacy reduced. Ixazomib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. In subjects who received ixazomib with another strong CYP3A4 inducer, the ixazomib Cmax and AUC values were decreased by 54% and 74%, respectively.
Ketoconazole: (Major) The use of phenytoin within 2 weeks of ketoconazole therapy is not recommended. If coadministration cannot be avoided, monitor for decreased efficacy of ketoconazole and increase the dose of ketoconazole as necessary. Monitor phenytoin concentrations during concomitant therapy due to risk for phenytoin toxicity. Concomitant use may increase phenytoin concentrations. Ketoconazole is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer.
Ketorolac: (Moderate) Monitor for increased seizures during concomitant use of phenytoin and ketorolac. Sporadic cases of seizures have been reported during coadministration of ketorolac and antiepileptic drugs like phenytoin.
Lacosamide: (Moderate) Use lacosamide with caution in patients taking concomitant medications that affect cardiac conduction including those that prolong PR interval, such as sodium channel blocking anticonvulsants (e.g., phenytoin), because of the risk of AV block, bradycardia, or ventricular tachyarrhythmia. If use together is necessary, obtain an ECG prior to lacosamide initiation and after treatment has been titrated to steady-state. In addition, monitor patients receiving lacosamide via the intravenous route closely.
Lamivudine, 3TC; Zidovudine, ZDV: (Minor) Coadministration with zidovudine has resulted in altered phenytoin concentrations. Reports have varied, with increased and decreased phenytoin concentrations being reported. Use combination with caution.
Lamotrigine: (Major) Adjustments in lamotrigine escalation and maintenance dose regimens are necessary with concomitant phenytoin use. Monitoring lamotrigine plasma concentrations may be indicated, particularly during dosage adjustments. Lamotrigine is metabolized predominantly by glucuronic acid conjugation, and phenytoin induces glucuronidation. During concurrent use of lamotrigine with phenytoin, lamotrigine steady-state concentration decreased by approximately 40%.
Lansoprazole: (Major) Avoid concomitant use of lansoprazole and phenytoin as lansoprazole exposure may be decreased, reducing its efficacy. Lansoprazole is a CYP3A substrate and phenytoin is a strong CYP3A inducer.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of lansoprazole and phenytoin as lansoprazole exposure may be decreased, reducing its efficacy. Lansoprazole is a CYP3A substrate and phenytoin is a strong CYP3A inducer. (Major) Coadministration of phenytoin and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking potent CYP3A4 inducers. Additionally, there have been postmarketing reports of interactions of clarithromycin and phenytoin. The clarithromycin manufacturer recommends caution if coadministered.
Lanthanum Carbonate: (Major) Oral compounds known to interact with antacids, like phenytoin, should not be taken within 2 hours of dosing with lanthanum carbonate. If these agents are used concomitantly, space the dosing intervals appropriately. Monitor serum concentrations and clinical condition.
Lapatinib: (Major) Avoid coadministration of lapatinib with phenytoin due to decreased plasma concentrations of lapatinib. If concomitant use is unavoidable, gradually titrate the dose of lapatinib from 1,250 mg per day to 4,500 mg per day in patients receiving concomitant capecitabine (HER2-positive metastatic breast cancer), and from 1,500 mg per day to 5,500 mg per day in patients receiving concomitant aromatase inhibitor therapy (HR-positive, HER2-positive breast cancer) based on tolerability. If phenytoin is discontinued, reduce lapatinib to the indicated dose. Lapatinib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased lapatinib exposure by 72%.
Larotrectinib: (Major) Avoid coadministration of larotrectinib with phenytoin due to decreased larotrectinib exposure and risk of decreased efficacy. If coadministration cannot be avoided, double the larotrectinib dose. If phenytoin is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of phenytoin. Larotrectinib is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the larotrectinib AUC by 81% in a drug interaction study.
Ledipasvir; Sofosbuvir: (Major) Avoid coadministration of ledipasvir with phenytoin. Taking these drugs together may decrease ledipasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of sofosbuvir with inducers of P-glycoprotein (P-gp), such as phenytoin. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy.
Lefamulin: (Major) Avoid coadministration of lefamulin with phenytoin unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 and P-gp substrate; phenytoin is a P-gp and strong CYP3A4 inducer. Coadministration of a combined P-gp and strong CYP3A4 inducer decreased the mean AUC of oral and intravenous lefamulin by 72% and 28%, respectively.
Leflunomide: (Minor) Phenytoin clearance can be decreased by drugs that inhibit hepatic microsomal enzymes, particularly those drugs that significantly inhibit the cytochrome P450 2C subset of isoenzymes including leflunomide. Clinical and/or therapeutic drug monitoring of phenytoin may be warranted on initiation of leflunomide therapy.
Lemborexant: (Major) Avoid coadministration of lemborexant and phenytoin as concurrent use may decrease lemborexant exposure which may reduce efficacy. Lemborexant is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer. Additive CNS effects, such as sedation or impairment, may also be possible.
Lenacapavir: (Contraindicated) Concurrent use of lenacapavir and phenytoin is contraindicated due to the risk of decreased lenacapavir exposure which may result in loss of therapeutic effect and development of resistance. Lenacapavir is a CYP3A substrate and phenytoin is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced lenacapavir overall exposure by 84%.
Leniolisib: (Major) Avoid concomitant use of leniolisib and phenytoin/fosphenytoin. Concomitant use may decrease leniolisib exposure which may reduce its efficacy. Leniolisib is a CYP3A substrate and phenytoin/fosphenytoin is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced leniolisib overall exposure by 78%.
Lesinurad: (Moderate) Phenytoin and fosphenytoin may decrease the systemic exposure and therapeutic effect of lesinurad; monitor for potential reduction in efficacy. Phenytoin and fosphenytoin are CYP2C9 inducers, and lesinurad is a CYP2C9 substrate.
Lesinurad; Allopurinol: (Moderate) Phenytoin and fosphenytoin may decrease the systemic exposure and therapeutic effect of lesinurad; monitor for potential reduction in efficacy. Phenytoin and fosphenytoin are CYP2C9 inducers, and lesinurad is a CYP2C9 substrate.
Letermovir: (Major) Concurrent administration of letermovir and phenytoin is not recommended. Use of these drugs together may decrease letermovir plasma concentrations, resulting in a potential loss of letermovir efficacy. Letermovir is a substrate of UDP-glucuronosyltransferase 1A1/3 (UGT1A1/3) and P-glycoprotein (P-gp). Phenytoin is an inducer of UGT and P-gp. Also, a clinically relevant decrease in the plasma concentration of phenytoin, a CYP2C9 and CYP2C19 substrate, may occur during concurrent administration with letermovir, an inducer of CYP2C9 and CYP2C19. If these drugs are used together, frequently monitor phenytoin plasma concentrations.
Leucovorin: (Moderate) Limited data suggest that leucovorin may interfere with the activity of anticonvulsants such as phenytoin. Because folic acid can decrease serum concentrations of these agents, leucovorin may interact similarly. Phenytoin is known to interfere with folic acid absorption, but whether leucovorin absorption is altered is unknown. Clinicians should consider careful monitoring of patients when leucovorin is added to these anticonvulsants or when they are added to leucovorin therapy. Because levoleucovorin is the l-isomer of leucovorin, levoleucovorin also shares metabolic pathways with folic acid, and a similar interaction with anticonvulsants is expected.
Leuprolide; Norethindrone: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Levamlodipine: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with hydantoins is necessary. Amlodipine is a CYP3A4 substrate and hydantoins are strong CYP3A4 inducers. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Levodopa: (Moderate) Monitor for loss of efficacy in during concomitant use of levodopa and phenytoin. The beneficial effects of levodopa in Parkinson disease have been reported to be revered by phenytoin.
Levoketoconazole: (Major) The use of phenytoin within 2 weeks of ketoconazole therapy is not recommended. If coadministration cannot be avoided, monitor for decreased efficacy of ketoconazole and increase the dose of ketoconazole as necessary. Monitor phenytoin concentrations during concomitant therapy due to risk for phenytoin toxicity. Concomitant use may increase phenytoin concentrations. Ketoconazole is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer.
Levoleucovorin: (Moderate) Limited data suggest that leucovorin may interfere with the activity of anticonvulsants such as phenytoin. Because folic acid can decrease serum concentrations of these agents, leucovorin may interact similarly. Phenytoin is known to interfere with folic acid absorption, but whether leucovorin absorption is altered is unknown. Clinicians should consider careful monitoring of patients when leucovorin is added to these anticonvulsants or when they are added to leucovorin therapy. Because levoleucovorin is the l-isomer of leucovorin, levoleucovorin also shares metabolic pathways with folic acid, and a similar interaction with anticonvulsants is expected.
Levomefolate: (Moderate) Numerous studies indicate that folate status is impaired with the chronic use of diphenylhydantoin (phenytoin or fosphenytoin). Prolonged administration of phenytoin reportedly has resulted in a folate deficiency. In addition, folic acid replacement has resulted in an increase in metabolism of phenytoin and a decrease in phenytoin concentration in some patients, apparently through increased metabolism and/or redistribution of phenytoin in the brain and CSF. Although no decrease in effectiveness of anticonvulsants has been reported with the concurrent use of L-methylfolate, caution still should be exercised with the coadministration of these agents, and patients should be monitored closely for seizure activity.
Levonorgestrel: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Levonorgestrel; Ethinyl Estradiol: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Levorphanol: (Moderate) Additive CNS depression could be seen with the combined use of the hydantoin and opiate agonists. Methadone is a primary substrate for the CYP3A4 isoenzyme. Serum concentrations of methadone may decrease due to CYP3A4 induction by phenytoin; withdrawal symptoms may occur.
Levothyroxine: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of thyroid hormones, leading to reduced efficacy of the thyroid hormone.
Levothyroxine; Liothyronine (Porcine): (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of thyroid hormones, leading to reduced efficacy of the thyroid hormone.
Levothyroxine; Liothyronine (Synthetic): (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of thyroid hormones, leading to reduced efficacy of the thyroid hormone.
Lidocaine: (Moderate) Concomitant use of systemic lidocaine and phenytoin may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; phenytoin induces both hepatic isoenzymes. Additionally, coadministration of lidocaine with oxidizing agents, such as phenytoin, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Lidocaine; Epinephrine: (Moderate) Concomitant use of systemic lidocaine and phenytoin may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; phenytoin induces both hepatic isoenzymes. Additionally, coadministration of lidocaine with oxidizing agents, such as phenytoin, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Lidocaine; Prilocaine: (Moderate) Coadministration of prilocaine with oxidizing agents, such as phenytoin, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Concomitant use of systemic lidocaine and phenytoin may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; phenytoin induces both hepatic isoenzymes. Additionally, coadministration of lidocaine with oxidizing agents, such as phenytoin, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Linagliptin: (Moderate) Monitor for a decrease in linagliptin efficacy during concomitant use of linagliptin and phenytoin/fosphenytoin if coadministration is required. Concomitant use may decrease linagliptin exposure. Linagliptin is a CYP3A and P-gp substrate and phenytoin/fosphenytoin is a strong CYP3A and P-gp inducer. Concomitant use with a strong CYP3A and P-gp inducer reduced linagliptin overall exposure by 0.6-fold.
Linagliptin; Metformin: (Moderate) Monitor for a decrease in linagliptin efficacy during concomitant use of linagliptin and phenytoin/fosphenytoin if coadministration is required. Concomitant use may decrease linagliptin exposure. Linagliptin is a CYP3A and P-gp substrate and phenytoin/fosphenytoin is a strong CYP3A and P-gp inducer. Concomitant use with a strong CYP3A and P-gp inducer reduced linagliptin overall exposure by 0.6-fold. (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Linezolid: (Minor) Coadministration of linezolid and phenytoin, which is metabolized by the CYP2C9 isoenzyme, does not substantially alter the pharmacokinetics of phenytoin. No changes in the phenytoin dosage regimen is necessary. Also, phenytoin is a strong inducer of the CYP450 enzyme system. The AUC and Cmax of linezolid were decreased when coadministered with another strong CYP450 inducer, rifampin. It is unknown if phenytoin could cause decreases in linezolid exposure if coadministered.
Liothyronine: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of thyroid hormones, leading to reduced efficacy of the thyroid hormone.
Liraglutide: (Minor) Phenytoin can decrease the hypoglycemic effects of liraglutide by producing an increase in blood glucose levels. Monitor for signs indicating loss of diabetic control when therapy with a hydantoin is instituted. Conversely, patients should be closely monitored for signs of hypoglycemia when therapy with a hydantoin is discontinued.
Lisdexamfetamine: (Moderate) Monitor for decreased efficacy of phenytoin during coadministration with lisdexamfetamine. Amphetamines may delay the intestinal absorption of phenytoin.
Lithium: (Moderate) Monitor lithium and phenytoin concentrations during concomitant therapy; dosage adjustments may be necessary. Concomitant use may increase risk of adverse reactions of these drugs.
Lixisenatide: (Minor) Phenytoin can decrease the hypoglycemic effects of lixisenatide by producing an increase in blood glucose levels. Monitor for signs indicating loss of diabetic control when therapy with a hydantoin is instituted. Conversely, patients should be closely monitored for signs of hypoglycemia when therapy with a hydantoin is discontinued.
Lonafarnib: (Contraindicated) Coadministration of lonafarnib and phenytoin is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Lonafarnib is a sensitive CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the exposure of lonafarnib by 98%.
Lopinavir; Ritonavir: (Major) Avoid concomitant use of lopinavir; ritonavir and hydantoins. If concomitant use is necessary, do not use once daily dosing of lopinavir; ritonavir. Concomitant use may decrease lopinavir plasma concentrations, resulting in reduced efficacy. Lopinavir is a CYP3A substrate and hydantoins are CYP3A inducers. (Major) Avoid concomitant use of ritonavir and hydantoins. Concomitant use may decrease the exposure of ritonavir and hydantoins, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the hydantoin. A dose increase of the hydantoin may be necessary. Ritonavir is a CYP3A substrate and inducer and hydantoins are CYP3A inducers.
Lorlatinib: (Contraindicated) Coadministration of lorlatinib with phenytoin is contraindicated due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. Discontinue phenytoin for 3 plasma half-lives prior to initiating therapy with lorlatinib. Lorlatinib is a CYP3A substrate and phenytoin is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients.
Losartan: (Minor) Phenytoin may inhibit the CYP2C9-mediated conversion of losartan to its active metabolite. A reduced clinical effect of losartan is possible via reduced formation of a metabolite which significantly contributes to the efficacy of losartan.
Losartan; Hydrochlorothiazide, HCTZ: (Minor) Phenytoin may inhibit the CYP2C9-mediated conversion of losartan to its active metabolite. A reduced clinical effect of losartan is possible via reduced formation of a metabolite which significantly contributes to the efficacy of losartan.
Lovastatin: (Moderate) Monitor for a decrease in lovastatin efficacy if concomitant use with phenytoin is necessary. Concomitant use may decrease lovastatin exposure. Lovastatin is a CYP3A substrate and phenytoin is a strong CYP3A inducer.
Loxapine: (Major) Hydantoins may induce hepatic microsomal enzymes, leading to increased clearance of antipsychotic agents including loxapine. Also, loxapine may lower the seizure threshold. Adequate dosages of the anticonvulsant should be continued when an antipsychotic drug is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either drug.
Lumacaftor; Ivacaftor: (Major) Coadministration of ivacaftor with phenytoin is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold.
Lumacaftor; Ivacaftor: (Major) Concomitant use of phenytoin or fosphenytoin and lumacaftor; ivacaftor is not recommended. Phenytoin may decrease the therapeutic effect of lumacaftor; ivacaftor by significantly decreasing the systemic exposure of ivacaftor. Ivacaftor is a substrate of CYP3A, and phenytoin is a potent CYP3A inducer. In a pharmacokinetic study, coadministration of lumacaftor; ivacaftor with rifampin, another potent CYP3A inducer, decreased ivacaftor exposure by 57%, with minimal effect on the exposure of lumacaftor. In vitro studies suggest lumacaftor; ivacaftor has the potential to induce CYP2C9 and CYP2C19; inhibition CYP2C9 has also been observed. Because phenytoin is a substrate of these enzymes, altered phenytoin exposure may occur.
Lumateperone: (Major) Avoid coadministration of lumateperone and phenytoin as concurrent use may decrease lumateperone exposure which may reduce efficacy. Lumateperone is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer. Coadministration of lumateperone with a strong CYP3A4 inducer decreased lumateperone overall exposure by greater than 30-fold.
Lurasidone: (Contraindicated) Concurrent use of lurasidone with strong CYP3A4 inducers, such as phenytoin or fosphenytoin, is contraindicated. Lurasidone is primarily metabolized by CYP3A4. Decreased blood concentrations of lurasidone are expected when the drug is co-administered with strong inducers of CYP3A4.
Lurbinectedin: (Major) Avoid coadministration of lurbinectedin and phenytoin due to the risk of decreased lurbinectedin exposure which may reduce its efficacy. Lurbinectedin is a CYP3A substrate and phenytoin is a strong CYP3A inducer.
Macimorelin: (Major) Discontinue phenytoin and allow a sufficient washout period to pass before administering macimorelin. Use of these drugs together can significantly decrease macimorelin plasma concentrations, and may result in a false positive test for growth hormone deficiency. No drug-drug interaction studies have been conducted; however, macimorelin is primarily metabolized by CYP3A4 and phenytoin is a strong CYP3A4 inducer.
Maprotiline: (Moderate) Maprotiline, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold. Ethotoin, phenytoin or fosphenytoin may increase antidepressant metabolism. Monitor patients on anticonvulsants carefully when maprotiline is used concurrently. Because of the lowering of seizure threshold, an alternative antidepressant may be a more optimal choice for patients taking drugs for epilepsy.
Maraviroc: (Major) Coadministration of maraviroc, a CYP3A substrate, and phenytoin, a strong CYP3A inducer, without a concomitant strong CYP3A inhibitor may decrease maraviroc concentrations, therefore, the adult maraviroc dose should be increased to 600 mg PO twice daily when coadministered with phenytoin without a concomitant strong CYP3A inhibitor. Coadministration of maraviroc and phenytoin is contraindicated in patients with CrCl less than 30 mL/min. For pediatric patients, concomitant use of maraviroc with a strong CYP3A inducer, without a strong CYP3A inhibitor, is not recommended. If the patient's medication regimen also contains a strong CYP3A inhibitor, the CYP3A inhibitor's actions are expected to exceed that of the inducer; overall, increased maraviroc concentrations are expected.
Maribavir: (Major) Increase maribavir dose to 1,200 mg PO twice daily when coadministered with phenytoin. Coadministration may decrease maribavir exposure resulting in reduced virologic response. Maribavir is a CYP3A substrate and phenytoin is a strong CYP3A inducer.
Mavacamten: (Contraindicated) Mavacamten is contraindicated for use with phenytoin due to risk for reduced mavacamten efficacy. Concomitant use decreases mavacamten exposure. Mavacamten is a CYP2C19 and CYP3A substrate and phenytoin is a moderate CYP2C19 inducer and strong CYP3A inducer. The impact that a CYP3A inducer may have on mavacamten overall exposure varies based on the patient's CYP2C19 metabolizer status. Concomitant use of a strong CYP3A inducer is predicted to decrease mavacamten overall exposure by 69% and 87% in poor and normal CYP2C19 metabolizers, respectively.
Mebendazole: (Moderate) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, including mebendazole, leading to reduced efficacy of the concomitant medication.
Medroxyprogesterone: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Mefloquine: (Moderate) The hydantoin anticonvulsants induce CYP3A4 and may increase the metabolism of mefloquine if coadministered. Concomitant administration can reduce the clinical efficacy of mefloquine, increasing the risk of Plasmodium falciparum resistance during treatment of malaria. Coadministration of mefloquine and hydantoin anticonvulsants may also result in lower than expected anticonvulsant concentrations and loss of seizure control. Monitoring of the hydantoin (e.g., phenytoin) anticonvulsant serum concentration, if the drug is monitored via therapeutic drug monitoring, is recommended. Mefloquine may cause CNS side effects that may cause seizures or alter moods or behaviors.
Meperidine: (Major) The coadministration of phenytoin, fosphenytoin, or ethotoin with meperidine may result in reduced analgesic efficacy of meperidine and increased meperidine/normeperidine related CNS adverse effects. Phenytoin may stimulate the metabolism of meperidine to its more toxic metabolite normeperidine. While the clinical relevance of this interaction is uncertain, concurrent use should be undertaken with care.
Mepivacaine: (Moderate) Coadministration of mepivacaine with oxidizing agents, such as phenytoin, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue mepivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Metformin: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Metformin; Repaglinide: (Moderate) Coadministration of repaglinide with hydantoins may increase or decrease blood glucose; if coadministration is necessary, repaglinide dosage adjustment may be required and an increased frequency of glucose monitoring is recommended. Hydantoins are potent CYP3A4 inducers and repaglinide is a CYP3A4 substrate. In addition, phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Metformin; Rosiglitazone: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Metformin; Saxagliptin: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients. (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Metformin; Sitagliptin: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients. (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Methadone: (Moderate) Additive CNS depression including respiratory depression, hypotension, profound sedation, or coma may occur with the combined use of the hydantoin (e.g., phenytoin, fosphenytoin, and ethotoin) and methadone. Prior to concurrent use of methadone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Methadone should be used with caution and in reduced dosages if used concurrently with a CNS depressant; in opioid-naive adults, use an initial methadone dose of 2.5 mg every 12 hours. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Methadone is a primary substrate for the CYP3A4 isoenzyme. Serum concentrations of methadone may decrease due to CYP3A4 induction by phenytoin, fosphenytoin, and possibly ethotoin; withdrawal symptoms may occur.
Methamphetamine: (Major) Methamphetamine may delay the intestinal absorption of orally-administered phenytoin; the extent of phenytoin absorption is not known to be effected. Monitor the patient's neurologic status closely, as the amphetamines may also lower the seizure threshold in some patients on phenytoin or fosphenytoin.
Methohexital: (Moderate) Barbiturates can stimulate the hydroxylating enzyme that metabolizes phenytoin or, conversely, may inhibit phenytoin (or fosphenytoin) metabolism. In general, therapeutic doses of phenobarbital induce the hepatic metabolism of phenytoin, producing lower phenytoin serum concentrations. Large doses of phenobarbital, however, tend to increase phenytoin serum concentrations due to competition for hepatic pathways. Thus, phenytoin serum concentrations can increase, decrease, or not change during concomitant therapy with barbiturates. Conversely, phenytoin can increase serum concentrations of the barbiturate, however this has not been as well studied. Similar interactions may occur with ethotoin, although specific data are lacking.
Methotrexate: (Major) Avoid concomitant use of methotrexate and phenytoin due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Methotrexate is approximately 50% protein bound; phenytoin is highly protein-bound. Coadministration may displace methotrexate from its protein binding sites, increasing methotrexate plasma concentrations.
Methoxsalen: (Major) Hydantoins may increase the clearance of methoxsalen. The mechanism may be due to phenytoin induction of hepatic metabolizing enzymes resulting in reduced methoxsalen serum concentrations.
Methsuximide: (Moderate) Concurrent administration of methsuximide and phenytoin may increase phenytoin concentrations resulting in side effects or toxicity. Other hydantoins such as ethotoin may be similarly affected by methsuximide.
Methylphenidate: (Moderate) Monitor phenytoin concentrations during concomitant therapy with phenytoin and methylphenidate; a phenytoin dosage decrease may be necessary. Methylphenidate may inhibit the metabolism of phenytoin.
Methylprednisolone: (Moderate) Monitor for decreased corticosteroid efficacy if methylprednisolone is used with phenytoin; a dosage increase may be necessary. Concurrent use may decrease the exposure of methylprednisolone. Methylprednisolone is a CYP3A substrate and phenytoin is a strong CYP3A inducer.
Metronidazole: (Moderate) Monitor phenytoin concentrations and for loss of metronidazole efficacy during concomitant therapy. Phenytoin may accelerate the elimination of metronidazole, resulting in reduced plasma concentrations; impaired clearance of phenytoin has also been reported.
Metyrapone: (Moderate) The metabolism of metyrapone is accelerated by phenytoin; therefore, results of the diagnostic test using metapyrone may be inaccurate in patients taking phenytoin within 2 weeks before. During use for Cushing's syndrome, phenytoin therapy may attenuate the response to metyrapone treatment. Monitor for evidence of clinical response to treatment, and adjust treatment as clinically indicated. Metapyrone may cause dizziness or drowsiness, which may be additive to phenytoin effects.
Mexiletine: (Moderate) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, such as mexiletine, leading to reduced efficacy of the concomitant medication.
Miconazole: (Moderate) No formal drug interaction studies have been performed with buccal miconazole. Miconazole is a known inhibitor of CYP2C9. Although the systemic absorption of miconazole following buccal miconazole administration is minimal and plasma concentrations of miconazole are substantially lower than when given intravenously, the potential for interaction with drugs metabolized through CYP2C9 (such as phenytoin or fosphenytoin) cannot be ruled out.
Midazolam: (Moderate) Hydantoins are potent inducers of the hepatic isoenzyme CYP3A4, one of the pathways responsible for the hepatic metabolism of midazolam. Patients receiving these drugs may require higher doses of midazolam to achieve the desired clinical effect.
Midostaurin: (Major) Avoid the concomitant use of midostaurin and phenytoin as significantly decreased exposure of midostaurin and its active metabolites may occur resulting in decreased efficacy. Midostaurin is primarily metabolized by CYP3A4; phenytoin is a strong CYP3A4 inducer. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 decreased by 96%, 92%, and 59%, respectively, when midostaurin was administered with another strong CYP3A4 inducer in a drug interaction study.
Mifepristone: (Major) When mifepristone is administered for the treatment of Cushing's syndrome, avoid coadministration of phenytoin. When mifepristone is administered for pregnancy termination, follow-up assessment to verify that treatment has been successful is recommended in patients receiving phenytoin. Monitor phenytoin concentrations during concomitant therapy with mifepristone due to risk for phenytoin toxicity. Coadministration may decrease mifepristone exposure reducing efficacy and increase phenytoin concentrations. Mifepristone is a CYP2C9 inhibitor and CYP3A4 substrate; phenytoin is a CYP2C9 substrate and strong CYP3A4 inducer. The impact of CYP3A4 inducers on mifepristone efficacy is unknown.
Mirtazapine: (Moderate) Monitor for decreased efficacy of mirtazapine if coadministration with phenytoin is necessary; an increased mirtazapine dose may be necessary. If phenytoin is discontinued, a decrease in mirtazapine dose may be needed. Concomitant use may decrease mirtazapine exposure. Mirtazapine is a CYP3A substrate and phenytoin is a strong CYP3A inducer. Coadministration with other strong CYP3A inducers increased mirtazapine clearance by approximately 2-fold, decreasing the average mirtazapine plasma concentrations by 45% to 60%.
Mitapivat: (Major) Avoid coadministration of mitapivat with phenytoin due to decreased mitapivat efficacy. Coadministration decreases mitapivat concentrations. Mitapivat is a CYP3A substrate and phenytoin is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased mitapivat overall exposure by 91% to 95%.
Mivacurium: (Moderate) Concomitant use of neuromuscular blockers and phenytoin may increase resistance to the neuromuscular blockade action of neuromuscular blockers, resulting in shorter durations of neuromuscular blockade and higher infusion rate requirements. The use of a peripheral nerve stimulator is strongly recommended to evaluate the level of neuromuscular blockade, to assess the need for additional doses of neuromuscular blocker, and to determine whether adjustments need to be made to the dose with subsequent administration.
Mobocertinib: (Major) Avoid concomitant use of mobocertinib and phenytoin/fosphenytoin. Coadministration may decrease mobocertinib exposure resulting in decreased efficacy. Mobocertinib is a CYP3A substrate and phenytoin/fosphenytoin are strong CYP3A inducers. Use of a strong CYP3A inducer is predicted to decrease the overall exposure of mobocertinib and its active metabolites by 92%.
Modafinil: (Moderate) Since modafinil is metabolized by the CYP3A4 isoenzyme, and hydantoins (e.g., phenytoin, fosphenytoin) are CYP3A4 inducers, decreased modafinil efficacy may result from increased modafinil metabolism. In addition, modafinil is an inhibitor of the CYP2C19 and CYP2C9 isoenzymes. Hydantoins are substrates of CYP2C19, and phenytoin is a substrate of CYP2C9. Hydantoin concentrations may increase. Monitor carefully for signs of toxicity; phenytoin concentration monitoring may be helpful.
Molindone: (Major) The oral absorption of phenytoin may be reduced by the Moban brand of molindone which contains calcium ions. Calcium products may form complexes with phenytoin that are nonabsorbable. Consistent with the pharmacology of molindone, additive effects may occur with other CNS active drugs such as anticonvulsants. In addition, seizures have been reported during the use of molindone, which is of particular significance in patients with a seizure disorder receiving anticonvulsants. Adequate dosages of anticonvulsants should be continued when molindone is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either molindone or the anticonvulsant.
Montelukast: (Minor) Hydantoin anticonvulsants may reduce the systemic exposure of montelukast. However, dosage adjustment is not likely to be needed. If used together, the manufacturer recommends monitoring for proper montelukast effectiveness as a precaution. Hydantoin anticonvulsants are a strong CYP3A inducers. Montelukast is metabolized by CYP2C8 (primary), and also CYP2C9 and CYP3A4.
Mycophenolate: (Moderate) Mycophenolic acid is more than 98% bound to albumin. Administration of mycophenolate mofetil decreased the protein binding of phenytoin by 3%. Monitor patients receiving mycophenolate with highly protein bound drugs, such as phenytoin for changes in clinical status.
Naldemedine: (Major) Avoid coadministration of naldemedine with strong CYP3A4 inducers. Naldemedine is metabolized primarily by the CYP3A enzyme system. Strong CYP3A4 inducers, such as hydantoins, significantly decrease plasma naldemedine concentrations and may decrease the efficacy of naldemedine treatment.
Naloxegol: (Major) Coadministration of naloxegol with phenytoin is not recommended due to the potential for decreased naloxegol efficacy. Naloxegol is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased naloxegol exposure by 89%.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for decreased efficacy of nab-paclitaxel if coadministration with phenytoin is necessary due to the risk of decreased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer.
Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid concomitant use of sirolimus and phenytoin/fosphenytoin as use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A and P-gp substrate and phenytoin/fosphenytoin is a strong CYP3A and P-gp inducer.
Naproxen: (Minor) Naproxen is 99% bound to albumin. Thus, naproxen may displace other highly protein bound drugs from albumin or vice versa. If naproxen is used concurrently with hydantoins, monitor patients for toxicity from either drug.
Naproxen; Esomeprazole: (Moderate) Monitor phenytoin concentrations during concomitant therapy with esomeprazole due to risk for phenytoin toxicity. Concomitant use may increase phenytoin concentrations. Phenytoin is a CYP2C19 substrate and esomeprazole is a CYP2C19 inhibitor. (Minor) Naproxen is 99% bound to albumin. Thus, naproxen may displace other highly protein bound drugs from albumin or vice versa. If naproxen is used concurrently with hydantoins, monitor patients for toxicity from either drug.
Naproxen; Pseudoephedrine: (Minor) Naproxen is 99% bound to albumin. Thus, naproxen may displace other highly protein bound drugs from albumin or vice versa. If naproxen is used concurrently with hydantoins, monitor patients for toxicity from either drug.
Nateglinide: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Nefazodone: (Moderate) Monitor for decreased efficacy of nefazodone if coadministration with phenytoin is necessary. Concomitant use may decrease nefazodone exposure. Nefazodone is a primary CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased nefazodone and hydroxynefazodone exposure by almost 95%.
Nelfinavir: (Major) The coadministration of nelfinavir and phenytoin results in decreased phenytoin concentrations. Hydantoins may also increase the metabolism of nelfinavir, leading to decreased antiretroviral efficacy. Careful monitoring is warranted with coadministration of nelfinavir with hydantoin anticonvulsants.
Neratinib: (Major) Avoid concomitant use of phenytoin with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased neratinib exposure by 87%, while exposure to active metabolites M6 and M7 were reduced by 37% to 49%. Concomitant use with other strong inducers of CYP3A4 may also decrease neratinib concentrations.
Netupitant, Fosnetupitant; Palonosetron: (Major) Netupitant is mainly metabolized by CYP3A4. Avoid coadministration of netupitant in patients who are chronically using a strong CYP3A4 inducer, such as phenytoin. A strong CYP3A inducer can decrease the efficacy of netupitant by substantially reducing plasma concentrations of netupitant. In addition, netupitant is a moderate inhibitor of CYP3A4 and the plasma concentrations of medications that are primarily metabolized through CYP3A4 can increase with coadministration; the inhibitory effect on CYP3A4 can last for multiple days. Phenytoin has been shown to be partially metabolized by CYP3A4. If coadministration is necessary, no dosage adjustment is necessary for single dose administration of netupitant; palonosetron.
Neuromuscular blockers: (Moderate) Concomitant use of neuromuscular blockers and phenytoin may increase resistance to the neuromuscular blockade action of neuromuscular blockers, resulting in shorter durations of neuromuscular blockade and higher infusion rate requirements. The use of a peripheral nerve stimulator is strongly recommended to evaluate the level of neuromuscular blockade, to assess the need for additional doses of neuromuscular blocker, and to determine whether adjustments need to be made to the dose with subsequent administration.
Nevirapine: (Major) Coadministration of phenytoin or fosphenytoin and nevirapine is not recommended due to the potential for loss of virologic response and possible resistance to nevirapine. Nevirapine may also decrease plasma concentrations of phenytoin/fosphenytoin. If concurrent use is necessary, monitor phenytoin concentrations and virologic response. Nevirapine is a CYP3A substrate and phenytoin/fosphenytoin are strong CYP3A inducers.
Niacin; Simvastatin: (Moderate) Monitor for a decrease in simvastatin efficacy if concomitant use with phenytoin is necessary. Concomitant use may decrease simvastatin exposure. Simvastatin is a CYP3A substrate and phenytoin is a strong CYP3A inducer.
Nicardipine: (Moderate) Hydantoin anticonvulsants (i.e., phenytoin, fosphenytoin, or ethotoin) may induce the CYP3A4 metabolism of calcium-channel blockers and thereby reduce their oral bioavailability. The dosage requirements of nicardipine may be increased in patients receiving concurrent hydantoin anticonvulsants.
Nifedipine: (Major) Avoid coadministration of nifedipine with phenytoin and consider alternative therapy if possible. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. The FDA-approved labeling for some nifedipine products contraindicates coadministration with strong CYP3A4 inducers, while other manufacturers classify the recommendation as a warning. Nifedipine is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration of nifedipine with another strong CYP3A4 inducer reduced the AUC and Cmax of nifedipine by approximately 70%.
Nilotinib: (Major) Avoid the concomitant use of nilotinib and phenytoin; significantly decreased nilotinib exposure and reduced nilotinib efficacy may occur. Nilotinib is a CYPA4 substrate and phenytoin is a strong CYP3A4 inducer. In a drug interaction study, coadministration with another strong CYP3A4 inducer decreased nilotinib exposure by approximately 80%.
Nilutamide: (Moderate) Nilutamide inhibits the activity of hepatic cytochrome P450 isoenzymes and may reduce the metabolism of drugs metabolized by these enzymes including phenytoin.
Nimodipine: (Moderate) Limited data suggest that nimodipine may potentiate the effects of phenytoin. Because fosphenytoin is metabolized to phenytoin, additive effects are possible with concomitant nimodipine and fosphenytoin therapy. In addition, in epileptic patients taking phenytoin, there is a 7-fold decrease in the AUC of nimodipine due to hepatic enzyme induction. Monitor closely for therapeutic effectiveness and toxicity of both drugs.
Nintedanib: (Major) Avoid the use of phenytoin with nintedanib if possible, as phenytoin is expected to decrease the exposure of nintedanib and compromise its efficacy. Phenytoin is a potent CYP3A4 and mild P-glycoprotein (P-gp) inducer; nintedanib is a P-gp substrate and a minor substrate of CYP3A4. In drug interaction studies, administration of a dual P-gp and CYP3A4 inducer with nintedanib decreased the AUC of nintedanib by 50%.
Niraparib; Abiraterone: (Major) Avoid coadministration of abiraterone with phenytoin if possible due to decreased plasma concentrations of abiraterone. If concomitant use is unavoidable, increase the dosing frequency of abiraterone to twice daily. Reduce the dose back to the previous dose and frequency if phenytoin is discontinued. Abiraterone is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased abiraterone exposure by 55%.
Nirmatrelvir; Ritonavir: (Contraindicated) Ritonavir-boosted nirmatrelvir is contraindicated for use within 2 weeks of administering phenytoin; consider an alternative COVID-19 therapy. Coadministration may decrease nirmatrelvir exposure resulting in reduced virologic response. The risk for reduced efficacy may persist following phenytoin discontinuation. Nirmatrelvir is a CYP3A substrate and phenytoin is a strong CYP3A inducer. (Major) Avoid concomitant use of ritonavir and hydantoins. Concomitant use may decrease the exposure of ritonavir and hydantoins, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the hydantoin. A dose increase of the hydantoin may be necessary. Ritonavir is a CYP3A substrate and inducer and hydantoins are CYP3A inducers.
Nisoldipine: (Major) Coadministration of nisoldipine with phenytoin should be avoided and alternative antihypertensive therapy should be considered. Coadministration of phenytoin with nisoldipine in epileptic patients lowered the nisoldipine plasma concentrations to undetectable levels.
Nitazoxanide: (Moderate) No interactions with other drugs have been reported by patients using nitazoxanide. The active metabolite of nitazoxanide, tizoxanide, is highly bound to plasma proteins (> 99%). No studies have been performed to determine if there are interactions with other drugs that exhibit high protein binding (e.g., hydantoins like phenytoin or fosphenytoin). Therefore, caution should be exercised when administering nitazoxanide concurrently with other highly plasma protein-bound drugs with narrow therapeutic indices because competition for binding sites may occur.
Nitisinone: (Major) Monitor phenytoin serum concentrations in patients receiving nitisinone as concurrent use may increase circulating phenytoin concentrations enhancing the risk of drug toxicity. A phenytoin dosage reduction may be necessary. Phenytoin is a CYP2C9 substrate with narrow therapeutic index (NTI); nitisinone is a moderate CYP2C9 inhibitor. FDA-approved labeling for nitisinone recommends reducing the dose of NTI CYP2C9 substrates by 50% with subsequent dosage adjustments to maintain therapeutic drug concentrations.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Norethindrone: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Norethindrone; Ethinyl Estradiol: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Norgestimate; Ethinyl Estradiol: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Norgestrel: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Nortriptyline: (Moderate) Tricyclic antidepressants (TCA), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently. In addition, hydantoins may increase TCA metabolism.
Olanzapine: (Major) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme, such as hydantoins, may increase olanzapine clearance. Clinicians should monitor for reduced effectiveness of the antipsychotic agent if hydantoin therapy is added.
Olanzapine; Fluoxetine: (Major) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme, such as hydantoins, may increase olanzapine clearance. Clinicians should monitor for reduced effectiveness of the antipsychotic agent if hydantoin therapy is added. (Moderate) Monitor phenytoin concentrations during concomitant therapy with fluoxetine due to risk for phenytoin toxicity. Concomitant use may increase phenytoin concentrations. Phenytoin is a CYP2C9 and CYP2C19 substrate and fluoxetine is a CYP2C9 and CYP2C19 inhibitor.
Olanzapine; Samidorphan: (Major) Avoid the concurrent use of samidorphan and phenytoin/fosphenytoin; decreased samidorphan exposure and loss of efficacy may occur. Samidorphan is a CYP3A substrate and phenytoin is a strong CYP3A inducer. Concomitant use of another strong CYP3A inducer reduced samidorphan exposure by 73%. (Major) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme, such as hydantoins, may increase olanzapine clearance. Clinicians should monitor for reduced effectiveness of the antipsychotic agent if hydantoin therapy is added.
Olaparib: (Major) Avoid coadministration of olaparib with phenytoin due to the risk of decreasing the efficacy of olaparib. Olaparib is a CYP3A substrate and phenytoin is a strong CYP3A4 inducer; concomitant use may decrease olaparib exposure. Coadministration with another strong CYP3A inducer decreased the olaparib Cmax by 71% and the AUC by 87%.
Oliceridine: (Moderate) Monitor for reduced efficacy of oliceridine and signs of opioid withdrawal if coadministration with phenytoin is necessary; consider increasing the dose of oliceridine as needed. If phenytoin is discontinued, consider a dose reduction of oliceridine and frequently monitor for signs of respiratory depression and sedation. Oliceridine is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease the plasma concentrations of oliceridine; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with hydantoins is necessary. Amlodipine is a CYP3A4 substrate and hydantoins are strong CYP3A4 inducers. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Olutasidenib: (Major) Avoid concurrent use of olutasidenib and phenytoin/fosphenytoin due to the risk of decreased olutasidenib exposure which may reduce its efficacy. Olutasidenib is a CYP3A substrate and phenytoin/fosphenytoin is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced olutasidenib exposure by approximately 80%.
Omaveloxolone: (Major) Avoid concurrent use of omaveloxolone and phenytoin/fosphenytoin. Concurrent use may decrease omaveloxolone exposure which may reduce its efficacy. Omaveloxolone is a CYP3A substrate and phenytoin/fosphenytoin is a strong CYP3A inducer.
Omeprazole: (Major) Avoid concomitant use of omeprazole and phenytoin as omeprazole exposure may be decreased, reducing its efficacy. Concomitant use may also increase phenytoin concentrations. Omeprazole is a CYP2C19 inhibitor and CYP3A substrate and phenytoin is a CYP2C19 substrate and strong CYP3A inducer.
Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid concomitant use of omeprazole and phenytoin as omeprazole exposure may be decreased, reducing its efficacy. Concomitant use may also increase phenytoin concentrations. Omeprazole is a CYP2C19 inhibitor and CYP3A substrate and phenytoin is a CYP2C19 substrate and strong CYP3A inducer. (Moderate) Drugs that induce hepatic microsomal enzymes, particularly those drugs that increase CYP2C9 or CYP2C19 metabolism, such as rifamycins, can accelerate hydantoin anticonvulsant clearance.
Omeprazole; Sodium Bicarbonate: (Major) Avoid concomitant use of omeprazole and phenytoin as omeprazole exposure may be decreased, reducing its efficacy. Concomitant use may also increase phenytoin concentrations. Omeprazole is a CYP2C19 inhibitor and CYP3A substrate and phenytoin is a CYP2C19 substrate and strong CYP3A inducer. (Moderate) Because the absorption of phenytoin suspension can be reduced by antacids containing magnesium, aluminum, or calcium, administration at the same time of day should be avoided when possible. Ingestion times of phenytoin capsules and calcium antacids should be staggered in patients with low serum phenytoin levels to prevent absorption difficulties. Studies evaluating the effects of magnesium-aluminium antacids on the absorption of phenytoin capsules or tablets have yielded conflicting results. Nevertheless, serum phenytoin levels and clinical response should be closely monitored if these agents are co-administered. The mechanisms by which antacids reduce phenytoin absorption may involve increased gastric transit time, chelation, adsorption, and/or altered solubility. The oral absorption of phenytoin may be reduced by calcium carbonate (e.g., as found in antacids) or other calcium salts. Calcium products may form complexes with phenytoin that are nonabsorbable. Although the magnitude of the interaction is not great, an occasional patient may be affected and the interaction may lead to subtherapeutic phenytoin concentrations. Separating the administration of phenytoin and antacids or calcium salts by at least 2 hours will help minimize the possibility of interaction.
Ondansetron: (Minor) Phenytoin may reduce the efficacy of ondansetron by decreasing its systemic exposure; however, based on available data, no ondansetron dosage adjustment is recommended. If used together, monitor patients for antiemetic efficacy. Phenytoin is a strong CYP3A inducer. Ondansetron is a substrate for CY1A2, CYP2D6, and CYP3A4, with CYP3A4 playing a predominant role in ondansetron turnover. During pharmacokinetic studies, patients treated with strong CYP3A inducers (i.e., phenytoin, carbamazepine, rifampin) and ondansetron had significantly increased ondansetron clearance, resulting in significant reductions in AUC, Cmax, and half-life. However, these changes in ondansetron exposure are not thought to be clinically relevant.
Oritavancin: (Moderate) Avoid use of oritavancin with drugs that have a narrow therapeutic window, such as phenytoin. Coadministration of oritavancin and phenytoin may result in increases or decreases in phenytoin exposure and may increase side effects or decrease efficacy of phenytoin. Phenytoin is primarily metabolized by CYP2C9, but is also metabolized by CYP3A4 and CYPC19. Oritavancin weakly induces CYP3A4, while weakly inhibiting CYP2C9 and CYP2C19. If these drugs are administered concurrently, monitor for signs of phenytoin toxicity or lack of phenytoin efficacy.
Osilodrostat: (Major) Monitor cortisol concentration and patient's signs and symptoms during coadministration of osilodrostat and phenytoin. Concurrent use may decrease osilodrostat exposure and reduce its efficacy; an increase in osilodrostat dose may be necessary. After discontinuation of phenytoin, monitor cortisol concentration and patient's signs and symptoms; a reduction in osilodrostat dose may be needed. Osilodrostat is a CYP3A4 and CYP2B6 substrate and phenytoin is a strong CYP3A4 inducer and also induces CYP2B6.
Osimertinib: (Major) Avoid coadministration of phenytoin with osimertinib due to decreased plasma concentrations of osimertinib which may lead to reduced efficacy. If concomitant use is unavoidable, increase the dose of osimertinib to 160 mg once daily. If phenytoin is discontinued, reduce the dose of osimertinib to 80 mg once daily after a washout period of 3 weeks. Osimertinib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased osimertinib exposure by 78%.
Ospemifene: (Moderate) Phenytoin is expected to decrease the systemic exposure of ospemifene, which may decrease the clinical effect. Phenytoin is a potent inducer of hepatic cytochrome P450 microsomal enzymes including CYP3A4, CYP2C9, and CYP2C19, the same enzymes that are responsible for the metabolism of ospemifene. In drug interaction studies, the use of another strong combined CYP inducer decreased the systemic exposure of ospemifene by 58%. Also, ospemifene is more than 99% bound to serum proteins and might affect the protein binding of other highly protein bound drugs; this action may lead to an increase in free phenytoin concentrations as phenytoin is a highly-protein bound narrow therapeutic index medication.
Oxazepam: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS-depressant effects of other CNS depressants including oxazepam. In addition to additive pharmacodynamic effects, potential hepatic enzyme inducers such as hydantoins can theoretically increase the clearance of benzodiazepines metabolized by oxidative metabolism, leading to lower benzodiazepine concentrations.
Oxcarbazepine: (Moderate) Monitor phenytoin concentrations during oxcarbazepine dosage titration or modification, and monitor plasma concentrations of MHD, the active metabolite of oxcarbazepine, during oxcarbazepine titration if oxcarbazepine and phenytoin are used concurrently. A dose adjustment of phenytoin or oxcarbazepine may be required. Phenytoin concentrations increased up to 40% with concomitant use of phenytoin (250 to 500 mg/day) and oxcarbazepine (1,200 to 2,400 mg/day). Coadministration of phenytoin (250 to 500 mg/day) with oxcarbazepine (600 to 2,400 mg/day) decreased MHD concentrations by 30%.
Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with phenytoin is necessary; consider increasing the dose of oxycodone as needed. If phenytoin is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Oxymorphone: (Moderate) Additive CNS depression could be seen with the combined use of the hydantoin and opiate agonists. Methadone is a primary substrate for the CYP3A4 isoenzyme. Serum concentrations of methadone may decrease due to CYP3A4 induction by phenytoin; withdrawal symptoms may occur.
Paclitaxel: (Minor) Paclitaxel is metabolized by hepatic cytochrome P450 isoenzymes 2C8 and 3A4. Potential interactions may occur in vivo with any agent that induces CYP2C8 or CYP3A4 isoenzymes including hydantoins. This combination could potentially decrease chemotherapy efficacy.
Pacritinib: (Contraindicated) Concurrent use of pacritinib with phenytoin is contraindicated due to decreased pacritinib exposure which may impair efficacy. Pacritinib is a CYP3A substrate and phenytoin is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased pacritinib exposure by 87%.
Palbociclib: (Major) Avoid coadministration of phenytoin with palbociclib due to decreased plasma concentrations of palbociclib, which may result in decreased efficacy. Palbociclib is primarily metabolized by CYP3A4 and phenytoin is a strong CYP3A4 inducer. In a drug interaction trial, coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of palbociclib by 85% and 70%, respectively.
Paliperidone: (Major) Avoid using a strong inducer of CYP3A4 if possible during the 1-month injectable dosing interval of Invega Sustenna or the 3-month injectable dosing interval of Invega Trinza. If use of strong CYP3A4 inducers such as hydantions is required in patients receiving injectable paliperidone, consider management with oral paliperidone. Paliperidone is a P-gp substrate, with minor contributions in metabolism by CYP3A4 and CYP2D6. A dosage increase of oral paliperidone may be required during coadministration of a strong inducer of both CYP3A4 and P-gp. However, concurrent use of oral paliperidone with a strong CYP3A4 inducer alone may not be clinically relevant since this isoenzyme contributes to only a small fraction of total body clearance of the drug.
Palovarotene: (Major) Avoid concomitant use of palovarotene and phenytoin. Concurrent use may decrease palovarotene exposure which may reduce its efficacy. Palovarotene is a CYP3A substrate and phenytoin is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced palovarotene overall exposure by 11%.
Pancuronium: (Moderate) Concomitant use of neuromuscular blockers and phenytoin may increase resistance to the neuromuscular blockade action of neuromuscular blockers, resulting in shorter durations of neuromuscular blockade and higher infusion rate requirements. The use of a peripheral nerve stimulator is strongly recommended to evaluate the level of neuromuscular blockade, to assess the need for additional doses of neuromuscular blocker, and to determine whether adjustments need to be made to the dose with subsequent administration.
Panobinostat: (Major) Avoid the concomitant use of panobinostat and phenytoin or fosphenytoin; panobinostat levels may be significantly decreased and its efficacy reduced. Phenytoin and fosphenytoin are strong CYP3A4 inducers and panobinostat is a CYP3A4 substrate. Using a physiologically-based pharmacokinetic model, the systemic exposure was estimated to be decreased by 70% when a strong CYP3A inducer was co-administered with panobinostat.
Paricalcitol: (Moderate) Antiepileptic drugs, such as barbiturates (i.e., phenobarbital and primidone), and phenytoin (or fosphenytoin which is metabolized to phenytoin) can increase the metabolism of endogenous vitamin D, thereby lowering serum concentrations and decreasing its activity. In rare cases, this has caused anticonvulsant-induced rickets and osteomalacia. In addition, hydantoins are CYP3A4 inducers and thus may further lower serum concentrations of paricalcitol through increased CYP3A4-mediated metabolism. Dosage adjustments of vitamin D analogs may be required in patients who are receiving chronic treatment with antiepileptic drugs.
Paroxetine: (Moderate) Monitor for loss of paroxetine efficacy during concomitant phenytoin use; a paroxetine dosage adjustment may be necessary. Phenytoin may impair paroxetine efficacy.
Pazopanib: (Moderate) Pazopanib is a substrate for CYP3A4. Plasma pazopanib concentrations may be decreased by concurrent administration with a CYP3A4 inducer such as phenytoin. Use caution if chronic use of CYP3A4 inducers and pazopanib can not be avoided.
Pemigatinib: (Major) Avoid coadministration of pemigatinib and phenytoin due to the risk of decreased pemigatinib exposure which may reduce its efficacy. Pemigatinib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased pemigatinib exposure by 85%.
Penicillin G Benzathine; Penicillin G Procaine: (Moderate) Coadministration of penicillin G procaine with oxidizing agents, such as phenytoin, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue penicillin G procaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Penicillin G Procaine: (Moderate) Coadministration of penicillin G procaine with oxidizing agents, such as phenytoin, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue penicillin G procaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Pentobarbital: (Moderate) Barbiturates can stimulate the hydroxylating enzyme that metabolizes phenytoin or, conversely, may inhibit phenytoin (or fosphenytoin) metabolism. In general, therapeutic doses of phenobarbital induce the hepatic metabolism of phenytoin, producing lower phenytoin serum concentrations. Large doses of phenobarbital, however, tend to increase phenytoin serum concentrations due to competition for hepatic pathways. Thus, phenytoin serum concentrations can increase, decrease, or not change during concomitant therapy with barbiturates. Conversely, phenytoin can increase serum concentrations of the barbiturate, however this has not been as well studied. Similar interactions may occur with ethotoin, although specific data are lacking.
Perampanel: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with phenytoin due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of phenytoin occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Phenytoin is a strong CYP3A4 inducer, and perampanel is a CYP3A4 substrate. The AUC of perampanel was reduced by 43% in patients taking phenytoin compared to patients not taking enzyme-inducing antiepileptic drugs.
Perindopril; Amlodipine: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with hydantoins is necessary. Amlodipine is a CYP3A4 substrate and hydantoins are strong CYP3A4 inducers. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Perphenazine: (Moderate) Monitor phenytoin concentrations during concomitant therapy with phenytoin and phenothiazines; a phenytoin dosage decrease may be necessary. Phenothiazines may inhibit the metabolism of phenytoin.
Perphenazine; Amitriptyline: (Moderate) Monitor phenytoin concentrations during concomitant therapy with phenytoin and phenothiazines; a phenytoin dosage decrease may be necessary. Phenothiazines may inhibit the metabolism of phenytoin. (Moderate) Tricyclic antidepressants (TCA), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently. In addition, hydantoins may increase TCA metabolism.
Pexidartinib: (Major) Avoid coadministration of pexidartinib with phenytoin as concurrent use may decrease pexidartinib exposure which may result in decreased therapeutic response. Additionally, both pexidartinib and phenytoin may cause hepatotoxicity and should be avoided in patients with increased serum transaminases, total bilirubin, or direct bilirubin (more than ULN) or active liver or biliary tract disease. Pexidartinib is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer. Coadministration of another strong CYP3A4 inducer decreased pexidartinib exposure by 65%.
Phenicol Derivatives: (Moderate) Chloramphenicol inhibits the cytochrome P-450 enzyme system and can affect the hepatic metabolism of phenytoin. Phenytoin toxicity can occur. Phenytoin dosage adjustments may be necessary in some patients who receive chloramphenicol concurrently; monitor for signs of phenytoin toxicity.
Phenobarbital: (Moderate) Barbiturates can stimulate the hydroxylating enzyme that metabolizes phenytoin or, conversely, may inhibit phenytoin (or fosphenytoin) metabolism. In general, therapeutic doses of phenobarbital induce the hepatic metabolism of phenytoin, producing lower phenytoin serum concentrations. Large doses of phenobarbital, however, tend to increase phenytoin serum concentrations due to competition for hepatic pathways. Thus, phenytoin serum concentrations can increase, decrease, or not change during concomitant therapy with barbiturates. Conversely, phenytoin can increase serum concentrations of the barbiturate, however this has not been as well studied. Similar interactions may occur with ethotoin, although specific data are lacking.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Barbiturates can stimulate the hydroxylating enzyme that metabolizes phenytoin or, conversely, may inhibit phenytoin (or fosphenytoin) metabolism. In general, therapeutic doses of phenobarbital induce the hepatic metabolism of phenytoin, producing lower phenytoin serum concentrations. Large doses of phenobarbital, however, tend to increase phenytoin serum concentrations due to competition for hepatic pathways. Thus, phenytoin serum concentrations can increase, decrease, or not change during concomitant therapy with barbiturates. Conversely, phenytoin can increase serum concentrations of the barbiturate, however this has not been as well studied. Similar interactions may occur with ethotoin, although specific data are lacking.
Phenothiazines: (Moderate) Monitor phenytoin concentrations during concomitant therapy with phenytoin and phenothiazines; a phenytoin dosage decrease may be necessary. Phenothiazines may inhibit the metabolism of phenytoin.
Phentermine; Topiramate: (Moderate) A dosage adjustment may be needed during coadministration of topiramate and hydantoins, closely monitor patients appropriately for increased adverse effects or altered clinical response to therapy. Serum phenytoin concentration may be needed for optimal dosage adjustments. Hydantoins have been shown to reduce topiramate serum concentrations. Topiramate may increase phenytoin concentrations through its inhibitory effects on CYP2C19. In some patients receiving phenytoin concurrently with topiramate, plasma concentrations of phenytoin were increased by 25% and topiramate plasma concentrations were decreased by 48%. These patients were generally receiving dosage regimens of phenytoin twice-daily. Other patients experienced a change of less than 10% in phenytoin plasma concentrations. A similar reaction would be expected with fosphenytoin.
Pimavanserin: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with strong CYP3A4 inducers, such as phenytoin. Strong inducers of CYP3A4 can reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
Pioglitazone; Metformin: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Pirtobrutinib: (Major) Avoid concurrent use of pirtobrutinib and phenytoin due to the risk of decreased pirtobrutinib exposure which may reduce its efficacy. The exposure of phenytoin may also be increased. Pirtobrutinib is a CYP3A substrate and CYP2C19 inhibitor; phenytoin is a CYP2C19 substrate and strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced pirtobrutinib overall exposure by 71%.
Pitolisant: (Major) Monitor for loss of pitolisant efficacy after initiation of phenytoin. Increase to double the original daily dose of pitolisant over 7 days in patients stable on 8.9 mg or 17.8 mg once daily (i.e., 17.8 mg or 35.6 mg, respectively). Decrease the pitolisant dose by half if phenytoin is discontinued. Pitolisant is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer. Coadministration of strong CYP3A4 inducers decreases pitolisant exposure by 50%.
Polatuzumab Vedotin: (Moderate) Monitor for decreased polatuzumab vedotin efficacy during coadministration of phenytoin due to the risk of decreased exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; phenytoin is a strong CYP3A4 inducer. Strong CYP3A4 inducers are predicted to decrease the exposure of MMAE by 63%.
Polycarbophil: (Major) The oral absorption of phenytoin may be reduced by calcium salts, and each 625 mg of calcium polycarbophil contains a substantial amount of calcium (approximately 125 mg). Calcium products may form complexes with phenytoin that are nonabsorbable. Although the magnitude of these interactions is not great, an occasional patient may be affected and the interaction may lead to subtherapeutic anticonvulsant concentrations. Separating the administration of calcium polycarbophil and either phenytoin by at least 2 hours will help minimize the possibility of such an interaction.
Pomalidomide: (Moderate) Use pomalidomide and phenytoin together with caution; decreased pomalidomide exposure may occur resulting in reduced pomalidomide effectiveness. Pomalidomide is a CYP1A2 substrate and phenytoin is a CYP1A2 inducer.
Ponatinib: (Major) Avoid coadministration of ponatinib with phenytoin due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Ponatinib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ponatinib exposure by 62%.
Ponesimod: (Major) Avoid concurrent use of ponesimod and phenytoin and monitor for decreased ponesimod efficacy if use is necessary. Ponesimod is a CYP3A and an UGT1A1 substrate and phenytoin is a strong CYP3A inducer and an UGT1A1 inducer that may decrease ponesimod exposure.
Posaconazole: (Major) The concurrent use of posaconazole and phenytoin should be avoided, if possible, due to the potential for decreased posaconazole efficacy and increased phenytoin plasma concentrations. If used in combination, closely monitor for breakthrough fungal infections as well as phenytoin plasma concentrations, with consideration for phenytoin dosage reductions. Phenytoin induces UDP-glucuronidase resulting in decreased posaconazole plasma concentrations. When posaconazole was administered with phenytoin (both 200 mg PO daily), the mean reductions in Cmax were 41% and the mean reductions in AUC were 50% for posaconazole. Additionally, posaconazole is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of phenytoin. Coadministration of posaconazole (200 mg PO daily) with phenytoin (200 mg PO daily) increased both the mean phenytoin Cmax and AUC by 16%. The concomitant use of phenytoin with posaconazole should be avoided unless the benefits outweigh the risks; dosage adjustment recommendations are not available.
Pralsetinib: (Major) Avoid coadministration of phenytoin with pralsetinib due to the risk of decreased pralsetinib exposure which may reduce its efficacy. If concomitant use is unavoidable, double the current dose of pralsetinib starting on day 7 of coadministration. After phenytoin has been discontinued for at least 14 days, resume the pralsetinib dose taken prior to initiating phenytoin. Pralsetinib is a CYP3A substrate and phenytoin is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the pralsetinib AUC by 68%.
Pramlintide: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Praziquantel: (Contraindicated) The concomitant use of phenytoin with praziquantel is contraindicated due to decreased exposure and efficacy of praziquantel. If treatment with praziquantel is necessary, treatment with phenytoin should be discontinued 4 weeks before administration of praziquantel. Treatment with phenytoin can then be restarted 1 day after completion of praziquantel treatment. Phenytoin is a strong CYP3A4 inducer and praziquantel is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of praziquantel. In a crossover study with a 2-week washout period, administration of praziquantel followed by another strong CYP3A inducer resulted in undetectable plasma concentrations of praziquantel in 7 out of 10 subjects. When praziquantel was administered two weeks after discontinuation of the strong inducer, the mean praziquantel AUC and Cmax were 23% and 35% lower, respectively, than when praziquantel was given alone.
Prednisolone: (Moderate) Monitor for decreased corticosteroid efficacy if prednisolone is used with phenytoin; a dosage increase may be necessary. Concurrent use may decrease the exposure of prednisolone. Prednisolone is a CYP3A substrate and phenytoin is a strong CYP3A inducer.
Prednisone: (Moderate) Monitor for decreased corticosteroid efficacy if prednisone is used with phenytoin; a dosage increase may be necessary. Concurrent use may decrease the exposure of prednisone. Prednisone is a CYP3A substrate and phenytoin is a strong CYP3A inducer.
Pretomanid: (Major) Avoid coadministration of pretomanid with phenytoin as concurrent use may decrease pretomanid exposure which may lead to decreased efficacy; concurrent use may also increase the risk for hepatotoxicity. Monitor for evidence of hepatotoxicity if coadministration is necessary. If new or worsening hepatic dysfunction occurs, discontinue hepatotoxic medications. Pretomanid is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased pretomanid exposure by 66%.
Prilocaine: (Moderate) Coadministration of prilocaine with oxidizing agents, such as phenytoin, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Prilocaine; Epinephrine: (Moderate) Coadministration of prilocaine with oxidizing agents, such as phenytoin, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Primidone: (Moderate) Barbiturates can stimulate the hydroxylating enzyme that metabolizes phenytoin or, conversely, may inhibit phenytoin (or fosphenytoin) metabolism. In general, therapeutic doses of phenobarbital induce the hepatic metabolism of phenytoin, producing lower phenytoin serum concentrations. Large doses of phenobarbital, however, tend to increase phenytoin serum concentrations due to competition for hepatic pathways. Thus, phenytoin serum concentrations can increase, decrease, or not change during concomitant therapy with barbiturates. Conversely, phenytoin can increase serum concentrations of the barbiturate, however this has not been as well studied. Similar interactions may occur with ethotoin, although specific data are lacking.
Prochlorperazine: (Moderate) Monitor phenytoin concentrations during concomitant therapy with phenytoin and phenothiazines; a phenytoin dosage decrease may be necessary. Phenothiazines may inhibit the metabolism of phenytoin.
Progesterone: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Progestins: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Promethazine: (Moderate) Monitor phenytoin concentrations during concomitant therapy with phenytoin and phenothiazines; a phenytoin dosage decrease may be necessary. Phenothiazines may inhibit the metabolism of phenytoin.
Promethazine; Dextromethorphan: (Moderate) Monitor phenytoin concentrations during concomitant therapy with phenytoin and phenothiazines; a phenytoin dosage decrease may be necessary. Phenothiazines may inhibit the metabolism of phenytoin.
Promethazine; Phenylephrine: (Moderate) Monitor phenytoin concentrations during concomitant therapy with phenytoin and phenothiazines; a phenytoin dosage decrease may be necessary. Phenothiazines may inhibit the metabolism of phenytoin.
Propranolol: (Minor) Phenytoin is an inducer of hepatic enzymes, and has been shown to accelerate the hepatic metabolism of propranolol.
Propranolol; Hydrochlorothiazide, HCTZ: (Minor) Phenytoin is an inducer of hepatic enzymes, and has been shown to accelerate the hepatic metabolism of propranolol.
Protriptyline: (Moderate) Tricyclic antidepressants (TCA), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently. In addition, hydantoins may increase TCA metabolism.
Pyridoxine, Vitamin B6: (Minor) Limited data suggests that large doses (greater than 80 mg per day) of pyridoxine, vitamin B6 may result in reduced serum phenytoin concentrations. Regular doses, such as in multivitamins, probably will have little effect. Monitor for reduced serum phenytoin concentrations or changes in seizure control if large doses of pyridoxine, vitamin B6 are coadminsitered.
Quazepam: (Moderate) Hydantoins are hepatic inducers and can theoretically increase the clearance of benzodiazepines metabolized by oxidative metabolism, leading to lower benzodiazepine concentrations.
Quetiapine: (Major) Increase the dose of quetiapine by up to 5-fold if coadministered with phenytoin. Coadministration may significantly decrease quetiapine exposure leading to reduced efficacy. If phenytoin is discontinued, reduce the quetiapine dose to the original level in 7 to 14 days. Quetiapine is a sensitive CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with phenytoin increased the mean oral clearance of quetiapine by 5-fold.
Quinidine: (Major) Quinidine is eliminated primarily via hepatic metabolism, primarily by the CYP3A4 isoenzyme. Inducers of CYP3A4, such as fosphenytoin or phenytoin, may increase hepatic elimination of quinidine and decrease its serum concentrations. Quinidine concentrations should be monitored closely after the anticonvulsant is added to the treatment regimen. No special precautions appear necessary if these agents are begun several weeks before quinidine is added but quinidine doses may require adjustment if one of these agents is added or discontinued during quinidine therapy.
Quinine: (Minor) Concomitant administration of phenytoin with quinine may decrease plasma quinine concentrations. Phenytoin is a CYP3A4 inducer, and quinine is a CYP3A4 substrate.
Quizartinib: (Major) Avoid concomitant use of phenytoin with quizartinib due to the risk of decreased quizartinib exposure which may reduce its efficacy. Quizartinib is a CYP3A substrate and phenytoin is a strong CYP3A inducer.
Rabeprazole: (Moderate) Some manufacturers recommend avoiding the coadministration of hepatic cytochrome P-450 enzyme inducers and proton pump inhibitors (PPIs). Phenytoin induces hepatic cytochrome P-450 enzymes, including those responsible for the metabolism of PPIs (e.g., CYP3A4, CYP2C19). A reduction in PPI concentrations may increase the risk of gastrointestinal (GI) adverse events such as GI bleeding. If phenytoin and PPIs must be used together, monitor the patient closely for signs and symptoms of GI bleeding or other signs and symptoms of reduced PPI efficacy.
Raltegravir: (Major) Coadministration of phenytoin with raltegravir is not recommended. Raltegravir is a substrate of uridine diphosphate glucuronosyltransferase (UGT) 1A1; phenytoin is a strong UGT1A1 inducer. Although not specifically studied with phenytoin, other strong UGT1A1 inducers have been shown to decrease plasma concentrations of raltegravir, which may lead to HIV treatment failure or to the development of viral resistance.
Ranolazine: (Contraindicated) Ranolazine is contraindicated in patients receiving drugs known to be CYP3A inducers including phenytoin. Induction of CYP3A metabolism could lead to decreased ranolazine plasma concentrations and decreased efficacy.
Red Yeast Rice: (Moderate) Since certain red yeast rice products (i.e., pre-2005 Cholestin formulations) contain lovastatin, clinicians should use red yeast rice cautiously in combination with drugs known to interact with lovastatin. CYP3A4 inducers can theoretically reduce the effectiveness of HMG-CoA reductase activity via induction of CYP3A4 metabolism. Examples of CYP3A4 inducers include phenytoin.
Regorafenib: (Major) Avoid coadministration of regorafenib with phenytoin due to decreased plasma concentrations of regorafenib and increased plasma concentrations of the M-5 active metabolite, which may lead to decreased efficacy. Regorafenib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the mean AUC of regorafenib by 50% and increased the mean AUC of M-5 by 264%; no change in the mean AUC of M-2 was observed.
Relugolix: (Major) Avoid concurrent use of relugolix and phenytoin. Concurrent use may decrease relugolix exposure and compromise the efficacy of relugolix therapy. If concurrent use is unavoidable, increase the relugolix maintenance dose to 240 mg once daily. If phenytoin is discontinued resume the recommended relugolix treatment dose of 120 mg once daily. Relugolix is a P-glycoprotein (P-gp) and CYP3A substrate and phenytoin is a P-gp and strong CYP3A inducer. Concurrent use of another P-gp and strong CYP3A inducer decreased relugolix overall exposure by 55%.
Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concurrent use of relugolix and phenytoin. Concurrent use may decrease relugolix exposure and compromise the efficacy of relugolix therapy. If concurrent use is unavoidable, increase the relugolix maintenance dose to 240 mg once daily. If phenytoin is discontinued resume the recommended relugolix treatment dose of 120 mg once daily. Relugolix is a P-glycoprotein (P-gp) and CYP3A substrate and phenytoin is a P-gp and strong CYP3A inducer. Concurrent use of another P-gp and strong CYP3A inducer decreased relugolix overall exposure by 55%. (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Remifentanil: (Moderate) Additive CNS depression could be seen with the combined use of the hydantoin and opiate agonists. Methadone is a primary substrate for the CYP3A4 isoenzyme. Serum concentrations of methadone may decrease due to CYP3A4 induction by phenytoin; withdrawal symptoms may occur.
Repaglinide: (Moderate) Coadministration of repaglinide with hydantoins may increase or decrease blood glucose; if coadministration is necessary, repaglinide dosage adjustment may be required and an increased frequency of glucose monitoring is recommended. Hydantoins are potent CYP3A4 inducers and repaglinide is a CYP3A4 substrate. In addition, phenytoi n and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically.
Ribociclib: (Major) Avoid coadministration of phenytoin with ribociclib due to decreased ribociclib exposure resulting decreased efficacy. Ribociclib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ribociclib exposure in healthy subjects by 89%.
Ribociclib; Letrozole: (Major) Avoid coadministration of phenytoin with ribociclib due to decreased ribociclib exposure resulting decreased efficacy. Ribociclib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ribociclib exposure in healthy subjects by 89%.
Rifabutin: (Moderate) Drugs that induce hepatic microsomal enzymes, particularly those drugs that increase CYP2C9 or CYP2C19 metabolism, such as rifamycins, can accelerate hydantoin anticonvulsant clearance.
Rifampin: (Major) Rifampin is a potent inducer of the cytochrome P-450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of the phenytoin.
Rilpivirine: (Contraindicated) Concurrent use of phenytoin or fosphenytoin and rilpivirine is contraindicated. When these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Phenytoin is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
Riluzole: (Moderate) Monitor for signs and symptoms of hepatic injury and decreased riluzole efficacy during coadministration of riluzole and phenytoin. Concomitant use may increase the risk for hepatotoxicity and may result in decreased riluzole efficacy. In vitro findings suggest decreased riluzole exposure is likely. Riluzole is a CYP1A2 substrate and phenytoin is a CYP1A2 inducer.
Rimegepant: (Major) Avoid coadministration of rimegepant with phenytoin; concurrent use may significantly decrease rimegepant exposure which may result in loss of efficacy. Rimegepant is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration of rimegepant with another strong CYP3A4 inducer decreased rimegepant exposure by 80%.
Riociguat: (Moderate) Coadministration of riociguat with phenytoin or fosphenytoin may significantly reduce riociguat exposure; however, riociguat dosage adjustment recommendations are not available. Riociguat is a CYP3A4 substrate and phenytoin and fosphenytoin are strong CYP3A4 inducers.
Ripretinib: (Major) Avoid coadministration of ripretinib with phenytoin. Coadministration may decrease the exposure of ripretinib and its active metabolite (DP-5439), which may decrease ripretinib anti-tumor activity. Ripretinib and DP-5439 are metabolized by CYP3A4 and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased ripretinib exposure by 61% and decreased DP-5439 exposure by 57%.
Risperidone: (Moderate) Monitor for a decrease in risperidone efficacy during concomitant use of risperidone and phenytoin and increase risperidone dosage as appropriate based on response. For patients receiving long-acting risperidone dosage forms, supplemental oral risperidone may be required. Concomitant use may decrease risperidone exposure. Risperidone is a CYP3A substrate and phenytoin is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced risperidone overall exposure by 50%.
Ritlecitinib: (Moderate) Monitor for a decrease in ritlecitinib efficacy during concomitant use of ritlecitinib and phenytoin/fosphenytoin. Concomitant use may decrease ritlecitinib exposure. Ritlecitinib is a CYP3A substrate and phenytoin is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced ritlecitinib overall exposure by 0.56-fold.
Ritonavir: (Major) Avoid concomitant use of ritonavir and hydantoins. Concomitant use may decrease the exposure of ritonavir and hydantoins, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the hydantoin. A dose increase of the hydantoin may be necessary. Ritonavir is a CYP3A substrate and inducer and hydantoins are CYP3A inducers.
Rivaroxaban: (Major) Avoid concomitant use of rivaroxaban with drugs that are combined P-glycoprotein and strong CYP3A4 inducers such as phenytoin. Consider increasing the rivaroxaban dose if phenytoin must be coadministered. In a drug interaction study, coadministration of rivaroxaban 20 mg single dose with food with a drug that is a combined P-glycoprotein and strong CYP3A4 inducer (rifampicin titrated up to 600 mg once daily) led to an approximate decrease of 50% in AUC and an approximate decrease of 22% in Cmax. Similar decreases in pharmacodynamic effects were also observed. These decreases in exposure to rivaroxaban may decrease efficacy.
Rocuronium: (Moderate) Concomitant use of neuromuscular blockers and phenytoin may increase resistance to the neuromuscular blockade action of neuromuscular blockers, resulting in shorter durations of neuromuscular blockade and higher infusion rate requirements. The use of a peripheral nerve stimulator is strongly recommended to evaluate the level of neuromuscular blockade, to assess the need for additional doses of neuromuscular blocker, and to determine whether adjustments need to be made to the dose with subsequent administration.
Roflumilast: (Major) Coadministration of phenytoin and roflumilast is not recommended, as significantly reduced systemic exposure to roflumilast is expected. Phenytoin is a strong CYP3A4 inducer; roflumilast is a CYP3A4 substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving another strong CYP3A4 inducer, rifampicin, resulted in decreased roflumilast Cmax and AUC, as well as increased Cmax and decreased AUC of the active metabolite roflumilast N-oxide.
Rolapitant: (Major) Avoid the use of rolapitant with chronic administration of phenytoin. Rolapitant is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. When another strong CYP3A4 inducer, rifampin (600 mg once daily), was administered for 7 days before and 7 days after a single dose of rolapitant (180 mg), the mean Cmax and AUC of rolapitant were decreased by 30% and 85%, respectively; additionally, the mean half-life decreased from 176 hours to 41 hours. Significantly reduced plasma concentrations and decreased half-life can decrease the efficacy of rolapitant.
Romidepsin: (Major) The concomitant use of romidepsin, a CYP3A4 substrate, and phenytoin, a strong CYP3A4 inducer, may result in significantly altered romidepsin plasma exposure. Therefore, avoid using romidepsin with potent CYP3A4 inducers if possible.
Ropivacaine: (Moderate) Coadministration of ropivacaine with oxidizing agents, such as phenytoin, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue ropivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Rucaparib: (Moderate) Monitor for an increase in phenytoin-related adverse reactions if coadministration with rucaparib is necessary. Phenytoin is a CYP2C9 and CYP2C19 substrate. Rucaparib is a weak inhibitor of both of these isoenzymes. Concomitant use may increase plasma concentrations of phenytoin.
Rufinamide: (Moderate) A population pharmacokinetic analysis showed an increase of 7 to 21% in phenytoin concentrations and a decrease of 25 to 46% in rufinamide concentrations during concurrent use. A similar interaction may be expected to occur with fosphenytoin.
Ruxolitinib: (Moderate) Monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy if coadministered with phenytoin; decreased ruxolitinib exposure is possible. Ruxolitinib is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer. Coadministration of another strong CYP3A4 inducer decreased ruxolitinib Cmax and AUC by 32% and 61%, respectively. The relative exposure to ruxolitinib's active metabolites increased approximately 100%.
Salicylates: (Minor) Large doses of salicylates can displace phenytoin from plasma protein-binding sites. Although increased serum concentrations of unbound phenytoin may lead to phenytoin toxicity, the liver may also more rapidly clear unbound drug. Displacement of phenytoin from binding sites can lead to a decrease in the total phenytoin serum concentration. Close monitoring for excessive phenytoin toxicity or decreased phenytoin efficacy is recommended.
Saquinavir: (Major) Complex interactions may occur when phenytoin or fosphenytoin are administered to patients receiving treatment for HIV infection. The combination regimens used to treat HIV often include substrates, inducers, and inhibitors of several CYP isoenzymes. An alternative anticonvulsant should be considered when possible. If phenytoin is used in patients being treated for HIV, the patient must be closely monitored for antiviral efficacy and seizure control; appropriate dose adjustments for phenytoin or the antiretroviral medications are unknown. Phenytoin will likely increase the metabolism of anti-retroviral protease inhibitors (PIs), leading to decreased antiretroviral efficacy. In addition, PIs may inhibit the CYP metabolism of phenytoin, resulting in increased phenytoin concentrations.
Sarilumab: (Moderate) Monitor phenytoin concentrations and watch for decreased efficacy of phenytoin if coadministration with sarilumab is necessary; adjust phenytoin dosage as necessary. Inhibition of IL-6 signaling by sarilumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as phenytoin, may have fluctuations in drug levels and therapeutic effect when sarilumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping sarilumab. In vitro, sarilumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Phenytoin is a substrate of both CYP2C9 and CYP2C19 and narrow therapeutic index drug.
Saxagliptin: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Secobarbital: (Moderate) Barbiturates can stimulate the hydroxylating enzyme that metabolizes phenytoin or, conversely, may inhibit phenytoin (or fosphenytoin) metabolism. In general, therapeutic doses of phenobarbital induce the hepatic metabolism of phenytoin, producing lower phenytoin serum concentrations. Large doses of phenobarbital, however, tend to increase phenytoin serum concentrations due to competition for hepatic pathways. Thus, phenytoin serum concentrations can increase, decrease, or not change during concomitant therapy with barbiturates. Conversely, phenytoin can increase serum concentrations of the barbiturate, however this has not been as well studied. Similar interactions may occur with ethotoin, although specific data are lacking.
Secukinumab: (Moderate) If secukinumab is initiated or discontinued in a patient taking phenytoin, monitor phenytoin concentrations; phenytoin dose adjustments may be needed. The formation of CYP450 enzymes may be altered by increased concentrations of cytokines during chronic inflammation. Thus, the formation of CYP450 enzymes could be normalized during secukinumab administration. In theory, clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as phenytoin.
Segesterone Acetate; Ethinyl Estradiol: (Major) Women taking both progestins and hydantoins should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of non-hormonal contraception should be considered in patients prescribed hydantoins. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of hydantoins. Patients taking progestins for other indications may need to be monitored for reduced clinical effect while on hydantoins, with dose adjustments made based on clinical efficacy. Hydantoins are strong hepatic CYP450 inducers. Concurrent administration may increase progestin elimination This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Selegiline: (Moderate) Monitor for a decrease in selegiline efficacy if coadministered with phenytoin. Although adequate studies have not been conducted, concurrent use may decrease selegiline exposure. Selegiline is a CYP3A substrate and phenytoin is a strong CYP3A inducer.
Selpercatinib: (Major) Avoid coadministration of selpercatinib and phenytoin due to the risk of decreased selpercatinib exposure which may reduce its efficacy. Selpercatinib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased selpercatinib exposure by 87%.
Selumetinib: (Major) Avoid coadministration of selumetinib and phenytoin due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased selumetinib exposure by 51%.
Semaglutide: (Moderate) Consider increased clinical or laboratory monitoring for oral phenytoin administered with oral semaglutide as the absorption of phenytoin may be altered. Semaglutide delays gastric emptying and therefore has the potential to affect absorption of other orally administered medications. Be sure to administer oral semaglutide as directed, separately from other oral medications. This absorption interaction does not occur with subcutaneous semaglutide or IV phenytoin. Patients should also be monitored for worsening of glycemic control when any form of systemic phenytoin is initiated in patients receiving antidiabetic agents, including semaglutide. Phenytoin has been reported to cause hyperglycemia.
Sertraline: (Moderate) Monitor phenytoin concentrations during concomitant sertraline use; a phenytoin dosage adjustment may be necessary. Sertraline may increase phenytoin concentrations.
Sevelamer: (Moderate) Although drug interaction studies have not been conducted, it may be prudent to separate the timing of administration of phenytoin from sevelamer. According to the manufacturer of sevelamer, clinicians should consider separating the timing of administration of sevelamer and drugs where a reduction in the bioavailability of would have a clinically significant effect on its safety or efficacy. The duration of separation should be based on the absorption characteristics of the coadministered drug. Because phenytoin has a narrow therapeutic index, consider monitoring clinical response and serum concentrations during concurrent use of sevelamer.
Sevoflurane: (Moderate) Caution is advised with the concomitant use of sevoflurane and phenytoin as concurrent use may increase the risk of hepatotoxicity.
Sildenafil: (Moderate) Monitor for decreased efficacy of sildenafil if coadministration with phenytoin is necessary as concurrent use may decrease sildenafil exposure. Sildenafil is a sensitive CYP3A substrate and phenytoin is a strong CYP3A inducer. Concomitant administration of strong CYP3A inducers is expected to substantially decrease plasma concentrations of sildenafil.
Siltuximab: (Moderate) Monitor phenytoin concentrations and watch for decreased efficacy of phenytoin if coadministration with siltuximab is necessary; adjust phenytoin dosage as necessary. Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as phenytoin, may have fluctuations in drug levels and therapeutic effect when siltuximab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping siltuximab. In vitro, siltuximab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Phenytoin is a substrate of both CYP2C9 and CYP2C19 and narrow therapeutic index drug.
Simvastatin: (Moderate) Monitor for a decrease in simvastatin efficacy if concomitant use with phenytoin is necessary. Concomitant use may decrease simvastatin exposure. Simvastatin is a CYP3A substrate and phenytoin is a strong CYP3A inducer.
Siponimod: (Major) Concomitant use of siponimod and phenytoin is not recommended due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; phenytoin is a moderate CYP2C9/strong CYP3A4 dual inducer. Coadministration with another moderate CYP2C9/strong CYP3A4 dual inducer decreased siponimod exposure by 57%.
Sirolimus: (Major) Avoid concomitant use of sirolimus and phenytoin/fosphenytoin as use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A and P-gp substrate and phenytoin/fosphenytoin is a strong CYP3A and P-gp inducer. Concomitant use of another strong CYP3A and P-gp inducer decreased sirolimus overall exposure by 82%.
Sitagliptin: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Sodium Bicarbonate: (Moderate) Because the absorption of phenytoin suspension can be reduced by antacids containing magnesium, aluminum, or calcium, administration at the same time of day should be avoided when possible. Ingestion times of phenytoin capsules and calcium antacids should be staggered in patients with low serum phenytoin levels to prevent absorption difficulties. Studies evaluating the effects of magnesium-aluminium antacids on the absorption of phenytoin capsules or tablets have yielded conflicting results. Nevertheless, serum phenytoin levels and clinical response should be closely monitored if these agents are co-administered. The mechanisms by which antacids reduce phenytoin absorption may involve increased gastric transit time, chelation, adsorption, and/or altered solubility. The oral absorption of phenytoin may be reduced by calcium carbonate (e.g., as found in antacids) or other calcium salts. Calcium products may form complexes with phenytoin that are nonabsorbable. Although the magnitude of the interaction is not great, an occasional patient may be affected and the interaction may lead to subtherapeutic phenytoin concentrations. Separating the administration of phenytoin and antacids or calcium salts by at least 2 hours will help minimize the possibility of interaction.
Sodium Oxybate: (Moderate) In primates, sodium oxybate blood levels were elevated with phenytoin pretreatment. The clinical relevance of these pharmacokinetic changes have not been evaluated.
Sofosbuvir: (Major) Avoid coadministration of sofosbuvir with inducers of P-glycoprotein (P-gp), such as phenytoin. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy.
Sofosbuvir; Velpatasvir: (Major) Avoid coadministration of sofosbuvir with inducers of P-glycoprotein (P-gp), such as phenytoin. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of velpatasvir with inducers of P-glycoprotein (P-gp) and CYP3A4, such as phenytoin. Taking these drugs together may significantly decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid coadministration of sofosbuvir with inducers of P-glycoprotein (P-gp), such as phenytoin. Taking these drugs together may decrease sofosbuvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of velpatasvir with inducers of P-glycoprotein (P-gp) and CYP3A4, such as phenytoin. Taking these drugs together may significantly decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of voxilaprevir with inducers of P-glycoprotein (P-gp) and CYP3A4, such as phenytoin. Taking these drugs together may significantly decrease voxilaprevir plasma concentrations, potentially resulting in loss of antiviral efficacy. Voxilaprevir is metabolized by P-gp and CYP3A4.
Sonidegib: (Major) Avoid the concomitant use of sonidegib and phenytoin; sonidegib exposure may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the geometric mean Cmax and AUC of sonidegib by 54% and 72%, respectively.
Sorafenib: (Major) Avoid coadministration of sorafenib with phenytoin due to decreased plasma concentrations of sorafenib. Sorafenib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased sorafenib exposure by 37%.
Sotagliflozin: (Moderate) Monitor for a decrease in sotagliflozin efficacy during concomitant use of sotagliflozin and phenytoin and adjust therapy as appropriate. Concomitant use may decrease sotagliflozin exposure. Sotagliflozin is a UGT substrate and phenytoin is a UGT inducer. Concomitant use with another UGT inducer reduced sotagliflozin overall exposure by 45%.
Sotorasib: (Major) Avoid concurrent use of sotorasib and phenytoin. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. Sotorasib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of sotorasib by 51%.
Sparsentan: (Major) Avoid concomitant use of sparsentan and phenytoin/fosphenytoin due to the risk for decreased sparsentan exposure which may reduce its efficacy. Sparsentan is a CYP3A substrate and phenytoin/fosphenytoin is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer is predicted to decrease sparsentan overall exposure by 47%.
St. John's Wort, Hypericum perforatum: (Major) Avoid if possible; St. John's wort could decrease the efficacy of hydantoins metabolized by CYP450 enzymes, including hydantoins as St. John's wort induces CYP2C9 and other CYP450 enzymes. Clinicians should observe patients closely if St. John's wort is used; careful monitoring of anticonvulsant drug concentrations may be needed.
Stiripentol: (Major) Avoid coadministration of stiripentol with phenytoin. If concurrent use is necessary, increase the dose of stiripentol. Coadministration may decrease stiripentol plasma concentrations resulting in a decrease in efficacy. Stiripentol is metabolized by CYP3A4, CYP1A2, and CYP2C19; phenytoin is a strong inducer of CYP3A4, and an inducer of CYP1A2 and CYP2C19.
Succinylcholine: (Moderate) Concomitant use of neuromuscular blockers and phenytoin may increase resistance to the neuromuscular blockade action of neuromuscular blockers, resulting in shorter durations of neuromuscular blockade and higher infusion rate requirements. The use of a peripheral nerve stimulator is strongly recommended to evaluate the level of neuromuscular blockade, to assess the need for additional doses of neuromuscular blocker, and to determine whether adjustments need to be made to the dose with subsequent administration.
Sucralfate: (Moderate) Sucralfate, because it contains aluminum in its structure and due to its mechanism of action, can bind with certain drugs in the GI tract, including phenytoin, reducing the bioavailability of these agents. Sucralfate should be given 2 hours before or after the oral administration of these agents. Be alert to altered clinical response to phenytoin and monitor blood concentrations as clinically indicated.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if phenytoin must be administered. Monitor for reduced efficacy of sufentanil injection and signs of opioid withdrawal if coadministration with phenytoin is necessary; consider increasing the dose of sufentanil injection as needed. If phenytoin is discontinued, consider a dose reduction of sufentanil injection and frequently monitor for signs or respiratory depression and sedation. Sufentanil is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease sufentanil concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Moderate) Monitor phenytoin concentrations during concomitant therapy with sulfamethoxazole due to risk for phenytoin toxicity. Concomitant use may increase phenytoin concentrations. Phenytoin is a CYP2C9 substrate and sulfamethoxazole is a CYP2C9 inhibitor. (Moderate) Monitor phenytoin concentrations during concomitant therapy with trimethoprim due to risk for phenytoin toxicity. Concomitant use may increase phenytoin concentrations. Trimethoprim may inhibit the hepatic metabolism of phenytoin. Trimethoprim, given at a common clinical dosage, increased the phenytoin half-life by 51% and decreased the phenytoin metabolic clearance rate by 30%.
Sulfonylureas: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. In addition, coadministration may result in decreased serum concentrations of chlorpropamide. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Sumatriptan; Naproxen: (Minor) Naproxen is 99% bound to albumin. Thus, naproxen may displace other highly protein bound drugs from albumin or vice versa. If naproxen is used concurrently with hydantoins, monitor patients for toxicity from either drug.
Sunitinib: (Major) Avoid coadministration of phenytoin with sunitinib if possible due to decreased exposure to sunitinib which could decrease efficacy. If concomitant use is unavoidable, consider increasing the daily dose of sunitinib to a maximum of 87.5 mg for patients with GIST or RCC, and to a maximum of 62.5 mg for patients with pNET; monitor carefully for toxicity. Sunitinib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased exposure to sunitinib and its primary active metabolite by 46%.
Suvorexant: (Moderate) Monitor for decreased efficacy of suvorexant if coadministration with phenytoin is necessary. Suvorexant is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased suvorexant exposure by 77% to 88%.
Tacrolimus: (Moderate) Phenytoin can induce the hepatic cytochrome P-450 enzyme system, thus decreasing plasma concentrations of tacrolimus. If phenytoin is added to tacrolimus, the levels of tacrolimus should be closely monitored and adjusted as needed until a new steady-state is achieved. Conversely, if phenytoin is discontinued, levels of tacrolimus could increase and result in toxicity.
Tadalafil: (Major) Avoid coadministration of tadalafil with phenytoin in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of phenytoin due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
Tamoxifen: (Major) Avoid coadministration of phenytoin with tamoxifen due to decreased exposure to tamoxifen which may affect efficacy. Tamoxifen is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of tamoxifen by 86% and 55%, respectively.
Tasimelteon: (Major) Concurrent use of tasimelteon and strong inducers of CYP3A4, such as hydantoins, should be avoided. Because tasimelteon is partially metabolized via CYP3A4, a large decrease in exposure is possible with the potential for reduced efficacy. During administration of tasimelteon with another potent inducer of CYP3A4, tasimelteon exposure decreased by about 90%.
Tazemetostat: (Major) Avoid coadministration of tazemetostat with phenytoin as concurrent use may decrease tazemetostat exposure, which may reduce its efficacy. Tazemetostat is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer.
Teduglutide: (Moderate) Teduglutide may increase absorption of phenytoin because of it's pharmacodynamic effect of improving intestinal absorption. Careful monitoring and possible dose adjustment of phenytoin is recommended.
Telmisartan; Amlodipine: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with hydantoins is necessary. Amlodipine is a CYP3A4 substrate and hydantoins are strong CYP3A4 inducers. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Temazepam: (Moderate) Hydantoins may increase the hepatic clearance of benzodiazepines. Interactions have been documented with benzodiazepines metabolized by oxidation or conjugation.
Temsirolimus: (Major) Avoid coadministration of temsirolimus and phenytoin/fosphenytoin due to the risk of decreased temsirolimus exposure which may reduce its efficacy. If concomitant use is unavoidable, consider increasing the dose of temsirolimus from 25 mg per week up to 50 mg per week. If phenytoin/fosphenytoin is discontinued, resume the original temsirolimus dose. Temsirolimus is a CYP3A4 substrate and phenytoin and fosphenytoin are strong CYP3A4 inducers. Coadministration with another strong CYP3A4 inducer did not have a significant effect on temsirolimus exposure but decreased the exposure of sirolimus (the primary and active metabolite) by 56%.
Teniposide: (Moderate) Monitor for reduced teniposide efficacy if coadministration with phenytoin is necessary; the concomitant use of teniposide and phenytoin may increase the clearance of teniposide resulting in reduced teniposide efficacy. Teniposide is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration of teniposide and enzyme-inducing antiepileptic drugs resulted in teniposide clearance values that were 2- to 3-times higher than values with teniposide alone.
Tenofovir Alafenamide: (Major) Administering tenofovir alafenamide with phenytoin is not recommended. Consider use of an alternative anticonvulsant. Taking these drugs together is expected to decrease tenofovir plasma concentrations, which may increase the potential for resistance and HIV treatment failure.
Tetracaine: (Moderate) Coadministration of tetracaine with oxidizing agents, such as phenytoin, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue tetracaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Tezacaftor; Ivacaftor: (Major) Coadministration of ivacaftor with phenytoin is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold. (Major) Do not administer tezacaftor; ivacaftor and phenytoin together; coadministration may reduce the efficacy of tezacaftor; ivacaftor. Exposure to ivacaftor is significantly decreased and exposure to tezacaftor may be reduced by the concomitant use of phenytoin, a strong CYP3A inducer; both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate). Coadministration of ivacaftor with a strong CYP3A inducer decreased ivacaftor exposure 89%.
Thalidomide: (Moderate) Avoid the concomitant use of thalidomide with other central nervous system depressants such as phenytoin due to the potential for additive sedative effects. Additionally, co-administration of thalidomide and agents that cause peripheral neuropathy such as phenytoin may increase the potential for additive neuropathy.
Theophylline, Aminophylline: (Moderate) Theophylline is primarily metabolized in the liver by the CYP1A2 isoenzyme, and also by the CYP3A4 isoenzyme. Medications that cause induction of hepatic CYP450 enzymes, such as phenytoin, ethotoin, or fosphenytoin, may increase the hepatic oxidative metabolism of theophylline or aminophylline. Theophylline doses may need to be increased if hydantoin anticonvulsants are added. More importantly, serious theophylline toxicity can result if any of these drugs are discontinued and the dose of theophylline is not correspondingly decreased. Also, theophylline may inhibit the oral absorption of phenytoin.
Thiazolidinediones: (Minor) Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
Thioridazine: (Moderate) Monitor phenytoin concentrations during concomitant therapy with phenytoin and phenothiazines; a phenytoin dosage decrease may be necessary. Phenothiazines may inhibit the metabolism of phenytoin.
Thiotepa: (Major) Avoid the concomitant use of thiotepa and phenytoin if possible; increased metabolism to the active thiotepa metabolite may result in increased thiotepa toxicity (e.g., infection, bleeding, skin toxicity). Consider an alternative agent with no or minimal potential to induce CYP3A4. If coadministration is necessary, monitor patients for signs and symptoms of thiotepa toxicity. In vitro, thiotepa is metabolized via CYP3A4 to the active metabolite, TEPA; phenytoin is a strong CYP3A4 inducer.
Thiothixene: (Major) Thiothixene, when used concomitantly with various anticonvulsants can increase CNS depression and also can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when thiothixene is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either the neuroleptic or the anticonvulsant.
Thyroid hormones: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of thyroid hormones, leading to reduced efficacy of the thyroid hormone.
Tiagabine: (Moderate) Population pharmacokinetic analyses indicate that tiagabine clearance is increased by about 60% when taken concomitantly with phenytoin (or fosphenytoin) or other hepatic enzyme-inducing antiepileptic drugs. Tiagabine had no effect on the steady-state plasma concentrations of phenytoin when evaluated in patients with epilepsy. Tiagabine does not appear to be an inducer or inhibitor of the hepatic microsomal enzyme system. Use of tiagabine WITHOUT enzyme-inducing antiepileptic drugs results in blood levels about two times those attained in the studies on which dosing recommendations for partial seizures are based. If tiagabine is used in patients that are not taking enzyme-inducing drugs, whether it be for the partial seizure indication or for other off-label uses, the dose of tiagabine must be adjusted down. Paradoxical seizures have occurred in patients receiving tiagabine for off-label (primarily psychiatric) indications; these seizures may be dose-related. However, many of these patients were also taking medications that can lower the seizure threshold and the FDA strongly discourage the use of tiagabine for off-label indications.
Ticagrelor: (Major) Avoid coadministration of ticagrelor with phenytoin due to decreased plasma concentrations of ticagrelor. Ticagrelor is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ticagrelor exposure by 86%.
Ticlopidine: (Moderate) Ticlopidine is an inhibitor of the hepatic isoenzyme CYP2C19 and has been shown to reduce the clearance of phenytoin in patients previously on a stable phenytoin dosage regimen. Hydantoin dosage adjustments may be necessary in some patients who receive ticlopidine concurrently.
Tinidazole: (Moderate) Although not reported with tinidazole, oral metronidazole, has been shown to decrease the clearance of intravenous phenytoin resulting in an increase in phenytoin plasma concentrations. Phenytoin levels should be checked regularly when tinidazole therapy is undertaken. Additionally, phenytoin is an inducer of hepatic cytochrome P450 enzymes and may accelerate the elimination of tinidazole and decrease plasma concentrations of tinidazole.
Tipranavir: (Major) Hydantoin anticonvulsants increase the metabolism of the protease inhibitors and may lead to decreased efficacy of these medications. In addition, tipranavir may inhibit the CYP metabolism of hydantoins, resulting in increased hydantoin concentrations.
Tivozanib: (Major) Avoid concomitant use of tivozanib with phenytoin due to decreased plasma concentrations of tivozanib, which may reduce its efficacy. Tivozanib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the overall exposure of tivozanib by 52%.
Tizanidine: (Minor) One case of increased phenytoin serum concentrations and associated drowsiness has been reported with the addition of tizanidine therapy. The mechanism and significance of this potential interaction with phenytoin is unknown.
Tocilizumab: (Moderate) Monitor phenytoin concentrations and watch for decreased efficacy of phenytoin if coadministration with tocilizumab is necessary; adjust phenytoin dosage as necessary. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as phenytoin, may have fluctuations in drug levels and therapeutic effect when tocilizumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Phenytoin is a substrate of both CYP2C9 and CYP2C19 and narrow therapeutic index drug.
Tofacitinib: (Major) Coadministration of tofacitinib and phenytoin is not recommended due to the potential for a loss of response or reduced clinical response to tofacitinib. Tofacitinib is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer. Tofacitinib exposure is decreased when coadministered with strong CYP3A4 inducers. In one study, the mean AUC and Cmax of tofacitinib were decreased by 84% and 74%, respectively when administered with another strong CYP3A4 inducer.
Tolvaptan: (Major) Avoid concurrent use of tolvaptan and phenytoin due to the risk for decreased tolvaptan plasma concentrations and reduced efficacy. Tolvaptan is a sensitive CYP3A substrate and phenytoin is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased tolvaptan exposure by 85%.
Topiramate: (Moderate) A dosage adjustment may be needed during coadministration of topiramate and hydantoins, closely monitor patients appropriately for increased adverse effects or altered clinical response to therapy. Serum phenytoin concentration may be needed for optimal dosage adjustments. Hydantoins have been shown to reduce topiramate serum concentrations. Topiramate may increase phenytoin concentrations through its inhibitory effects on CYP2C19. In some patients receiving phenytoin concurrently with topiramate, plasma concentrations of phenytoin were increased by 25% and topiramate plasma concentrations were decreased by 48%. These patients were generally receiving dosage regimens of phenytoin twice-daily. Other patients experienced a change of less than 10% in phenytoin plasma concentrations. A similar reaction would be expected with fosphenytoin.
Toremifene: (Major) Avoid coadministration of phenytoin with toremifene due to decreased plasma concentrations of toremifene which may result in decreased efficacy. Toremifene is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with strong CYP3A4 inducers lowers steady-state serum concentrations of toremifene. Phenytoin concentrations may also increase, as phenytoin is a CYP2C9 substrate and toremifene is a weak CYP2C9 inhibitor.
Torsemide: (Moderate) The concomitant use of phenytoin, a substrate of CYP2C9 with a narrow therapeutic range, and torsemide, a CYP2C9 inhibitor, may result in increased plasma concentrations of phenytoin. If these drugs are coadministered, monitor patients for signs of phenytoin toxicity. Monitoring phenytoin concentrations may be necessary.
Trabectedin: (Major) Avoid the concomitant use of trabectedin with phenytoin due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and phenytoin is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the systemic exposure of a single dose of trabectedin by 31% compared to a single dose of trabectedin given alone.
Tramadol: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with hydantoins is necessary; consider increasing the dose of tramadol as needed. If hydantoins are discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A substrate and hydantoins are strong CYP3A inducers. Concomitant use with CYP3A inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Tramadol; Acetaminophen: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with hydantoins is necessary; consider increasing the dose of tramadol as needed. If hydantoins are discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A substrate and hydantoins are strong CYP3A inducers. Concomitant use with CYP3A inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Trandolapril; Verapamil: (Moderate) Monitor blood pressure and heart rate if coadministration of verapamil with hydantoins is necessary. Concomitant use may decrease plasma concentrations of verapamil. Verapamil is a CYP3A4 substrate and hydantoins are strong CYP3A4 inducers.
Trazodone: (Moderate) Monitor phenytoin concentrations and consider increasing the trazodone dose based on therapeutic response when coadministered with phenytoin; a phenytoin dose adjustment may also be necessary. Concurrent use may increase serum phenytoin concentrations and decrease trazodone exposure. Trazodone is a CYP3A substrate; phenytoin is a strong CYP3A inducer. Coadministration with other strong CYP3A inducers decreased the exposure of trazodone compared to the use of trazodone alone.
Triamcinolone: (Moderate) Monitor for decreased corticosteroid efficacy if triamcinolone is used with phenytoin; a dosage increase may be necessary. Concurrent use may decrease the exposure of triamcinolone.
Triazolam: (Moderate) Monitor for withdrawal symptoms or lack of triazolam efficacy if coadministration with phenytoin/fosphenytoin is necessary. Triazolam is a CYP3A substrate and phenytoin/fosphenytoin are strong CYP3A inducers.
Triclabendazole: (Moderate) Monitor phenytoin concentrations if triclabendazole is initiated or discontinued in a patient taking phenytoin; phenytoin dose adjustments may be needed. Coadministration of triclabendazole and phenytoin may result in increased phenytoin concentrations; however, this elevation may be transient due to the short treatment duration of triclabendazole. Triclabendazole is an inhibitor of CYP2C19 in vitro and phenytoin is partially metabolized by CYP2C19.
Tricyclic antidepressants: (Moderate) Tricyclic antidepressants (TCA), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently. In addition, hydantoins may increase TCA metabolism.
Trifluoperazine: (Moderate) Monitor phenytoin concentrations during concomitant therapy with phenytoin and phenothiazines; a phenytoin dosage decrease may be necessary. Phenothiazines may inhibit the metabolism of phenytoin.
Trimethoprim: (Moderate) Monitor phenytoin concentrations during concomitant therapy with trimethoprim due to risk for phenytoin toxicity. Concomitant use may increase phenytoin concentrations. Trimethoprim may inhibit the hepatic metabolism of phenytoin. Trimethoprim, given at a common clinical dosage, increased the phenytoin half-life by 51% and decreased the phenytoin metabolic clearance rate by 30%.
Trimipramine: (Moderate) Tricyclic antidepressants (TCA), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently. In addition, hydantoins may increase TCA metabolism.
Tucatinib: (Major) Avoid coadministration of tucatinib and phenytoin due to the risk of decreased tucatinib exposure which may reduce its efficacy. Tucatinib is a CYP3A4 and CYP2C8 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with a strong CYP3A4/moderate CYP2C8 inducer decreased tucatinib exposure by 50%.
Ubrogepant: (Major) Avoid the coadministration of ubrogepant and phenytoin as concurrent use may decrease ubrogepant exposure and reduce the efficacy. Ubrogepant is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer resulted in an 80% reduction in ubrogepant exposure.
Ulipristal: (Major) Avoid administration of ulipristal with drugs that induce CYP3A4. Ulipristal is a substrate of CYP3A4 and phenytoin is a CYP3A4 inducer. Concomitant use may decrease the plasma concentration and effectiveness of ulipristal.
Upadacitinib: (Major) Coadministration of upadacitinib with phenytoin is not recommended as upadacitinib exposure may be decreased leading to reduced therapeutic effect. Upadacitinib is CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer. Concurrent use of a strong CYP3A4 inducer decreased upadacitinib exposure by 61%.
Valacyclovir: (Minor) The addition of valacyclovir to phenytoin may lead to a clinically significant decrease in phenytoin serum concentrations and loss of seizure control. Clinicians should be prepared to make adjustments in phenytoin dosing if valacyclovir therapy is added or discontinued.
Valbenazine: (Major) Co-administration of strong CYP3A4 inducers, such as Phenytoin, and valbenazine, a CYP3A4 substrate, is not recommended. Strong CYP3A4 inducers can decrease systemic exposure of valbenazine and its active metabolite compared to the use of valbenazine alone. Reduced exposure of valbenazine and its active metabolite may reduce efficacy.
Valproic Acid, Divalproex Sodium: (Moderate) Monitor valproic acid and phenytoin plasma concentrations periodically and adjust doses as needed during concomitant therapy due to risk for breakthrough seizures in persons with epilepsy. Also monitor for signs and symptoms of hyperammonemia due to an increased risk of valproate-induced hyperammonemia. Valproic acid displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. A 60% increase in the phenytoin free fraction and 30% increases in phenytoin total plasma clearance and apparent volume of distribution were observed during coadministration of valproate (400 mg 3 times daily) with phenytoin (250 mg) in normal volunteers (n = 7). Phenytoin may double the clearance of valproate.
Vandetanib: (Major) Avoid coadministration of vandetanib with phenytoin due to decreased plasma concentrations of vandetanib and increased concentrations of the active metabolite. Vandetanib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased the geometric mean AUC of vandetanib by 40%; the geometric mean AUC and Cmax of N-desmethylvandetanib increased by 266% and 414%, respectively.
Vecuronium: (Moderate) Concomitant use of neuromuscular blockers and phenytoin may increase resistance to the neuromuscular blockade action of neuromuscular blockers, resulting in shorter durations of neuromuscular blockade and higher infusion rate requirements. The use of a peripheral nerve stimulator is strongly recommended to evaluate the level of neuromuscular blockade, to assess the need for additional doses of neuromuscular blocker, and to determine whether adjustments need to be made to the dose with subsequent administration.
Vemurafenib: (Major) Avoid the concomitant use of vemurafenib and phenytoin; significantly decreased vemurafenib exposure may occur resulting in reduced vemurafenib efficacy. Consider the use of an alternative agent. If use with phenytoin cannot be avoided, increase the vemurafenib dose by 240 mg (as tolerated). If phenytoin is discontinued, the previous (lower) vemurafenib dose may be resumed 2 weeks after the last phenytoin dose. Vemurafenib is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer. In a drug interaction study, the vemurafenib AUC value decreased by 40% (90% CI, 24% to 53%) when a single 960-mg vemurafenib dose was administered with another strong CYP3A4 inducer; the vemurafenib Cmax was not changed.
Venetoclax: (Major) Avoid the concomitant use of venetoclax and phenytoin or fosphenytoin; venetoclax levels may be significantly decreased and its efficacy reduced. Venetoclax is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Consider alternative agents. In a drug interaction study in healthy subjects (n = 10), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the co-administration of multiple doses of a strong CYP3A4 inducer.
Verapamil: (Moderate) Monitor blood pressure and heart rate if coadministration of verapamil with hydantoins is necessary. Concomitant use may decrease plasma concentrations of verapamil. Verapamil is a CYP3A4 substrate and hydantoins are strong CYP3A4 inducers.
Vigabatrin: (Moderate) Vigabatrin is not significantly metabolized; however, it is an inducer of CYP2C9. Decreased exposure of drugs that are extensively metabolized by CYP2C9, such as phenytoin, may occur during concurrent use of vigabatrin. During clinical trials, average reductions in total phenytoin plasma levels of 16% to 20% were reported during concurrent use of vigabatrin. If combination therapy is indicated, determinations for dosage adjustments of phenytoin should be made on an individual basis.
Vilazodone: (Moderate) Consider increasing the dose of vilazodone up to 2-fold over 1 to 2 weeks (maximum, 80 mg per day) based on clinical response if coadministration with phenytoin is necessary for more than 14 days. After discontinuation of phenytoin, resume the previous vilazodone dose over 1 to 2 weeks. Vilazodone is primarily metabolized by CYP3A4 and phenytoin is a strong CYP3A4 inducer. Decreased plasma concentrations of vilazodone are expected if vilazodone is used concomitantly with strong CYP3A4 inducers.
Vincristine Liposomal: (Major) Avoid the concomitant use of phenytoin and vincristine. Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP 3A4 such as phenytoin may increase the metabolism of vincristine and decrease the efficacy of drug. Also, simultaneous oral or intravenous administration of phenytoin and antineoplastic chemotherapy combinations that included non-liposomal vincristine sulfate have been reported to reduce blood levels of phenytoin and to increase seizure activity. Concurrent treatment with vinca alkaloids and phenytoin has resulted in 50% decreases in phenytoin concentrations and seizures. Reduced phenytoin concentrations may be noted within 24 hours and continue for up to 10 days.
Vincristine: (Major) Avoid the concomitant use of phenytoin and vincristine. Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP 3A4 such as phenytoin may increase the metabolism of vincristine and decrease the efficacy of drug. Also, simultaneous oral or intravenous administration of phenytoin and antineoplastic chemotherapy combinations that included non-liposomal vincristine sulfate have been reported to reduce blood levels of phenytoin and to increase seizure activity. Concurrent treatment with vinca alkaloids and phenytoin has resulted in 50% decreases in phenytoin concentrations and seizures. Reduced phenytoin concentrations may be noted within 24 hours and continue for up to 10 days.
Vitamin D: (Moderate) Phenytoin and fosphenytoin can decrease the activity of vitamin D (e.g., cholecalciferol) by increasing its metabolism. In rare cases, this has caused anticonvulsant-induced rickets and osteomalacia. Vitamin D supplementation or dosage adjustments may be required in patients who are receiving chronic treatment with anticonvulsants. (Moderate) Phenytoin and fosphenytoin can decrease the activity of vitamin D (e.g., cholecalciferol, ergocalciferol) by increasing its metabolism. In rare cases, this has caused anticonvulsant-induced rickets and osteomalacia. Vitamin D supplementation or dosage adjustments may be required in patients who are receiving chronic treatment with anticonvulsants.
Voclosporin: (Major) Avoid coadministration of voclosporin with phenytoin. Coadministration may decrease voclosporin exposure resulting in decreased efficacy. Voclosporin is a sensitive CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased voclosporin exposure by 87%.
Vonoprazan; Amoxicillin: (Major) Avoid concomitant use of vonoprazan and phenytoin due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Concomitant use may also increase phenytoin concentrations. Vonoprazan is a CYP3A substrate and CYP2C19 inhibitor and phenytoin is a CYP2C19 substrate and strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of vonoprazan and phenytoin due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Concomitant use may also increase phenytoin concentrations. Vonoprazan is a CYP3A substrate and CYP2C19 inhibitor and phenytoin is a CYP2C19 substrate and strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer. (Major) Coadministration of phenytoin and clarithromycin may decrease clarithromycin serum concentrations due to CYP3A4 enzyme induction. While the 14-OH-clarithromycin active metabolite concentrations are increased, this metabolite has different antimicrobial activity compared to clarithromycin. The intended therapeutic effect of clarithromycin could be decreased. It is not clear if clarithromycin activity against other organisms would be reduced, but reduced efficacy is possible. Alternatives to clarithromycin should be considered in patients who are taking potent CYP3A4 inducers. Additionally, there have been postmarketing reports of interactions of clarithromycin and phenytoin. The clarithromycin manufacturer recommends caution if coadministered.
Vorapaxar: (Major) Avoid coadministration of vorapaxar and phenytoin. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with phenytoin, a strong CYP3A inducer.
Voriconazole: (Major) Phenytoin and fosphenytoin clearance can be decreased by drugs that significantly inhibit the cytochrome P450 2C subset of isoenzymes (e.g., CYP2C9 or 2C19), like voriconazole. In a pharmacokinetic study using volunteers, voriconazole increased the mean Cmax and AUC of phenytoin by approximately 70% and 80%, respectively. Frequent monitoring of plasma phenytoin concentrations and observation of the patient for phenytoin toxicity is recommended. In the same study, phenytoin reduced the mean Cmax and AUC of voriconazole by approximately 50% and 70%, respectively. This reduction was due to CYP3A4 or CYP2C9 induction by phenytoin. Recommendations from the manufacturer of voriconazole state that phenytoin or fosphenytoin can be given with voriconazole if the maintenance dose of voriconazole is increased to 5 mg/kg IV every 12 hours or to 400 mg PO every 12 hours (or 200 mg PO every 12 hours in patients >= 12 years old and weighing < 40 kg). This interaction has not been specifically studied with ethotoin, another hydantoin anticonvulsant.
Vortioxetine: (Major) Vortioxetine is extensively metabolized by CYP isoenzymes, primarily CYP2D6 and by CYP3A4 and other isoenzymes to a lesser extent. Therefore, the manufacturer recommends that the practitioner consider an increase in dose of vortioxetine when a strong CYP inducer, such as phenytoin or fosphenytoin, is co-administered for more than 14 days. In such cases, the maximum recommended dose of vortioxetine should not exceed three times the original dose. When the inducer is discontinued, the dose of vortioxetine should be reduced to the original level within 14 days.
Voxelotor: (Major) Avoid coadministration of voxelotor and phenytoin/fosphenytoin as concurrent use may decrease voxelotor exposure and lead to reduced efficacy. If coadministration is unavoidable, increase voxelotor dosage to 2,500 mg PO once daily in patients 12 years and older. In patients 4 to 11 years old, weight-based dosage adjustments are recommended; consult product labeling for specific recommendations. Voxelotor is a substrate of CYP3A; phenytoin/fosphenytoin is a strong CYP3A inducer. Coadministration of voxelotor with a strong CYP3A inducer is predicted to decrease voxelotor exposure by up to 40%.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with hydantoins is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Hydantoins are CYP1A2, moderate CYP2C9, and strong CYP3A4 inducers and the enantiomers of warfarin are substrates of CYP1A2/CYP2C9/CYP3A4. Additionally, an immediate interaction may occur as phenytoin can displace warfarin from protein binding sites causing rapid increases in the INR. Warfarin dosage adjustments may also be necessary on discontinuation of the anticonvulsant.
Zafirlukast: (Minor) Zafirlukast inhibits the CYP2C9 isoenzymes and should be used cautiously in patients stabilized on drugs metabolized by CYP2C9, such as phenytoin.
Zaleplon: (Moderate) Monitor for decreased efficacy when zaleplon is coadministered with phenytoin due to decreased zaleplon exposure. Zaleplon is partially metabolized by CYP3A; phenytoin is a strong CYP3A inducer. Consider using an alternative non-CYP3A substrate hypnotic in patients taking strong CYP3A inducers. Coadministration with another strong CYP3A inducer reduced zaleplon exposure by approximately 80%.
Zanubrutinib: (Major) Avoid the concomitant use of zanubrutinib and phenytoin. Coadministration may result in decreased zanubrutinib exposure and reduced efficacy. Zanubrutinib is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer. The AUC of zanubrutinib was decreased by 93% when coadministered with another strong CYP3A4 inducer.
Zidovudine, ZDV: (Minor) Coadministration with zidovudine has resulted in altered phenytoin concentrations. Reports have varied, with increased and decreased phenytoin concentrations being reported. Use combination with caution.
Ziprasidone: (Major) Hydantoins may induce hepatic microsomal enzymes, leading to increased clearance of ziprasidone. Some antipsychotics may also increase CNS depression and also may lower the seizure threshold, producing a pharmacodynamic interaction with anticonvulsants. Adequate dosages of the anticonvulsant should be continued when an antipsychotic drug is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either drug.
Zolpidem: (Major) Avoid concurrent use of zolpidem with potent CYP3A4 inducers, such as hydantoins, if possible due to the potential for decreased zolpidem exposure and potential reduction of efficacy. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during coadministration with another potent CYP3A4 inducer. Consider if an alternative sleep agent would be appropriate for the patient.
Zonisamide: (Moderate) Zonisamide is metabolized by hepatic cytochrome P450 enzyme 3A4. Inducers of CYP3A4, such as phenytoin, can reduce the systemic exposure to zonisamide by increasing the metabolism of the drug.
How Supplied
Dilantin/Dilantin Infatabs/Phenytoin Oral Tab Chew: 50mg
Dilantin/Dilantin-125/Phenytoin Oral Susp: 5mL, 125mg
Dilantin/Phenytek/Phenytoin/Phenytoin Sodium Oral Cap ER: 30mg, 100mg, 200mg, 300mg
Phenytoin/Phenytoin Sodium Intramuscular Inj Sol: 1mL, 50mg
Phenytoin/Phenytoin Sodium Intravenous Inj Sol: 1mL, 50mg
Maximum Dosage
As with all anticonvulsant-type medications, particularly those with narrow therapeutic windows, phenytoin dosage must be individualized.
Mechanism Of Action
Anticonvulsant drugs can elevate the seizure threshold and/or limit the spread of seizure discharge. Phenytoin exerts its anticonvulsant effect mainly by limiting the spread of seizure activity and reducing seizure propagation, unlike phenobarbital and carbamazepine, which elevate the seizure threshold. Because phenytoin does not elevate the seizure threshold, it is less effective against drug-induced or electroconvulsive-induced seizures. Phenytoin's anticonvulsant effects are mediated through effects on sodium channels on the neuronal cell membrane. Phenytoin exerts its anticonvulsant effects with less CNS sedation than does phenobarbital. In toxic concentrations, phenytoin is excitatory and can induce seizures. Phenytoin is also a weak antiarrhythmic. Antiarrhythmic actions are also mediated through effects on sodium channels, in this case, in Purkinje fibers.
Pharmacokinetics
Phenytoin is administered orally and parenterally. Phenytoin dosage forms are available as either phenytoin acid (chewable tablets and oral suspension) or phenytoin sodium (capsules and injection). While phenytoin acid is 100% phenytoin, phenytoin sodium is 92% phenytoin. Dosage adjustment may be necessary when switching from salt form to acid form (or vice versa) to account for this 8% difference; small changes may lead to significant serum phenytoin concentration fluctuation in some patients. Phenytoin is extensively protein bound (90% to 95% in adults); protein binding is lower in neonates and approaches adult values during later infancy. Hyperbilirubinemia, hypoalbuminemia, renal dysfunction, and uremia all decrease protein binding and increase the free fraction of phenytoin available for therapeutic action. Phenytoin distributes into all fluids in its free acid form. The mean steady state Vd of phenytoin in children and adults is about 0.75 L/kg (range 0.7 to 0.8 L/kg); however, neonates have a larger volume of distribution.
Phenytoin is primarily metabolized in the liver via CYP2C9 and to a lesser extent via CYP2C19. It exhibits non-linear, Michaelis-Menten pharmacokinetics; hepatic metabolism of phenytoin is saturable, leading to AUC values that increase disproportionately with increasing dose. Metabolism of phenytoin is also highly variable. Phenytoin is 1 of only a few drugs in which metabolic capacity can be saturated at therapeutic concentrations. Below the saturation point, phenytoin is eliminated in a linear, first-order process. Beyond the saturation point, elimination is much slower and occurs via a zero-order process. Because of this saturable metabolism, it is inaccurate to report a fixed value for phenytoin half-life; it can range from 7 to 60 hours (mean: 22 hours) in most populations, depending on dosage and various patient factors. In addition, small increases in dose can produce large increases in plasma concentrations. Maximal elimination rate (Vmax) is higher and more variable in children than in adults; therefore, children require higher doses on a mg/kg basis than adults in order to achieve the same serum concentrations. Febrile illness may increase the clearance of phenytoin by enhancing biotransformation. Phenytoin is excreted in the bile as inactive metabolites which are then reabsorbed from the intestinal tract and less than 5% is excreted unchanged in the urine.
Affected cytochrome P450 isoenzymes and drug transporters: CYP2C9, CYP2C19, CYP3A4, P-gp, UGT
Phenytoin is a potent inducer of hepatic cytochrome P450 microsomal enzymes including CYP3A4, CYP2C9, and CYP2C19 isoenzymes. However, a patient's susceptibility to enzyme-induction interactions may be influenced by factors such as age, cigarette smoking, or the presence of liver disease. Limited data suggest phenytoin is also a mild inducer of P-glycoprotein (P-gp) and induces UGT. Phenytoin is metabolized primarily by CYP2C9 (major) and CYP2C19 (minor), thus several drugs may inhibit or induce phenytoin's metabolism. Patients who are intermediate or poor metabolizers of CYP2C9 may exhibit increased phenytoin serum concentrations compared to normal metabolizers and, hence, may require reduction of the starting maintenance dose to reduce the risk of toxicity.
Oral formulations of phenytoin are generally considered to be 90% to 100% bioavailable; however, absorption rates vary for different products. In general, absorption is slow due to the poor dissolution of phenytoin in aqueous fluids. Immediate release products reach peak concentrations in 1.5 to 3 hours, whereas extended-release capsules reach peak concentrations in 4 to 12 hours. The absorption rate is also dose-dependent. For example, time to achieve peak concentration (Tmax) may occur 1 to 2 hours after a 200 mg oral dose, whereas Tmax may not be observed for up to 18 hours after an 800 mg dose. Because the absorption rate of phenytoin is dose-dependent, oral loading doses should be administered in divided doses. Extent of absorption is also multifactorial. The amount of phenytoin absorbed (AUC) in infants is less than in children and adolescents. An absorption study of enteral phenytoin (exact formulation not defined) 75 mg/m2 reported an AUC of 194 mcg/mL, 409 mcg/mL, and 809 mcg/mL in patients younger than 12 months (mean 4 months), 1 to 6 years (mean 2.9 years), and 7 to 18 years (mean 9.2 years), respectively when given without food. When doses were administered with food, AUC increased to 285 mcg/mL, 517 mcg/mL, and 918 mcg/mL, respectively. When using phenytoin oral suspension, concomitant administration with enteral nutritional products will significantly reduce phenytoin bioavailability. While food does not affect the absorption of branded Dilantin Kapseals, generic extended-release phenytoin products exhibit reduced absorption in the presence of a high-fat meal. It may be best to administer generic extended-release capsules on an empty stomach or in a consistent manner in relation to food to avoid fluctuation in bioavailability.
Intravenous RouteIntravenous (IV) phenytoin rapidly penetrates the brain, reaching peak concentrations within 10 to 30 minutes. IV administration is the preferred route for rapidly achieving therapeutic concentrations.
Intramuscular RouteAfter intramuscular (IM) administration, phenytoin is more slowly absorbed compared to oral administration; phenytoin exhibits poor water solubility and forms a depot in the muscle. Peak plasma concentrations of IM phenytoin may not be attained for up to 24 hours. The intravenous (IV) route is preferable to the IM route for rapidly producing therapeutic serum concentrations. During interchange of oral and IM routes of administration, dosage adjustments are necessary to maintain therapeutic plasma concentrations and avoid toxicity.
Pregnancy And Lactation
Phenytoin is a known teratogen, and a recognizable pattern of malformations has been observed. Congenital malformations (e.g., orofacial clefts, cardiac defects) and abnormalities characteristic of fetal hydantoin syndrome (e.g., dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities, cognitive deficits) have been observed. Several cases of malignancies, including neuroblastoma, have been reported in pediatric patients whose mothers received phenytoin during pregnancy. In a prospective, multi-center, long-term, observational study (n = 333) of fetal death and malformations during in utero exposure to monotherapy with phenytoin, carbamazepine, lamotrigine, or valproate, 10.7% of patients who received phenytoin experienced serious adverse outcomes, including fetal death or major congenital abnormalities. Serious adverse outcomes occurred in 1% of lamotrigine-treated patients, 8.2% of carbamazepine-treated patients, and 20.3% of valproate-treated patients. Fetal deaths and congenital malformations occurred in 3.6% and 7.1% of phenytoin-treated patients, respectively. Congenital malformations in the phenytoin group included agenesis of corpus callosum, ventricular septal defect, hydronephrosis and extra renal pelvis, and undescended testicle. Additionally, neonatal coagulation defects have been reported in neonates with in utero exposure to phenytoin and appear to result from drug-induced vitamin K deficiency in the fetus. Administration of vitamin K to the mother before obstetric delivery and to the neonate at birth can prevent this defect. Plasma clearance of phenytoin is generally increased during pregnancy, peaking in the third trimester and returning to baseline a few weeks or months after delivery. An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Monitor serum phenytoin concentrations periodically to guide appropriate adjustment of dosage. Postpartum, restoration of the original dose will probably be indicated. Counsel pregnant women and women of childbearing potential that use of phenytoin during pregnancy can cause fetal harm, and when appropriate, about alternative therapeutic options. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to phenytoin; information about the registry can be obtained at www.aedpregnancyregistry.org or by calling 1-888-233-2334.