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    Anticonvulsants, Hydantoins

    BOXED WARNING

    Adams-Stokes syndrome, AV block, bradycardia, bundle-branch block, cardiac arrhythmias, cardiac disease, coronary artery disease, heart failure, hypotension, intravenous administration

    Phenytoin injection is contraindicated in patients with sinus bradycardia, sino-atrial block, second or third degree AV block, and Adams-Stokes syndrome because of the effects of the drug on ventricular automaticity. Intravenous phenytoin should not be used in patients with other cardiac conduction abnormalities (e.g., bundle-branch block) and should be used with caution in any patient with cardiac disease, such as cardiac arrhythmias, congestive heart failure, or coronary artery disease, because symptoms may be potentiated or exacerbated. In addition, FDA-approved labeling for parenteral phenytoin contains a boxed warning that highlights the cardiovascular risks associated with rapid intravenous administration rates. Severe cardiovascular reactions have occurred, including bradycardia, heart block, ventricular tachycardia, and ventricular fibrillation, which have resulted in asystole, cardiac arrest, and death in some cases. The rate of intravenous administration is critically important to avoid or limit adverse events; do not exceed recommended infusion rates. In elderly or debilitated patients, some experts suggest infusing IV no faster than 25 mg/minute; consider slower infusion rates if concurrent cardiac disease is present. Though the manufacturer recommends a pediatric infusion rate of 1 to 3 mg/kg/minute (not to exceed 50 mg/minute) most experts recommend not exceeding a rate of 1 mg/kg/minute in any pediatric patient. Hypotension may occur, especially after high doses are given at high rates of administration. Although the risk of cardiovascular toxicity is increased with rapid intravenous administration, cardiac events have also been reported at or below the recommended infusion rates. Reactions to parenteral phenytoin occur more often in elderly or debilitated patients, children (particularly infants), those who are critically ill, or those with pre-existing hypotension or severe myocardial insufficiency. Careful cardiac and respiratory monitoring is required during and after intravenous phenytoin administration. A reduction in the rate of administration or discontinuation of the drug may be necessary if cardiac reactions occur. Some cardiac effects are thought to be secondary to the propylene glycol (PEG) diluent of the parenteral product.

    DEA CLASS

    Rx

    DESCRIPTION

    Oral and parenteral hydantoin anticonvulsant with narrow therapeutic window; used for tonic-clonic seizures and complex partial seizures; switching dosage forms may produce significant changes in serum concentrations; close monitoring for emerging or worsening suicidal thoughts/behavior or depression is recommended.

    COMMON BRAND NAMES

    Dilantin, Phenytek

    HOW SUPPLIED

    Dilantin/Phenytek/Phenytoin/Phenytoin Sodium Oral Cap ER: 30mg, 100mg, 200mg, 300mg
    Dilantin/Phenytoin Oral Susp: 5mL, 125mg
    Dilantin/Phenytoin Oral Tab Chew: 50mg
    Phenytoin/Phenytoin Sodium Intramuscular Inj Sol: 1mL, 2mL, 5mL, 50mg, 100mg, 250mg
    Phenytoin/Phenytoin Sodium Intravenous Inj Sol: 1mL, 2mL, 5mL, 50mg, 100mg, 250mg

    DOSAGE & INDICATIONS

    For the treatment of status epilepticus.
    Intravenous dosage
    Adults

    15 to 20 mg/kg via slow IV push or via IV infusion in patients with unknown, undetectable, or low (i.e. less than or equal to 10 mcg/mL) phenytoin concentrations. In patients with detectable serum phenytoin, reduce loading dose correspondingly. Because of the increased risk of cardiovascular toxicity associated with rapid infusion, do not exceed an infusion rate of 50 mg/minute in adults. If seizures are not terminated after the initial loading dose, consider additional anticonvulsants. The full antiepileptic effect of phenytoin is not immediate; a concurrent IV benzodiazepine (e.g., lorazepam or diazepam) or short-acting IV barbiturate is usually necessary. Some experts advocate an additional phenytoin dose of 5 to 10 mg/kg IV if the initial loading dose fails to terminate seizures. Total loading dose should not exceed 30 mg/kg. Continuously monitor electrocardiogram, blood pressure, and respiratory status throughout infusion and until 1 hour post-infusion. Ideally, begin maintenance dose within 12 hours.

    Infants, Children, and Adolescents

    20 mg/kg IV (Max: 1,000 mg IV) is recommended by most experts. The product labeling recommends a range of 15 to 20 mg/kg for the loading dose. Do not exceed an IV infusion rate of 0.5 to 1 mg/kg/minute in pediatric patients (Max rate: 50 mg/minute). 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 phenytoin dose of 5 to 10 mg/kg IV if the initial loading dose fails to terminate seizures. Total loading dose Max: 30 mg/kg. Continuously monitor electrocardiogram, blood pressure, and respiratory status throughout infusion and until 1 hour post-infusion.

    Neonates

    15 to 20 mg/kg IV administered at a rate not to exceed 0.5 to 1 mg/kg/minute. 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, blood pressure, and respiratory status throughout infusion and until 1 hour post-infusion.

    For the treatment of tonic-clonic seizures or partial seizures.
    For maintenance dosing to treat tonic-clonic or complex partial seizures.
    Oral dosage
    Adults

    4 to 7 mg/kg/day PO is appropriate for most patients; the dosing of phenytoin is highly variable. If sustained-release capsules are used, the dose can be given as a single daily oral dose in many patients once dosage is stabilized. If chewable tablets, oral suspension, or prompt-release capsules are used, the daily dosage should be divided into 2, or in some patients, 3 doses per day. Multiple daily doses should be given at regular intervals. Monitor phenytoin concentrations.

    Children and Adolescents

    Initial maintenance dose: 5 mg/kg/day PO (range: 4 to 8 mg/kg/day PO), divided into 2 or 3 doses per day. If the daily dose cannot be divided evenly, administer the larger dose in the evening. Usual product label Max: 300 mg/day PO; however, this dosage is sometimes exceeded in clinical practice with careful titration and monitoring. Pharmacokinetic data suggest the following maintenance doses are often required to maintain plasma concentrations in the therapeutic range in pediatric patients: CHILDREN LESS THAN 3 YEARS: 10 mg/kg/day PO; CHILDREN 4 TO 6 YEARS: 7.5 mg/kg/day PO; CHILDREN 7 TO 9 YEARS: 7 mg/kg/day PO; CHILDREN AND ADOLESCENTS 10 TO 16 YEARS: 6 mg/kg/day PO.

    Infants

    Initial maintenance dose: 5 mg/kg/day PO (range: 4 to 8 mg/kg/day PO), divided into 2 or 3 doses per day initially and then titrate to clinical response and phenytoin concentrations. If the daily dose cannot be divided evenly, administer larger dose in evening. Infants may require larger maintenance doses due to the enhanced hepatic clearance seen until 1 year of age.

    Neonates

    Initial maintenance dose: 4 to 8 mg/kg/day PO, divided into 2 or more doses per day and then titrate to clinical response and phenytoin concentrations. Some neonates, particularly after the first week of life, may have difficulty maintaining therapeutic concentrations within this dosage range and require higher maintenance doses (e.g., 10 mg/kg/day PO).

    Intravenous dosage
    Adults

    4 to 7 mg/kg/day IV is appropriate for most patients; the dosing of phenytoin is highly variable. Give phenytoin injection in multiple daily doses, at regular intervals. Monitor phenytoin concentrations. Do not exceed an IV infusion rate of 50 mg/minute in adults because of the increased risk of cardiovascular toxicity associated with rapid administration. IV phenytoin should only be used when oral administration is not possible.

    Children and Adolescents

    Initial maintenance dose: 5 mg/kg/day IV (range: 4 to 8 mg/kg/day IV), divided into 2 or more doses per day initially and then titrate to clinical response and phenytoin concentrations. Do not exceed max IV infusion rate of 0.5 to 1 mg/kg/minute (Max: 50 mg/minute) in pediatric patients. Due to faster clearance in pediatric patients, dosing frequencies of at least every 8 hours may provide more consistent concentrations. Pharmacokinetic data from oral formulations (chewable tablets and capsules) suggest higher maintenance doses are typically required to maintain therapeutic concentrations for pediatric patients. Use IV phenytoin only when oral administration is not possible, due to potential cardiovascular and local toxicity.

    Infants

    Initial maintenance dose: 5 mg/kg/day IV (range: 4 to 8 mg/kg/day IV), divided into 2 or more doses per day initially and then titrate to clinical response and phenytoin concentrations. Do not exceed max IV infusion rate of 0.5 to 1 mg/kg/minute in pediatric patients. Infants may require larger maintenance doses due to the enhanced hepatic clearance seen until 1 year of age. Due to fast clearance, dosing frequencies of at least every 8 hours may provide more consistent plasma concentrations. Use IV phenytoin only when oral administration is not possible, due to potential cardiovascular and local toxicity.

    Neonates

    Initial maintenance dose: 4 to 8 mg/kg/day IV, divided into 2 or 3 doses per day initially and then titrate to clinical response and phenytoin concentrations. Do not exceed max IV infusion rate of 0.5 to 1 mg/kg/minute in pediatric patients. Some neonates, particularly after the first week of life, may have difficulty maintaining therapeutic concentrations within this dosage range and require higher maintenance doses (e.g., 10 mg/kg/day).

    Intramuscular dosage
    Adults

    Avoid intramuscular (IM) phenytoin administration if possible since absorption is erratic and there is an increased risk of tissue injury, necrosis, or abscess formation from IM use. If IM route is the only available option, and the patient is currently stable on an oral regimen with plasma levels within the therapeutic range, an IM dose of 50% greater than the oral dose is necessary to maintain these plasma levels. Experience for periods greater than 1 week is lacking and phenytoin concentration monitoring is recommended. When returning to oral dosing, the oral dose should be reduced by 50% of the original oral dose for 1 week to prevent excessive plasma levels caused by sustained release from muscle tissue sites. Continue to monitor phenytoin concentrations. Do not use IM phenytoin for the treatment of status epilepticus or other emergent conditions because peak plasma levels may require up to 24 hours to achieve.

    For non-emergent treatment to increase phenytoin serum concentrations in a patient currently receiving phenytoin, but who has subtherapeutic serum concentrations; or to initiate phenytoin therapy for seizures in non-emergent situations.
    Oral non-emergent loading dosage (immediate-release formulations)
    Adults

    15 to 20 mg/kg PO for non-emergent loading doses in a patient not currently on phenytoin; the loading dose should be divided and administered in no more than 400 mg/dose every 2 to 3 hours. Although loading doses of phenytoin have been administered successfully via the oral route, this approach requires several hours to achieve a therapeutic concentration. Sustained-release dosage forms should not be used for loading doses. In patients with detectable but subtherapeutic serum phenytoin, reduce the loading dose correspondingly; following the completion of oral loading, begin maintenance dose within 12 hours. Do not use the oral route in emergent situations.

    Infants, Children, and Adolescents

    For the loading dose†, give 10 to 20 mg/kg PO; divide total dose into 3 doses and administer each portion 2 to 3 hours apart. Sustained-release dosage forms should not be used for loading doses. Do not use the oral route in emergent situations.

    Neonates

    Due to erratic absorption and challenges related to frequent feeding schedules, oral loading is typically not practical in neonates.

    Intravenous non-emergent loading dosage
    Adults

    Loading dose: 10 to 20 mg/kg (Usual Max: 1,000 mg) via IV infusion. Because of the increased risk of cardiovascular toxicity associated with rapid IV administration, do not exceed an infusion rate of 50 mg/minute in adults. Intravenous phenytoin should only be used when oral phenytoin administration is not possible. Continuously monitor electrocardiogram, blood pressure, and respiratory status during and until 1 hour after the infusion.

    Neonates, Infants, Children, and Adolescents

    Loading dose: 10 to 20 mg/kg IV (Not to exceed 1,000 mg IV in older pediatric patients) administered via IV infusion. Do not exceed max IV infusion rate of 0.5 to 1 mg/kg/minute (Max: 50 mg/minute) in pediatric patients. Continuously monitor electrocardiogram, blood pressure, and respiratory status during and until 1 hour after the infusion. Use IV phenytoin only when oral administration is not possible, due to potential cardiovascular and local toxicity.

    For seizure prophylaxis due to specific neurologic conditions, including neurosurgery, head trauma† or traumatic brain injury†, or subarachnoid hemorrhage†.
    For seizure prophylaxis following traumatic brain injury† or head trauma† or for seizure prophylaxis or treatment during neurosurgery.
    Intravenous dosage
    Adults

    The loading dose is 10 to 20 mg/kg (Usual Max: 1,000 mg) via IV infusion. Do not exceed an IV infusion rate of 50 mg/minute in adults. Continuously monitor electrocardiogram, blood pressure, and respiratory function throughout infusion until 1 hour post-infusion. A typical initial maintenance dose is 4 to 6 mg/kg/day IV, divided into 2 or more doses. Do not exceed an IV administration rate of 50 mg/minute. Use IV route only when oral phenytoin administration is not possible. Titrate to therapeutic effect and phenytoin concentrations. Routine seizure prophylaxis beyond 1 week is not recommended by clinical practice guidelines for the treatment of traumatic brain injury.

    Children and Adolescents

    Loading dose: 10 to 20 mg/kg via IV infusion. Do not exceed an IV infusion rate of 0.5 to 1 mg/kg/minute (Max: 50 mg/minute) in pediatric patients. Max initial IV load: 1,000 mg IV. Continuously monitor electrocardiogram, blood pressure, and respiratory function throughout infusion until 1 hour post-infusion. Initial maintenance dose: 5 mg/kg/day IV (range: 4 to 8 mg/kg/day IV), divided into 2 or more doses per day. Max IV administration rate: 0.5 to 1 mg/kg/minute (Max: 50 mg/minute). Due to faster clearance, dosing frequencies of at least every 8 hours may provide more consistent concentrations. Pharmacokinetic data from oral formulations (chewable tablets and capsules) suggest higher maintenance doses are typically required to maintain therapeutic concentrations for pediatric patients. Limited studies are available for traumatic brain injury seizure prophylaxis; efficacy data are inconsistent. Clinical practice guidelines state that prophylactic phenytoin may be considered in pediatric patients with severe traumatic brain injury to reduce incidence of early post-traumatic seizures; however, the data do not suggest prophylaxis improves neurologic outcome or reduces the risk of seizures long-term. Phenytoin concentrations should be monitored.

    Infants

    Loading dose: 10 to 20 mg/kg IV administered at a rate no faster than 0.5 to 1 mg/kg/minute in pediatric patients. Continuously monitor electrocardiogram, blood pressure, and respiratory function throughout infusion until 1 hour post-infusion. Initial maintenance dose: 5 mg/kg/day IV (range: 4 to 8 mg/kg/day IV), divided into 2 or more doses per day. Max IV administration rate: 0.5 to 1 mg/kg/minute. Infants may require larger maintenance doses due to enhanced hepatic clearance seen until 1 year of age. Due to fast clearance, a dosing frequency of at least every 8 hours may provide more consistent plasma concentrations. Limited studies are available for traumatic brain injury seizure prophylaxis; efficacy data are inconsistent. Clinical practice guidelines state that prophylactic phenytoin may be considered in pediatric patients with severe traumatic brain injury to reduce incidence of early post-traumatic seizures; however, the data do not suggest prophylaxis improves neurologic outcome or reduces the risk of seizures long-term. Phenytoin concentrations should be monitored.

    For the treatment of serious cardiac arrhythmias secondary to digoxin toxicity†.
    Intravenous dosage
    Adults

    100 mg IV every 5 minutes as needed until desired effect obtained to control the arrhythmia or adverse events limit tolerance, or up to a maximum total dose of 1,000 mg IV is administered. Oral therapy may follow use of IV dosing. Monitor serum concentrations. Phenytoin exhibits class IB anti-arrhythmic activity but is not commonly used due to limited utility. Historically used for arrhythmias due to digoxin toxicity.

    For seizure prophylaxis† during antenatal care in pregnant females with eclampsia† or severe preeclampsia†.
    Intravenous dosage
    Adult and Adolescent females

    Not recommended by practice guidelines; phenytoin has been inferior to magnesium sulfate in clinical trials. 10 mg/kg IV infusion initially, then 5 mg/kg IV infusion 2 hours later is a traditionally administered phenytoin regimen for eclampsia (Ryan regimen) in the obstetric setting. A 1,000 mg phenytoin loading dose via IV infusion, followed by 100 mg IV every 6 hours for 24 hours has also been used. Due to the increased risk of cardiovascular toxicity associated with rapid IV administration, do not exceed an infusion rate of 50 mg/minute in adults. Magnesium sulfate is the preferred agent for use and is initiated in patients with preeclampsia who are showing signs of progression to severe preeclampsia or to eclampsia and in all women with diagnosed eclampsia (Strong recommendation, Quality of evidence level - High). For example, in the Eclampsia Trial Collaborative Group multicenter trial, phenytoin was inferior to magnesium sulfate IV; women who received magnesium sulfate IV had a 67% lower risk of recurrent seizures than those who received phenytoin. Also, maternal and neonatal morbidity were lower in the group which received magnesium.

    †Indicates off-label use

    MAXIMUM DOSAGE

    As with all anticonvulsant-type medications, particularly those with narrow therapeutic windows, phenytoin dosage must be individualized.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Patients with hepatic disease may show early signs of phenytoin toxicity. In addition, serum concentrations of 'free' phenytoin may be increased by the hypoalbuminemia that is commonly present in cirrhotic liver disease. Dosing adjustments may be required based upon serum phenytoin level monitoring and clinical response.

    Renal Impairment

    CrCl more than 10 mL/min: No dosage adjustment needed.
    CrCl 10 mL/min or less: Dosage adjustment and serum concentration monitoring may be necessary; decreased protein binding occurs in uremia and the unbound ('free') fraction of phenytoin may be increased. Dosing adjustments may be required based upon serum phenytoin level monitoring and clinical response. 'Free' (i.e., unbound) phenytoin levels may be helpful in these patients.
     
    Intermittent hemodialysis
    See dosage in renal impairment for CrCl less than 10 mL/min. Phenytoin is not significantly removed during a standard hemodialysis session; therefore, supplemental dosing after hemodialysis is not necessary.
     
    Continuous hemodialysis (CAVHD, CVVHD)
    See dosage in renal impairment for CrCl less than 10 mL/min. Supplementation to maintenance phenytoin dosing has not been recommended.
     
    Peritoneal dialysis
    See dosage in renal impairment for CrCl less than 10 mL/min. Supplemental phenytoin dosing is not necessary during CAPD.
     
    Other Dosage Adjustments
    -Patients who are HLA-B 1502 carriers: Do not use if phenytoin-naive due to an increased risk of phenytoin-induced Stevens-Johnson syndrome and toxic epidermal necrolysis.
    -Patients who are intermediate metabolizers (IMs) of CYP2C9: Standard loading dose. Consider at least a 25% reduction of the recommended starting maintenance dose; subsequent doses should be adjusted based on response and close therapeutic drug monitoring.
    -Patients who are poor metabolizers (PMs) of CYP2C9: Standard loading dose. Consider at least a 50% reduction of the recommended starting maintenance dose; subsequent doses should be adjusted based on response and close therapeutic drug monitoring.

    ADMINISTRATION

    Oral Administration

    Different oral dosage forms are not directly interchangeable. Check with the prescriber prior to substituting one oral dosage form for another. Phenytoin capsules contain phenytoin sodium, which is 92% phenytoin. Chewable tablets and suspensions contain 100% phenytoin.

    Oral Solid Formulations

    Chewable tablets: Crush or chew tablet well before swallowing.
    Prompt-release capsules: For patients with difficulty swallowing, the capsules may be opened and the contents mixed with food or fluids. To prevent direct contact with the oral mucosa, the patient should swallow a liquid first, followed by the drug mixture, then followed with food or a full glass of water or milk.
    Extended-release capsules (e.g. Dilantin Kapseals, Phenytek, or Extended Phenytoin Sodium Capsules, USP): Administer intact; do not crush, cut or chew. While food does not affect the absorption of Dilantin Kapseals, some generic products (i.e., Extended Phenytoin Sodium Capsules, USP) exhibit reduced absorption in the presence of a high-fat meal. It may be best to administer generic extended-release phenytoin capsules on an empty stomach or in a consistent manner in relation to food to avoid bioavailability problems.

    Oral Liquid Formulations

    Oral suspension: Shake well prior to each dose. Administer using a calibrated measuring device. If given via an enteral tube, adsorption to the tubing can be minimized by diluting the suspension with a compatible diluent (e.g., at least 20 ml of NS or sterile water for administration to adults) before administering. After administration, flush the tube with at least 20 ml of the diluent (adults). Continuous enteral feedings interfere with phenytoin absorption and lower serum phenytoin concentrations by up to 80% in some patients (see Drug Interactions). Tube feedings should generally be discontinued for 1—2 hours before and after administration of each phenytoin dose. Alternatively, in some situations, rather than holding tube feedings, phenytoin doses can be adjusted to compensate for reduced bioavailability, provided serum phenytoin concentrations and the patient's clinical status are carefully monitored.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior administration whenever solution and container permit.

    Intravenous Administration

    NOTE: Dosage and route conversions: Intravenous phenytoin solutions contain phenytoin sodium, which is 92% phenytoin. Phenytoin capsules contain phenytoin sodium, which is 92% phenytoin. Chewable tablets and suspensions contain 100% phenytoin. Different phenytoin dosage forms are not directly interchangeable for one another. Check with the prescriber prior to substituting one dosage form for another.
    General Precautions for intravenous administration:
    Parenteral phenytoin is generally for intravenous administration only.  Avoid intramuscular (IM) administration of phenytoin if possible (see precautions for IM administration).
    Prior to IV administration, the patient should preferably have good intravenous access. In emergency situations, the treatment of the emergency will dictate the importance of these intravenous access recommendations.. Acceptable IV access includes: a) vein available for peripheral infusion that is at least as large as the antecubital fossa vein, preferably accessed with a catheter size 20 gauge or larger to help reduce the risk of vascular injury; or b) pre-existing central venous access. The vein utilized should be free from injury or thrombophlebitis. Avoid the use of scalp veins for infusion in infants.
    Phenytoin IV injections or infusions should be administered through a free-flowing IV of NS or other non-dextrose containing saline IV solution. Prior to administration, the patency of the IV catheter should be tested with a flush of sterile saline. Thereafter, each injection should be followed by a flush of sterile saline through the same catheter to reduce the risk of local vein irritation.
    Avoid extravasation; phenytoin is irritating to tissues and may cause injury.
    Treatment can be initiated either with a loading dose or an infusion.
    The rate of administration of IV phenytoin is critically important; do not exceed recommended infusion rates.
     
    Loading dose administration instructions:
    Adults: Inject IV at a rate not to exceed 50 mg/minute. Consider slower infusion rates in those with concurrent cardiac disease.
    Elderly or debilitated adults: Inject IV at a rate not to exceed 25—50 mg/minute.
    Children: Inject IV at a rate of 0.5—1 mg/kg/minute, not to exceed 50 mg/minute or 1—3 mg/kg/min, whichever is slower. Rates of administration of up to 3 mg/kg/min have been used, but are associated with an increased frequency of rate-related adverse events. However, the higher infusion rate may be indicated in selected circumstances.
    Infants and Neonates: Inject IV at a rate not to exceed 0.5—1 mg/kg/minute. Due to their small veins, infants may be more at risk of thrombophlebitis or other tissue injury from the use of phenytoin IV; do not infuse via scalp veins. Rates of administration of up to 3 mg/kg/min have been used, but are associated with an increased frequency of rate-related adverse events. However, the higher infusion rate may be indicated in selected circumstances.
    Concomitant use of other IV anticonvulsants will usually be necessary for rapid control of status epilepticus because of the required slow infusion rate of phenytoin.
    Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential during loading dose administration and the patient should be observed throughout the period where maximal serum phenytoin concentrations occur, up to 1 hour after the end of a loading dose infusion.The loading dose should be followed by administration of maintenance doses of oral or intravenous phenytoin every 6—8 hours (see Dosage).
     
    IV infusion preparation:
    Dilute in normal saline (0.9% NaCl solution for injection) for a final concentration of no less than 5 mg/ml of phenytoin.
    An in-line filter of 0.22—0.55 microns should be used.
    Administer immediately after preparation and complete the infusion within 1 to 4 hours. Do not refrigerate the diluted infusion mixture.
    If undiluted parenteral phenytoin is refrigerated or frozen, precipitation is possible; however, this will dissolve during exposure to room temperature and the product is still suitable for use. A faint yellow coloration may develop, but this has no effect on the potency of the solution.
     
    IV infusion administration:
    Careful cardiac monitoring (rate, rhythm, blood pressure) and close clinical observation are recommended during and after dose administration.
    Adults: Infuse IV at a rate not to exceed 50 mg/minute. Slower infusion rates are recommended to reduce the risk of adverse cardiovascular events.
    Elderly or debilitated adults: Infuse IV at a rate not to exceed 25—50 mg/minute. Slower infusion rates are recommended to reduce the risk of adverse cardiovascular events.
    Children: Infuse IV at a rate of 0.5—1 mg/kg/minute, not to exceed 50 mg/minute or 1—3 mg/kg/min, whichever is slower. While rates of administration of up to 3 mg/kg/min have been used, they are associated with an increased frequency of infusion-related adverse events.
    Infants and Neonates: Infuse IV at a rate not to exceed 0.5—1 mg/kg/minute. Due to their small veins, infants may be more at risk of thrombophlebitis or other tissue injury from the use of phenytoin IV; do not infuse via scalp veins. While rates of administration of up to 3 mg/kg/min have been used, they are associated with an increased frequency of infusion-related adverse events.

    Intramuscular Administration

    General precautions for intramuscular administration:
    Avoid intramuscular administration if possible since absorption is erratic and phenytoin may cause tissue injury, necrosis, or abscess formation at the injection site.
    If intramuscular administration is the only available option, and the patient is currently stable on an oral regimen with plasma levels within the therapeutic range, an intramuscular dose of 50% greater than the oral dose is necessary to maintain these plasma levels. Experience for periods greater than one week is lacking and blood level monitoring is recommended. When returning to oral administration, the dose should be reduced by 50% of the original oral dose for one week to prevent excessive plasma levels caused by sustained release from muscle tissue sites.
    Do not use intramuscular phenytoin for the treatment of status epilepticus or other emergent conditions because peak plasma levels may not be achieved for up to 24 hours.

    STORAGE

    Generic:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Dilantin:
    - Protect from light
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Phenytek:
    - Protect from light
    - Protect from moisture
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Barbiturate hypersensitivity, carbamazepine hypersensitivity, hydantoin hypersensitivity, succinimide hypersensitivity

    Phenytoin 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 phenytoin if the patient or an immediate family member has a carbamazepine hypersensitivity, barbiturate hypersensitivity, succinimide hypersensitivity, or oxazolidinedione hypersensitivity. Hypersensitivity reactions to phenytoin have been reported in patients who previously experienced hypersensitivity to fosphenytoin, 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. If a hypersensitivity reaction which includes a rash occurs, the patient should also be evaluated for signs and symptoms of Drug Reaction with Eosinophilia and Systemic Symptom (DRESS). DRESS, also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including phenytoin. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Phenytoin should be discontinued if an alternative etiology for the signs or symptoms cannot be established. Patients should be advised that hypersensitivity reactions may include, but are not limited to, fever, sore throat, skin rash, periorbital or facial edema, myalgia, arthralgia, easy bruising, lymphadenopathy and petechial or purpuric hemorrhage, and in the case of hepatic hypersenstivity reactions, anorexia, nausea/vomiting, or yellowing of the eyes or skin. These signs and symptoms should be reported even if mild or occurring after extended use. Patients who have or are suspected to have a hypersensitivity syndrome should stop phenytoin immediately and begin alternative therapy.

    Asian patients, serious rash

    Phenytoin may cause life-threatening serious rash, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). The onset of symptoms is usually within 28 days, but can occur later. Phenytoin should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. If a rash occurs, the patient should also be evaluated for signs and symptoms of Drug Reaction with Eosinophilia and Systemic Symptom (DRESS). DRESS, also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including phenytoin. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Phenytoin should be discontinued if an alternative etiology for the signs or symptoms cannot be established. There appears to be an association between the risk of developing SJS/TEN or hypersensitivity and the presence of HLA-B 1502, an inherited allelic variant of the human leukocyte antigen B (HLA B) gene. 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. Because of an association of HLA-B 1502 and reactions to carbamazepine, 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 as an alternative to carbamazepine in patients who test positive for HLA-B 1502 and are phenytoin naive, unless the benefits outweigh the risk.

    Depression, suicidal ideation

    Antiepileptic drugs (AEDs), including phenytoin, increase the risk of suicidal ideation, thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted RR 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients taking placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately 1 case of suicidal thinking or behavior for every 530 patients treated. There were 4 suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior was observed as early as 1 week after starting drug treatment and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years of age) in the clinical trials analyzed. The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Closely monitor patients for emerging or worsening depression or suicidal thoughts/behavior. Patients and caregivers should be informed of the increased risk of suicidal thoughts and behaviors and should be advised to immediately report the emergence or worsening of depression, the emergence of suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior. Phenytoin should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose.

    Abrupt discontinuation

    Abrupt discontinuation of phenytoin in epileptic patients may precipitate acute seizures/status epilepticus. When, in the judgment of the clinician, the need for dosage reduction, discontinuation, or substitution of alternative antiepileptic medication arises, this should be done gradually. However, in the event of an allergic or hypersensitivity reaction to phenytoin, rapid substitution of alternative therapy may be necessary. In this case, alternative therapy should be an antiepileptic drug not belonging to the hydantoin chemical class.

    Hypoglycemia, hyponatremia, petit mal (absence) seizures

    Phenytoin 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. Phenytoin 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.

    Hepatic disease, hepatotoxicity, hypoalbuminemia, jaundice

    The liver is the chief site of biotransformation of phenytoin; patients with hepatic disease or impaired liver function may show early signs of toxicity. Also use phenytoin cautiously in patients with hyperbilirubinemia as bilirubin displaces phenytoin from protein-binding sites, resulting in increased free phenytoin concentrations. Serum concentrations of free phenytoin can also be increased by the hypoalbuminemia commonly seen with cirrhotic liver disease. The measurement of unbound ('free') phenytoin concentrations may be more useful in these patient populations. A small percentage of individuals metabolize phenytoin slowly due to limited enzyme availability and lack of induction; slow metabolism appears to be genetically determined. Reduced phenytoin clearance may increase the frequency and severity of adverse events. Dose adjustments may be necessary in patients with genetic polymorphism that slows drug metabolism. Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with phenytoin. These hepatic events may be part of the spectrum of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), or may occur in isolation. Other common manifestations include jaundice, hepatomegaly, elevated serum transaminase levels, leukocytosis, and eosinophilia. The clinical course of acute phenytoin hepatotoxicity ranges from prompt recovery to fatal outcomes. In these patients with acute hepatotoxicity, phenytoin should be immediately discontinued and not readministered. Baseline and periodic evaluations of liver function, particularly in patients with a history of hepatic disease, must be performed during treatment and phenytoin should be discontinued if there is evidence of new or worsening liver dysfunction.

    Agranulocytosis, bone marrow suppression, hematological disease, porphyria

    Use phenytoin with caution in patients with hematological disease or pre-existing blood dyscrasias. Although uncommon, phenytoin can cause hematological toxicity, which may exacerbate or worsen other hematological abnormalities. Hematopoietic complications, some fatal, have occasionally been reported. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. Baseline and periodic hematologic counts should be obtained; if a patient develops abnormalities, the patient should be closely monitored. Discontinuation of phenytoin 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 phenytoin in patients suffering from this disease.

    Hodgkin's disease, lymphoma

    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's disease. 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 of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). 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, coronary artery disease, heart failure, hypotension, intravenous administration

    Phenytoin injection is contraindicated in patients with sinus bradycardia, sino-atrial block, second or third degree AV block, and Adams-Stokes syndrome because of the effects of the drug on ventricular automaticity. Intravenous phenytoin should not be used in patients with other cardiac conduction abnormalities (e.g., bundle-branch block) and should be used with caution in any patient with cardiac disease, such as cardiac arrhythmias, congestive heart failure, or coronary artery disease, because symptoms may be potentiated or exacerbated. In addition, FDA-approved labeling for parenteral phenytoin contains a boxed warning that highlights the cardiovascular risks associated with rapid intravenous administration rates. Severe cardiovascular reactions have occurred, including bradycardia, heart block, ventricular tachycardia, and ventricular fibrillation, which have resulted in asystole, cardiac arrest, and death in some cases. The rate of intravenous administration is critically important to avoid or limit adverse events; do not exceed recommended infusion rates. In elderly or debilitated patients, some experts suggest infusing IV no faster than 25 mg/minute; consider slower infusion rates if concurrent cardiac disease is present. Though the manufacturer recommends a pediatric infusion rate of 1 to 3 mg/kg/minute (not to exceed 50 mg/minute) most experts recommend not exceeding a rate of 1 mg/kg/minute in any pediatric patient. Hypotension may occur, especially after high doses are given at high rates of administration. Although the risk of cardiovascular toxicity is increased with rapid intravenous administration, cardiac events have also been reported at or below the recommended infusion rates. Reactions to parenteral phenytoin occur more often in elderly or debilitated patients, children (particularly infants), those who are critically ill, or those with pre-existing hypotension or severe myocardial insufficiency. Careful cardiac and respiratory monitoring is required during and after intravenous phenytoin administration. A reduction in the rate of administration or discontinuation of the drug may be necessary if cardiac reactions occur. Some cardiac effects are thought to be secondary to the propylene glycol (PEG) diluent of the parenteral product.

    Intramuscular administration

    In general, intramuscular administration of phenytoin is not recommended because of the risk of aseptic tissue necrosis, abscess formation, and erratic absorption. Due to delayed and erratic absorption, intramuscular administration should never be used in the treatment of status epilepticus. Parenteral phenytoin has an alkaline pH (pH range approximately 10 to 12) and causes a high degree of local irritation and pain. Intramuscular administration of phenytoin is not recommended unless intravenous access and other treatment alternatives (e.g., fosphenytoin intramuscular injections) are not available.

    Alcoholism, ethanol ingestion, ethanol intoxication

    Acute ethanol ingestion may increase phenytoin serum levels while chronic ethanol ingestion can induce hepatic oxidative enzymes which metabolize phenytoin, decreasing serum concentrations. Such parameters may need to be considered when treating patients with a history of alcoholism or acute intermittent binge drinking (ethanol intoxication). In addition, concomitant use of phenytoin and ethanol can decrease the ability to perform tasks requiring mental alertness. Alcohol intoxication may alter seizure control in epileptic patients.

    Driving or operating machinery, encephalopathy, psychosis

    Phenytoin 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 phenytoin adversely affects their mental and/or motor performance. Patients should be aware of the early symptoms of phenytoin toxicity such as problems with speech, walking or coordination. 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 is recommended. A dosage reduction is indicated if plasma concentrations are excessive; if symptoms persist, termination of phenytoin therapy is recommended.

    Renal disease, renal failure, renal impairment

    Patients with renal disease, renal impairment or renal failure leading to uremia should be monitored for phenytoin toxicity. High serum concentrations of urea displace phenytoin from protein-binding sites. Due to an increased fraction of unbound phenytoin, the interpretation of total phenytoin plasma concentrations should be made with caution. Unbound ('free') phenytoin concentrations may be more useful in these patient populations.

    Diabetes mellitus

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

    Hypothyroidism

    Patients with thyroid disease, especially hypothyroidism, should be monitored for signs of hypothyroidism. Phenytoin may decrease serum concentrations of T4. Phenytoin reduces serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.

    Bone fractures, osteomalacia, osteoporosis

    The chronic use of phenytoin in patients with epilepsy has been associated with decreased bone mineral density (osteopenia, osteoporosis, and osteomalacia) and bone fractures. Phenytoin induces hepatic metabolizing enzymes which may enhance the metabolism of vitamin D and decrease vitamin D levels. This action may lead to vitamin D deficiency, hypocalcemia, and hypophosphatemia. Consideration should be given to screening with bone-related laboratory and radiological tests as appropriate and initiating treatment plans according to established guidelines.

    Myasthenia gravis

    Phenytoin, as with some other antiepileptic drugs (AEDs) has been very rarely reported to exacerbate symptoms of myasthenia gravis.

    Dental disease

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

    Extravasation

    Local soft tissue irritation, ranging from tenderness to extensive necrosis, and inflammation can occur at the site of administration with and without extravasation of intravenous phenytoin. Edema, discoloration and pain distal to the injection site ("purple glove syndrome") have been reported. To minimize the risk for these adverse effects, administer phenytoin directly into a large peripheral or central vein through a large-gauge catheter. Confirm the patency of the catheter prior to each dose using a sterile saline flush.

    Geriatric

    Phenytoin use may require extra care 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 level determinations may be necessary to achieve optimal dosage adjustments. Phenytoin serum levels sustained above the optimal range may produce confusional states similar to delirium or encephalopathy, or rarely induce irreversible cerebellar dysfunction; the elderly patient should be carefully monitored for symptoms of acute toxicity. Adverse reactions to parenteral phenytoin occur more often in patients who are geriatric, critically ill, or those with pre-existing hypotension or severe myocardial insufficiency. In geriatic patients, some experts suggest infusing IV no faster than 25 mg/minute; consider slower infusion rates if concurrent cardiac disease is present; careful cardiac monitoring is needed during and after an infusion of phenytoin and a reduction in the rate of administration or discontinuation of the drug may be needed. According to the Beers Criteria, anticonvulsants are considered potentially inappropriate medications (PIMs) in geriatric patients with a history of falls or fractures and should be avoided in these patient populations, with the exception of treating seizure and mood disorders, since anticonvulsants can produce ataxia, impaired psychomotor function, syncope, and additional falls. If phenytoin must be used, consider reducing use of other CNS-active medications that increase the risk of falls and fractures and implement other strategies to reduce fall risk. The federal Omnibus Budget Reconciliation Act (OBRA) provides guidance for the use of anticonvulsants in residents of long-term care facilities. The need for indefinite continuation should be based on confirmation of the condition and its potential cause(s). When the 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 in accordance with OBRA guidelines.

    Neonates, obstetric delivery, pregnancy, vitamin K deficiency

    Phenytoin is classified by the FDA in pregnancy risk category D. Phenytoin is a known teratogen, and a recognizable pattern of malformations has been observed (known as fetal hydantoin syndrome; see Adverse Reactions). There have also been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy. Women of child-bearing age taking phenytoin should be counseled regarding the risks to the fetus should they become pregnant; some of the malformations associated with phenytoin use may develop early in pregnancy, even before some women discover that they are pregnant. If a woman taking phenytoin does become pregnant, there is debate as to what course of action is best; other anticonvulsants also have been associated with fetal disorders, and seizures themselves can be equally harmful to both the fetus and the mother. Maintenance of anticonvulsant therapy may be essential for the mother. Results from a prospective, multi-center, long-term, observational study of fetal death and malformations during in utero exposure to phenytoin, carbamazepine, lamotrigine, or valproate indicate that valproate poses the greatest risk for serious adverse outcomes. Enrollment was limited to pregnant women receiving monotherapy with one of the four agents for epilepsy. The outcomes of 333 infants were analyzed. The total percentages of serious adverse outcomes (fetal death or congenital malformations) were as follows: lamotrigine 1%, carbamazepine 8.2%, phenytoin 10.7%, and valproate 20.3%. Fetal deaths occurred in 3.6% of the carbamazepine and phenytoin groups, 2.9% of the valproate group, and no deaths occurred with lamotrigine. Congenital malformations were reported as follows: lamotrigine 1%, carbamazepine 4.5%, phenytoin 7.1%, and valproate 17.4%. Congenital malformations in the phenytoin group included agenesis of the corpus callosum, hydronephrosis and extra renal pelvis, undescended testicle, and ventricular septal defect. Retrospective case reviews suggest that, compared with monotherapy, there may be a higher prevalence of teratogenic effects associated with the combination use of anticonvulsants; monotherapy may be preferable during pregnancy. Appropriate intake of folic acid prior to conception and during pregnancy, particularly in the first trimester, should be considered. Regular evaluation of phenytoin serum concentrations should be made because higher levels are more likely to be harmful. Especially during the 2nd and 3rd trimester, the protein-binding, distribution, and metabolism of phenytoin may be altered, necessitating close clinical monitoring to guide dose adjustments in the gravid woman. Tests to detect birth-defects using currently accepted procedures should be considered a part of routine prenatal care. Neonatal coagulation defects have been reported within the first 24 hours in neonates born to epileptic mothers receiving phenobarbital and/or phenytoin, and appear to result from drug-induced vitamin K deficiency in the fetus. Administration of vitamin K to the mother before obstetric delivery (NOTE: various protocols are used) and to the neonate at birth has been shown to prevent or correct this defect. Physicians are advised to recommend that pregnant patients receiving phenytoin enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry to provide information about the effects of in utero exposure to the drug. 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

    Infant breast-feeding is not recommended for women taking phenytoin because the drug appears to be secreted in low concentrations in human milk. Milk to plasma ratios 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; phenytoin is generally considered by experts to be compatible with breast-feeding. The risk for adverse effects such as sedation in the infant appears to be higher in patients taking multiple antiepileptic drugs (AEDs). Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    ADVERSE REACTIONS

    Severe

    hepatic failure / Delayed / 1.0-10.0
    cerebral edema / Early / 4.5-4.5
    suicidal ideation / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    coma / Early / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    scarlatiniform exanthema / Rapid / Incidence not known
    lupus-like symptoms / Delayed / Incidence not known
    diabetic ketoacidosis / Delayed / Incidence not known
    hepatic necrosis / Delayed / Incidence not known
    hemolytic anemia / Delayed / Incidence not known
    aplastic anemia / Delayed / Incidence not known
    megaloblastic anemia / Delayed / Incidence not known
    porphyria / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    bone fractures / Delayed / Incidence not known
    nephrotic syndrome / Delayed / Incidence not known
    interstitial nephritis / Delayed / Incidence not known
    glomerulonephritis / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    bradycardia / Rapid / Incidence not known
    ventricular fibrillation / Early / Incidence not known
    vasculitis / Delayed / Incidence not known
    cardiac arrest / Early / Incidence not known
    AV block / Early / Incidence not known
    skin necrosis / Early / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    teratogenesis / Delayed / Incidence not known

    Moderate

    ataxia / Delayed / 1.0-10.0
    nystagmus / Delayed / 1.0-10.0
    constipation / Delayed / 1.0-10.0
    hypotension / Rapid / 0-9.1
    amblyopia / Delayed / 0-9.1
    peripheral vasodilation / Rapid / 0-4.5
    gingival hyperplasia / Delayed / 10.0
    depression / Delayed / Incidence not known
    peripheral neuropathy / Delayed / Incidence not known
    confusion / Early / Incidence not known
    respiratory depression / Rapid / Incidence not known
    dysarthria / Delayed / Incidence not known
    bullous rash / Early / Incidence not known
    eosinophilia / Delayed / Incidence not known
    lymphadenopathy / Delayed / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    hepatomegaly / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    osteoporosis / Delayed / Incidence not known
    hypocalcemia / Delayed / Incidence not known
    hypophosphatemia / Delayed / Incidence not known
    osteomalacia / Delayed / Incidence not known
    osteopenia / Delayed / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known
    nephrolithiasis / Delayed / Incidence not known
    priapism / Early / Incidence not known
    secondary malignancy / Delayed / Incidence not known
    hypothyroidism / Delayed / Incidence not known
    dystonic reaction / Delayed / Incidence not known
    choreoathetosis / Delayed / Incidence not known
    dyskinesia / Delayed / Incidence not known
    cataracts / Delayed / Incidence not known

    Mild

    paresthesias / Delayed / 1.0-10.0
    insomnia / Early / 1.0-10.0
    vertigo / Early / 1.0-10.0
    headache / Early / 1.0-10.0
    asthenia / Delayed / 1.0-10.0
    dizziness / Early / 1.0-10.0
    drowsiness / Early / 1.0-10.0
    hyporeflexia / Delayed / 1.0-10.0
    vomiting / Early / 1.0-10.0
    abdominal pain / Early / 1.0-10.0
    nausea / Early / 1.0-10.0
    dysgeusia / Early / 1.0-10.0
    tinnitus / Delayed / 0-9.1
    tremor / Early / 10.0
    hypertrichosis / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known
    skin hyperpigmentation / Delayed / Incidence not known
    purpura / Delayed / Incidence not known
    hirsutism / Delayed / Incidence not known
    macrocytosis / Delayed / Incidence not known
    libido decrease / Delayed / Incidence not known
    injection site reaction / Rapid / Incidence not known
    asterixis / Delayed / Incidence not known
    metallic taste / Early / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: Avoid concurrent use of dolutegravir with phenytoin, as coadministration may result in decreased dolutegravir plasma concentrations. Currently, there are insufficient data to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Phenytoin is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
    Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: Coadministration with zidovudine has resulted in altered phenytoin concentrations. Reports have varied, with increased and decreased phenytoin concentrations being reported. Use combination with caution.
    Abiraterone: Avoid or cautiously use strong inducers of CYP3A4 during abiraterone treatment. In vitro, abiraterone is a CYP3A4 substrate. The in vivo effects of strong CYP3A4 inducers such as phenytoin on the pharmacokinetic parameters of abiraterone have not been evaluated.
    Acetaminophen: 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: 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. 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: 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. 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: 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. 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. 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: 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. In vitro studies have shown no effect of carbamazepine and phenytoin on the conversion of codeine to morphine. However, CYP450 inducers (e.g., rifampin, barbiturates, carbamazepine, and phenytoin or fosphenytoin) may induce the metabolism of codeine and, therefore, may cause increased clearance of the drug which could lead to a decrease in codeine plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome in a patient who had developed physical dependence to codeine. If co-administration with codeine is necessary, caution is advised when initiating therapy with, currently taking, or discontinuing any potent CYP3A4 inducers. Evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved. When using barbiturates with codeine, additive sedation and respiratory depression will be expected to occur. 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. 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: 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. 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. 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: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers. 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. 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: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers. 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. 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: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers. 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: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers. 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: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers. 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: In vitro studies have shown no effect of carbamazepine and phenytoin on the conversion of codeine to morphine. However, CYP450 inducers (e.g., rifampin, barbiturates, carbamazepine, and phenytoin or fosphenytoin) may induce the metabolism of codeine and, therefore, may cause increased clearance of the drug which could lead to a decrease in codeine plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome in a patient who had developed physical dependence to codeine. If co-administration with codeine is necessary, caution is advised when initiating therapy with, currently taking, or discontinuing any potent CYP3A4 inducers. Evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved. When using barbiturates with codeine, additive sedation and respiratory depression will be expected to occur. 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: 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: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers. 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: 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: 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: 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: Phenytoin theoretically can add to the CNS-depressant effects of other CNS depressants. 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: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers. 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: 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: Additive CNS depression may occur when hydantoins are when given with hydrocodone. Also, hydrocodone is metabolized by CYP3A4. Fosphenytoin, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with fosphenytoin. 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: Oxycodone is metabolized by CYP3A4. Phenytoin or fosphenytoin, an inducer of CYP3A4, may cause increased clearance of oxycodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to oxycodone. If coadministration of these agents is necessary, monitor patients at frequent intervals and consider dose adjustments if needed. 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: 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: 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. 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: 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: 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. 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: Acitretin reduces the protein binding of phenytoin. Free phenytoin concentrations may be useful for therapeutic monitoring if both acitretin and phenytoin are administered concurrently.
    Acrivastine; Pseudoephedrine: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Acyclovir: 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: If the concomitant chronic use of phenytoin and afatinib is necessary, consider increasing the afatinib dose by 10 mg per day as tolerated; resume the previous dose of afatinib 2 to 3 days after discontinuation of phenytoin. Afatinib is a P-glycoprotein (P-gp) substrate in vitro. There is weak evidence that phenytoin may be a P-gp inducer; coadministration may decrease plasma concentrations of afatinib. Pre-treatment with a strong P-gp inducer, rifampicin (600 mg daily for 7 days), decreased the afatinib AUC by 34% and the Cmax by 22%.
    Albendazole: 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: 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: 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: 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: 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: Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
    Alogliptin; Metformin: 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. Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
    Alogliptin; Pioglitazone: Phenytoin and other hydantoins have the potential to increase blood glucose and thus interact with antidiabetic agents pharmacodynamically. Monitor blood glucose for changes in glycemic control. Dosage adjustments may be necessary in some patients.
    Alosetron: Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of aolsetron, leading to reduced efficacy of alosetron.
    Alpha-glucosidase Inhibitors: 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: 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: Altretamine undergoes significant metabolism by the cytochrome P450 system. Phenytoin is known to induce CYP450 enzymes. In theory, co-administration may increase the rate of altretamine metabolism thus decreasing altretamine effect; one study in mice has suggested that hepatic enzyme induction antagonizes antitumor activity of altretamine.
    Ambrisentan: Although in vivo studies with rifampin, a CYP3A and CYP2C19 inducer, did not result in induction of ambrisentan metabolism, hepatic enzyme inducers such as fosphenytoin and phenytoin may affect the metabolism of ambrisentan and may necessitate dosage adjustments of ambrisentan.
    Amiodarone: 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: 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: 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. Phenytoin is a hepatic inducer and can theoretically increase the clearance of chlordiazepoxide oxidative metabolism, leading to lower benzodiazepine concentrations. In addition, chlordiazepoxide has been reported to have an unpredictable effect on phenytoin serum concentrations (e.g., to increase, decrease, or cause no change in phenytoin serum concentrations). Conflicting results may have been observed due to saturable phenytoin metabolism and/or other conditions associated with the reported data. Since definitive controlled trial data are lacking, phenytoin concentrations should be monitored more closely when chlordiazepoxide is added or discontinued.
    Amlodipine: 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: 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. Phenytoin, which is a CYP3A4 inducer, may decrease the efficacy of HMG-Co-A reductase inhibitors which are CYP3A4 substrates including atorvastatin.
    Amlodipine; Benazepril: 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: 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: 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: 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: 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: 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: 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: 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: Penicillin G is 60% bound to albumin or moderately protein bound. Displacement of penicillins from plasma protein binding sites by highly protein bound drugs (e.g., phenytoin, fosphenytoin) will elevate the level of free penicillin in the serum. The clinical significance of this interaction is unclear. It is recommended to monitor these patients for increased adverse effects.
    Amoxicillin; Clarithromycin; Lansoprazole: 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. Penicillin G is 60% bound to albumin or moderately protein bound. Displacement of penicillins from plasma protein binding sites by highly protein bound drugs (e.g., phenytoin, fosphenytoin) will elevate the level of free penicillin in the serum. The clinical significance of this interaction is unclear. It is recommended to monitor these patients for increased adverse effects.
    Amoxicillin; Clarithromycin; Omeprazole: 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. Penicillin G is 60% bound to albumin or moderately protein bound. Displacement of penicillins from plasma protein binding sites by highly protein bound drugs (e.g., phenytoin, fosphenytoin) will elevate the level of free penicillin in the serum. The clinical significance of this interaction is unclear. It is recommended to monitor these patients for increased adverse effects.
    Amoxicillin; Clavulanic Acid: Penicillin G is 60% bound to albumin or moderately protein bound. Displacement of penicillins from plasma protein binding sites by highly protein bound drugs (e.g., phenytoin, fosphenytoin) will elevate the level of free penicillin in the serum. The clinical significance of this interaction is unclear. It is recommended to monitor these patients for increased adverse effects.
    Amphetamine; Dextroamphetamine Salts: 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.
    Ampicillin: Penicillin G is 60% bound to albumin or moderately protein bound. Displacement of penicillins from plasma protein binding sites by highly protein bound drugs (e.g., phenytoin, fosphenytoin) will elevate the level of free penicillin in the serum. The clinical significance of this interaction is unclear. It is recommended to monitor these patients for increased adverse effects.
    Ampicillin; Sulbactam: Penicillin G is 60% bound to albumin or moderately protein bound. Displacement of penicillins from plasma protein binding sites by highly protein bound drugs (e.g., phenytoin, fosphenytoin) will elevate the level of free penicillin in the serum. The clinical significance of this interaction is unclear. It is recommended to monitor these patients for increased adverse effects.
    Amprenavir: 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.
    Antacids: Because the absorption of phenytoin suspension can be reduced by antacids containing magnesium, aluminum, or calcium, administration at the same time of day should be avoided when possible. Ingestion times of phenytoin capsules and calcium antacids should be staggered in patients with low serum phenytoin levels to prevent absorption difficulties. Studies evaluating the effects of magnesium-aluminium antacids on the absorption of phenytoin capsules or tablets have yielded conflicting results. Nevertheless, serum phenytoin levels and clinical response should be closely monitored if these agents are co-administered. The mechanisms by which antacids reduce phenytoin absorption may involve increased gastric transit time, chelation, adsorption, and/or altered solubility. The oral absorption of phenytoin may be reduced by calcium carbonate (e.g., as found in antacids) or other calcium salts. Calcium products may form complexes with phenytoin that are nonabsorbable. Although the magnitude of the interaction is not great, an occasional patient may be affected and the interaction may lead to subtherapeutic phenytoin concentrations. Separating the administration of phenytoin and antacids or calcium salts by at least 2 hours will help minimize the possibility of interaction.
    Apixaban: Avoid the concomitant administration of apixaban and drugs that are both strong inducers of CYP3A4 and P-gp, such as phenytoin. Concomitant administration of apixaban and phenytoin results in decreased exposure to apixaban and an increase in the risk of stroke.
    Apremilast: The coadministration of apremilast and phenytoin is not recommended. Apremilast is metabolized primarily by CYP3A4; phenytoin is a strong CYP3A4 inducer. Coadministration of rifampin, another strong CYP3A4 inducer, with a single dose of apremilast resulted in a decrease in apremilast AUC and Cmax by 72% and 43%, respectively. A similar reduction in systemic exposure may be seen with coadministration of apremilast and phenytoin which may result in a loss of efficacy of apremilast.
    Aprepitant, Fosaprepitant: Avoid the concurrent use of phenytoin with aprepitant, fosaprepitant due to substantially decreased exposure of aprepitant. If these drugs must be coadministered, monitor for a decrease in the efficacy of aprepitant as well as an increase in phenytoin-related adverse effects for several days after administration of a multi-day aprepitant regimen. Phenytoin is a strong CYP3A4 inducer and aprepitant is a CYP3A4 substrate. When a single dose of aprepitant (375 mg, or 3 times the maximum recommended dose) was administered on day 9 of a 14-day rifampin regimen (a strong CYP3A4 inducer), the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased by 3-fold. Additionally, phenytoin is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may also increase plasma concentrations of phenytoin. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. Finally, aprepitant is a CYP2C9 inducer and phenytoin is a CYP2C9 substrate. Administration of a CYP2C9 substrate, tolbutamide, on days 1, 4, 8, and 15 with a 3-day regimen of oral aprepitant (125 mg/80 mg/80 mg) decreased the tolbutamide AUC by 23% on day 4, 28% on day 8, and 15% on day 15. The AUC of tolbutamide was decreased by 8% on day 2, 16% on day 4, 15% on day 8, and 10% on day 15 when given prior to oral administration of aprepitant 40 mg on day 1, and on days 2, 4, 8, and 15. The effects of aprepitant on tolbutamide were not considered significant.
    Aripiprazole: Because aripiprazole is metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be doubled when a potential CYP3A4 inducer, such as ethotoin, phenytoin, or fosphenytoin, is added to aripiprazole therapy. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. When the CYP3A4 inducer is withdrawn from the combination therapy, the aripiprazole dose in adults should be reduced to 10 mg to 15 mg. Avoid concurrent use of the extended-release intramuscular injection with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal.
    Armodafinil: 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: Concomitant use of phenytoin and artemether; lumefantrine is contraindicated. Phenytoin is an inducer of CYP3A4 and both components of artemether; lumefantrine are substrates of this isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations and possible reduction in antimalarial activity.
    Aspirin, ASA; Butalbital; Caffeine: 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. 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: 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. In vitro studies have shown no effect of carbamazepine and phenytoin on the conversion of codeine to morphine. However, CYP450 inducers (e.g., rifampin, barbiturates, carbamazepine, and phenytoin or fosphenytoin) may induce the metabolism of codeine and, therefore, may cause increased clearance of the drug which could lead to a decrease in codeine plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome in a patient who had developed physical dependence to codeine. If co-administration with codeine is necessary, caution is advised when initiating therapy with, currently taking, or discontinuing any potent CYP3A4 inducers. Evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved. When using barbiturates with codeine, additive sedation and respiratory depression will be expected to occur. 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: 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. 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: Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. If carisoprodol is combined with an inducer of hepatic enzymes, such as phenytoin, the potential exists for increased metabolism of carisoprodol and meprobamate, the active metabolite, plasma concentrations could be increased.
    Aspirin, ASA; Carisoprodol; Codeine: In vitro studies have shown no effect of carbamazepine and phenytoin on the conversion of codeine to morphine. However, CYP450 inducers (e.g., rifampin, barbiturates, carbamazepine, and phenytoin or fosphenytoin) may induce the metabolism of codeine and, therefore, may cause increased clearance of the drug which could lead to a decrease in codeine plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome in a patient who had developed physical dependence to codeine. If co-administration with codeine is necessary, caution is advised when initiating therapy with, currently taking, or discontinuing any potent CYP3A4 inducers. Evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved. When using barbiturates with codeine, additive sedation and respiratory depression will be expected to occur. Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. If carisoprodol is combined with an inducer of hepatic enzymes, such as phenytoin, the potential exists for increased metabolism of carisoprodol and meprobamate, the active metabolite, plasma concentrations could be increased.
    Aspirin, ASA; Omeprazole: 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: Oxycodone is metabolized by CYP3A4. Phenytoin or fosphenytoin, an inducer of CYP3A4, may cause increased clearance of oxycodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to oxycodone. If coadministration of these agents is necessary, monitor patients at frequent intervals and consider dose adjustments if needed.
    Atazanavir: Coadministration of phenytoin and atazanavir may increase the metabolism of atazanavir and lead to decreased antiretroviral efficacy resulting in reduction of antiretroviral efficacy and development of viral resistance. Avoid coadministration of atazanavir with phenytoin unless atazanavir is boosted with ritonavir. If atazanavir is boosted with cobicistat, the manufacturer of cobicistat contraindicates coadministration with phenytoin while the manufacturer of atazanavir; cobicistat recommends avoiding coadministration with phenytoin. Consider use of an alternative anticonvulsant or antiretroviral therapy.
    Atazanavir; Cobicistat: Coadministration of phenytoin and atazanavir may increase the metabolism of atazanavir and lead to decreased antiretroviral efficacy resulting in reduction of antiretroviral efficacy and development of viral resistance. Avoid coadministration of atazanavir with phenytoin unless atazanavir is boosted with ritonavir. If atazanavir is boosted with cobicistat, the manufacturer of cobicistat contraindicates coadministration with phenytoin while the manufacturer of atazanavir; cobicistat recommends avoiding coadministration with phenytoin. Consider use of an alternative anticonvulsant or antiretroviral therapy. Coadministration of phenytoin with regimens containing cobicistat and atazanavir or darunavir should be avoided. If these drugs are used together, significant decreases in the plasma concentrations of cobicistat, atazanavir and potentally darunavir may occur, resulting in reduction of antiretroviral efficacy and development of viral resistance. Consider use of an alternative anticonvulsant or antiretroviral therapy. If coadministration is required, monitor phenytoin concentrations.
    Atorvastatin: Phenytoin, which is a CYP3A4 inducer, may decrease the efficacy of HMG-Co-A reductase inhibitors which are CYP3A4 substrates including atorvastatin.
    Atorvastatin; Ezetimibe: Phenytoin, which is a CYP3A4 inducer, may decrease the efficacy of HMG-Co-A reductase inhibitors which are CYP3A4 substrates including atorvastatin.
    Atracurium: 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: Concurrent administration of diphenoxylate/difenoxin with hydantoins can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
    Atropine; Diphenoxylate: Concurrent administration of diphenoxylate/difenoxin with hydantoins can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: 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.
    Auranofin: One patient receiving concomitant phenytoin and auranofin therapy developed an increased blood concentration of phenytoin. Further studies of this potential interaction are warranted.
    Avanafil: Avanafil is primarily metabolized by CYP3A4, and although no studies have been performed, concomitant administration of CYP3A4 inducers, such as phenytoin, may decrease avanafil plasma levels. Concomitant use is not recommended.
    Axitinib: Avoid coadministration of axitinib with phenytoin, due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1. Phenytoin is a strong CYP3A4 inducer and a moderate inducer of CYP1A2 and CYP2C19. Coadministration with another strong CYP3A4/5 inducer, rifampin, significantly decreased the plasma exposure of axitinib in healthy volunteers.
    Azelaic Acid; Copper; Folic Acid; Nicotinamide; Pyridoxine; Zinc: 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. Concurrent use of folic acid, vitamin B9 and phenytoin may result in decreased folic acid serum concentrations and decreased anticonvulsant effect. It is important to maintain adequate folic acid concentrations in epileptic patients taking enzyme-inducing anticonvulsants, and maintenance doses may require upward adjustment. However, in large amounts, folic acid may counteract the anticonvulsant effect of some agents, including phenytoin. Therefore, it has been recommended that oral folic acid supplementation not exceed 1 mg/day in epileptic patients taking anticonvulsants. If large doses are used, monitor phenytoin concentrations upon folic acid initiation, dose titration, and discontinuation and adjust the anticonvulsant dosage as appropriate. Prolonged administration of phenytoin reportedly has resulted in a folate deficiency in 27% to 91% of patients. Megaloblastic anemia occurs in fewer than 1% of patients receiving phenytoin. The proposed mechanisms of this phenomenon include an increase in folate catabolism, folate malabsorption, or use of folic acid secondary to enzyme induction by phenytoin. Some evidence suggests that the anticonvulsant effect of phenytoin is partially the result of a reduction in folic acid concentrations. Folic acid replacement has resulted in an increase in metabolism of phenytoin and a decrease in phenytoin concentration in some patients, apparently through increased metabolism and/or redistribution of phenytoin in the brain and CSF. A clinically significant increase in seizure activity has occurred with this drug combination in rare instances, especially when doses of 4 mg/day or more were utilized. Limited data suggests that large doses (greater than 80 mg per day) of pyridoxine, vitamin B6 may result in reduced serum phenytoin concentrations. Regular doses, such as in multivitamins, probably will have little effect. Monitor for reduced serum phenytoin concentrations or changes in seizure control if large doses of pyridoxine, vitamin B6 are coadminsitered.
    Azelastine; Fluticasone: Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of the concomitant medication. Medications that may be affected include the corticosteroids. 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: Of the macrolides, azithromycin does not inhibit cytochrome P450 enzymes and is not likely to be implicated in clinically significant drug-drug interactions involving the CYP450 system. However, azithromycin is a substrate of p-glycoprotein (P-gp), and may undergo increased efflux resulting in lowered serum concentrations if administered with P-gp inducers such as phenytoin. Azithromycin was not implicated in clinical trials with drug interactions with phenytoin. However, specific drug interaction studies have not been performed with the combination of azithromycin and phenytoin. Until more data are available, the manufacturer of azithromycin recommends caution and careful monitoring of patients who receive azithromycin with phenytoin.
    Barbiturates: 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.
    Beclomethasone: Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of the concomitant medication. Medications that may be affected include the corticosteroids. Depending on the individual clinical situation and the indication for the interacting medication, enzyme-induction interactions may not always produce reductions in treatment efficacy.
    Bedaquiline: Avoid concurrent use of phenytoin with bedaquiline. Phenytoin may induce CYP3A4 metabolism resulting in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: 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: 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.
    Benzphetamine: Patients who are taking anticonvulsants for epilepsy/seizure control should use benzphetamine with caution. Amphetamines may decrease the seizure threshold and increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary. Additionally, the amphetamines may delay the intestinal absorption of phenytoin; the extent of absorption of these seizure medications is not known to be affected.
    Bepridil: 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.
    Betamethasone: Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of the concomitant medication. Medications that may be affected include the corticosteroids. Depending on the individual clinical situation and the indication for the interacting medication, enzyme-induction interactions may not always produce reductions in treatment efficacy.
    Bexarotene: Bexarotene is metabolized by cytochrome P450 3A4. Inducers of cytochrome P450 3A4, such as hydantoins may cause a reduction in bexarotene plasma concentrations following oral administration of bexarotene. However, due to low systemic exposure to bexarotene after low to moderate intense gel regimens, clinically significant metabolic drug interactions are unlikely with bexarotene gel.
    Bicalutamide: Bicalutamide is metabolized by cytochrome P450 3A4. Drugs that are potent inducers of CYP3A4 activity, such as hydantoin anticonvulsants, will decrease the plasma concentrations of bicalutamide.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: Metronidazole can decrease the clearance of phenytoin, 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: Metronidazole can decrease the clearance of phenytoin, which can lead to an increase in phenytoin plasma concentrations. Phenytoin levels should be checked regularly when metronidazole therapy is undertaken.
    Bleomycin: 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: No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as phenytoin. The dose of the concomitant drug may need to be adjusted.
    Boceprevir: The potential for boceprevir treatment failure exists when boceprevir is administered with phenytoin; therefore, the concurrent use of these medications is contraindicated. Phenytoin 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: 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: Bosentan is a significant inducer of CYP2C9 hepatic enzymes. Theoretically, bosentan can increase phenytoin clearance via hepatic induction. Monitor phenytoin levels.
    Bosutinib: Avoid concomitant use of bosutinib, a CYP3A4 substrate, with a strong CYP3A4 inducer such as phenytoin, as a large decrease in bosutinib plasma exposure may occur.
    Brentuximab vedotin: 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: 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.
    Brivaracetam: Phenytoin plasma concentrations may increase up to 20% during concomitant treatment with brivaracetam. Monitoring of phenytoin concentrations is recommended when brivaracetam is added to or discontinued from ongoing phenytoin treatment. A 21% decrease in the plasma concentration of brivaracetam has also been observed during co-administration with phenytoin. No dose adjustment is recommended for brivaracetam during concomitant phenytoin therapy.
    Brompheniramine: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Brompheniramine; Carbetapentane; Phenylephrine: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Brompheniramine; Dextromethorphan; Guaifenesin: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Brompheniramine; Guaifenesin; Hydrocodone: Additive CNS depression may occur when hydantoins are when given with hydrocodone. Also, hydrocodone is metabolized by CYP3A4. Fosphenytoin, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with fosphenytoin. Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Brompheniramine; Hydrocodone; Pseudoephedrine: Additive CNS depression may occur when hydantoins are when given with hydrocodone. Also, hydrocodone is metabolized by CYP3A4. Fosphenytoin, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with fosphenytoin. Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Brompheniramine; Pseudoephedrine: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Budesonide: Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of the concomitant medication. Medications that may be affected include the corticosteroids. 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: Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of the concomitant medication. Medications that may be affected include the corticosteroids. 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: Bupivacaine is metabolized by CYP3A4. Hydantoins induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
    Bupivacaine: Bupivacaine is metabolized by CYP3A4. Hydantoins induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
    Bupivacaine; Lidocaine: Lidocaine is a substrate for the cytochrome P450 isoenzymes 1A2 and 3A4. Phenytoin may enhance lidocaine clearance by inducing cytochrome P-450 enzymes. Additive cardiac depression is possible when phenytoin is administered with lidocaine. Phenytoin injection contains 40% propylene glycol. Too rapid IV administration of phenytoin can produce cardiac arrhythmias, hypotension, and/or death. Bupivacaine is metabolized by CYP3A4. Hydantoins induce these isoenzymes and if given concurrently with bupivacaine may decrease the efficacy of bupivacaine.
    Buprenorphine: 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: 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: It should be noted that when anticonvulsants are used for the purpose of treating epilepsy (versus use in mood disorders or neuropathic pain or other non-epilepsy conditions), that bupropion should not be used by patients with a preexisting seizure disorder; this represents a disease-drug interaction, and not a drug-drug interaction per se. 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).
    Bupropion; Naltrexone: It should be noted that when anticonvulsants are used for the purpose of treating epilepsy (versus use in mood disorders or neuropathic pain or other non-epilepsy conditions), that bupropion should not be used by patients with a preexisting seizure disorder; this represents a disease-drug interaction, and not a drug-drug interaction per se. 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).
    Buspirone: 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: Phenytoin may increase the metabolism of some antineoplastic drugs, which could potentially affect chemotherapy efficacy. Increased antineoplastic clearance has been reported with busulfan when phenytoin was administered concurrently.
    Butabarbital: 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.
    Cabazitaxel: Cabazitaxel is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Repeated administration of another strong CYP3A4 inducer, rifampin, decreased the exposure of cabazitaxel (15 mg/m2 IV) by 17% in a drug interaction study of patients with advanced cancers (n = 21). If coadministration is necessary, monitor for changes in the efficacy of cabazitaxel.
    Cabozantinib: Avoid concomitant use of cabozantinib with phenytoin due to the risk of decreased cabozantinib efficacy. If the use of both agents is necessary, increase the daily cabozantinib capsules (Cometriq) dose (as tolerated) by 40 mg (e.g., 140 mg/day to 180 mg/day; 100 mg/day to 140 mg/day; max 180 mg/day) and the cabozantinib tablet (Cabometyx) dose by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day; max 80 mg/day). Resume the prior cabozantinib dose after 2 to 3 days if phenytoin is discontinued. Cabozantinib is primarily metabolized by CYP3A4 and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%.
    Caffeine: 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: The metabolism of caffeine, can be increased by concurrent use with medications that cause induction of hepatic CYP450 enzymes like the hydantoin anticonvulsants.
    Calcifediol: Dose adjustment of calcifediol may be necessary during coadministration with phenytoin. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with phenytoin. Phenytoin stimulates microsomal hydroxylation and reduces the half-life of calcifediol. In rare cases, this has caused anticonvulsant-induced rickets and osteomalacia.
    Calcitriol: 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.
    Calcium Carbonate: Calcium carbonate can significantly decrease the oral bioavailability of phenytoin. Calcium carbonate should not affect the pharmacokinetics of parenteral phenytoin. If calcium carbonate is to be used with oral phenytoin, calcium carbonate should be administered at least 1 hour before or 6 hours after the phenytoin dose.
    Calcium Carbonate; Magnesium Hydroxide: Calcium carbonate can significantly decrease the oral bioavailability of phenytoin. Calcium carbonate should not affect the pharmacokinetics of parenteral phenytoin. If calcium carbonate is to be used with oral phenytoin, calcium carbonate should be administered at least 1 hour before or 6 hours after the phenytoin dose.
    Calcium Carbonate; Risedronate: Calcium carbonate can significantly decrease the oral bioavailability of phenytoin. Calcium carbonate should not affect the pharmacokinetics of parenteral phenytoin. If calcium carbonate is to be used with oral phenytoin, calcium carbonate should be administered at least 1 hour before or 6 hours after the phenytoin dose.
    Calcium Salts: Oral absorption of phenytoin can be reduced by calcium salts. Calcium salts can form complexes that are nonabsorbable. Separating the administration of phenytoin and calcium salts by at least 2 hours will help avoid this interaction. A similar interaction may occur with ethotoin. Oral absorption of phenytoin can be reduced by calcium salts. Calcium salts can form complexes that are nonabsorbable. Separating the administration of phenytoin and calcium salts by at least 2 hours will help avoid this interaction.
    Calcium; Vitamin D: Oral absorption of phenytoin can be reduced by calcium salts. Calcium salts can form complexes that are nonabsorbable. Separating the administration of phenytoin and calcium salts by at least 2 hours will help avoid this interaction. A similar interaction may occur with ethotoin. Calcium carbonate can significantly decrease the oral bioavailability of phenytoin. Calcium carbonate should not affect the pharmacokinetics of parenteral phenytoin. If calcium carbonate is to be used with oral phenytoin, calcium carbonate should be administered at least 1 hour before or 6 hours after the phenytoin dose. 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. 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.
    Canagliflozin: In patients taking canagliflozin (UGT substrate) concomitantly with phenytoin (UGT enzyme inducer), consider increasing the dosage of canagliflozin to 300 mg once daily in patients currently tolerating canagliflozin 100 mg once daily who have an eGFR >= 60 ml/min/1.73 m2 and require additional glycemic control. Consider other antihyperglycemic therapy in patients with an eGFR of 45 to 59 ml/min/1.73 m2 receiving concurrent therapy with a UGT inducer and require additional glycemic control. Phenytoin and other hydantoins have also been reported to increase blood glucose. If co-therapy is continued, monitor blood glucose for changes in glycemic control.
    Canagliflozin; Metformin: In patients taking canagliflozin (UGT substrate) concomitantly with phenytoin (UGT enzyme inducer), consider increasing the dosage of canagliflozin to 300 mg once daily in patients currently tolerating canagliflozin 100 mg once daily who have an eGFR >= 60 ml/min/1.73 m2 and require additional glycemic control. Consider other antihyperglycemic therapy in patients with an eGFR of 45 to 59 ml/min/1.73 m2 receiving concurrent therapy with a UGT inducer and require additional glycemic control. Phenytoin and other hydantoins have also been reported to increase blood glucose. If co-therapy is continued, monitor blood glucose for changes in glycemic control. 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.
    Capecitabine: Use caution if coadministration of capecitabine with phenytoin is necessary, monitoring phenytoin levels and watching for phenytoin-related adverse reactions (e.g., nystagmus, diplopia, ataxia, and confusion); adjust the dose of phenytoin as necessary. Phenytoin is a CYP2C9 substrate; capecitabine and/or its metabolites are thought to be inhibitors of CYP2C9. Postmarketing reports indicate that some patients receiving both phenytoin and capecitabine have had toxicity associated with elevated phenytoin levels.
    Carbamazepine: 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.
    Carbenicillin: Penicillin G is 60% bound to albumin or moderately protein bound. Displacement of penicillins from plasma protein binding sites by highly protein bound drugs (e.g., phenytoin, fosphenytoin) will elevate the level of free penicillin in the serum. The clinical significance of this interaction is unclear. It is recommended to monitor these patients for increased adverse effects.
    Carbetapentane; Chlorpheniramine: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Carbetapentane; Chlorpheniramine; Phenylephrine: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Carbetapentane; Diphenhydramine; Phenylephrine: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Carbetapentane; Phenylephrine; Pyrilamine: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Carbetapentane; Pyrilamine: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Carbidopa; Levodopa: 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: 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: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Carbinoxamine; Hydrocodone; Phenylephrine: Additive CNS depression may occur when hydantoins are when given with hydrocodone. Also, hydrocodone is metabolized by CYP3A4. Fosphenytoin, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with fosphenytoin. Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: Additive CNS depression may occur when hydantoins are when given with hydrocodone. Also, hydrocodone is metabolized by CYP3A4. Fosphenytoin, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with fosphenytoin. Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Carbinoxamine; Phenylephrine: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Carbinoxamine; Pseudoephedrine: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Carbonic anhydrase inhibitors: 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: 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: 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: Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. If carisoprodol is combined with an inducer of hepatic enzymes, such as phenytoin, the potential exists for increased metabolism of carisoprodol and meprobamate, the active metabolite, plasma concentrations could be increased.
    Carmustine, BCNU: Patients receiving carmustine 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 carmustine. Concurrent therapy with phenytoin and carmustine 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.
    Caspofungin: Co-administration of inducers of hepatic cytochrome P450 along with caspofungin may result in reduced caspofungin blood concentrations. The reductions may be clinically significant. According to the manufacturer, drugs that may lead to reductions in caspofungin concentrations include phenytoin and fosphenytoin. In adult patients taking phenytoin or fosphenytoin, the caspofungin dose may require an increase to 70 mg/day in adult patients. For pediatric patients, a daily caspofungin dosage of 70 mg/meter-squared (BSA), not to exceed 70 mg/day total, should be considered.
    Ceritinib: Ceritinib is a CYP3A4 substrate, and both phenytoin and fosphenytoin are strong CYP3A4 inducers; additionally, ceritinib inhibits CYP2C9, which is the primary enzyme responsible for metabolism of phenytoin. Phenytoin and fosphenytoin have a narrow therapeutic index. Co-administration will result in a decrease in systemic exposure of ceritinib and compromised efficacy, as well as a possible increase in phenytoin exposure and toxicity. Avoid co-administration of ceritinib and phenytoin or fosphenytoin.
    Cevimeline: Inducers of cytochrome P450 3A4 or CYP 2D6, such as the hydantoin anticonvulsants, may cause a reduction in cevimeline plasma concentrations.
    Charcoal: 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; Dexchlorpheniramine; Pseudoephedrine: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Chlorcyclizine: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Chlordiazepoxide: Phenytoin is a hepatic inducer and can theoretically increase the clearance of chlordiazepoxide oxidative metabolism, leading to lower benzodiazepine concentrations. In addition, chlordiazepoxide has been reported to have an unpredictable effect on phenytoin serum concentrations (e.g., to increase, decrease, or cause no change in phenytoin serum concentrations). Conflicting results may have been observed due to saturable phenytoin metabolism and/or other conditions associated with the reported data. Since definitive controlled trial data are lacking, phenytoin concentrations should be monitored more closely when chlordiazepoxide is added or discontinued.
    Chlordiazepoxide; Clidinium: Phenytoin is a hepatic inducer and can theoretically increase the clearance of chlordiazepoxide oxidative metabolism, leading to lower benzodiazepine concentrations. In addition, chlordiazepoxide has been reported to have an unpredictable effect on phenytoin serum concentrations (e.g., to increase, decrease, or cause no change in phenytoin serum concentrations). Conflicting results may have been observed due to saturable phenytoin metabolism and/or other conditions associated with the reported data. Since definitive controlled trial data are lacking, phenytoin concentrations should be monitored more closely when chlordiazepoxide is added or discontinued.
    Chlorpheniramine: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Chlorpheniramine; Codeine: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers. In vitro studies have shown no effect of carbamazepine and phenytoin on the conversion of codeine to morphine. However, CYP450 inducers (e.g., rifampin, barbiturates, carbamazepine, and phenytoin or fosphenytoin) may induce the metabolism of codeine and, therefore, may cause increased clearance of the drug which could lead to a decrease in codeine plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome in a patient who had developed physical dependence to codeine. If co-administration with codeine is necessary, caution is advised when initiating therapy with, currently taking, or discontinuing any potent CYP3A4 inducers. Evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved. When using barbiturates with codeine, additive sedation and respiratory depression will be expected to occur.
    Chlorpheniramine; Dextromethorphan: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: 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. Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: 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. Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: Additive CNS depression may occur when hydantoins are when given with hydrocodone. Also, hydrocodone is metabolized by CYP3A4. Fosphenytoin, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with fosphenytoin. Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Chlorpheniramine; Hydrocodone: Additive CNS depression may occur when hydantoins are when given with hydrocodone. Also, hydrocodone is metabolized by CYP3A4. Fosphenytoin, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with fosphenytoin. Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Chlorpheniramine; Hydrocodone; Phenylephrine: Additive CNS depression may occur when hydantoins are when given with hydrocodone. Also, hydrocodone is metabolized by CYP3A4. Fosphenytoin, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with fosphenytoin. Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: Additive CNS depression may occur when hydantoins are when given with hydrocodone. Also, hydrocodone is metabolized by CYP3A4. Fosphenytoin, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with fosphenytoin. Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Chlorpheniramine; Phenylephrine: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Chlorpheniramine; Pseudoephedrine: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Cholecalciferol, Vitamin D3: 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.
    Cimetidine: 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: 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: Use ciprofloxacin and phenytoin 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.
    Cisapride: Cisapride is metabolized by the hepatic cytochrome P450 enzyme system, specifically the CYP3A4 isoenzyme. Inducers of CYP3A4, such as phenytoin may increase the clearance of cisapride.
    Cisatracurium: 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: 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.
    Citalopram: Citalopram is metabolized by CYP2C19 and CYP3A4. Phenytoin can induce the metabolism of various CYP 450 isoenzymes, including those involved in citalopram metabolism. Although no clinical data are available to support a clinically significant interaction, citalopram may need to be administered in higher doses in patients chronically taking phenytoin.
    Clemastine: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Clobazam: Concomitant administration of clobazam with other CNS-depressant drugs including phenytoin can potentiate the CNS effects (i.e., increased sedation or respiratory depression) of either agent. The primary metabolic pathway of clobazam is CYP3A4, and to a lesser extent, CYP2C19 and CYP2B6. Metabolism of N-desmethylclobazam occurs primarily through CYP2C19. A population pharmacokinetic analysis indicated that phenytoin, an inducer of CYP2C19, CYP3A4, and CYP2C9, did not significantly affect the kinetics of clobazam or its active metabolite N-desmethylclobazam. It should be noted that because clobazam is metabolized by multiple enzyme systems, induction of one pathway may not appreciably increase its clearance.
    Clomipramine: 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: Phenytoin is a hepatic enzyme inducer and can theoretically increase the clearance of benzodiazepines metabolized by oxidative metabolism, leading to lower benzodiazepine concentrations.
    Clopidogrel: Because phenytoin is metabolized by cytochrome P450 2C9, concomitant therapy with clopidogrel at high concentrations could increase plasma concentrations and cause symptoms of toxicity. Phenytoin concentrations should be monitored more closely when initiating clopidogrel therapy. In addition, clopidogrel is metabolized by CYP 3A; phenytoin induces cytochrome P450 3A4 isozymes. Therefore, the therapeutic effectiveness of clopidogrel should be monitored when used concomitantly with phenytoin.
    Clorazepate: Phenytoin is a hepatic inducer and can theoretically increase the clearance of benzodiazpines metabolized by oxidative metabolism, leading to lower benzodiazepine concentrations.
    Clozapine: Phenytoin may interact with the antipsychotics via multiple mechanisms. Pharmacokinetically, phenytoin may induce hepatic microsomal enzymes, leading to increased clearance of the antipsychotic agents (e.g., clozapine). Clinicians should monitor for reduced effectiveness of the antipsychotic agent if hydantoin therapy is added. The phenothiazines and some other antipsychotics may also increase CNS depression and also may lower the seizure threshold, producing a pharmacodynamic interaction with anticonvulsants. Adequate dosages of the anticonvulsant should be continued when an antipsychotic drug is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either drug.
    Cobicistat: Coadministration of phenytoin with regimens containing cobicistat and atazanavir or darunavir should be avoided. If these drugs are used together, significant decreases in the plasma concentrations of cobicistat, atazanavir and potentally darunavir may occur, resulting in reduction of antiretroviral efficacy and development of viral resistance. Consider use of an alternative anticonvulsant or antiretroviral therapy. If coadministration is required, monitor phenytoin concentrations.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: Coadministration may result in significant decreases in the plasma concentrations of elvitegravir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Phenytoin induces the CYP3A4 metabolism of elvitegravir. Consider an alternative anticonvulsant when using elvitegravir. The combination product cobicistat; elvitegravir; emtricitabine; tenofovir is contraindicated in combination with phenytoin as the concentrations of both elvitegravir and cobicistat may be significantly decreased. Coadministration of phenytoin with regimens containing cobicistat and atazanavir or darunavir should be avoided. If these drugs are used together, significant decreases in the plasma concentrations of cobicistat, atazanavir and potentally darunavir may occur, resulting in reduction of antiretroviral efficacy and development of viral resistance. Consider use of an alternative anticonvulsant or antiretroviral therapy. If coadministration is required, monitor phenytoin concentrations.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: Coadministration may result in significant decreases in the plasma concentrations of elvitegravir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Phenytoin induces the CYP3A4 metabolism of elvitegravir. Consider an alternative anticonvulsant when using elvitegravir. The combination product cobicistat; elvitegravir; emtricitabine; tenofovir is contraindicated in combination with phenytoin as the concentrations of both elvitegravir and cobicistat may be significantly decreased. Coadministration of phenytoin with regimens containing cobicistat and atazanavir or darunavir should be avoided. If these drugs are used together, significant decreases in the plasma concentrations of cobicistat, atazanavir and potentally darunavir may occur, resulting in reduction of antiretroviral efficacy and development of viral resistance. Consider use of an alternative anticonvulsant or antiretroviral therapy. If coadministration is required, monitor phenytoin concentrations.
    Cobimetinib: Avoid the concurrent use of cobimetinib with phenytoin due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro; phenytoin is a strong inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 83% when coadministered with a strong CYP3A inducer.
    Cod Liver Oil: 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. Vitamin D supplementation, as found in cod liver oil, may be required in patients who are receiving chronic treatment with anticonvulsants. Anticonvulsants, such phenytoin and fosphenytoin (which is metabolized to phenytoin), can decrease the activity of vitamin D by increasing its metabolism. In rare cases, this has caused anticonvulsant-induced rickets and osteomalacia. Therapeutic effect of cod liver oil should be monitored when used concomitantly with anticonvulsants.
    Codeine: In vitro studies have shown no effect of carbamazepine and phenytoin on the conversion of codeine to morphine. However, CYP450 inducers (e.g., rifampin, barbiturates, carbamazepine, and phenytoin or fosphenytoin) may induce the metabolism of codeine and, therefore, may cause increased clearance of the drug which could lead to a decrease in codeine plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome in a patient who had developed physical dependence to codeine. If co-administration with codeine is necessary, caution is advised when initiating therapy with, currently taking, or discontinuing any potent CYP3A4 inducers. Evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved. When using barbiturates with codeine, additive sedation and respiratory depression will be expected to occur.
    Codeine; Guaifenesin: In vitro studies have shown no effect of carbamazepine and phenytoin on the conversion of codeine to morphine. However, CYP450 inducers (e.g., rifampin, barbiturates, carbamazepine, and phenytoin or fosphenytoin) may induce the metabolism of codeine and, therefore, may cause increased clearance of the drug which could lead to a decrease in codeine plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome in a patient who had developed physical dependence to codeine. If co-administration with codeine is necessary, caution is advised when initiating therapy with, currently taking, or discontinuing any potent CYP3A4 inducers. Evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved. When using barbiturates with codeine, additive sedation and respiratory depression will be expected to occur.
    Codeine; Phenylephrine; Promethazine: In vitro studies have shown no effect of carbamazepine and phenytoin on the conversion of codeine to morphine. However, CYP450 inducers (e.g., rifampin, barbiturates, carbamazepine, and phenytoin or fosphenytoin) may induce the metabolism of codeine and, therefore, may cause increased clearance of the drug which could lead to a decrease in codeine plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome in a patient who had developed physical dependence to codeine. If co-administration with codeine is necessary, caution is advised when initiating therapy with, currently taking, or discontinuing any potent CYP3A4 inducers. Evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved. When using barbiturates with codeine, additive sedation and respiratory depression will be expected to occur. The combination of anticonvulsants (e.g., ethotoin, phenytoin or fosphenytoin) and phenothiazines should be approached with caution. The phenothiazines are known to lower seizure threshold, and this may be a particular risk for patients receiving anticonvulsants. Additive CNS depression may also occur.
    Codeine; Promethazine: In vitro studies have shown no effect of carbamazepine and phenytoin on the conversion of codeine to morphine. However, CYP450 inducers (e.g., rifampin, barbiturates, carbamazepine, and phenytoin or fosphenytoin) may induce the metabolism of codeine and, therefore, may cause increased clearance of the drug which could lead to a decrease in codeine plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome in a patient who had developed physical dependence to codeine. If co-administration with codeine is necessary, caution is advised when initiating therapy with, currently taking, or discontinuing any potent CYP3A4 inducers. Evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved. When using barbiturates with codeine, additive sedation and respiratory depression will be expected to occur. The combination of anticonvulsants (e.g., ethotoin, phenytoin or fosphenytoin) and phenothiazines should be approached with caution. The phenothiazines are known to lower seizure threshold, and this may be a particular risk for patients receiving anticonvulsants. Additive CNS depression may also occur.
    Colesevelam: 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: 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: Bazedoxifene undergoes metabolism by UGT enzymes in the intestinal tract and liver. The metabolism of bazedoxifene may be increased by concomitant use of substances known to induce UGTs, such as phenytoin. A reduction in bazedoxifene exposure may be associated with an increase risk of endometrial hyperplasia. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. 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: 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. 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.
    Corticosteroids: Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of the concomitant medication. Medications that may be affected include the corticosteroids. Depending on the individual clinical situation and the indication for the interacting medication, enzyme-induction interactions may not always produce reductions in treatment efficacy.
    Corticotropin, ACTH: Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of the concomitant medication. Medications that may be affected include the corticosteroids. Depending on the individual clinical situation and the indication for the interacting medication, enzyme-induction interactions may not always produce reductions in treatment efficacy.
    Cortisone: Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of the concomitant medication. Medications that may be affected include the corticosteroids. Depending on the individual clinical situation and the indication for the interacting medication, enzyme-induction interactions may not always produce reductions in treatment efficacy.
    Crizotinib: Avoid the concomitant use of crizotinib with phenytoin, due to the risk of decreased crizotinib efficacy. Phenytoin is a CYP3A substrate and strong inducer; crizotinib is a CYP3A4 substrate and inhibitor. Coadministration may decrease plasma concentrations of crizotinib, or potentially increase concentrations of phenytoin. Coadministration with another strong CYP3A4 inducer, rifampin, decreased the steady state AUC of crizotinib by 82% and the Cmax by 69%.
    Cyclizine: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Cyclophosphamide: Use caution if cyclophosphamide is used concomitantly with phenytoin, and monitor for a possible increase in cyclophosphamide-related adverse events. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2C9 and 2C19. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are inactivated by aldehyde dehydrogenase-mediated oxidation. Phenytoin is a strong CYP3A4 inducer, as well as an inducer of CYP2C9 and 2C19. It is not yet clear what effects CYP450 inducers have on the activation and/or toxicity of cyclophosphamide; the production of active or neurotoxic metabolites may be increased.
    Cyclosporine: 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: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Dabigatran: 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: Avoid the concomitant use of dabrafenib, a CYP3A4 substrate and a CYP2C9 and CYP2C19 inducer, with phenytoin, a strong CYP3A4 inducer and a CYP2C9 and CYP2C19 substrate, may result in decreased levels of either agent. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for loss of dabrafenib and phenytoin efficacy.
    Dacarbazine, DTIC: Subtherapeutic phenytoin concentrations may occur during the use of selected concurrent chemotherapy treatments. Because case reports of this interaction often include chemotherapy regimens of several different agents, it is not always clearly known which agent may be involved in the interaction, or the precise mechanism of interaction.
    Daclatasvir: 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: 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: 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. 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.
    Darifenacin: Phenytoin may induce the CYP3A4 metabolism of darifenacin and thereby reduce its oral bioavailability. The dosage requirements of darifenacin may be increased in patients receiving concurrent enzyme inducers.
    Darunavir: Coadministration of phenytoin and darunavir may increase the metabolism of darunavir and lead to decreased antiretroviral efficacy resulting in reduction of antiretroviral efficacy and development of viral resistance. Avoid coadministration of darunavir with phenytoin. If darunavir is boosted with cobicistat, the manufacturer of cobicistat contraindicates coadministration with phenytoin while the manufacturer of darunavir; cobicistat recommends avoiding coadministration with phenytoin. Consider use of an alternative anticonvulsant or antiretroviral therapy.
    Darunavir; Cobicistat: Coadministration of phenytoin and darunavir may increase the metabolism of darunavir and lead to decreased antiretroviral efficacy resulting in reduction of antiretroviral efficacy and development of viral resistance. Avoid coadministration of darunavir with phenytoin. If darunavir is boosted with cobicistat, the manufacturer of cobicistat contraindicates coadministration with phenytoin while the manufacturer of darunavir; cobicistat recommends avoiding coadministration with phenytoin. Consider use of an alternative anticonvulsant or antiretroviral therapy. Coadministration of phenytoin with regimens containing cobicistat and atazanavir or darunavir should be avoided. If these drugs are used together, significant decreases in the plasma concentrations of cobicistat, atazanavir and potentally darunavir may occur, resulting in reduction of antiretroviral efficacy and development of viral resistance. Consider use of an alternative anticonvulsant or antiretroviral therapy. If coadministration is required, monitor phenytoin concentrations.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with phenytoin 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. 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. Concurrent use of ritonavir with ethotoin, phenytoin, or fosphenytoin should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may lead to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required.
    Dasatinib: Dasatinib is metabolized by CYP3A4. Concurrent administration of CYP3A4 inducers like phenytoin may decrease concentrations of dasatinib. If dasatinib must be administered with an inducer of CYP3A4, an increased dose of dasatinib should be considered.
    Deferasirox: Deferasirox undergoes UGT metabolism, and phenytoin is a potent inducer of this enzyme system. The concomitant administration of deferasirox (single dose of 30 mg/kg) and the potent UGT inducer rifampin (i.e., rifampicin 600 mg/day for 9 days) resulted in a decrease in deferasirox AUC by 44%. Although specific drug interaction studies of deferasirox and phenytoin are not available, a similar interaction may occur. Avoid the concomitant use of phenytoin and deferasirox if possible. If phenytoin and deferasirox coadministration is necessary, consider increasing the initial dose of deferasirox. Monitor serum ferritin concentrations and clinical response for further modifications.
    Delavirdine: Concurrent use of hydantoins (phenytoin, fosphenytoin, ethotoin) and delavirdine is contraindicated due to the potential for subtherapeutic antiretroviral activity and development of resistant mutations of HIV. In addition, delavirdine may inhibit the CYP metabolism of phenytoin, resulting in increased phenytoin concentrations.
    Desiccated Thyroid: Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of thyroid hormones, leading to reduced efficacy of the thyroid hormone.
    Desipramine: 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: Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of the concomitant medication. Medications that may be affected include the corticosteroids. 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: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Dexlansoprazole: 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.
    Dexmethylphenidate: According to some manufacturers of methylphenidate, human pharmacologic studies have shown that methylphenidate may inhibit the metabolism of certain anticonvulsants (particularly fosphenytoin, phenytoin, phenobarbital, and primidone), which can lead to increased serum concentrations. However, according to the manufacturer of methylphenidate extended-release capsules (i.e., Ritalin LA), the drug does not appear to be a relevant inhibitor of CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A. Nevertheless, dosage reduction of these medications may be necessary if methylphenidate is coadministered. Monitor the patient's neurologic status closely, as methylphenidate may lower the seizure threshold in some patients. A similar interaction may occur with the hydantoin anticonvulsant ethotoin, although data are lacking. Methylphenidate may inhibit the metabolism of hydantoins, which can lead to increased serum concentrations. Dosage reduction of phenytoin may be necessary if methylphenidate is co-administered. Similar interactions may occur with dexmethylphenidate. Monitor the patient's neurologic status closely, as psychostimulants may also lower the seizure threshold in some patients; however, some clinical trials have not reported seizure control problems in concomitantly treated patients.
    Dextromethorphan; Diphenhydramine; Phenylephrine: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Dextromethorphan; Promethazine: The combination of anticonvulsants (e.g., ethotoin, phenytoin or fosphenytoin) and phenothiazines should be approached with caution. The phenothiazines are known to lower seizure threshold, and this may be a particular risk for patients receiving anticonvulsants. Additive CNS depression may also occur.
    Dextromethorphan; Quinidine: 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: 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. Phenytoin should be used cautiously with diazepam, as decreased 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). 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 diazepam is added or discontinued.
    Diazoxide: 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.
    Dicloxacillin: Penicillin G is 60% bound to albumin or moderately protein bound. Displacement of penicillins from plasma protein binding sites by highly protein bound drugs (e.g., phenytoin, fosphenytoin) will elevate the level of free penicillin in the serum. The clinical significance of this interaction is unclear. It is recommended to monitor these patients for increased adverse effects.
    Dienogest; Estradiol valerate: 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. 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: Concurrent administration of hepatic enzyme inducers with estrogens, including hydantoin anticonvulsants, may increase the elimination of estrogen.
    Digoxin: Hepatic enzyme-inducing drugs, such as phenytoin and fosphenytoin, can accelerate the metabolism of digoxin. Decreasing digoxin 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: 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.
    Diltiazem: Hydantoin anticonvulsants (i.e., phenytoin, fosphenytoin, or ethotoin) induce hepatic microsomal enzymes and may increase the metabolism of other drugs,such as diltiazem, leading to reduced efficacy of the concomitant medication.
    Dimenhydrinate: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Diphenhydramine: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Diphenhydramine; Hydrocodone; Phenylephrine: Additive CNS depression may occur when hydantoins are when given with hydrocodone. Also, hydrocodone is metabolized by CYP3A4. Fosphenytoin, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with fosphenytoin. Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Diphenhydramine; Ibuprofen: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Diphenhydramine; Phenylephrine: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Disopyramide: 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: 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: Docetaxel is metabolized by cytochrome P450 3A (CYP3A4 and CYP3A5) enzymes. Potential hepatic CYP3A induction interactions can occur when agents such as hydantoins are given concurrently with docetaxel. Use docetaxel cautiously when administered concurrently with inducers or inhibitors of CYP3A enzymes.
    Dolutegravir: Avoid concurrent use of dolutegravir with phenytoin, as coadministration may result in decreased dolutegravir plasma concentrations. Currently, there are insufficient data to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Phenytoin is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
    Donepezil: Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, including donepezil, leading to reduced efficacy of the concomitant medication.
    Donepezil; Memantine: Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, including donepezil, leading to reduced efficacy of the concomitant medication.
    Dopamine: Patients stabilized on dopamine infusions can experience sudden hypotension and/or cardiac arrest if IV phenytoin is administered. At least two deaths have occurred as a result of this interaction. Intravenous phenytoin should be administered extremely cautiously, if at all, to critically ill patients receiving dopamine infusions. It is unclear if oral phenytoin can produce a similar reaction in patients receiving dopamine.
    Doxacurium: 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: 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: 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: 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: 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: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Doxylamine; Pyridoxine: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the sedating H1 blockers.
    Dronabinol, THC: Use caution if coadministration of dronabinol with phenytoin is necessary, and monitor for an increase in phenytoin levels and phenytoin-related adverse effects, as well as a decrease in the efficacy of dronabinol. Dronabinol is a CYP2C9 and 3A4 substrate; phenytoin is a strong inducer of CYP3A4 and a moderate CYP2C9 inducer. Concomitant use may result in decreased plasma concentrations of dronabinol. Additionally, dronabinol is highly bound to plasma proteins, and may displace and increase the free fraction of other concomitantly administered protein-bound drugs; caution is recommended with other drugs with a narrow therapeutic index.
    Dronedarone: The concomitant use of dronedarone and CYP3A4 inducers should be avoided. Dronedarone is metabolized by CYP3A. Phenytoin induces CYP3A4. Coadministration of CYP3A4 inducers, such as phenytoin, with dronedarone may result in reduced plasma concentration and subsequent reduced effectiveness of dronedarone therapy.
    Droperidol: Hydantoin anticonvulsants can theoretically add to the CNS depressant effects of other CNS depressants including the droperidol.
    Drospirenone; Estradiol: 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. 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: 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. 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: 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. 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. 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.
    Efavirenz: 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: 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.
    Elbasvir; Grazoprevir: Concurrent administration of elbasvir; grazoprevir with phenytoin is contraindicated. Phenytoin is a strong CYP3A inducer, while both elbasvir and grazoprevir are substrates of CYP3A. Use of these drugs together is expected to significantly decrease the plasma concentrations of both elbasvir and grazoprevir, and may result in decreased virologic response.
    Eliglustat: 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: Coadministration may result in significant decreases in the plasma concentrations of elvitegravir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Phenytoin induces the CYP3A4 metabolism of elvitegravir. Consider an alternative anticonvulsant when using elvitegravir. The combination product cobicistat; elvitegravir; emtricitabine; tenofovir is contraindicated in combination with phenytoin as the concentrations of both elvitegravir and cobicistat may be significantly decreased.
    Empagliflozin: 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: Potent inducers of CYP3A4 (e.g. phenytoin) can decrease exposure to linagliptin and result in subtherapeutic and likely ineffective concentrations. For patients requiring use of phenytoin, 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. 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: 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. 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: 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: 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: 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.
    Enflurane: Caution is advised with the concomitant use of enflurane and phenytoin as concurrent use may increase the risk of hepatotoxicity.
    Enteral Feedings: The oral absorption of phenytoin suspension can be reduced substantially (i.e., up to 80%) by the concurrent administration of enteral feedings. Conversely, when enteral feedings are halted, phenytoin levels may rise substantially. The interaction is one of the most clinically significant nutrient-drug interactions. How enteral feedings reduce the absorption of phenytoin is controversial. Enteral feedings may decrease phenytoin's GI residence time, preventing complete drug absorption. Magnesium or calcium in some feedings may form complexes with phenytoin suspension that are non-absorbable, as can certain proteins (e.g., caseinates). The acidic pH of most enteral feedings may also reduce the solubility of phenytoin suspensions. Finally, the enteral tube itself may bind and prevent the proper absorption of phenytoin suspension. Other oral dosage forms of phenytoin (e.g., phenytoin sodium) do not interact with enteral feedings to the same extent as the oral phenytoin suspension. There are several ways in which one can manage a patient on enteral feedings who must receive phenytoin. If feedings are intermittent, administer phenytoin suspension at least 12 hours following a feeding and delay feeding until at least 12 hours after the phenytoin dose is administered. Continuous enteral feedings are more difficult to manage; the tube feedings may be held as for intermittent feedings if practical. Alternatively, consider the use of parenteral phenytoin/fosphenytoin if practical and IV administration does not pose a significant risk to the patient. Any patients receiving phenytoin orally through a feeding tube should have the suspension diluted prior to administration and the tubing flushed following administration, preferably with water or normal saline. Monitor serum phenytoin levels and clinical status; adjusting dosage to achieve desired therapeutic outcomes.
    Enzalutamide: Avoid the concomitant use of enzalutamide, a CYP3A4 substrate, with a strong CYP3A4 inducer such as phenytoin. Although this interaction has not been evaluated in vivo, use of enzalutamide in combination with a strong CYP3A4 inducer may decrease plasma exposure of enzalutamide. Therefore, using an agent with no or minimal CYP3A4 induction potential is recommended. Additionally, because phenytoin is a CYP2C9 and CYP2C19 substrate and enzalutamide is a moderate CYP2C9 and CYP2C19 inducer, phenytoin plasma exposure may be decreased.
    Ergocalciferol, Vitamin D2: 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: Avoid the coadministration of erlotinib with hydantoins (e.g., phenytoin, fosphenytoin, ethotoin) if possible due to the risk of decreased erlotinib efficacy; if concomitant use is unavoidable, increase the dose of erlotinib by 50 mg increments at 2-week intervals, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Phenytoin (and fosphenytoin) is a strong CYP3A4 inducer as well as a moderate inducer of CYP1A2. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days. In a single-dose pharmacokinetics trial in healthy volunteers, cigarette smoking (moderate CYP1A2 inducer) decreased the AUC of erlotinib by 64% (95% CI, 46% to 76%) in current smokers compared with former/never smokers. Steady-state trough concentrations of erlotinib were approximately 2-fold less in current smokers compared with former/never smokers in a separate study of patients with NSCLC. Coadministration with phenytoin / fosphenytoin may also decrease erlotinib exposure.
    Erythromycin; Sulfisoxazole: Hydantoin anticonvulsant clearance can be decreased by drugs that inhibit hepatic microsomal enzymes, particularly those drugs that significantly inhibit the cytochrome P450 2C subset of isoenzymes including sulfonamides. Phenytoin, ethotoin or fosphenytoin dosage adjustments may be necessary in some patients who receive sulfonamides concurrently; monitor for signs of hydantoin toxicity.
    Escitalopram: Escitalopram is metabolized by CYP2C19 and CYP3A4. Phenytoin can induce the metabolism of various CYP 450 isoenzymes, including those involved in escitalopram metabolism. Escitalopram may need to be administered in higher doses in patients chronically taking enzyme-inducing drugs like phenytoin.
    Eslicarbazepine: Phenytoin 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 based on clinical response and serum concentration.
    Esomeprazole: 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 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. In addition, phenytoin is both a substrate as well as an inducer for the CYP2C19 isoenzyme. Esomeprazole, which is a strong inhibitor of CYP2C19, may lead to increased levels of phenytoin, a substrate of CYP2C19. The manufacturer reports that esomeprazole does not significantly change the pharmacokinetics of phenytoin. In addition, the manufacturer states that phenytoin does not appear to alter the pharmacokinetic profile or esomeprazole (CYP2C19 substrate).
    Esomeprazole; Naproxen: 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 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. In addition, phenytoin is both a substrate as well as an inducer for the CYP2C19 isoenzyme. Esomeprazole, which is a strong inhibitor of CYP2C19, may lead to increased levels of phenytoin, a substrate of CYP2C19. The manufacturer reports that esomeprazole does not significantly change the pharmacokinetics of phenytoin. In addition, the manufacturer states that phenytoin does not appear to alter the pharmacokinetic profile or esomeprazole (CYP2C19 substrate). 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: 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: 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: 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: 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. 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: 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: 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. 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: 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. 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: 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. 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: Estrogens are metabolized by CYP3A4. Concurrent administration of hepatic enzyme inducers with estrogens, including hydantoin anticonvulsants, may increase the elimination of estrogen.
    Estropipate: Estrogens are metabolized by CYP3A4. Concurrent administration of hepatic enzyme inducers with estrogens, including hydantoin anticonvulsants, may increase the elimination of estrogen.
    Eszopiclone: 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: 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: 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: 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. 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: 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. 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: 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. 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: 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. 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: 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. 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. 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. Concurrent use of folic acid, vitamin B9 and phenytoin may result in decreased folic acid serum concentrations and decreased anticonvulsant effect. It is important to maintain adequate folic acid concentrations in epileptic patients taking enzyme-inducing anticonvulsants, and maintenance doses may require upward adjustment. However, in large amounts, folic acid may counteract the anticonvulsant effect of some agents, including phenytoin. Therefore, it has been recommended that oral folic acid supplementation not exceed 1 mg/day in epileptic patients taking anticonvulsants. If large doses are used, monitor phenytoin concentrations upon folic acid initiation, dose titration, and discontinuation and adjust the anticonvulsant dosage as appropriate. Prolonged administration of phenytoin reportedly has resulted in a folate deficiency in 27% to 91% of patients. Megaloblastic anemia occurs in fewer than 1% of patients receiving phenytoin. The proposed mechanisms of this phenomenon include an increase in folate catabolism, folate malabsorption, or use of folic acid secondary to enzyme induction by phenytoin. Some evidence suggests that the anticonvulsant effect of phenytoin is partially the result of a reduction in folic acid concentrations. Folic acid replacement has resulted in an increase in metabolism of phenytoin and a decrease in phenytoin concentration in some patients, apparently through increased metabolism and/or redistribution of phenytoin in the brain and CSF. A clinically significant increase in seizure activity has occurred with this drug combination in rare instances, especially when doses of 4 mg/day or more were utilized.
    Ethinyl Estradiol; Norelgestromin: 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. 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: 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. 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: 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. 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: 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. 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: 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. 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: 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. 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: 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. 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.
    Ethosuximide: Phenytoin induces hepatic microsomal enzymes. Increased hepatic metabolism of ethosuximide leads to a decrease in its plasma concentration and a reduction in its half-life. To maintain a therapeutic dosage, serum concentrations of ethosuximide should be measured, especially if additional anticonvulsant therapy is added to or withdrawn from ethosuximide therapy.
    Etonogestrel: 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: 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: Coadministration of phenytoin or fosphenytoin with etravirine may result in reduced etravirine concentrations, subtherapeutic antiretroviral activity, and possibility development of resistant HIV mutations. In addition, etravirine may inhibit the CYP metabolism of phenytoin, resulting in increased phenytoin concentrations. 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.
    Everolimus: Everolimus is metabolized by CYP3A4. Coadministration with strong CYP3A4 inducers, such as phenytoin, may require a dose increase of Afinitor. If Zortress and phenytoin are coadministered, close monitoring of everolimus whole blood trough concentrations is recommended. Concurrent administration of everolimus and rifampin, a strong CYP3A4 and Pgp inducer, decreased everolimus Cmax and AUC by 58% and 64% respectively. A similar interaction is expected with fosphenytoin.
    Exemestane: If coadministration of exemestane with phenytoin is necessary, increase the dose of exemestane to 50 mg once daily after a meal. Exemestane is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer. Concomitant use may result in decreased exemestane exposure and possibly decreased efficacy. In a pharmacokinetic interaction study (n = 10) with another strong CYP3A4 inducer, rifampicin (600 mg daily for 14 days), the mean Cmax and AUC of exemestane (single dose) decreased by 41% and 54%, respectively.
    Ezetimibe; Simvastatin: Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, such as simvastatin, leading to reduced efficacy of simvastatin.
    Ezogabine: During concurrent use of ezogabine 300-1200 mg/day and phenytoin 120-600 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.
    Felbamate: Hydantoins are hepatic enzyme inducers and thus may accelerate the metabolism of several other anticonvulsants, including felbamate.
    Felodipine: 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: 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: 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: Drugs that induce the hepatic cytochrome P450 3A4 isoenzyme, such as hydantoins, may induce fentanyl metabolism and thus, may decrease the effectiveness of fentanyl, a substrate of CYP3A4. Induction of fentanyl metabolism may take several days. An upward dosage adjustment of fentanyl may be eventually needed. Conversely, a downward dosage adjustment of fentanyl may be needed when a CYP3A4 inducer is stopped. Additive CNS depression could also be seen with the combined use of the hydantoin and opiate agonists.
    Ferric Citrate: Although drug interaction studies have not been conducted, it may be prudent to separate the timing of administration of phenytoin from ferric citrate. According to the manufacturer of ferric citrate, clinicians should consider separating the timing of administration of ferric citrate and drugs where a reduction in the bioavailability of would have a clinically significant effect on its safety or efficacy. Because phenytoin has a narrow therapeutic index, consider monitoring clinical response and serum concentrations during concurrent use of ferric citrate.
    Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): 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: 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: 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: 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.
    Fludrocortisone: Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of the concomitant medication. Medications that may be affected include the corticosteroids. Depending on the individual clinical situation and the indication for the interacting medication, enzyme-induction interactions may not always produce reductions in treatment efficacy.
    Flunisolide: Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of the concomitant medication. Medications that may be affected include the corticosteroids. Depending on the individual clinical situation and the indication for the interacting medication, enzyme-induction interactions may not always produce reductions in treatment efficacy.
    Fluorouracil, 5-FU: 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: Cytochrome CYP2C19 is one of two pathways by which phenytoin is metabolized, and fluoxetine inhibits this pathway. Phenytoin toxicity has been described in several patients after the addition of fluoxetine.
    Fluoxetine; Olanzapine: Cytochrome CYP2C19 is one of two pathways by which phenytoin is metabolized, and fluoxetine inhibits this pathway. Phenytoin toxicity has been described in several patients after the addition of fluoxetine. 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: 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: Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of the concomitant medication. Medications that may be affected include the corticosteroids. 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: Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of the concomitant medication. Medications that may be affected include the corticosteroids. 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: Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of the concomitant medication. Medications that may be affected include the corticosteroids. 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: 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. Patients receiving phenytoin should be monitored more closely when fluvastatin therapy is initiated or when the fluvastatin dosage is changed.
    Fluvoxamine: Phenytoin clearance can be decreased by drugs that inhibit hepatic microsomal enzymes, particularly those drugs that significantly inhibit the cytochrome P450 2C subset of isoenzymes including fluvoxamine.Phenytoin dosage adjustments may be necessary in some patients who receive any of these drugs concurrently; monitor for signs of phenytoin toxicity.
    Folic Acid, Vitamin B9: 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. Concurrent use of folic acid, vitamin B9 and phenytoin may result in decreased folic acid serum concentrations and decreased anticonvulsant effect. It is important to maintain adequate folic acid concentrations in epileptic patients taking enzyme-inducing anticonvulsants, and maintenance doses may require upward adjustment. However, in large amounts, folic acid may counteract the anticonvulsant effect of some agents, including phenytoin. Therefore, it has been recommended that oral folic acid supplementation not exceed 1 mg/day in epileptic patients taking anticonvulsants. If large doses are used, monitor phenytoin concentrations upon folic acid initiation, dose titration, and discontinuation and adjust the anticonvulsant dosage as appropriate. Prolonged administration of phenytoin reportedly has resulted in a folate deficiency in 27% to 91% of patients. Megaloblastic anemia occurs in fewer than 1% of patients receiving phenytoin. The proposed mechanisms of this phenomenon include an increase in folate catabolism, folate malabsorption, or use of folic acid secondary to enzyme induction by phenytoin. Some evidence suggests that the anticonvulsant effect of phenytoin is partially the result of a reduction in folic acid concentrations. Folic acid replacement has resulted in an increase in metabolism of phenytoin and a decrease in phenytoin concentration in some patients, apparently through increased metabolism and/or redistribution of phenytoin in the brain and CSF. A clinically significant increase in seizure activity has occurred with this drug combination in rare