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    Anticonvulsants, Hydantoins

    BOXED WARNING

    Adams-Stokes syndrome, AV block, bradycardia, bundle-branch block, cardiac arrhythmias, cardiac disease, hypotension, infusion-related reactions, intravenous administration

    Fosphenytoin is contraindicated in patients with conduction abnormalities such as sinus bradycardia, sino-atrial block, second or third degree AV block (atrioventricular block) or bundle-branch block, and Adams-Stokes syndrome because of the effect of parenteral phenytoin on ventricular automaticity. Infusion-related reactions, specifically cardiovascular risks (e.g., hypotension, cardiac arrhythmias), have been associated with rapid intravenous infusion rates. The rate of intravenous administration of fosphenytoin is critically important to avoid or limit adverse cardiovascular events; do not exceed recommended infusion rates (i.e., 150 mg PE/minute). In adults with hypotension or other cardiac disease, lower infusion rates may be considered (i.e., 25 to 50 mg PE/minute), if necessary. Careful cardiac monitoring is needed during and after administering intravenous fosphenytoin. 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. Reduction in rate of administration or discontinuation of dosing may be needed if cardiovascular adverse events occur during or following intravenous infusion. Adverse cardiovascular reactions include severe hypotension and cardiac arrhythmias. Cardiac arrhythmias have included bradycardia, heart block, QT interval prolongation, ventricular tachycardia, and ventricular fibrillation which have resulted in asystole, cardiac arrest, and death. Cardiovascular adverse events to fosphenytoin occur more often in patients who are elderly or debilitated, children (especially infants), critically ill, or those with pre-existing hypotension or severe myocardial insufficiency or cardiac disease. However, cardiac events have also been reported in adults and children without underlying cardiac disease or comorbidities and at recommended doses and infusion rates.

    DEA CLASS

    Rx

    DESCRIPTION

    Parenteral prodrug of phenytoin; hydantoin anticonvulsant
    Well absorbed via IM route; IV doses can be given at a faster rate than phenytoin
    May cause transient, infusion-related, paresthesias and pruritus; systemic adverse reactions identical to phenytoin

    COMMON BRAND NAMES

    Cerebyx

    HOW SUPPLIED

    Cerebyx/Fosphenytoin/Fosphenytoin Sodium Intramuscular Inj Sol: 1mL, 75mg
    Cerebyx/Fosphenytoin/Fosphenytoin Sodium Intravenous Inj Sol: 1mL, 75mg

    DOSAGE & INDICATIONS

    For the treatment of status epilepticus.
    Intravenous dosage

    NOTE: IV administration is preferred for rapid loading for status epilepticus since therapeutic concentrations are not reached as quickly with IM administration.

    Adults

    15 to 20 mg PE/kg/dose IV administered at a rate not to exceed 150 mg PE/minute.[25481] Patients who are intermediate or poor metabolizers of CYP2C9 should receive a standard loading dose.[59510] [59511] The full antiepileptic effect of phenytoin is not immediate; IV benzodiazepines should be given initially or concurrently. If seizures are not terminated after the initial loading dose, consider additional anticonvulsants. Some experts give an additional dose of 5 to 10 mg PE/kg IV if the initial loading dose fails to terminate seizures. Max total loading dose: 30 mg PE/kg.[25481] Continuously monitor electrocardiogram (ECG), blood pressure, and respiratory function throughout infusion until 10 to 20 minutes post-infusion (when maximal phenytoin concentrations are achieved).[28535]

    Infants, Children, and Adolescents

    15 to 20 mg PE/kg/dose IV (Max: 1,500 mg/dose) administered at a rate of 2 mg PE/kg/minute (Max rate: 150 mg PE/minute).[28535] [61569] Patients who are intermediate or poor metabolizers of CYP2C9 should receive a standard loading dose.[59510] [59511] The full antiepileptic effect of phenytoin is not immediate; IV benzodiazepines should be given initially or concurrently. If seizures are not terminated after the initial loading dose, consider additional anticonvulsants.[28535] Some experts give an additional dose of 5 to 10 mg PE/kg IV if the initial loading dose fails to terminate seizures. Max total loading dose: 30 mg PE/kg.[25481] Continuously monitor electrocardiogram (ECG), blood pressure, and respiratory function throughout infusion until 10 to 20 minutes post-infusion (when maximal phenytoin concentrations are achieved).[28535]

    Neonates

    15 to 20 mg PE/kg/dose IV administered at a rate of 2 mg PE/kg/minute (Max rate: 150 mg PE/minute).[28535] Patients who are intermediate or poor metabolizers of CYP2C9 should receive a standard loading dose.[59510] [59511] The full antiepileptic effect of phenytoin is not immediate; IV benzodiazepines should be given initially or concurrently. If seizures are not terminated after the initial loading dose, consider additional anticonvulsants. Continuously monitor electrocardiogram (ECG), blood pressure, and respiratory function throughout infusion until 10 to 20 minutes post-infusion (when maximal phenytoin concentrations are achieved).[28535]

    For the non-emergent treatment of tonic-clonic seizures or partial seizures.
    For seizure prophylaxis as a short-term phenytoin substitute when oral phenytoin administration is not possible or inappropriate.
    Intravenous or Intramuscular dosage
    Adults

    Fosphenytoin IV or IM can be substituted for oral phenytoin sodium at the same total daily dose and frequency (1 mg phenytoin = 1 mg PE fosphenytoin). IV doses should be administered at a rate no faster than 150 mg PE/minute. The total daily dose may need to be divided into 2 or more doses to maintain seizure control; some patients may require more frequent dosing. Of note, fosphenytoin solution for injection and phenytoin capsules contain phenytoin sodium, which is 92% phenytoin. Chewable tablets and suspensions contain 100% phenytoin, and dosage adjustments may be needed when switching from these formulations to fosphenytoin, as small changes in dosage may lead to significant changes in serum phenytoin concentrations.

    Infants, Children, and Adolescents

    Fosphenytoin IV or IM can be substituted for oral phenytoin sodium at the same total daily dose and frequency (1 mg phenytoin = 1 mg PE fosphenytoin). IV doses should be administered at a rate of 1 to 2 mg PE/kg/minute (Max: 100 mg PE/minute). The total daily dose may need to be divided into 2 or more doses to maintain seizure control; some patients may require more frequent dosing. Of note, fosphenytoin solution for injection and phenytoin capsules contain phenytoin sodium, which is 92% phenytoin. Chewable tablets and suspensions contain 100% phenytoin, and dosage adjustments may be needed when switching from these formulations to fosphenytoin, as small changes in dosage may lead to significant changes in serum phenytoin concentrations.

    Neonates

    Fosphenytoin IV or IM can be substituted for oral phenytoin sodium at the same total daily dose and frequency (1 mg phenytoin = 1 mg PE fosphenytoin). IV doses should be administered at a rate of 1 to 2 mg PE/kg/minute (Max: 100 mg PE/minute). The total daily dose may need to be divided into 2 or more doses to maintain seizure control; some patients may require more frequent dosing. Of note, fosphenytoin solution for injection and phenytoin capsules contain phenytoin sodium, which is 92% phenytoin. Chewable tablets and suspensions contain 100% phenytoin, and dosage adjustments may be needed when switching from these formulations to fosphenytoin, as small changes in dosage may lead to significant changes in serum phenytoin concentrations.

    For non-emergent loading doses.
    Intravenous or Intramuscular dosage
    Adults

    15 to 20 mg PE/kg IV administered at a rate not to exceed 150 mg PE/minute. 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 10 to 20 minutes post-infusion (when maximal phenytoin concentrations are achieved).

    Infants, Children, and Adolescents

    10 to 15 mg PE/kg IV or IM. Administer IV doses at a rate of 1 to 2 mg PE/kg/minute (Max rate: 150 mg PE/minute). 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 10 to 20 minutes post-infusion (when maximal phenytoin concentrations are achieved).

    Neonates

    10 to 15 mg PE/kg IV or IM. Administer IV doses at a rate of 1 to 2 mg PE/kg/minute (Max rate: 150 mg PE/minute). 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 10 to 20 minutes post-infusion (when maximal phenytoin concentrations are achieved).

    For maintenance dosing when the use of oral phenytoin is not possible.
    Intravenous or Intramuscular dosage
    Adults

    4 to 6 mg PE/kg/day IV or IM, divided into 2 or more doses, administered at a rate not to exceed 150 mg PE/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. Continuously monitor electrocardiogram (ECG), blood pressure, and respiratory function throughout infusion until 10 to 20 minutes post-infusion (when maximal phenytoin concentrations are achieved). After the initial maintenance dose, individualize subsequent maintenance doses by monitoring serum phenytoin concentrations to achieve a target therapeutic phenytoin concentration.

    Children and Adolescents

    2 to 4 mg PE/kg IV or IM every 12 hours. Administer IV doses at a rate of 1 to 2 mg PE/kg/minute (Max rate: 100 mg PE/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. Continuously monitor electrocardiogram (ECG), blood pressure, and respiratory function throughout infusion until 10 to 20 minutes post-infusion (when maximal phenytoin concentrations are achieved). After the initial maintenance dose, individualize subsequent maintenance doses by monitoring serum phenytoin concentrations to achieve a target therapeutic phenytoin concentration.

    Neonates and Infants

    2 to 4 mg PE/kg IV or IM every 12 hours. Administer IV doses at a rate of 1 to 2 mg PE/kg/minute (Max rate: 100 mg PE/minute). Term neonates older than 7 days and infants may require larger maintenance doses due to enhanced hepatic clearance seen until 1 year of age; a dosing frequency of every 8 hours may also be preferred due to increased clearance. 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. A limited number of clinical studies have been conducted in neonates; there have been case reports of neonates having difficulty maintaining therapeutic concentrations and requiring higher than usual maintenance doses (up to 10 mg PE/kg/day). Continuously monitor electrocardiogram (ECG), blood pressure, and respiratory function throughout infusion until 10 to 20 minutes post-infusion (when maximal phenytoin concentrations are achieved). After the initial maintenance dose, individualize subsequent maintenance doses by monitoring serum phenytoin concentrations to achieve a target therapeutic phenytoin concentration.

    For seizure prophylaxis or for seizure treatment during neurosurgery.
    Intravenous and Intramuscular dosage
    Adults

    The loading dose is 10 to 20 mg PE/kg IV or IM. Administer IV doses at a rate no faster than 150 mg PE/minute. The initial maintenance dose is 4 to 6 mg PE/kg/day IV or IM, divided into 2 or more doses. Patients who are intermediate or poor metabolizers of CYP2C9 should receive a standard loading dose. 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. Continuously monitor electrocardiogram (ECG), blood pressure, and respiratory function throughout infusion until 10 to 20 minutes post-infusion (when maximal phenytoin concentrations are achieved). After the initial maintenance dose, individualize subsequent maintenance doses by monitoring serum phenytoin concentrations to achieve a target therapeutic phenytoin concentration.

    Children and Adolescents

    The loading dose is 10 to 15 mg PE/kg IV or IM. Administer IV doses at a rate of 1 to 2 mg PE/kg/minute (Max rate: 150 mg PE/minute). The initial maintenance dose is 2 to 4 mg PE/kg IV or IM every 12 hours; if IV give no faster than 1 to 2 mg PE/kg/minute (Max rate: 100 mg PE/minute). Patients who are intermediate or poor metabolizers of CYP2C9 should receive a standard loading dose. 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. Continuously monitor electrocardiogram (ECG), blood pressure, and respiratory function throughout infusion until 10 to 20 minutes post-infusion (when maximal phenytoin concentrations are achieved). After the initial maintenance dose, individualize subsequent maintenance doses by monitoring serum phenytoin concentrations to achieve a target therapeutic phenytoin concentration.

    Neonates and Infants

    The loading dose is 10 to 15 mg PE/kg IV or IM. Administer IV doses at a rate of 1 to 2 mg PE/kg/minute (Max rate: 150 mg PE/minute). The initial maintenance dose is 2 to 4 mg PE/kg IV or IM every 12 hours; if IV give no faster than 1 to 2 mg PE/kg/minute (Max rate: 100 mg PE/minute). Term neonates older than 7 days and infants may require larger maintenance doses due to enhanced hepatic clearance seen until 1 year of age; a dosing frequency of every 8 hours may also be preferred due to increased clearance. Patients who are intermediate or poor metabolizers of CYP2C9 should receive a standard loading dose. 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. A limited number of clinical studies have been conducted in neonates; there have been case reports of neonates having difficulty maintaining therapeutic concentrations and requiring higher than usual maintenance doses (up to 10 mg PE/kg/day). Continuously monitor electrocardiogram (ECG), blood pressure, and respiratory function throughout infusion until 10 to 20 minutes post-infusion (when maximal phenytoin concentrations are achieved). After the initial maintenance dose, individualize subsequent maintenance doses by monitoring serum phenytoin concentrations to achieve a target therapeutic phenytoin concentration.

    MAXIMUM DOSAGE

    Adults

    Specific maximum dosage information not available; individualize dosage based on monitoring of serum phenytoin concentrations and clinical parameters.

    Geriatric

    Specific maximum dosage information not available; individualize dosage based on monitoring of serum phenytoin concentrations and clinical parameters.

    Adolescents

    Specific maximum dosage information not available; individualize dosage based on monitoring of serum phenytoin concentrations and clinical parameters.

    Children

    Specific maximum dosage information not available; individualize dosage based on monitoring of serum phenytoin concentrations and clinical parameters.

    Infants

    Specific maximum dosage information not available; individualize dosage based on monitoring of serum phenytoin concentrations and clinical parameters.

    Neonates

    Specific maximum dosage information not available; individualize dosage based on monitoring of serum phenytoin concentrations and clinical parameters.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Dosage adjustments may be required based upon serum phenytoin concentrations and clinical response. Fosphenytoin is converted to phenytoin in the systemic circulation; phenytoin is primarily metabolized in the liver. Patients with hepatic disease may have an increased fraction of unbound phenytoin. Fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance, potentially increasing the frequency and severity of adverse reactions.

    Renal Impairment

    Dosing adjustments may be required based upon serum phenytoin concentrations and clinical response. Patients with renal disease may have an increased fraction of unbound phenytoin. Fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance, potentially increasing the frequency and severity of adverse reactions. Of note, during the conversion of fosphenytoin to phenytoin, phosphate and formaldehyde are liberated. The phosphate load provided by fosphenytoin (0.0037 mmol phosphate/mg PE) should be considered when treating patients with severe renal impairment.
     
    Intermittent hemodialysis
    Phenytoin is not significantly removed during a standard hemodialysis session; therefore, supplemental dosing after hemodialysis is not necessary.

    ADMINISTRATION

    Injectable Administration

    Always express the dosage, concentration, and infusion rate of fosphenytoin in phenytoin sodium equivalents (PE).
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
    Storage: Discard any unused product from single-use vials immediately.

    Intravenous Administration

    Intermittent IV Infusion
    Prior to infusion, dilute in 5% Dextrose Injection or 0.9% Sodium Chloride Injection to a concentration ranging from 1.5 to 25 mg PE/mL.
    Because of the risk of hypotension and other side effects, the rate of IV administration is important; do not exceed recommended infusion rates.
    Continuously monitor electrocardiogram (ECG), blood pressure, and respiratory function throughout infusion until 10 to 20 minutes post-infusion (when maximal phenytoin concentrations are achieved).
    Loading doses should always be followed by maintenance doses of fosphenytoin or phenytoin. Begin maintenance dosing at the next identified dosing interval.
     
    Rate of IV Administration; do not exceed these recommended rates:
    Adults: 150 mg PE/minute.
    Elderly, debilitated adults, or adults with pre-existing hypotension or cardiac disease: 150 mg PE/minute. Consider lower infusion rates (e.g., 25 to 50 mg PE/minute).
    Pediatric patients (loading dose): 1 to 2 mg PE/kg/minute. Max: 150 mg PE/minute.
    Pediatric patients (maintenance dose): 1 to 2 mg PE/kg/minute. Max: 100 mg PE/minute.

    Intramuscular Administration

    Do not administer fosphenytoin IM for the treatment of status epilepticus, as therapeutic concentrations may not be reached as quickly as with IV administration.
    Administer undiluted.
    Inject deeply into a large muscle mass (e.g., anterolateral thigh or deltoid [deltoid for children and adolescents only]). Aspirate prior to injection to avoid injection into a blood vessel.
    Doses may be divided into smaller volumes for simultaneous administration in more than 1 site. In controlled trials, IM doses were given as a single daily dose utilizing either 1 or 2 injection sites in volumes up to 20 mL for adult patients.
    Some patients may need to receive the daily dosage of fosphenytoin in divided doses (2 or 3 times per day) to provide adequate seizure control.

    STORAGE

    Cerebyx:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Product should not be stored at room temperature for more than 48 hours
    - Refrigerate (between 36 and 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Asian patients

    Fosphenytoin is converted to phenytoin in vivo. Phenytoin may cause life-threatening rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis. HLA-B 1502, the variant allele of human leukocyte antigen B, has been associated with an increased risk of hypersensitivity in response to phenytoin treatment. HLA-B 1502 is most prevalent in Asian patients; prevalence ranges from 1% to over 10% in Oceania, East Asian, and South/Central Asian populations. It is less frequent in European populations (0 to 1%) and largely absent in African, Hispanic, and Native American populations. The FDA is evaluating preliminary data suggesting that Asian patients, specifically those with Han Chinese, Filipino, Malaysian, South Asian Indian, and Thai ancestry, who test positive for HLA-B 1502, are at an increased risk for developing these potentially fatal conditions while receiving phenytoin. A similar precaution was issued for carbamazepine with subsequent changes to the product labeling; it is now recommended that patients with ancestry in genetically at-risk populations be screened for the presence of HLA-B 1502 prior to initiating carbamazepine therapy. The strength of association between phenytoin and serious hypersensitivity reactions is weaker than that of carbamazepine and similar reactions because of the limited number of studies and observations in the literature. However, until further information becomes available, it is recommended to avoid the use of phenytoin or fosphenytoin in patients who test positive for HLA-B 1502 and are phenytoin naive, unless the benefits outweigh the risk.

    Hypoglycemia, hyponatremia, petit mal (absence) seizures

    Fosphenytoin is not effective for petit mal (absence) seizures. If tonic-clonic (grand-mal) and absence (petit mal) seizures are present, combined drug therapy is needed. Fosphenytoin and other hydantoins are not indicated for seizures due to hypoglycemia or other metabolic causes (e.g., hyponatremia). Appropriate diagnostic procedures should be performed as indicated.

    Depression, suicidal ideation

    In January 2008, the FDA alerted healthcare professionals of an increased risk of suicidal ideation and behavior in patients receiving anticonvulsants (like fosphenytoin) to treat epilepsy, psychiatric disorders, or other conditions (e.g., migraine, neuropathic pain). This alert followed an initial request by the FDA in March 2005 for manufacturers of marketed anticonvulsants to provide data from existing controlled clinical trials for analysis. Prior to this request, preliminary evidence had suggested a possible link between anticonvulsant use and suicidality. The primary analysis consisted of 199 placebo-controlled clinical studies with a total of 27,863 patients in drug treatment groups and 16,029 patients in placebo groups (>= 5 years of age). There were 4 completed suicides among patients in drug treatment groups versus none in the placebo groups. Patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) as patients receiving placebo (0.22%), corresponding to an estimated 2.1 per 1000 (95% CI: 0.7—4.2) more patients in the drug treatment groups who experienced suicidal behavior or ideation. The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions. Age was not a determining factor. The increased risk of suicidal ideation and behavior was observed between 1 and 24 weeks after therapy initiation. However, a longer duration of therapy should not preclude the possibility of an association to the drug since most studies included in the analysis did not continue beyond 24 weeks. Data were analyzed from drugs with adequately designed clinical trials including carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide. However, this is considered to be a class effect. All patients beginning treatment with anticonvulsants or currently receiving such treatment should be closely monitored for emerging or worsening suicidal thoughts/behavior or depression. Anticonvulsants should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose.

    Abrupt discontinuation

    Like other antiepileptic drugs, the abrupt discontinuation of fosphenytoin therapy can lead to increased seizure activity, including status epilepticus. Reductions in dosage, discontinuation of therapy, or substitutions in therapy should be done gradually. Some situations, however, such as allergic or hypersensitivity reactions may require rapid substitutions. In these cases, the manufacturer recommends using an antiepileptic drug not belonging to the hydantoin class.

    Barbiturate hypersensitivity, carbamazepine hypersensitivity, hydantoin hypersensitivity, succinimide hypersensitivity

    Fosphenytoin is contraindicated in patients with a hydantoin hypersensitivity (e.g., phenytoin, fosphenytoin, ethotoin). Hypersensitivity reactions to anticonvulsants may be severe and sometimes fatal. Consider an alternative to fosphenytoin if the patient or an immediate family member has a carbamazepine hypersensitivity, barbiturate hypersensitivity, succinimide hypersensitivity, or oxazolidinedione hypersensitivity.[28535] Hypersensitivity reactions to fosphenytoin have been reported in patients who previously experienced hypersensitivity to phenytoin, barbiturates, or carbamazepine. Estimates of cross-sensitivity vary but may range from 30% to 80%. Phenytoin, carbamazepine, and phenobarbital are all metabolized to hydroxylated aromatic compounds via the cytochrome P450 hepatic oxidative enzymes; arene oxide intermediates are formed during metabolism and are thought to be responsible for cross-sensitivity among these anticonvulsants in susceptible individuals. Some individuals may have a reduced ability to detoxify the intermediate toxic metabolites (e.g., arene oxides) of these anticonvulsants, which may be genetically mediated. However, studies of familial reactions have also shown that allergies to one anticonvulsant may not translate to allergies to others. There is no way to predict with certainty which patients will exhibit cross-sensitivity.[26220]

    Agranulocytosis, bone marrow suppression, hematological disease, hemolytic anemia, leukopenia, methemoglobin reductase deficiency, methemoglobinemia, neutropenia, porphyria, thrombocytopenia

    Fosphenytoin should be used with caution in patients with blood dyscrasias caused by drug therapies or hematological disease because of the potential increased risk of hematologic toxicity. Although uncommon, phenytoin can cause hematological toxicity consisting of transient leukopenia, neutropenia, thrombocytopenia, or more severe reactions like agranulocytosis or aplastic anemia. Case-control population data have demonstrated that the risk of developing these reactions is greater in patients treated with anticonvulsants than in the general population. However aplastic anemia and agranulocytosis are rare in the untreated general population (i.e., 1—2 persons per one million population per year). It would be uncommon for a patient who is taking fosphenytoin to develop a severe blood dyscrasia, even if hematologic changes occur during treatment. Pretreatment baseline hematologic counts should be obtained. Periodic hematologic testing during treatment is recommended; if a patient develops neutropenia or thrombocytopenia the patient should be closely monitored. Discontinuation of fosphenytoin should be considered if significant bone marrow suppression develops. In view of isolated reports associating phenytoin with exacerbation of porphyria, caution should be exercised in using fosphenytoin in patients suffering from this disease. Also use with caution in patients with hemolytic anemia, phenytoin is known to rarely cause hemolysis as an adverse reaction. Methemoglobinemia is rare with normal therapeutic doses of phenytoin; however, this adverse effect has occasionally been reported, especially in the setting of overdose or in patients with methemoglobin reductase deficiency.

    Hodgkin's disease, lymphoma

    Fosphenytoin is converted to phenytoin in vivo. There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local or generalized) including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin lymphoma. Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of lymph node pathology. Lymph node involvement may occur with or without symptoms and signs resembling serum sickness and liver involvement. In all cases of lymphadenopathy, follow-up observation for an extended period is indicated and every effort should be made to achieve seizure control using alternative antiepileptic drugs.

    Adams-Stokes syndrome, AV block, bradycardia, bundle-branch block, cardiac arrhythmias, cardiac disease, hypotension, infusion-related reactions, intravenous administration

    Fosphenytoin is contraindicated in patients with conduction abnormalities such as sinus bradycardia, sino-atrial block, second or third degree AV block (atrioventricular block) or bundle-branch block, and Adams-Stokes syndrome because of the effect of parenteral phenytoin on ventricular automaticity. Infusion-related reactions, specifically cardiovascular risks (e.g., hypotension, cardiac arrhythmias), have been associated with rapid intravenous infusion rates. The rate of intravenous administration of fosphenytoin is critically important to avoid or limit adverse cardiovascular events; do not exceed recommended infusion rates (i.e., 150 mg PE/minute). In adults with hypotension or other cardiac disease, lower infusion rates may be considered (i.e., 25 to 50 mg PE/minute), if necessary. Careful cardiac monitoring is needed during and after administering intravenous fosphenytoin. 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. Reduction in rate of administration or discontinuation of dosing may be needed if cardiovascular adverse events occur during or following intravenous infusion. Adverse cardiovascular reactions include severe hypotension and cardiac arrhythmias. Cardiac arrhythmias have included bradycardia, heart block, QT interval prolongation, ventricular tachycardia, and ventricular fibrillation which have resulted in asystole, cardiac arrest, and death. Cardiovascular adverse events to fosphenytoin occur more often in patients who are elderly or debilitated, children (especially infants), critically ill, or those with pre-existing hypotension or severe myocardial insufficiency or cardiac disease. However, cardiac events have also been reported in adults and children without underlying cardiac disease or comorbidities and at recommended doses and infusion rates.

    Alcoholism

    Acute alcoholic intake may increase phenytoin serum levels while chronic ethanol ingestion can induce hepatic oxidative enzymes, decreasing phenytoin serum concentrations. Such parameters may need to be considered when treating patients with a history of alcoholism or acute intermittent binge drinking. In addition, concomitant use of fosphenytoin and ethanol can decrease the ability to perform tasks requiring mental alertness.

    Hepatic disease, hepatotoxicity, hypoalbuminemia, jaundice

    Fosphenytoin is contraindicated in patients with a history of prior acute hepatotoxicity secondary to fosphenytoin or phenytoin therapy. Phenytoin-induced hepatotoxicity has been reported. Hepatotoxicity may be associated with jaundice, hepatomegaly, elevated serum transaminase levels, leukocytosis, rash, and eosinophilia; hepatotoxicity may be the result of hypersensitivity to the drug. It may be part of the spectrum of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) or may occur in isolation. Baseline and periodic evaluations of liver function, particularly in patients with a history of liver disease, must be performed during treatment. Discontinue fosphenytoin if there is evidence of new or worsening hepatotoxicity. In patients with acute hepatotoxicity, do not re-administer fosphenytoin. Use fosphenytoin cautiously in patients with hyperbilirubinemia (which may manifest clinically as jaundice). Bilirubin displaces phenytoin from protein-binding sites, resulting in increased free phenytoin concentrations. Fosphenytoin should also be used with caution in hepatic disease. Fosphenytoin is a prodrug of phenytoin; phenytoin is eliminated via hepatic metabolism. A small percentage of individuals metabolize phenytoin slowly. Slow metabolism may be due to limited enzyme availability and lack of induction; slow metabolism appears to be genetically determined. Fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance in patients with hepatic disease, potentiating the frequency and severity of adverse events. Dose adjustments may be necessary in patients with hepatic disease or genetic polymorphism. Patients with hepatic impairment may show early signs of phenytoin toxicity; serum concentrations of free phenytoin can be increased by the hypoalbuminemia commonly seen with cirrhotic liver disease.

    Driving or operating machinery, encephalopathy, psychosis

    Fosphenytoin may cause blurred vision, dizziness, drowsiness, and fatigue. Patients should be advised to use caution when driving or operating machinery, or performing other tasks that require mental alertness until they are aware of whether fosphenytoin adversely affects their mental and/or motor performance. Serum concentrations of phenytoin sustained above the optimal range may produce confusional states referred to as 'delirium,' 'psychosis,' or 'encephalopathy,' or rarely irreversible cerebellar dysfunction and/or cerebellar atrophy. Accordingly, at the first sign of acute toxicity, measuring of plasma concentrations are recommended. A dosage reduction is indicated if plasma concentrations are excessive; if symptoms persist, termination of fosphenytoin therapy is recommended.

    Renal disease, renal failure, renal impairment

    Fosphenytoin is converted to phenytoin in vivo, and also liberates formate (formaldehyde) and phosphate by-products during the conversion process. The phosphate load provided by fosphenytoin injection (0.0037 mmol phosphate/mg PE) should be considered when treating patients who require phosphate restriction, such as those with severe renal impairment or renal failure. Patients with renal failure or renal impairment leading to uremia should also be monitored for phenytoin toxicity. High serum concentrations of urea displace phenytoin from protein-binding sites. Unbound phenytoin concentrations may need to be monitored; dose adjustments may be necessary. In addition, phenytoin may rarely cause interstitial nephritis or other renal disease; occasional monitoring of renal parameters or urinalysis has been suggested for all patients.

    Dental disease, dental work

    The chronic use of fosphenytoin may cause gingival hyperplasia. Patients should be instructed on proper oral hygiene in order to minimize the development of gingival hyperplasia and its complications (e.g., dental disease). Adherence to scheduled dental work is encouraged to limit the risk of gum disease.

    Neonates, obstetric delivery, pregnancy, vitamin K deficiency

    Fosphenytoin may cause fetal harm when administered to a pregnant woman. Fosphenytoin is converted to phenytoin in vivo and produces phosphate and formate by-products. 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 (i.e., 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 born to epileptic mothers receiving 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 has been shown to prevent or correct 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, specifically the unbound fraction, 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. Encourage pregnant patients receiving phenytoin to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. Patients must call 1-888-233-2334 to enroll in the registry. Information on the registry can also be found at the website at www.aedpregnancyregistry.org.

    Breast-feeding

    It is not known whether fosphenytoin in excreted in human milk. Fosphenytoin is converted to phenytoin in vivo, and phenytoin is secreted into human milk. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for fosphenytoin and any potential adverse effects on the breast-fed infant from fosphenytoin or the underlying maternal condition. Milk to plasma ratios of phenytoin range from roughly 0.1 to 0.6. However, infant adverse events from phenytoin monotherapy have rarely been noted, and the risks to the infant are thought to be minimized if maternal serum concentrations are kept within accepted therapeutic ranges. The risk for adverse effects such as sedation in the infant appears to be higher in patients taking multiple antiepileptic drugs. Previous American Academy of Pediatrics recommendations considered phenytoin usually compatible with breast-feeding.

    Contraception requirements, reproductive risk

    Phenytoin, the active metabolite of fosphenytoin, is a known teratogen and poses a reproductive risk. Discuss contraception requirements with the patient. Women of childbearing potential who are not planning a pregnancy must use effective contraception while using fosphenytoin, acknowledging that there is a potential for decreased hormonal contraceptive efficacy.

    Diabetes mellitus

    Fosphenytoin is converted to phenytoin in vivo. Phenytoin can stimulate glucagon secretion and can impair insulin secretion. Either of these effects could cause hyperglycemia. There are case reports of hyperglycemia and even diabetic ketoacidosis occurring as a result of fosphenytoin administration. Blood sugar should be monitored closely when fosphenytoin is administered to patients with diabetes mellitus.

    Hypothyroidism, thyroid disease

    Patients with thyroid disease, especially hypothyroidism, should be monitored for signs of underactive thyroid. Fosphenytoin is converted to phenytoin in vivo. Phenytoin stimulates hepatic enzyme activity, which may cause an increased degradation of circulating concentrations of thyroid hormone (T3 and T4), with an accompanying increase in thyroid-stimulating hormone (TSH). Phenytoin reduces serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%; however, most patients are clinically euthyroid.

    Osteomalacia, osteoporosis

    Fosphenytoin is converted to phenytoin in vivo. Osteomalacia has been associated with chronic phenytoin therapy and is considered to be due to phenytoin's interference with vitamin D metabolism. There may be an increased risk of osteopenia/osteoporosis in patients on chronic fosphenytoin therapy.

    Radiation therapy

    Cranial irradiation administered to patients receiving phenytoin has been associated with erythema multiforme and/or Stevens-Johnson syndrome. Fosphenytoin should be used cautiously, if at all, in patients receiving radiation therapy.

    Myasthenia gravis

    Fosphenytoin is converted to phenytoin in vivo. Phenytoin has been reported to decrease acetylcholine receptor sensitivity; this action may exacerbate symptoms of myasthenia gravis.

    Geriatric

    Use of fosphenytoin (a prodrug for phenytoin) requires care and close monitoring in the geriatric patient. The liver is the chief site of biotransformation of phenytoin; elderly patients may show early signs of reduced biotransformation and toxicity. Phenytoin serum concentration monitoring may be necessary to guide dosage adjustments. Phenytoin serum concentrations above the optimal range may produce confusional states or cerebellar dysfunction. Risk factors for cardiovascular adverse reactions include elderly age, critically ill, pre-existing hypotension, or severe myocardial insufficiency. In geriatric or debilitated adults, consider lower fosphenytoin infusion rates (i.e., 25 to 50 mg PE/minute) to avoid or limit adverse cardiovascular events; do not exceed maximum infusion rates (e.g., 150 mg PE/minute in adults).[26240] Careful cardiac monitoring is needed during and after an infusion of fosphenytoin.[50763] According to the Beers Criteria, anticonvulsants are considered potentially inappropriate medications (PIMs) in geriatric patients with a history of falls or fractures. Avoid in at-risk patients except for treating seizure and mood disorders, since anticonvulsants can produce ataxia, impaired psychomotor function, syncope, and additional falls. If fosphenytoin must be used, consider reducing the use of other CNS-active medications that increase the risk of falls and fractures and implement strategies to reduce fall risk.[63923] The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities; the use of any anticonvulsant for any condition should be based on confirmation of the condition and its potential cause(s). Determine effectiveness and tolerability by evaluating symptoms, and use these as the basis for dosage adjustment for most patients. Therapeutic drug monitoring is available for phenytoin and periodic serum concentrations should be monitored as clinically indicated. Serum medication concentrations (when available) may assist in identifying toxicity. High or toxic serum concentrations should become a consideration for dosage adjustments. Monitor the treated patient for drug efficacy and side effects. Fosphenytoin can cause liver dysfunction, blood dyscrasias, and serious skin rashes requiring discontinuation of treatment. Anticonvulsants can cause a variety of other side effects; some adverse reactions can increase the risk of falls. When an anticonvulsant is being used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt periodic tapering of the medication or provide documentation of medical necessity as outlined in the OBRA guidelines.[60742]

    ADVERSE REACTIONS

    Severe

    cerebral edema / Early / 0.1-2.2
    hearing loss / Delayed / 0.1-2.2
    bradycardia / Rapid / 0.1-1.0
    stroke / Early / 0.1-1.0
    heart failure / Delayed / 0.1-1.0
    pulmonary embolism / Delayed / 0.1-1.0
    cardiac arrest / Early / 0.1-1.0
    atrial flutter / Early / 0.1-1.0
    cyanosis / Early / 0.1-1.0
    apnea / Delayed / 0.1-1.0
    bronchospasm / Rapid / 0.1-1.0
    pneumothorax / Early / 0.1-1.0
    GI bleeding / Delayed / 0.1-1.0
    ileus / Delayed / 0.1-1.0
    coma / Early / 0.1-1.0
    seizures / Delayed / 0.1-1.0
    proteinuria / Delayed / 0.1-1.0
    oliguria / Early / 0.1-1.0
    renal failure (unspecified) / Delayed / 0.1-1.0
    diabetes insipidus / Delayed / 0.1-1.0
    hyperkalemia / Delayed / 0.1-1.0
    suicidal ideation / Delayed / Incidence not known
    ventricular fibrillation / Early / Incidence not known
    hepatic failure / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    teratogenesis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    lupus-like symptoms / Delayed / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
    acute generalized exanthematous pustulosis (AGEP) / Delayed / Incidence not known
    skin necrosis / Early / Incidence not known

    Moderate

    gingival hyperplasia / Delayed / 50.0-50.0
    nystagmus / Delayed / 15.1-44.4
    ataxia / Delayed / 8.4-11.1
    hypotension / Rapid / 5.0-7.7
    peripheral vasodilation / Rapid / 5.6-5.6
    sinus tachycardia / Rapid / 2.2-2.2
    dysarthria / Delayed / 1.0-2.2
    hyperesthesia / Delayed / 2.2-2.2
    amblyopia / Delayed / 2.2-2.2
    hostility / Early / 0.1-1.0
    confusion / Early / 0.1-1.0
    psychosis / Early / 0.1-1.0
    depression / Delayed / 0.1-1.0
    amnesia / Delayed / 0.1-1.0
    QT prolongation / Rapid / 0.1-1.0
    palpitations / Early / 0.1-1.0
    bundle-branch block / Early / 0.1-1.0
    orthostatic hypotension / Delayed / 0.1-1.0
    elevated hepatic enzymes / Delayed / 0.1-1.0
    leukopenia / Delayed / 0.1-1.0
    thrombocytopenia / Delayed / 0.1-1.0
    anemia / Delayed / 0.1-1.0
    myopathy / Delayed / 0.1-1.0
    hypoxia / Early / 0.1-1.0
    hemoptysis / Delayed / 0.1-1.0
    dyspnea / Early / 0.1-1.0
    gastritis / Delayed / 0.1-1.0
    dysphagia / Delayed / 0.1-1.0
    migraine / Early / 0.1-1.0
    aphasia / Delayed / 0.1-1.0
    akathisia / Delayed / 0.1-1.0
    myoclonia / Delayed / 0.1-1.0
    meningitis / Delayed / 0.1-1.0
    hypotonia / Delayed / 0.1-1.0
    subdural hematoma / Early / 0.1-1.0
    encephalopathy / Delayed / 0.1-1.0
    hyperacusis / Delayed / 0.1-1.0
    photophobia / Early / 0.1-1.0
    conjunctivitis / Delayed / 0.1-1.0
    urinary incontinence / Early / 0.1-1.0
    urethral pain / Early / 0.1-1.0
    dysuria / Early / 0.1-1.0
    urinary retention / Early / 0.1-1.0
    vaginitis / Delayed / 0.1-1.0
    dehydration / Delayed / 0.1-1.0
    hypophosphatemia / Delayed / 0.1-1.0
    hyperglycemia / Delayed / 0.1-1.0
    edema / Delayed / 0.1-1.0
    contact dermatitis / Delayed / 0.1-1.0
    hypertension / Early / 1.0
    myasthenia / Delayed / 1.0
    constipation / Delayed / 1.0
    hyperreflexia / Delayed / 1.0
    hypokalemia / Delayed / 1.0
    infusion-related reactions / Rapid / Incidence not known
    osteomalacia / Delayed / Incidence not known
    lymphadenopathy / Delayed / Incidence not known
    hepatomegaly / Delayed / Incidence not known
    eosinophilia / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known
    hyperphosphatemia / Delayed / Incidence not known
    bullous rash / Early / Incidence not known
    vitamin D deficiency / Delayed / Incidence not known
    folate deficiency / Delayed / Incidence not known

    Mild

    pruritus / Rapid / 2.8-48.9
    dizziness / Early / 5.0-31.1
    vomiting / Early / 2.2-21.0
    drowsiness / Early / 6.0-20.0
    tremor / Early / 3.3-9.5
    nausea / Early / 4.5-8.9
    headache / Early / 2.2-8.9
    tinnitus / Delayed / 8.9-8.9
    ecchymosis / Delayed / 0-7.3
    paresthesias / Delayed / 3.9-4.4
    pelvic pain / Delayed / 4.4-4.4
    xerostomia / Early / 4.4-4.4
    asthenia / Delayed / 2.2-3.9
    agitation / Early / 3.3-3.3
    diplopia / Early / 3.3-3.3
    dysgeusia / Early / 1.0-3.3
    hyporeflexia / Delayed / 2.8-2.8
    back pain / Delayed / 2.2-2.2
    vertigo / Early / 2.2-2.2
    emotional lability / Early / 0.1-1.0
    syncope / Early / 0.1-1.0
    leukocytosis / Delayed / 0.1-1.0
    petechiae / Delayed / 0.1-1.0
    arthralgia / Delayed / 0.1-1.0
    myalgia / Early / 0.1-1.0
    muscle cramps / Delayed / 0.1-1.0
    epistaxis / Delayed / 0.1-1.0
    hyperventilation / Early / 0.1-1.0
    sinusitis / Delayed / 0.1-1.0
    cough / Delayed / 0.1-1.0
    pharyngitis / Delayed / 0.1-1.0
    rhinitis / Early / 0.1-1.0
    tenesmus / Delayed / 0.1-1.0
    anorexia / Delayed / 0.1-1.0
    flatulence / Early / 0.1-1.0
    dyspepsia / Early / 0.1-1.0
    hypersalivation / Early / 0.1-1.0
    diarrhea / Early / 0.1-1.0
    insomnia / Early / 0.1-1.0
    hyperkinesis / Delayed / 0.1-1.0
    parosmia / Delayed / 0.1-1.0
    mydriasis / Early / 0.1-1.0
    ocular pain / Early / 0.1-1.0
    otalgia / Early / 0.1-1.0
    polyuria / Early / 0.1-1.0
    infection / Delayed / 0.1-1.0
    malaise / Early / 0.1-1.0
    chills / Rapid / 0.1-1.0
    skin discoloration / Delayed / 0.1-1.0
    maculopapular rash / Early / 0.1-1.0
    hyperhidrosis / Delayed / 0.1-1.0
    urticaria / Rapid / 0.1-1.0
    photosensitivity / Delayed / 0.1-1.0
    hypoesthesia / Delayed / 1.0
    fever / Early / 1.0
    rash / Early / 1.0
    injection site reaction / Rapid / 0.1
    hypertrichosis / Delayed / Incidence not known
    hirsutism / Delayed / Incidence not known
    purpura / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Major) Avoid concurrent use of dolutegravir with phenytoin or fosphenytoin, 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 may result in either increased or decreased phenytoin concentrations.
    Abemaciclib: (Major) Avoid coadministration of fosphenytoin 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 fosphenytoin 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 the concomitant use of abiraterone and fosphenytoin. If fosphenytoin must be coadministered with abiraterone, increase the abiraterone dosing frequency to twice daily (i.e., 1,000 mg once daily to 1,000 mg twice daily). Reduce the dose back to the previous dose and frequency when fosphenytoin is discontinued. Abiraterone is a substrate of CYP3A4; fosphenytoin is a strong inducer of CYP3A4. Concomitant use may result in decreased concentrations of abiraterone resulting in reduced efficacy. In a drug interaction study, administration of abiraterone with another strong CYP3A inducer decreased exposure of abiraterone by 55%.
    Acalabrutinib: (Major) Avoid the concomitant use of acalabrutinib and fosphenytoin. 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; fosphenytoin 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: (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. (Minor) The metabolism of caffeine, can be increased by concurrent use with medications that cause induction of hepatic CYP450 enzymes like the hydantoin anticonvulsants.
    Acetaminophen; Butalbital: (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.
    Acetaminophen; 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. (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. (Minor) The metabolism of caffeine, can be increased by concurrent use with medications that cause induction of hepatic CYP450 enzymes like the hydantoin anticonvulsants.
    Acetaminophen; Butalbital; 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 fosphenytoin 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 fosphenytoin 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, the active metabolite of fosphenytoin, 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. (Minor) The metabolism of caffeine, can be increased by concurrent use with medications that cause induction of hepatic CYP450 enzymes like the hydantoin anticonvulsants.
    Acetaminophen; Caffeine: (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. (Minor) The metabolism of caffeine, can be increased by concurrent use with medications that cause induction of hepatic CYP450 enzymes like the hydantoin anticonvulsants.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with fosphenytoin 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 fosphenytoin is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Fosphenytoin is a strong inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. (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. (Minor) The metabolism of caffeine, can be increased by concurrent use with medications that cause induction of hepatic CYP450 enzymes like the hydantoin anticonvulsants.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers. (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. (Minor) The metabolism of caffeine, can be increased by concurrent use with medications that cause induction of hepatic CYP450 enzymes like the hydantoin anticonvulsants.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers. (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. (Minor) The metabolism of caffeine, can be increased by concurrent use with medications that cause induction of hepatic CYP450 enzymes like the hydantoin anticonvulsants.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers. (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: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers. (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; Phenyltoloxamine: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers. (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 fosphenytoin 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 fosphenytoin 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, the active metabolite of fosphenytoin, 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: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers. (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; Phenylephrine: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers. (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: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers. (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 fosphenytoin 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 fosphenytoin 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 (the active metabolite of fosphenytoin) 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; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with fosphenytoin is necessary; consider increasing the dose of oxycodone as needed. If fosphenytoin is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; 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; Pentazocine: (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; Propoxyphene: (Moderate) Enzyme-inducing agents, such as hydantoins, may induce cytochrome P450 metabolism of propoxyphene. The analgesic activity of propoxyphene may be reduced. Hydantoins may also cause additive CNS depression with propoxyphene. (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.
    Acetaminophen; Tramadol: (Major) Tramadol may decrease the seizure threshold in some patients and thus potentially interfere with the ability of anticonvulsants to control seizures. The use of tramadol in patients on anticonvulsant medications for seizure therapy is not recommended. In addition, the hepatic metabolism of tramadol may be accelerated by the use of ethotoin, phenytoin, or fosphenytoin. (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 may reduce the protein binding of phenytoin. Free fosphenytoin concentrations may be useful for therapeutic monitoring if both acitretin and fosphenytoin are administered concurrently.
    Acrivastine; Pseudoephedrine: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    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.
    Afatinib: (Major) Increase the daily dose of afatinib by 10 mg as tolerated if the concomitant use with fosphenytoin is necessary; resume the previous dose of afatinib 2 to 3 days after discontinuation of fosphenytoin. Afatinib is a P-glycoprotein (P-gp) substrate and fosphenytoin 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.
    Aliskiren; Amlodipine: (Moderate) Hydantoins (phenytoin, fosphenytoin, or ethotoin) may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving hydantoins.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Hydantoins (phenytoin, fosphenytoin, or ethotoin) may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving hydantoins.
    Alogliptin: (Minor) Fosphenytoin 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) Fosphenytoin 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) Fosphenytoin 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) Fosphenytoin 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 fosphenytoin due to decreased exposure to alpelisib which could decrease efficacy; fosphenytoin exposure may also decrease. Alpelisib is a CYP3A4 substrate and may induce CYP2C9; fosphenytoin 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) Hydantoin anticonvulsants can theoretically add to the CNS-depressant effects of other CNS depressants including the benzodiazepines. In addition, potential hepatic enzyme inducers such as hydantoins can theoretically increase the clearance of benzodiazepines metabolized by oxidative metabolism, leading to lower benzodiazepine concentrations.
    Altretamine: (Minor) Altretamine undergoes significant metabolism by the cytochrome P450 system. Fosphenytoin 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: (Major) Concomitant administration of amiodarone and phenytoin (or fosphenytoin) may result in phenytoin toxicity, secondary to a two- or three-fold increase in total, steady-state serum phenytoin concentrations likely due to a amiodarone-induced decrease in phenytoin metabolism. In addition, reduced amiodarone serum concentrations may occur during phenytoin coadministration. A similar interaction may occur with ethotoin. Close monitoring for symptoms of hydantoin anticonvulsant toxicity including nystagmus, lethargy and ataxia; and evaluation of serum concentrations with appropriate dosage reduction as necessary, is essential in patients receiving these medications. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    Amitriptyline: (Major) 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.
    Amitriptyline; Chlordiazepoxide: (Major) 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. (Moderate) Hydantoin anticonvulsants can theoretically increase the clearance of benzodiazepines metabolized by oxidative metabolism, such as chlordiazepoxide, leading to lower benzodiazepine concentrations. In addition, chlordiazepoxide has been reported to have an unpredictable effect on 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.
    Amlodipine: (Moderate) Hydantoins (phenytoin, fosphenytoin, or ethotoin) may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving hydantoins.
    Amlodipine; Atorvastatin: (Moderate) Hydantoins (phenytoin, fosphenytoin, or ethotoin) may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving hydantoins. (Moderate) Phenytoin, which is a CYP3A4 inducer, may decrease the efficacy of HMG-Co-A reductase inhibitors which are CYP3A4 substrates including atorvastatin.
    Amlodipine; Benazepril: (Moderate) Hydantoins (phenytoin, fosphenytoin, or ethotoin) may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving hydantoins.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Hydantoins (phenytoin, fosphenytoin, or ethotoin) may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving hydantoins.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Hydantoins (phenytoin, fosphenytoin, or ethotoin) may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving hydantoins.
    Amlodipine; Olmesartan: (Moderate) Hydantoins (phenytoin, fosphenytoin, or ethotoin) may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving hydantoins.
    Amlodipine; Telmisartan: (Moderate) Hydantoins (phenytoin, fosphenytoin, or ethotoin) may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving hydantoins.
    Amlodipine; Valsartan: (Moderate) Hydantoins (phenytoin, fosphenytoin, or ethotoin) may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving hydantoins.
    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; Lansoprazole: (Major) Coadministration of fosphenytoin 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, which may also occur with fosphenytoin. The clarithromycin manufacturer recommends caution if coadministered. (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.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Coadministration of fosphenytoin 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, which may also occur with fosphenytoin. The clarithromycin manufacturer recommends caution if coadministered. (Moderate) Omeprazole can exhibit a dose-dependent inhibition of the hepatic cytochrome P-450 enzyme system, specifically CYP2C19. Because of this, omeprazole can interfere with the clearance of drugs metabolized via this pathway, such as phenytoin or fosphenytoin, resulting in increased phenytoin plasma concentrations. Clinical data do not exist, but an interaction is possible based on the known pathways of elimination. Patients should be monitored carefully for signs of increased drug effect if omeprazole is used with these drugs. In addition, 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.
    Amphetamine; Dextroamphetamine Salts: (Major) Amphetamine or dextroamphetamine 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.
    Amprenavir: (Major) Hydantoins like phenytoin, ethotoin, fosphenytoin may increase the metabolism of amprenavir and lead to decreased efficacy. In addition, amprenavir may inhibit the CYP metabolism of hydantoins, resulting in increased hydantoin concentrations.
    Apixaban: (Major) Avoid the concomitant administration of apixaban and drugs that are both strong inducers of CYP3A4 and P-gp, such as phenytoin or fosphenytoin. Concomitant administration of apixaban with either phenytoin or fosphenytoin results in decreased exposure to apixaban and an increase in the risk of stroke.
    Apremilast: (Major) The coadministration of apremilast and phenytoin or fosphenytoin 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 fosphenytoin 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. Fosphenytoin 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, fosphenytoin 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 fosaprepitant. 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 fosphenytoin 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) Because aripiprazole is metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be doubled over 1 to 2 weeks when potent CYP3A4 inducers, such as phenytoin or other hydantoins, are added to aripiprazole therapy. Carefully monitor the patient for evidence of a decrease in aripiprazole efficacy. When the CYP3A4 inducer is withdrawn from the combination therapy, the oral aripiprazole dose in adults should be reduced to the previous dose over 1 to 2 weeks. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. In adults receiving Aristada with a strong CYP3A4 inducer, no dosage adjustment is necessary for the 662 mg, 882 mg, or 1,064 mg dose; increase the 441 mg dose to 662 mg if the CYP inducer is added for more than 2 weeks. Avoid concurrent use of Aristada Initio and strong CYP3A4 inducers. Additive CNS effects are possible, including drowsiness or dizziness. Patients should report any unusual changes in moods or behaviors while taking this combination.
    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: (Severe) Concomitant use of phenytoin or fosphenytoin 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.
    Articaine; Epinephrine: (Moderate) Coadministration of articaine with oxidizing agents, such as fosphenytoin, 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. (Minor) The metabolism of caffeine, can be increased by concurrent use with medications that cause induction of hepatic CYP450 enzymes like the hydantoin anticonvulsants.
    Aspirin, ASA; Butalbital; 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 fosphenytoin 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 fosphenytoin 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, the active metabolite of fosphenytoin, is a strong CYP3A4 inducer. (Minor) The metabolism of caffeine, can be increased by concurrent use with medications that cause induction of hepatic CYP450 enzymes like the hydantoin anticonvulsants.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with fosphenytoin 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 fosphenytoin is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Fosphenytoin is a strong inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. (Minor) The metabolism of caffeine, can be increased by concurrent use with medications that cause induction of hepatic CYP450 enzymes like the hydantoin anticonvulsants.
    Aspirin, ASA; Caffeine; Orphenadrine: (Minor) The metabolism of caffeine, can be increased by concurrent use with medications that cause induction of hepatic CYP450 enzymes like the hydantoin anticonvulsants.
    Aspirin, ASA; Carisoprodol: (Minor) Carisoprodol is metabolized by CYP2C19 to form meprobamate. Inducers of CYP2C19 like fosphenytoin could result in decreased exposure of carisoprodol and increased exposure of meprobamate. The clinical significance of these potential alterations of carisoprodol exposure is unknown.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with fosphenytoin 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 fosphenytoin 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, the active metabolite of fosphenytoin, is a strong CYP3A4 inducer. (Minor) Carisoprodol is metabolized by CYP2C19 to form meprobamate. Inducers of CYP2C19 like fosphenytoin could result in decreased exposure of carisoprodol and increased exposure of meprobamate. The clinical significance of these potential alterations of carisoprodol exposure is unknown.
    Aspirin, ASA; Omeprazole: (Moderate) Omeprazole can exhibit a dose-dependent inhibition of the hepatic cytochrome P-450 enzyme system, specifically CYP2C19. Because of this, omeprazole can interfere with the clearance of drugs metabolized via this pathway, such as phenytoin or fosphenytoin, resulting in increased phenytoin plasma concentrations. Clinical data do not exist, but an interaction is possible based on the known pathways of elimination. Patients should be monitored carefully for signs of increased drug effect if omeprazole is used with these drugs. In addition, 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.
    Aspirin, ASA; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with fosphenytoin is necessary; consider increasing the dose of oxycodone as needed. If fosphenytoin is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Atazanavir: (Major) Coadministration of fosphenytoin 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 fosphenytoin unless atazanavir is boosted with ritonavir. Coadministration may also result in decreased phenytoin concentrations. If atazanavir and fosphenytoin are used together, the patient must be closely monitored for antiviral efficacy and decreased fosphenytoin efficacy; clinical monitoring of phenytoin concentrations with dosage titration if necessary is also warranted.
    Atazanavir; Cobicistat: (Severe) Coadministration of fosphenytoin 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 fosphenytoin 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 fosphenytoin unless atazanavir is boosted with ritonavir. Coadministration may also result in decreased phenytoin concentrations. If atazanavir and fosphenytoin are used together, the patient must be closely monitored for antiviral efficacy and decreased fosphenytoin efficacy; clinical monitoring of phenytoin concentrations with dosage titration if necessary is also warranted.
    Atorvastatin: (Moderate) Phenytoin, which is a CYP3A4 inducer, may decrease the efficacy of HMG-Co-A reductase inhibitors which are CYP3A4 substrates including atorvastatin.
    Atorvastatin; Ezetimibe: (Moderate) Phenytoin, which is a CYP3A4 inducer, may decrease the efficacy of HMG-Co-A reductase inhibitors which are CYP3A4 substrates including atorvastatin.
    Atracurium: (Moderate) Chronic antiepileptic drug therapy with phenytoin may antagonize the effects of nondepolarizing neuromuscular blockers. This interaction lengthens the onset and shortens the duration of neuromuscular blockade. The exact mechanism for this interaction is unknown, but could involve neuromuscular and hepatic enzyme induction effects of phenytoin.
    Atropine; Difenoxin: (Moderate) Concurrent administration of diphenoxylate/difenoxin with hydantoins can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
    Atropine; Diphenoxylate: (Moderate) Concurrent administration of diphenoxylate/difenoxin with hydantoins can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
    Atropine; Hyoscyamine; Phenobarbital; 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.
    Avanafil: (Minor) Avanafil is primarily metabolized by CYP3A4, and although no studies have been performed, concomitant administration of CYP3A4 inducers, such as fosphenytoin, may decrease avanafil plasma levels. Concomitant use is not recommended.
    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 fosphenytoin. In patients starting fosphenytoin 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 fosphenytoin decrease avatrombopag exposure, which may reduce efficacy.
    Axitinib: (Major) Avoid coadministration of axitinib with fosphenytoin, 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 primarily metabolized by CYP3A4. Fosphenytoin 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) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of fluticasone, leading to reduced efficacy. Depending on the individual clinical situation and the indication for the interacting medication, enzyme-induction interactions may not always produce reductions in treatment efficacy.
    Azithromycin: (Minor) Until more data are available, the manufacturer of azithromycin recommends caution and careful monitoring of patients who receive azithromycin with fosphenytoin. Azithromycin was not implicated in clinical trials with drug interactions with fosphenytoin. However, specific drug interaction studies have not been performed with the combination of azithromycin and fosphenytoin.
    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 fosphenytoin with bedaquiline. Fosphenytoin is a strong CYP3A4 inducer, which may result in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
    Belladonna Alkaloids; Ergotamine; 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.
    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.
    Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with fosphenytoin 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 fosphenytoin may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. If fosphenytoin is discontinued, consider a benzhydrocodone dosage reduction and monitor patients for respiratory depression and sedation at frequent intervals. Benzhydrocodone is a prodrug of hydrocodone. Fosphenytoin is a prodrug of phenytoin. 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.
    Bepridil: (Moderate) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, such as beprildil, leading to reduced efficacy of the concomitant medication. The dosage requirements of bepridil may be increased in patients receiving concurrent enzyme inducers.
    Betrixaban: (Major) Avoid the concomitant administration of betrixaban and fosphenytoin. Concomitant administration of betrixaban and fosphenytoin 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 fosphenytoin is a P-gp inducer.
    Bicalutamide: (Major) Bicalutamide is metabolized by cytochrome P450 3A4. Drugs that are potent inducers of CYP3A4 activity, such as fosphenytoin, will decrease the plasma concentrations of bicalutamide. Clinical trials have not been conducted to determine if bicalutamide dosing adjustments are necessary.
    Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Consider an alternative anticonvulsant during treatment with bictegravir. Concomitant use of bictegravir and fosphenytoin 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; fosphenytoin is a strong inducer of CYP3A4.
    Biotin: (Moderate) Fosphenytoin use for greater than one year while taking biotin can lead to decreased concentrations of biotin. Anticonvulsants that are potent CYP3A4 inducers, like fosphenytoin, 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) Metronidazole can decrease the clearance of phenytoin or fosphenytoin, which can lead to an increase in phenytoin plasma concentrations. Phenytoin levels should be checked regularly when metronidazole therapy is undertaken.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Metronidazole can decrease the clearance of phenytoin or fosphenytoin, which can lead to an increase in phenytoin plasma concentrations. Phenytoin levels should be checked regularly when metronidazole therapy is undertaken.
    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/fosphenytoin. The dose of the concomitant drug may need to be adjusted.
    Boceprevir: (Severe) The potential for boceprevir treatment failure exists when boceprevir is administered with fosphenytoin; therefore, the concurrent use of these medications is contraindicated. Fosphenytoin is a potent inducer of CYP3A4, which is partially responsible for boceprevir metabolism. Coadministration may result in decreased boceprevir serum concentrations, which could result in impaired virologic response to boceprevir.
    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 and CYP3A4 hepatic isoenzymes. Theoretically, bosentan can increase the hepatic clearance of phenytoin, a CYP2C9 substrate, after its conversion from fosphenytoin. However, this interaction has not been studied.
    Bosutinib: (Major) Avoid concomitant use of bosutinib, a CYP3A4 substrate, with a strong CYP3A4 inducer such as phenytoin or fosphenytoin, 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 fosphenytoin due to decreased plasma exposure to brigatinib, which may result in decreased efficacy. Brigatinib is a CYP3A4 substrate; phenytoin (the active metabolite of fosphenytoin) is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the AUC and Cmax of brigatinib by 80% and 60%, respectively.
    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 fosphenytoin 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 fosphenytoin therapy.
    Brodalumab: (Moderate) If brodalumab is initiated or discontinued in a patient taking fosphenytoin, monitor phenytoin concentrations; fosphenytoin 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 fosphenytoin.
    Bromocriptine: (Moderate) Caution and close monitoring are advised if bromocriptine and fosphenytoin 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; fosphenytoin is a strong inducer of CYP3A4.
    Brompheniramine: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with fosphenytoin 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 fosphenytoin 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 (the active metabolite of fosphenytoin) is a strong CYP3A4 inducer. (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with fosphenytoin 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 fosphenytoin 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 (the active metabolite of fosphenytoin) is a strong CYP3A4 inducer. (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Brompheniramine; Pseudoephedrine: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Budesonide: (Moderate) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of budesonide, leading to reduced efficacy. Depending on the individual clinical situation and the indication for the interacting medication, enzyme-induction interactions may not always produce reductions in treatment efficacy.
    Budesonide; Formoterol: (Moderate) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of budesonide, leading to reduced efficacy. Depending on the individual clinical situation and the indication for the interacting medication, enzyme-induction interactions may not always produce reductions in treatment efficacy.
    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; Lidocaine: (Moderate) Concomitant use of systemic lidocaine and fosphenytoin may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; fosphenytoin induces both hepatic isoenzymes. Additionally, coadministration of lidocaine with oxidizing agents, such as fosphenytoin, 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.
    Buprenorphine: (Moderate) Close monitoring of the patient is recommended if a CYP3A4 inducer is used with buprenorphine. Inducers of CYP3A4 such as phenytoin or fosphenytoin may induce the hepatic metabolism of buprenorphine, which may lead to opiate withdrawal or inadequate pain control. This interaction is most significant if the enzyme-inducing agent is added after buprenorphine therapy has begun. Buprenorphine doses may need to be increased if phenytoin or fosphenytoin is added. Conversely, buprenorphine doses may need to be decreased if these drugs are discontinued. The induction of buprenorphine metabolism may take several days. Prior to concurrent use of buprenorphine 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. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Buprenorphine; Naloxone: (Moderate) Close monitoring of the patient is recommended if a CYP3A4 inducer is used with buprenorphine. Inducers of CYP3A4 such as phenytoin or fosphenytoin may induce the hepatic metabolism of buprenorphine, which may lead to opiate withdrawal or inadequate pain control. This interaction is most significant if the enzyme-inducing agent is added after buprenorphine therapy has begun. Buprenorphine doses may need to be increased if phenytoin or fosphenytoin is added. Conversely, buprenorphine doses may need to be decreased if these drugs are discontinued. The induction of buprenorphine metabolism may take several days. Prior to concurrent use of buprenorphine 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. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Bupropion: (Moderate) When anticonvulsants are used for the purpose of treating epilepsy (versus use in mood disorders or neuropathic pain or other non-epilepsy conditions), bupropion should not be used since bupropion lowers the seizure threshold. Bupropion may be combined with anticonvulsant treatments with caution when an anticonvulsant is used for non-epilepsy conditions (e.g., neuropathic pain, mood disorders). Bupropion may interact pharmacokinetically with anticonvulsant drugs that induce hepatic microsomal isoenzyme function such as phenytoin (as well as other hydantoins like fosphenytoin or ethotoin). Monitor for reduced bupropion efficacy.
    Bupropion; Naltrexone: (Moderate) When anticonvulsants are used for the purpose of treating epilepsy (versus use in mood disorders or neuropathic pain or other non-epilepsy conditions), bupropion should not be used since bupropion lowers the seizure threshold. Bupropion may be combined with anticonvulsant treatments with caution when an anticonvulsant is used for non-epilepsy conditions (e.g., neuropathic pain, mood disorders). Bupropion may interact pharmacokinetically with anticonvulsant drugs that induce hepatic microsomal isoenzyme function such as phenytoin (as well as other hydantoins like fosphenytoin or ethotoin). Monitor for reduced bupropion efficacy.
    Buspirone: (Moderate) Hydantoins are potent inducers of hepatic cytochrome P450 isoenzyme CYP3A4 and may increase the rate of buspirone metabolism. In a study of healthy volunteers, co-administration of buspirone with rifampin decreased the plasma concentrations (83.7% decrease in Cmax; 89.6% decrease in AUC) and pharmacodynamic effects of buspirone. An in vitro study indicated that buspirone did not displace highly protein-bound drugs such as phenytoin. If a patient has been titrated to a stable dosage on buspirone, a dose adjustment of buspirone may be necessary to maintain anxiolytic effect. In addition, CNS depressants like the barbiturates may also enhance drowsiness or CNS depression.
    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. Documentation of these interactions is limited, but could be significant.
    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.
    Cabozantinib: (Major) Avoid coadministration of cabozantinib with fosphenytoin 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 fosphenytoin 2 to 3 days after discontinuation of fosphenytoin. Cabozantinib is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased single-dose cabozantinib exposure by 77%.
    Caffeine: (Minor) The metabolism of caffeine, can be increased by concurrent use with medications that cause induction of hepatic CYP450 enzymes like the hydantoin anticonvulsants.
    Caffeine; Ergotamine: (Minor) The metabolism of caffeine, can be increased by concurrent use with medications that cause induction of hepatic CYP450 enzymes like the hydantoin anticonvulsants.
    Calcifediol: (Moderate) Dose adjustment of calcifediol may be necessary during coadministration with fosphenytoin. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with fosphenytoin. Fosphenytoin stimulates microsomal hydroxylation and reduces the half-life of calcifediol. In rare cases, this has caused anticonvulsant-induced rickets and osteomalacia.
    Calcitriol: (Moderate) Anticonvulsants, such phenytoin and 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. Dosage adjustments of vitamin D analogs may be required in patients who are receiving chronic treatment with anticonvulsants.
    Canagliflozin: (Moderate) Monitor for decreased efficacy of canagliflozin if coadministration with fosphenytoin is necessary. In patients taking fosphenytoin who have an eGFR greater than 60 mL/min/1.73 m2, and are currently tolerating a canagliflozin dose of 100 mg once daily, increase the dose of canagliflozin to 200 mg (taken as two 100 mg tablets) once daily. In patients who are tolerating canagliflozin to 200 mg and who require additional glycemic control, the dose may be increased to 300 mg once daily. In patients taking fosphenytoin who have an eGFR less than 60 mL/min/1.73 m2, and are currently tolerating a canagliflozin dose of 100 mg once daily, increase the dose of canagliflozin to 200 mg (taken as two 100 mg tablets) once daily. Consider other antihyperglycemic therapy in patients who require additional glycemic control. Canagliflozin is a UGT1A9 and 2B4 substrate and fosphenytoin is a UGT inducer. Coadministration with a nonselective inducer of several UGT enzymes decreased canagliflozin exposure by 51%.
    Canagliflozin; Metformin: (Moderate) Monitor for decreased efficacy of canagliflozin if coadministration with fosphenytoin is necessary. In patients taking fosphenytoin who have an eGFR greater than 60 mL/min/1.73 m2, and are currently tolerating a canagliflozin dose of 100 mg once daily, increase the dose of canagliflozin to 200 mg (taken as two 100 mg tablets) once daily. In patients who are tolerating canagliflozin to 200 mg and who require additional glycemic control, the dose may be increased to 300 mg once daily. In patients taking fosphenytoin who have an eGFR less than 60 mL/min/1.73 m2, and are currently tolerating a canagliflozin dose of 100 mg once daily, increase the dose of canagliflozin to 200 mg (taken as two 100 mg tablets) once daily. Consider other antihyperglycemic therapy in patients who require additional glycemic control. Canagliflozin is a UGT1A9 and 2B4 substrate and fosphenytoin is a UGT inducer. Coadministration with a nonselective inducer of several UGT enzymes decreased canagliflozin exposure by 51%. (Minor) Fosphenytoin 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.
    Canakinumab: (Moderate) If canakinumab is initiated or discontinued in a patient taking fosphenytoin, monitor phenytoin concentrations; fosphenytoin 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 canakinumab administration. In theory, clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as fosphenytoin.
    Cannabidiol: (Moderate) Consider a dose increase of cannabidiol and monitor serum phenytoin concentrations if coadministered. Consider a dose reduction of fosphenytoin if fosphenytoin 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 of fosphenytoin with capecitabine is necessary; a dose reduction of fosphenytoin may be necessary. Fosphenytoin 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.
    Carbamazepine: (Moderate) Carbamazepine induces hepatic microsomal enzymes, which, in turn, accelerates carbamazepine metabolism or the metabolism of other drugs. Interactions between carbamazepine and other anticonvulsants, such as the hydantoins, are complex. Despite the fact that one anticonvulsant may interact with another, combinations of anticonvulsants are frequently used in patients who are refractory to one agent alone and may change the profile of expected drug interactions. Phenytoin or fosphenytoin (and possibly ethotoin) can potentially be affected by carbamazepine enzyme induction. Phenytoin plasma concentrations have also been reported to increase and decrease in the presence of carbamazepine. As carbamazepine is metabolized by CYP3A4, the potential exists for an interaction between carbamazepine and hydantoins, which induce CYP3A4 and therefore may decrease plasma concentrations of carbamazepine. Careful monitoring of carbamazepine and hydantoin plasma concentrations, along with close clinical monitoring of response to therapy, is advised.
    Carbetapentane; Chlorpheniramine: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Carbetapentane; Pyrilamine: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Carbidopa; Levodopa: (Moderate) Phenytoin or fosphenytoin can possibly interfere with the effects of levodopa; the mechanism of the interaction has not been established. The beneficial effects of levodopa in Parkinson's disease have been reported to be reversed by phenytoin. Monitor carefully for loss of therapeutic response.
    Carbidopa; Levodopa; Entacapone: (Moderate) Phenytoin or fosphenytoin can possibly interfere with the effects of levodopa; the mechanism of the interaction has not been established. The beneficial effects of levodopa in Parkinson's disease have been reported to be reversed by phenytoin. Monitor carefully for loss of therapeutic response.
    Carbinoxamine: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with fosphenytoin 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 fosphenytoin 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 (the active metabolite of fosphenytoin) is a strong CYP3A4 inducer. (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with fosphenytoin 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 fosphenytoin 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 (the active metabolite of fosphenytoin) is a strong CYP3A4 inducer. (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Carbinoxamine; Phenylephrine: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Carbinoxamine; Pseudoephedrine: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    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 metabolized by CYP2C19 to form meprobamate. Inducers of CYP2C19 like fosphenytoin could result in decreased exposure of carisoprodol and increased exposure of meprobamate. The clinical significance of these potential alterations of carisoprodol exposure is unknown.
    Carmustine, BCNU: (Moderate) Use fosphenytoin and carmustine together with caution; phenytoin serum concentration may be reduced resulting in decreased fosphenytoin efficacy. Consider using an alternative agent in place of fosphenytoin. fthese drugs are used together, anticonvulsant therapy should be monitored closely during and after administration of carmustine.
    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 fosphenytoin. Administering inducers of hepatic cytochrome P450, such as fosphenytoin, concurrently with caspofungin may reduce the plasma concentrations of caspofungin.
    Ceritinib: (Major) Avoid coadministration of ceritinib with fosphenytoin due to decreased ceritinib exposure, resulting in decreased efficacy of treatment. Ceritinib is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of ceritinib by 70% and 44%, respectively.
    Cevimeline: (Minor) Inducers of cytochrome P450 3A4 or CYP 2D6, such as the hydantoin anticonvulsants, may cause a reduction in cevimeline plasma concentrations.
    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.
    Chlophedianol; Dexbrompheniramine: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Chlorcyclizine: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Chlordiazepoxide: (Moderate) Hydantoin anticonvulsants can theoretically increase the clearance of benzodiazepines metabolized by oxidative metabolism, such as chlordiazepoxide, leading to lower benzodiazepine concentrations. In addition, chlordiazepoxide has been reported to have an unpredictable effect on 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; Clidinium: (Moderate) Hydantoin anticonvulsants can theoretically increase the clearance of benzodiazepines metabolized by oxidative metabolism, such as chlordiazepoxide, leading to lower benzodiazepine concentrations. In addition, chlordiazepoxide has been reported to have an unpredictable effect on 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 fosphenytoin, 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.
    Chlorpheniramine: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with fosphenytoin 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 fosphenytoin 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, the active metabolite of fosphenytoin, is a strong CYP3A4 inducer. (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Chlorpheniramine; Dextromethorphan: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with fosphenytoin 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 fosphenytoin is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Fosphenytoin is a strong inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with fosphenytoin 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 fosphenytoin is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Fosphenytoin is a strong inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with fosphenytoin 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 fosphenytoin 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 (the active metabolite of fosphenytoin) is a strong CYP3A4 inducer. (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with fosphenytoin 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 fosphenytoin 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 (the active metabolite of fosphenytoin) is a strong CYP3A4 inducer. (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with fosphenytoin 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 fosphenytoin 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 (the active metabolite of fosphenytoin) is a strong CYP3A4 inducer. (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with fosphenytoin 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 fosphenytoin 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 (the active metabolite of fosphenytoin) is a strong CYP3A4 inducer. (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Chlorpheniramine; Phenylephrine: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Chlorpheniramine; Pseudoephedrine: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Cimetidine: (Major) Cimetidine inhibits the hepatic metabolism of the following anticonvulsants: fosphenytoin, phenytoin, and possibly ethotoin. Serum concentrations of these drugs may increase and produce clinically undesirable side effects or drug toxicity. Where possible, the use of cimetidine in the presence of these medications should be avoided.
    Cinacalcet: (Moderate) Co-administration of cinacalcet with a CYP3A4 enzyme inducer may result in a decreased effect of cinacalcet. Agents that may significantly induce the CYP3A4 metabolism of cinacalcet include phenytoin and fosphenytoin (which is metabolized to phenytoin). Since these medications may increase the metabolism of cinacalcet, intact parathyroid hormone (iPTH), serum calcium and serum phosphorous levels may need to be monitored.
    Ciprofloxacin: (Moderate) Use ciprofloxacin and fosphenytoin together with caution as ciprofloxacin has been reported to both increase and decrease phenytoin concentrations. Monitor phenytoin serum concentrations and response to therapy during and shorty after coadministration to avoid the loss of seizure control associated with decreased phenytoin levels and to prevent overdose-related adverse events upon the discontinuation of ciprofloxacin.
    Cisatracurium: (Moderate) Chronic antiepileptic drug therapy with phenytoin may antagonize the effects of nondepolarizing neuromuscular blockers. This interaction lengthens the onset and shortens the duration of neuromuscular blockade. The exact mechanism for this interaction is unknown, but could involve neuromuscular and hepatic enzyme induction effects of phenytoin.
    Cisplatin: (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 theoretically fosphenytoin or ethotoin) and cisplatin 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.
    Clarithromycin: (Major) Coadministration of fosphenytoin 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, which may also occur with fosphenytoin. The clarithromycin manufacturer recommends caution if coadministered.
    Clemastine: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Clindamycin: (Moderate) Concomitant use of clindamycin and fosphenytoin may increase clindamycin clearance and result in loss of efficacy of clindamycin. Clindamycin is a CYP3A4 substrate; fosphenytoin is a strong inducer of CYP3A4. Caution and close monitoring are advised if these drugs are used together.
    Clobazam: (Moderate) Concomitant administration of clobazam with other CNS-depressant drugs including fosphenytoin (prodrug of phenytoin) can potentiate the CNS effects (i.e., increased sedation or respiratory depression) of either agent.
    Clomipramine: (Major) 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) Closely monitor for loss of seizure control, increased anxiety, or panic attacks if clonazepam and fosphenytoin, a prodrug of phenytoin, are used concurrently. Monitoring of phenytoin serum concentrations is recommended. Monitor for increased adverse effects from phenytoin, such as nystagmus, ataxia, slurred speech, nausea, vomiting, confusion, or lethargy. The metabolism of clonazepam by CYP3A4 may be induced by phenytoin resulting in decreased clonazepam concentrations. Clonazepam is a CYP3A4 substrate, and phenytoin is a strong CYP3A4 inducer. Clonazepam concentration decreases of approximately 38% have been reported when clonazepam was used with potent CYP3A4 inducers. The effect of the interaction on phenytoin concentrations is unpredictable, and the mechanism of interaction is unclear. In 1 case report, phenytoin concentrations decreased approximately 28% when clonazepam was added to phenytoin therapy in an epileptic patient and a corresponding increase in seizures was seen. In a study that assessed the effect of clonazepam on phenytoin plasma concentrations, 9 patients experienced increased phenytoin concentrations when clonazepam was introduced. The magnitude of concentration increase is not reported. 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.
    Clorazepate: (Moderate) Hydantoins are hepatic inducers and can theoretically increase the clearance of benzodiazepines 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 fosphenytoin converted to 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. Fosphenytoin 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 fosphenytoin in treating seizures may be reduced. Dosage adjustments may be necessary, and close monitoring is warranted.
    Cobicistat: (Severe) Coadministration of fosphenytoin 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 fosphenytoin due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro; fosphenytoin 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 fosphenytoin 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 fosphenytoin 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, the active metabolite of fosphenytoin, is a strong CYP3A4 inducer.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with fosphenytoin 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 fosphenytoin 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, the active metabolite of fosphenytoin, is a strong CYP3A4 inducer.
    Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with fosphenytoin 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 fosphenytoin 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, the active metabolite of fosphenytoin, is a strong CYP3A4 inducer.
    Codeine; Promethazine: (Moderate) Concomitant use of codeine with fosphenytoin 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 fosphenytoin 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, the active metabolite of fosphenytoin, is a strong CYP3A4 inducer.
    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: (Moderate) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormones including hormonal contraceptives. Pregnancy has been reported during therapy with estrogens, oral contraceptives, non-oral combination contraceptives, or progestins in patients receiving phenytoin concurrently. A similar interaction may be expected with other hydantoin anticonvulsants (i.e., fosphenytoin and ethotoin). Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on a hydantoin anticonvulsant, with dose adjustments made based on clinical efficacy.
    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 or fosphenytoin. 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. (Moderate) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormones including hormonal contraceptives. Pregnancy has been reported during therapy with estrogens, oral contraceptives, non-oral combination contraceptives, or progestins in patients receiving phenytoin concurrently. A similar interaction may be expected with other hydantoin anticonvulsants (i.e., fosphenytoin and ethotoin). Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on a hydantoin anticonvulsant, with dose adjustments made based on clinical efficacy.
    Conjugated Estrogens; Medroxyprogesterone: (Major) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with progestin contraceptives in patients receiving hydantoins. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. (Moderate) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormones including hormonal contraceptives. Pregnancy has been reported during therapy with estrogens, oral contraceptives, non-oral combination contraceptives, or progestins in patients receiving phenytoin concurrently. A similar interaction may be expected with other hydantoin anticonvulsants (i.e., fosphenytoin and ethotoin). Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on a hydantoin anticonvulsant, with dose adjustments made based on clinical efficacy.
    Copanlisib: (Major) Avoid the concomitant use of copanlisib and fosphenytoin; decreased copanlisib exposure and loss of efficacy may occur. Copanlisib is a CYP3A substrate; fosphenytoin 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 fosphenytoin due to decreased plasma concentrations of crizotinib, which may result in decreased efficacy. Crizotinib is primarily metabolized by CYP3A and fosphenytoin 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.
    Cyclizine: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    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.
    Cyproheptadine: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Dabigatran: (Moderate) In general, avoid coadministration of dabigatran with P-glycoprotein (P-gp) inducers, such as phenytoin or fosphenytoin. Concomitant administration of dabigatran and rifampin, another P-gp inducer, resulted in a significant decrease in dabigatran AUC and Cmax.
    Dabrafenib: (Major) Use dabrafenib and fosphenytoin together with caution; concentrations of either agent may be decreased. Use an alternate agent in place of fosphenytoin if possible. If concomitant use cannot be avoided, monitor patients for loss of fosphenytoin efficacy. Fosphenytoin 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; patients receiving phenytoin or fosphenytoin may require close clinical monitoring to ensure appropriate clinical outcomes are achieved during and following the completion of chemotherapy cycles.
    Daclatasvir: (Severe) 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) Fosphenytoin 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 fosphenytoin is necessary; dapsone efficacy may also be compromised. Dapsone is a CYP3A4 metabolite and fosphenytoin 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 fosphenytoin may increase the risk of developing methemoglobinemia. Advise patients to discontinue treatment and seek immediate medical attention with any signs or symptoms of methemoglobinemia.
    Darifenacin: (Minor) Fosphenytoin may induce the CYP3A4 metabolism of darifenacin and thereby reduce its oral bioavailability. Depending on the individual clinical situation and the indication for the interacting medication, enzyme-induction interactions may not always produce reductions in treatment efficacy.
    Darolutamide: (Major) Avoid coadministration of darolutamide with fosphenytoin due to the risk of decreased darolutamide plasma concentrations which may decrease efficacy. fosphenytoin 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 fosphenytoin efficacy during coadministration; clinical monitoring of phenytoin concentrations with dosage titration if necessary is also warranted. Coadministration of darunavir and fosphenytoin may result in decreased phenytoin concentrations. In drug interaction studies, the concentration of darunavir was unaffected during coadministration with phenytoin.
    Darunavir; Cobicistat: (Severe) Coadministration of fosphenytoin 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 fosphenytoin efficacy during coadministration; clinical monitoring of phenytoin concentrations with dosage titration if necessary is also warranted. Coadministration of darunavir and fosphenytoin 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: (Severe) Coadministration of fosphenytoin 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 fosphenytoin efficacy during coadministration; clinical monitoring of phenytoin concentrations with dosage titration if necessary is also warranted. Coadministration of darunavir and fosphenytoin may result in decreased phenytoin concentrations. In drug interaction studies, the concentration of darunavir was unaffected during coadministration with phenytoin.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Severe) Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with fosphenytoin is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to dasabuvir, ombitasvir, paritaprevir and ritonavir. Phenytoin is a potent inducer and substrate of the hepatic isoenzyme CYP3A4; dasabuvir (minor), paritaprevir and ritonavir are substrates of this isoenzyme. In addition, phenytoin may induce P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates. (Severe) Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with phenytoin or fosphenytoin is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to dasabuvir, ombitasvir, paritaprevir and ritonavir. Phenytoin is a potent inducer and substrate of the hepatic isoenzyme CYP3A4; dasabuvir (minor), paritaprevir and ritonavir are substrates of this isoenzyme. In addition, phenytoin may induce P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates. (Major) Concurrent use of ritonavir with ethotoin, phenytoin, or fosphenytoin should be avoided when possible. Increased doses of anticonvulsants may be required due to metabolism induction by ritonavir. Additionally, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required.
    Dasatinib: (Major) Avoid coadministration of dasatinib and fosphenytoin due to the potential for decreased dasatinib exposure and reduced efficacy. Consider an alternative to fosphenytoin 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; fosphenytoin 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 or fosphenytoin are not available, a similar interaction may occur. Avoid the concomitant use of phenytoin or fosphenytoin and deferasirox if possible. If 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 fosphenytoin. Concurrent use may significantly decrease concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in loss of efficacy. Deflazacort is a CYP3A4 substrate; fosphenytoin 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: (Severe) Concurrent use of fosphenytoin 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 fosphenytoin, resulting in increased phenytoin concentrations and possible side effects.
    Desipramine: (Major) 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.
    Dexamethasone: (Moderate) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of dexamethasone, leading to reduced efficacy. Depending on the individual clinical situation and the indication for the interacting medication, enzyme-induction interactions may not always produce reductions in treatment efficacy.
    Dexchlorpheniramine: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    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; Diphenhydramine; Phenylephrine: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    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) Phenytoin is a hepatic enzyme inducer and thus may accelerate the metabolism of several other anticonvulsants, and can theoretically add to the CNS-depressant effects of other CNS depressants, including the anxiolytics, sedatives, and hypnotics which may be used concomitantly for seizure control or as psychotropics. Fosphenytoin should be used cautiously with clonazepam and diazepam, as decreased clonazepam or diazepam serum concentrations may be seen. In addition, diazepam 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).
    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) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with progestin contraceptives in patients receiving hydantoins. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. (Moderate) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormones including hormonal contraceptives. Pregnancy has been reported during therapy with estrogens, oral contraceptives, non-oral combination contraceptives, or progestins in patients receiving phenytoin (the active metabolite of fosphenytoin) concurrently. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on phenytoin or fosphenytoin, with dose adjustments made based on clinical efficacy.
    Diethylstilbestrol, DES: (Moderate) Concurrent administration of hepatic enzyme inducers with estrogens, including hydantoin anticonvulsants, may increase the elimination of estrogen.
    Digoxin: (Moderate) Hepatic enzyme-inducing drugs, such as phenytoin and fosphenytoin, can accelerate the metabolism of cardiac glycosides, including digoxin. Decreasing cardiac glycoside serum concentrations could result. The manufacturer of digoxin recommends measuring serum digoxin concentrations prior to initiation of phenytoin. Continue monitoring during concomitant treatment and increase the digoxin dose by 20-40% as necessary.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with fosphenytoin 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 fosphenytoin is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Fosphenytoin is a strong inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Diltiazem: (Major) Avoid coadministration of diltiazem and fosphenytoin due to decreased plasma concentrations of diltiazem. Diltiazem is a CYP3A4 substrate and phenytoin, the active metabolite of fosphenytoin, is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer lowered diltiazem plasma concentrations to undetectable.
    Dimenhydrinate: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Diphenhydramine: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with fosphenytoin 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 fosphenytoin 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 (the active metabolite of fosphenytoin) is a strong CYP3A4 inducer. (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Diphenhydramine; Ibuprofen: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Diphenhydramine; Naproxen: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers. (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.
    Diphenhydramine; Phenylephrine: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    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 fosphenytoin due to decreased plasma concentrations of docetaxel. Docetaxel is a CYP3A4 substrate and fosphenytoin 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 or fosphenytoin, 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 or fosphenytoin, 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: (Severe) 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 or fosphenytoin, 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) Fosphenytoin 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) Fosphenytoin induces hepatic microsomal enzymes and may increase the metabolism of other drugs, including donepezil, leading to reduced efficacy of the concomitant medication.
    Doravirine: (Severe) Concurrent administration of doravirine and fosphenytoin 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 (the active metabolite of fosphenytoin) is a strong CYP3A4 inducer.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Severe) Concurrent administration of doravirine and fosphenytoin 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 (the active metabolite of fosphenytoin) is a strong CYP3A4 inducer.
    Doxacurium: (Moderate) Chronic antiepileptic drug therapy with phenytoin may antagonize the effects of nondepolarizing neuromuscular blockers. This interaction lengthens the onset and shortens the duration of neuromuscular blockade. The exact mechanism for this interaction is unknown, but could involve neuromuscular and hepatic enzyme induction effects of phenytoin.
    Doxepin: (Major) 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: (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: (Major) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, including doxycycline, leading to reduced efficacy of the concomitant medication.
    Doxylamine: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Doxylamine; Pyridoxine: (Moderate) Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Dronabinol: (Major) Use caution if coadministration of dronabinol with fosphenytoin is necessary, and monitor for an increase in phenytoin levels and fosphenytoin-related adverse effects, as well as a decrease in the efficacy of dronabinol. Dronabinol is a CYP2C9 and 3A4 substrate; fosphenytoin 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. Fosphenytoin induces CYP3A4. Coadministration of CYP3A4 inducers, such as fosphenytoin, 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) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with progestin contraceptives in patients receiving hydantoins. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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.
    Drospirenone; Estradiol: (Major) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with progestin contraceptives in patients receiving hydantoins. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. (Moderate) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormones including hormonal contraceptives. Pregnancy has been reported during therapy with estrogens, oral contraceptives, non-oral combination contraceptives, or progestins in patients receiving phenytoin (the active metabolite of fosphenytoin) concurrently. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on phenytoin or fosphenytoin, with dose adjustments made based on clinical efficacy.
    Drospirenone; Ethinyl Estradiol: (Major) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with progestin contraceptives in patients receiving hydantoins. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. (Major) Hydantoins induce hepatic enzymes and can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with oral contraceptives in patients receiving phenytoin concurrently. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants; or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on hydantoins.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with progestin contraceptives in patients receiving hydantoins. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. (Major) Hydantoins induce hepatic enzymes and can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with oral contraceptives in patients receiving phenytoin concurrently. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants; or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on hydantoins. (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.
    Dupilumab: (Moderate) Coadministration of dupilumab may result in altered exposure to fosphenytoin. 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 fosphenytoin. Monitor phenytoin concentrations if dupilumab is initiated or discontinued in a patient taking fosphenytoin; fosphenytoin dose adjustments may be needed.
    Duvelisib: (Major) Avoid coadministration of duvelisib with fosphenytoin. Coadministration may decrease the exposure of duvelisib, which may reduce the efficacy of duvelisib. Duvelisib is a CYP3A substrate; fosphenytoin 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.
    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: (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.
    Elagolix: (Moderate) Concomitant use of elagolix and fosphenytoin may result in decreased concentrations of elagolix; monitor for decreased efficacy with coadministration. Elagolix is a CYP3A substrate; fosphenytoin is a strong inducer of CYP3A.
    Elbasvir; Grazoprevir: (Severe) Concurrent administration of elbasvir with fosphenytoin (a prodrug of phenytoin) is contraindicated. Phenytoin is a strong CYP3A inducer, while elbasvir is a substrate of CYP3A. Use of these drugs together is expected to significantly decrease the plasma concentration of elbasvir, and may result in decreased virologic response. (Severe) Concurrent administration of grazoprevir with fosphenytoin (a prodrug of phenytoin) is contraindicated. Phenytoin is a strong CYP3A inducer, while grazoprevir is a substrate of CYP3A. Use of these drugs together is expected to significantly decrease the plasma concentration of grazoprevir, and may result in decreased virologic response.
    Elexacaftor; tezacaftor; ivacaftor: (Major) Coadministration of elexacaftor; tezacaftor; ivacaftor with fosphenytoin 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). Fosphenytoin 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 fosphenytoin is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and fosphenytoin 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 fosphenytoin 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 fosphenytoin, 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: (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. Fosphenytoin 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 fosphenytoin as the concentrations of both elvitegravir and cobicistat may be significantly decreased.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Severe) Coadministration of fosphenytoin 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. Fosphenytoin 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 fosphenytoin as the concentrations of both elvitegravir and cobicistat may be significantly decreased.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Severe) Coadministration of fosphenytoin 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. Fosphenytoin 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 fosphenytoin as the concentrations of both elvitegravir and cobicistat may be significantly decreased.
    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: (Major) Potent inducers of CYP3A4 (e.g. fosphenytoin) can decrease exposure to linagliptin and result in subtherapeutic and likely ineffective concentrations. For patients requiring use of fosphenytoin, an alternative to linagliptin is strongly recommended. If these drugs must be used together, blood glucose should be closely monitored for changes in glycemic control. Phenytoin and other hydantoins have additionally been reported to cause an increase in blood glucose and interfere with antidiabetic agents pharnacodynamically. (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) Fosphenytoin 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: (Severe) 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: (Severe) 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.
    Enalapril; 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.
    Encorafenib: (Major) Avoid coadministration of encorafenib and fosphenytoin due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; fosphenytoin 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.
    Enflurane: (Moderate) Caution is advised with the concomitant use of enflurane and fosphenytoin as concurrent use may increase the risk of hepatotoxicity.
    Entrectinib: (Major) Avoid coadministration of entrectinib with fosphenytoin due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; fosphenytoin 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 fosphenytoin with enzalutamide if possible due to decreased enzalutamide exposure which may compromise efficacy; phenytoin (the active metabolite of fosphenytoin) 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 fosphenytoin is discontinued. Monitor phenytoin serum concentrations and adjust fosphenytoin doses as needed. Enzalutamide is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Enzalutamide is also a moderate CYP2C9 and CYP2C19 inducer and fosphenytoin 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 fosphenytoin. 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 fosphenytoin due to the risk of decreased plasma concentrations of erdafitinib resulting in decreased efficacy. Erdafitinib is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer.
    Ergocalciferol, Vitamin D2: (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.
    Erlotinib: (Major) Avoid coadministration of erlotinib with fosphenytoin 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 fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased erlotinib exposure by 58% to 80%.
    Ertugliflozin; Metformin: (Minor) Fosphenytoin 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.
    Escitalopram: (Moderate) Monitor for altered clinical effect of escitalopram when fosphenytoin is coadministered. CYP3A4 and CYP2C19 are the primary isozymes involved in the N-demethylation of escitalopram. Given the enzyme-inducing properties of fosphenytoin, the possibility that the drug may increase the clearance of escitalopram should be considered if the 2 drugs are coadministered. Additive CNS effects, such as sedation, may also be possible.
    Eslicarbazepine: (Major) Phenytoin (and fosphenytoin) may induce the metabolism of eslicarbazepine resulting in decreased plasma concentrations of and potentially reduced efficacy of eslicarbazepine. An increased dose of eslicarbazepine may be necessary if these drugs are coadministered. 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 or fosphenytoin based on clinical response and serum concentration.
    Esomeprazole: (Moderate) Esomeprazole, which is an inhibitor of CYP2C19, may lead to increased levels of fosphenytoin, a substrate of CYP2C19. During clinical drug interaction studies, the changes in phenytoin concentrations appeared unlikely to be of clinical significance for most patients. However, it is advisable to monitor phenytoin levels and for hydantoin toxicity during concurrent treatment. Drugs known to induce CYP2C19 or CYP3A4 or both, such as fosphenytoin, may lead to decreased esomeprazole serum levels and patients should be monitored for expected clinical benefit during PPI treatment.
    Esomeprazole; Naproxen: (Moderate) Esomeprazole, which is an inhibitor of CYP2C19, may lead to increased levels of fosphenytoin, a substrate of CYP2C19. During clinical drug interaction studies, the changes in phenytoin concentrations appeared unlikely to be of clinical significance for most patients. However, it is advisable to monitor phenytoin levels and for hydantoin toxicity during concurrent treatment. Drugs known to induce CYP2C19 or CYP3A4 or both, such as fosphenytoin, may lead to decreased esomeprazole serum levels and patients should be monitored for expected clinical benefit during PPI treatment. (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.
    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.
    Esterified Estrogens: (Moderate) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormones including hormonal contraceptives. Pregnancy has been reported during therapy with estrogens, oral contraceptives, non-oral combination contraceptives, or progestins in patients receiving phenytoin (the active metabolite of fosphenytoin) concurrently. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on fosphenytoin, with dose adjustments made based on clinical efficacy.
    Esterified Estrogens; Methyltestosterone: (Moderate) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormones including hormonal contraceptives. Pregnancy has been reported during therapy with estrogens, oral contraceptives, non-oral combination contraceptives, or progestins in patients receiving phenytoin (the active metabolite of fosphenytoin) concurrently. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on fosphenytoin, with dose adjustments made based on clinical efficacy.
    Estradiol Cypionate; Medroxyprogesterone: (Major) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with progestin contraceptives in patients receiving hydantoins. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. (Moderate) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormones including hormonal contraceptives. Pregnancy has been reported during therapy with estrogens, oral contraceptives, non-oral combination contraceptives, or progestins in patients receiving phenytoin (the active metabolite of fosphenytoin) concurrently. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on phenytoin or fosphenytoin, with dose adjustments made based on clinical efficacy.
    Estradiol: (Moderate) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormones including hormonal contraceptives. Pregnancy has been reported during therapy with estrogens, oral contraceptives, non-oral combination contraceptives, or progestins in patients receiving phenytoin (the active metabolite of fosphenytoin) concurrently. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on phenytoin or fosphenytoin, with dose adjustments made based on clinical efficacy.
    Estradiol; Levonorgestrel: (Major) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with progestin contraceptives in patients receiving hydantoins. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. (Moderate) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormones including hormonal contraceptives. Pregnancy has been reported during therapy with estrogens, oral contraceptives, non-oral combination contraceptives, or progestins in patients receiving phenytoin (the active metabolite of fosphenytoin) concurrently. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on phenytoin or fosphenytoin, with dose adjustments made based on clinical efficacy.
    Estradiol; Norethindrone: (Major) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with progestin contraceptives in patients receiving hydantoins. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. (Moderate) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormones including hormonal contraceptives. Pregnancy has been reported during therapy with estrogens, oral contraceptives, non-oral combination contraceptives, or progestins in patients receiving phenytoin (the active metabolite of fosphenytoin) concurrently. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on phenytoin or fosphenytoin, with dose adjustments made based on clinical efficacy.
    Estradiol; Norgestimate: (Major) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with progestin contraceptives in patients receiving hydantoins. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. (Moderate) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormones including hormonal contraceptives. Pregnancy has been reported during therapy with estrogens, oral contraceptives, non-oral combination contraceptives, or progestins in patients receiving phenytoin (the active metabolite of fosphenytoin) concurrently. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on phenytoin or fosphenytoin, with dose adjustments made based on clinical efficacy.
    Estradiol; Progesterone: (Major) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with progestin contraceptives in patients receiving hydantoins. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. (Moderate) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormones including hormonal contraceptives. Pregnancy has been reported during therapy with estrogens, oral contraceptives, non-oral combination contraceptives, or progestins in patients receiving phenytoin (the active metabolite of fosphenytoin) concurrently. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on phenytoin or fosphenytoin, with dose adjustments made based on clinical efficacy.
    Estramustine: (Moderate) Estrogens are metabolized by CYP3A4. Concurrent administration of hepatic enzyme inducers with estrogens, including hydantoin anticonvulsants, may increase the elimination of estrogen.
    Estropipate: (Moderate) Estrogens are metabolized by CYP3A4. Concurrent administration of hepatic enzyme inducers with estrogens, including hydantoin anticonvulsants, may increase the elimination of estrogen.
    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 ethanol. Chronic ingestion of ethanol induces hepatic microsomal isozymes and increases the clearance of phenytoin. Ethanol also exhibits epileptogenic potential. Ethanol 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: (Major) Hydantoins induce hepatic enzymes and can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with oral contraceptives in patients receiving phenytoin concurrently. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants; or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on hydantoins.
    Ethinyl Estradiol; Desogestrel: (Major) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with progestin contraceptives in patients receiving hydantoins. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. (Major) Hydantoins induce hepatic enzymes and can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with oral contraceptives in patients receiving phenytoin concurrently. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants; or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on hydantoins.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Major) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with progestin contraceptives in patients receiving hydantoins. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. (Major) Hydantoins induce hepatic enzymes and can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with oral contraceptives in patients receiving phenytoin concurrently. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants; or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on hydantoins.
    Ethinyl Estradiol; Etonogestrel: (Major) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with progestin contraceptives in patients receiving hydantoins. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. (Major) Hydantoins induce hepatic enzymes and can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with oral contraceptives in patients receiving phenytoin concurrently. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants; or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on hydantoins.
    Ethinyl Estradiol; Levonorgestrel: (Major) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with progestin contraceptives in patients receiving hydantoins. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. (Major) Hydantoins induce hepatic enzymes and can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with oral contraceptives in patients receiving phenytoin concurrently. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants; or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on hydantoins.
    Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Major) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with progestin contraceptives in patients receiving hydantoins. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. (Major) Hydantoins induce hepatic enzymes and can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with oral contraceptives in patients receiving phenytoin concurrently. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants; or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on hydantoins.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Major) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with progestin contraceptives in patients receiving hydantoins. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. (Major) Hydantoins induce hepatic enzymes and can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with oral contraceptives in patients receiving phenytoin concurrently. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants; or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on hydantoins. (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. (Minor) Concurrent use of folic acid, vitamin B9 and phenytoin (and fosphenytoin) 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.
    Ethinyl Estradiol; Norelgestromin: (Major) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with progestin contraceptives in patients receiving hydantoins. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. (Major) Hydantoins induce hepatic enzymes and can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with oral contraceptives in patients receiving phenytoin concurrently. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants; or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on hydantoins.
    Ethinyl Estradiol; Norethindrone Acetate: (Major) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with progestin contraceptives in patients receiving hydantoins. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. (Major) Hydantoins induce hepatic enzymes and can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with oral contraceptives in patients receiving phenytoin concurrently. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants; or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on hydantoins.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Major) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with progestin contraceptives in patients receiving hydantoins. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. (Major) Hydantoins induce hepatic enzymes and can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with oral contraceptives in patients receiving phenytoin concurrently. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants; or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on hydantoins.
    Ethinyl Estradiol; Norethindrone: (Major) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with progestin contraceptives in patients receiving hydantoins. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. (Major) Hydantoins induce hepatic enzymes and can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with oral contraceptives in patients receiving phenytoin concurrently. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants; or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on hydantoins.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Major) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with progestin contraceptives in patients receiving hydantoins. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. (Major) Hydantoins induce hepatic enzymes and can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with oral contraceptives in patients receiving phenytoin concurrently. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants; or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on hydantoins.
    Ethinyl Estradiol; Norgestimate: (Major) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with progestin contraceptives in patients receiving hydantoins. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. (Major) Hydantoins induce hepatic enzymes and can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with oral contraceptives in patients receiving phenytoin concurrently. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants; or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on hydantoins.
    Ethinyl Estradiol; Norgestrel: (Major) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with progestin contraceptives in patients receiving hydantoins. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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. (Major) Hydantoins induce hepatic enzymes and can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with oral contraceptives in patients receiving phenytoin concurrently. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants; or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on hydantoins.
    Etonogestrel: (Major) Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormonal contraceptives. Pregnancy has been reported during therapy with progestin contraceptives in patients receiving hydantoins. Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs 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.
    Etoposide, VP-16: (Major) Monitor for clinical efficacy of etoposide, VP-16 when coadministered with phenytoin or fosphenytoin, as concomitant use is associated with increased etoposide clearance and reduced efficacy.
    Etravirine: (Major) Etravirine should not be coadministered with fosphenytoin 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) Depending on the indication, coadministration of fosphenytoin with everolimus may need to be avoided or an everolimus dose adjustment may be necessary due to decreased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), avoid concomitant use where alternatives exist. If concurrent use cannot be avoided, double the daily dose of everolimus using increments of 5 mg or less. Resume the previous dose after the inducer has been discontinued for 5 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, double the daily dose of everolimus using increments of 5 mg or less; multiple increments may be required. Addition of a second strong CYP3A4 inducer may not require additional dosage modifications. Assess trough concentrations when initiating and discontinuing the inducer. Subsequent dosing should be guided by therapeutic drug monitoring. Resume the previous dose of everolimus once all inducers are discontinued for 5 days. Coadministration of fosphenytoin with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer.
    Exemestane: (Major) If coadministration of exemestane with fosphenytoin is necessary, increase the dose of exemestane to 50 mg once daily after a meal. Exemestane is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased exemestane exposure by 54%.
    Ezetimibe; Simvastatin: (Moderate) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, such as simvastatin, leading to reduced efficacy of simvastatin.
    Ezogabine: (Major) During concurrent use of ezogabine 300 to1200 mg/day and phenytoin 120 to 600 mg/day, the AUC and Cmax of ezogabine were reduced by 34% and 18%, respectively. An increase in the dose of ezogabine should be considered during concurrent use of phenytoin or fosphenytoin.
    Fedratinib: (Major) Avoid coadministration of fedratinib with fosphenytoin 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; fosphenytoin is a strong CYP3A4 inducer and CYP2C19 substrate. The coadministration of fedratinib with a strong CYP3A4 inducer has not been evaluated.
    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.
    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 coadministration with fosphenytoin is necessary. If fosphenytoin is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a strong CYP3A4 inducer like fosphenytoin 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.
    Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (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.
    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) Fluconazole can decrease the metabolism of phenytoin. A mean increase of 88% in phenytoin serum AUC has been seen in some normal male volunteers taking both fluconazole and phenytoin. Concentrations of phenytoin should be carefully monitored if fluconazole is added. A similar interaction would be expected with fosphenytoin.
    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: (Major) Cytochrome CYP2C19 is one of two pathways by which hydantoins are metabolized, and fluoxetine inhibits this pathway. Hydantoin toxicity has been described in several patients after the addition of fluoxetine.
    Fluoxetine; Olanzapine: (Major) Cytochrome CYP2C19 is one of two pathways by which hydantoins are metabolized, and fluoxetine inhibits this pathway. Hydantoin toxicity has been described in several patients after the addition of 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.
    Flurazepam: (Moderate) Hydantoin anticonvulsants are hepatic enzyme inducers and can theoretically increase the clearance of benzodiazepines metabolized by oxidative metabolism, leading to lower benzodiazepine concentrations. In addition, the potential for additive CNS depression may occur.
    Fluticasone: (Moderate) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of fluticasone, leading to reduced efficacy. Depending on the individual clinical situation and the indication for the interacting medication, enzyme-induction interactions may not always produce reductions in treatment efficacy.
    Fluticasone; Salmeterol: (Moderate) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of fluticasone, leading to reduced efficacy. Depending on the individual clinical situation and the indication for the interacting medication, enzyme-induction interactions may not always produce reductions in treatment efficacy.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of fluticasone, leading to reduced efficacy. Depending on the individual clinical situation and the indication for the interacting medication, enzyme-induction interactions may not always produce reductions in treatment efficacy.
    Fluticasone; Vilanterol: (Moderate) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of fluticasone, leading to reduced efficacy. Depending on the individual clinical situation and the indication for the interacting medication, enzyme-induction interactions may not always produce reductions in treatment efficacy.
    Fluvastatin: (Moderate) Fosphenytoin is converted to phenytoin. Both phenytoin and fluvastatin are metabolized via the CYP 2C9 isoenzyme. Concomitant administration of fluvastatin and phenytoin increased the levels of phenytoin and fluvastatin, suggesting predominant involvement of CYP 2C9 in fluvastatin metabolism. Single morning dose administration of phenytoin (300 mg extended-release) increased the mean steady-state fluvastatin Cmax by 27% and AUC by 40% whereas fluvastatin (40 mg) increased the mean phenytoin Cmax by 5% and AUC by 20%. Patients receiving fosphenytoin should be monitored more closely when fluvastatin therapy is initiated or when the fluvastatin dosage is changed.
    Fluvoxamine: (Major) Hydantoin anticonvulsant clearance can be decreased by drugs that inhibit the cytochrome P450 2C subset of isoenzymes, including fluvoxamine. Phenytoin, ethotoin or fosphenytoin dosage adjustments may be necessary in some patients who receive fluvoxamine concurrently; monitor for signs of hydantoin toxicity.
    Folic Acid, Vitamin B9: (Minor) Concurrent use of folic acid, vitamin B9 and phenytoin (and fosphenytoin) 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.
    Food: (Moderate) The incidence of marijuana associated adverse effects may change following coadministration with phenytoin or fosphenytoin. Phenytoin is an inhibitor of CYP2C9 and an inducer of CYP3A4, two isoenzymes responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with phenytoin, the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be altered. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile.
    Fosamprenavir: (Major) Anticonvulsants, such as hydantoin anticonvuls