Version July 2025
The rate of fosphenytoin intravenous (IV) administration should not exceed 150 mg phenytoin sodium equivalent (PE)/minute because of the risk of severe hypotension and cardiac arrhythmias. Careful cardiac monitoring is needed during and after administering fosphenytoin IV. Although the risk of cardiovascular toxicity increases with infusion rates above the recommended infusion rate, these events have also been reported at or below the recommended infusion rate. Reduction in rate of administration or discontinuation of dosing may be needed.
Dosage guidance:
Safety: Before use, consider testing for HLA-B*1502 allele in patients at increased risk of developing serious cutaneous adverse reactions (ie, those of Asian ancestry, including South Asian Indian patients) (Ref).
Dosing: Always prescribe and dispense fosphenytoin as phenytoin sodium equivalents (mg PE); 1 mg PE is equivalent to 1 mg phenytoin sodium.
Clinical considerations: Continuous cardiac and blood pressure monitoring is recommended for rapid infusion in urgent indications (eg, status epilepticus). For nonurgent monitoring requirements when slow infusion is appropriate, refer to institutional protocol (Ref).
Seizures:
Craniotomy, seizure prophylaxis (alternative agent):
Loading dose: IV: 10 to 20 mg PE/kg at a rate of ≤150 mg PE/minute prior to incision (Ref).
Postoperative prophylaxis: IV: 5 to 7.5 mg PE/kg/day in 2 to 3 divided doses, until postoperative day 7; usual daily dose: 300 to 400 mg PE; adjust dose based on response and serum concentrations (Ref). Note: Duration individualized based on underlying intracranial pathology and other clinical considerations (Ref).
Focal (partial) onset seizures and generalized onset seizures (short-term alternative to oral therapy): Note: Use of a loading dose is suggested for patients who require rapid attainment of a therapeutic serum level; in the absence of a loading dose, full effect is typically observed in 1 to 3 weeks when steady-state serum concentrations are reached.
Loading dose (optional) (fosphenytoin/phenytoin naive): IV, IM: 10 to 20 mg PE/kg given in 1 to 3 divided doses over 24 hours; administer IV loading dose at a rate of 100 to 150 mg PE/minute; usual total loading dose is 1 to 1.5 g PE (Ref); begin maintenance dose 8 to 12 hours after loading dose.
Maintenance dose: IV, IM: Initial: 4 to 7 mg PE/kg/day (usual daily dose: 300 to 400 mg PE) given in 2 to 4 divided doses; adjust dose based on response and serum concentrations (Ref). Some experts recommend initiating maintenance therapy with 5 mg PE/kg/day in 2 divided doses (Ref). A maximum dose has not been established; use caution when prescribing maintenance doses >600 mg PE/day.
Status epilepticus (convulsive and nonconvulsive): Note: Do not use the IM route due to delay in onset of action/bioavailability. Generally, fosphenytoin is administered as part of initial therapy with or immediately after a benzodiazepine (eg, lorazepam IV) (Ref).
Loading dose (fosphenytoin/phenytoin naive): IV: 20 mg PE/kg at a rate of 100 to 150 mg PE/minute in combination with a parenteral benzodiazepine (eg, lorazepam) under continuous cardiac and blood pressure monitoring; reduce infusion rate if significant adverse events occur; if necessary, may give an additional 5 to 10 mg PE/kg 10 minutes after the loading dose; maximum total loading dose: 30 mg PE/kg (Ref). Begin maintenance dose 8 to 12 hours after loading dose.
Maintenance dose: IV: Initial: 4 to 7 mg PE/kg/day (usual daily dose: 300 to 400 mg PE) given in 2 to 4 divided doses; adjust dose based on response and serum concentrations (Ref). Some experts recommend initiating maintenance therapy with 5 mg PE/kg/day in 2 divided doses (Ref). A maximum dose has not been established; use caution when prescribing maintenance doses >600 mg PE/day.
Traumatic brain injury, prevention of early posttraumatic seizure (alternative agent) (off-label use): Note: Dosing based on phenytoin data and may be center specific; refer to institutional protocols. For use in select patients at elevated risk of early seizures with concerns for secondary complications.
Loading dose: IV: 17 to 20 mg PE/kg at a rate of 100 to 150 mg PE/minute; usual maximum dose: 2 g PE (Ref); begin maintenance dose 8 to 12 hours after loading dose.
Maintenance dose: IV: 100 mg PE every 8 hours or 5 mg PE/kg/day (round to the nearest 100 mg PE) given in divided doses every 8 hours (Ref). Note: Duration of prophylaxis varies, but is generally short term (eg, ~7 days) (Ref).
Trigeminal neuralgia, rescue therapy (off-label use):
Note: For use during oral medication titration and/or acute exacerbation of refractory trigeminal neuralgia (Ref).
IV: 250 mg to 1 g PE as a one-time dose or 15 mg/kg PE (maximum dose not established) over 30 to 120 minutes; administer at a rate ≤150 mg PE/minute (Ref).
Dosage form conversion: Use the same total daily dose when converting between oral/IV phenytoin and IV/IM fosphenytoin. Fosphenytoin is 100% bioavailable by both the IM and IV routes; oral phenytoin is 70% to 95% bioavailable (dependent on product and/or salt) (Ref). Plasma phenytoin concentrations may modestly increase when switching from oral phenytoin to IM or IV fosphenytoin (or decrease when switching from fosphenytoin to oral phenytoin) due to differences in bioavailability.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling. Free (unbound) phenytoin levels should be monitored closely in patients with renal disease or in those with hypoalbuminemia; furthermore, fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance in these patients leading to increase frequency and severity of adverse events.
There are no dosage adjustments provided in the manufacturer's labeling. Free (unbound) phenytoin levels should be monitored closely in patients with hepatic disease or in those with hypoalbuminemia or hyperbilirubinemia; furthermore, fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance in these patients leading to increased frequency and severity of adverse events.
The recommendations for dosing in patients with obesity are based upon the best available evidence and clinical expertise. Senior Editorial Team: Jeffrey F. Barletta, PharmD, FCCM; Manjunath P. Pai, PharmD, FCP; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC.
Class 1 or 2 obesity (BMI 30 to 39 kg/m2): No dosage adjustment necessary; use a standard, non–weight-based dose (based on indication) or actual body weight for weight-based dose calculations (Ref). Refer to adult dosing for indication-specific doses.
Class 3 obesity (BMI ≥ 40 kg/m2):
Status epilepticus (convulsive and nonconvulsive):
Loading dose: IV: Initial: 15 mg PE/kg (using actual body weight; no maximum dose); administer at a rate of 100 to 150 mg PE/minute; doses up to 2.3 g PE have been reported (Ref); begin maintenance dose 8 to 12 hours after loading dose.
Maintenance dose: IV, IM: Initial: 4 to 7 mg PE/kg/day (using ideal body weight; usual dose: 300 to 400 mg PE/day) given in 2 to 4 divided doses; adjust dose based on response and serum concentrations (Ref). A maximum dose has not been established; use caution when prescribing maintenance doses >600 mg PE/day.
Other indications:Evidence currently does not exist for other indications in patients with obesity; however, the same dosing principles and use of actual body weight (for loading doses) and ideal body weight (for maintenance doses) with subsequent appropriate therapeutic drug monitoring would apply (Ref).
Rationale for recommendations: For loading doses, use of actual body weight in patients with obesity is recommended to ensure adequate concentrations and efficacy. For maintenance doses, use of ideal body weight (IBW) for initial dosing is recommended to prevent toxicity (Ref). There is a paucity of studies evaluating the influence of obesity on fosphenytoin dosing or pharmacokinetics. Evidence from one small pharmacokinetic study comparing patients with obesity to nonobese patients receiving phenytoin demonstrated a slightly increased Vd (0.68 ± 0.03 L/kg vs 0.61 ± 0.02 L/kg) in patients with obesity and distribution into weight in excess of IBW was disproportionately greater (by a factor of 1.33) (Ref). Based on an unpublished comparison, a loading dose based on actual body weight (dose = 15 mg/kg) compared to an approach based on IBW (dose = [14 × IBW] + [19 × (actual body weight − IBW)]) yielded similar dose estimates when factoring population height and weight distributions (Ref).
Refer to adult dosing; clearance is decreased in geriatric patients; lower doses or less frequent dosing may be required. In addition, older adults may have lower serum albumin, which may increase the free fraction and, therefore, pharmacologic response including adverse events.
(For additional information see "Fosphenytoin: Pediatric drug information")
Dosage guidance:
Dosing: The dose, concentration in solutions, and infusion rates for fosphenytoin are expressed as PHENYTOIN SODIUM EQUIVALENTS (PE):
Fosphenytoin should ALWAYS be prescribed and dispensed in mg of PE; otherwise significant medication errors may occur.
Based on pharmacokinetic studies, experts recommend the following (Ref): Use the pediatric IV phenytoin dosing guidelines to dose fosphenytoin using doses in PE equal to the phenytoin doses (ie, phenytoin 1 mg = fosphenytoin 1 mg PE). Dosage should be individualized based upon clinical response and serum concentrations.
Clinical considerations: In pediatric patients, intravenous is the preferred route of administration. Due to the risks of cardiac and local toxicity, transition to oral phenytoin as soon as possible.
Seizures, maintenance therapy; short-term when oral route not available or appropriate:
Infants, Children, and Adolescents: IV (preferred), IM: Initial: 4 to 8 mg PE/kg/day in 2 divided doses; initiate maintenance dose ≥12 hours after loading dose. Based on data for phenytoin, some experts suggest higher maintenance doses (8 to 10 mg PE/kg/day) may be necessary in infants and young children (Ref); in adult patients, treatment duration >5 days has not been evaluated.
Seizures, nonemergent: Infants, Children, and Adolescents: Loading dose (if required): IV (preferred), IM: 10 to 15 mg PE/kg; then initiate maintenance doses ≥12 hours after loading dose.
Seizures, substitution for oral phenytoin therapy : Infants, Children, and Adolescents: IV (preferred), IM: May be substituted for oral phenytoin sodium at the same total daily dose; however, phenytoin capsules are ~90% bioavailable by the oral route; phenytoin, supplied as fosphenytoin, is 100% bioavailable by both the IM and IV routes; for this reason, plasma phenytoin concentrations may increase when IM or IV fosphenytoin is substituted for oral phenytoin sodium therapy; monitor serum concentrations closely; in adult clinical trials, IM fosphenytoin was administered as a single daily dose utilizing either 1 or 2 injection sites; some patients may require more frequent dosing.
Status epilepticus: Note: In management of status epilepticus, a benzodiazepine should be used for initial management; if seizures are refractory to benzodiazepines, fosphenytoin is a therapeutic option for second phase therapy along with levetiracetam and valproic acid; there is no preference on which agent and all 3 have been shown similarly effective (Ref).
Infants, Children, and Adolescents: Loading dose: IV (preferred), IM: 20 mg PE/kg/dose; maximum dose: 1,500 mg PE/dose; reported range: 15 to 20 mg PE/kg/dose; an additional load of 5 mg PE/kg administered 10 minutes after initial loading infusion has also been suggested if seizure activity continues (Ref).
Traumatic brain injury; seizure prophylaxis: Limited data available:
Note: Current guidelines suggest 7 days of prophylactic phenytoin (fosphenytoin) may be considered to reduce the incidence of early posttraumatic seizures in pediatric patients with severe traumatic brain injuries; however, it has not been shown to reduce the risk of long-term seizures or improve neurologic outcome (Ref). Dosing based on experience with phenytoin.
Infants, Children, and Adolescents: IV: Initial: 18 mg PE/kg loading dose, followed by 6 mg PE/kg/day divided every 8 hours for 48 hours was used in a double-blind, placebo-controlled trial of 102 pediatric patients (n=46 treatment group; median age: 6.4 years) and showed no significant difference in seizure frequency between groups; however, the trial was stopped early due to a very low seizure frequency among both study groups (Ref). In a retrospective trial, reduced seizure frequency with prophylactic phenytoin use was described (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Infants, Children, and Adolescents: There are no dosage adjustments provided in the manufacturer's labeling. Free (unbound) phenytoin serum concentrations should be monitored closely in patients with renal disease or in those with hypoalbuminemia; free phenytoin serum concentrations may be increased; furthermore, fosphenytoin conversion to phenytoin may be increased without a similar increase in phenytoin conversion in these patients, leading to increased frequency and severity of adverse events.
Infants, Children, and Adolescents: There are no dosage adjustments provided in the manufacturer's labeling. Free (unbound) phenytoin concentrations should be monitored closely in patients with hepatic disease or in those with hypoalbuminemia; free phenytoin concentrations may be increased; furthermore, fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance in these patients, leading to increased frequency and severity of adverse events.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Also refer to the phenytoin monograph for additional adverse reactions.
>10%:
Dermatologic: Pruritus (IM: 3%; IV: 49%; often reported in groin area)
Nervous system: Ataxia (IM: ≤8%; IV: ≤11%), dizziness (IM: 5%; IV: 31%), drowsiness (IM: 7%; IV: 20%)
Ophthalmic: Nystagmus disorder (IM: 15%; IV: 44%)
1% to 10%:
Cardiovascular: Bundle branch block (≤1%), cardiac arrhythmia (≤1%; including atrial flutter and sinus bradycardia), cardiomegaly (≤1%), edema (≤1%), heart failure (≤1%), hypertension (>1%), hypotension (IV: 8%; including severe hypotension), orthostatic hypotension (≤1%), palpitations (≤1%), prolonged QT interval on ECG (≤1%), pulmonary embolism (≤1%), shock (≤1%), syncope (≤1%), tachycardia (IV: 2%), thrombophlebitis (≤1%), vasodilation (IV: 6%), ventricular premature contractions (≤1%)
Dermatologic: Contact dermatitis (≤1%), cutaneous nodule (≤1%), diaphoresis (≤1%), ecchymoses (IM: 7%), maculopapular rash (≤1%), pustular rash (≤1%), skin discoloration (≤1%), skin photosensitivity (≤1%), skin rash (>1%), urticaria (≤1%)
Endocrine & metabolic: Acidosis (≤1%), albuminuria (≤1%), alkalosis (≤1%), cachexia (≤1%), dehydration (≤1%), diabetes insipidus (≤1%), hyperglycemia (≤1%), hyperkalemia (≤1%), hypokalemia (>1%), hypophosphatemia (≤1%), ketosis (≤1%)
Gastrointestinal: Ageusia (≤1%), anorexia (≤1%), constipation (>1%), diarrhea (≤1%), dysgeusia (IV: 3%), dyspepsia (≤1%), dysphagia (≤1%), flatulence (≤1%), gastritis (≤1%), gastrointestinal hemorrhage (≤1%), intestinal obstruction (≤1%), nausea (5% to 9%), oral paresthesia (≤1%), sialorrhea (≤1%), tenesmus (≤1%), tongue disease (IV: 4%), vomiting (2% to 3%), xerostomia (IV: 4%)
Genitourinary: Dysuria (≤1%), genital edema (≤1%), oliguria (≤1%), pelvic pain (IV: 4%), urethral pain (≤1%), urinary incontinence (≤1%), urinary retention (≤1%), vaginitis (≤1%), vulvovaginal candidiasis (≤1%)
Hematologic & oncologic: Anemia (≤1%), hypochromic anemia (≤1%), leukocytosis (≤1%), leukopenia (≤1%), lymphadenopathy (≤1%), petechia (≤1%), thrombocytopenia (≤1%)
Hepatic: Abnormal hepatic function tests (≤1%)
Hypersensitivity: Facial edema (>1%), tongue edema (≤1%)
Infection: Cryptococcosis (≤1%), infection (>1%), sepsis (≤1%)
Local: Bleeding at injection site (≤1%), inflammation at injection site (≤1%), injection-site reaction (>1%; including purple glove syndrome), pain at injection site (>1%), swelling at injection site (≤1%)
Nervous system: Abnormality in thinking (>1%), agitation (IV: 3%), akathisia (≤1%), altered sense of smell (≤1%), amnesia (≤1%), aphasia (≤1%), asthenia (IM: 9%; IV: 2%), brain edema (IV: 2%), central nervous system depression (≤1%), cerebral hemorrhage (≤1%), cerebral infarction (≤1%), chills (>1%), coma (≤1%), confusion (≤1%), delirium (≤1%), depersonalization (≤1%), depression (≤1%), dysarthria (≤2%), emotional lability (≤1%), encephalitis (≤1%), encephalopathy (≤1%), extrapyramidal reaction (IV: ≤4%), headache (IM: 9%; IV: 2%), hemiplegia (≤1%), hostility (≤1%), hyperacusis (≤1%), hyperesthesia (≤1%), hyperreflexia (>1%), hypoesthesia (IV: 2%), hyporeflexia (IM: 3%), hypotonia (≤1%), insomnia (≤1%), intracranial hypertension (>1%), malaise (≤1%), meningitis (≤1%), migraine (≤1%), myasthenia (>1%), myoclonus (≤1%), nervousness (>1%), neurosis (≤1%), paralysis (≤1%), paresthesia (4%; often reported in the groin area), personality disorder (≤1%), positive Babinski sign (≤1%), psychosis (≤1%), seizure (≤1%), speech disturbance (>1%), stupor (IV: 8%), subdural hematoma (≤1%), tremor (IM: 10%; IV: 3%), twitching (≤1%), vertigo (IV: 2%)
Neuromuscular & skeletal: Arthralgia (≤1%), back pain (IV: 2%), hyperkinetic muscle activity (≤1%), hypokinesia (≤1%), lower limb cramp (≤1%), myalgia (≤1%), myopathy (≤1%)
Ophthalmic: Amblyopia (IV: 2%), conjunctivitis (≤1%), diplopia (IV: 3%), eye pain (≤1%), mydriasis (≤1%), photophobia (≤1%), visual field defect (≤1%)
Otic: Deafness (IV: 2%), otalgia (≤1%), tinnitus (IV: 9%)
Renal: Polyuria (≤1%), renal failure syndrome (≤1%)
Respiratory: Apnea (≤1%), aspiration pneumonia (≤1%), asthma (≤1%), atelectasis (≤1%), bronchitis (≤1%), cyanosis (≤1%), dyspnea (≤1%), epistaxis (≤1%), flu-like symptoms (≤1%), hemoptysis (≤1%), hyperventilation (≤1%), hypoxia (≤1%), increased bronchial secretions (≤1%), increased cough (≤1%), pharyngitis (≤1%), pneumonia (>1%), pneumothorax (≤1%), rhinitis (≤1%), sinusitis (≤1%)
Miscellaneous: Fever (>1%)
Postmarketing:
Hypersensitivity: Angioedema, drug reaction with eosinophilia and systemic symptoms
Nervous system: Burning sensation (often reported in groin area)
Neuromuscular & skeletal: Dyskinesia
Hypersensitivity to fosphenytoin, phenytoin, other hydantoins, or any component of the formulation; sinus bradycardia, sinoatrial block, second- and third-degree AV block, or Adams-Stokes syndrome; history of prior acute hepatotoxicity attributable to fosphenytoin or phenytoin; concurrent use with delavirdine.
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Concerns related to adverse effects:
• Anemia: Macrocytosis, megaloblastic anemia, and pure red cell aplasia have occurred with phenytoin; macrocytosis and megaloblastic anemia can usually be treated with folic acid therapy.
• Blood dyscrasias: A spectrum of hematologic effects have been reported with phenytoin (eg, leukopenia, granulocytopenia, agranulocytosis, thrombocytopenia, and pancytopenia with or without bone marrow suppression) and may be fatal; patients with a previous history of adverse hematologic reaction to any drug may be at increased risk. Early detection of hematologic change is important; advise patients of early signs and symptoms including fever, sore throat, mouth ulcers, infections, easy bruising, petechial or purpuric hemorrhage.
• Cardiovascular events: [US Boxed Warning]: The rate of fosphenytoin IV administration should not exceed 150 mg phenytoin equivalents (PE)/minute in adults. In pediatric patients when treating status epilepticus, do not exceed a maximum IV administration rate of 2 mg PE/kg/minute (up to 150 mg PE/minute); for maintenance doses, the rate should not exceed 1 to 2 mg PE/kg/minute (up to 100 mg PE/minute). Severe hypotension and cardiac arrhythmias (eg, bradycardia, heart block, QT interval prolongation, ventricular tachycardia, ventricular fibrillation) may occur with rapid administration (may be fatal) and commonly occur in critically ill patients, elderly patients, and patients with hypotension and severe myocardial insufficiency. Careful cardiac (including respiratory) monitoring is necessary during and after administration of fosphenytoin IV; reduction in rate of administration or discontinuation of infusion may be necessary. Although the risk of cardiovascular toxicity increases with infusion rates above the recommended infusion rate, these events have also been reported at or below the recommended infusion rate.
• Dermatologic reactions: Severe cutaneous adverse reactions (some fatal), including acute generalized exanthematous pustulosis (AGEP), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and Stevens-Johnson syndrome (SJS) have been reported; the onset of symptoms is usually within 28 days, but can occur later. Data suggest a genetic susceptibility for serious skin reactions in patients of Asian descent (see "Special populations" below).
• Hepatotoxicity: Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with phenytoin. Other 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. Immediately discontinue fosphenytoin in patients who develop acute hepatotoxicity and do not readminister.
• Hypersensitivity: Hypersensitivity, including angioedema, has been reported; discontinue immediately if hypersensitivity reaction occurs. Consider alternative therapy in patients who have experienced hypersensitivity to structurally similar drugs such as carboxamides (eg, carbamazepine), barbiturates, succinimides, and oxazolidinediones (eg, trimethadione).
• Local toxicity: The "purple glove syndrome" (ie, discoloration with edema and pain of distal limb) may occur following peripheral IV administration of fosphenytoin. This syndrome may or may not be associated with drug extravasation. Symptoms may resolve spontaneously; however, skin necrosis and limb ischemia may occur. In general, fosphenytoin has significantly less venous irritation and phlebitis compared with an equimolar dose of phenytoin (Jamerson 1994).
• Lymphadenopathy: May occur (local or generalized), including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin disease. Discontinue if lymphadenopathy occurs.
• Multiorgan hypersensitivity reactions: Potentially serious, sometimes fatal multiorgan hypersensitivity reactions (also known as DRESS) have been reported with some antiseizure drugs; including fosphenytoin; monitor for signs and symptoms of possible manifestations associated with lymphatic, hepatic, renal, and/or hematologic organ systems; gradual discontinuation and conversion to alternate therapy may be required.
• Sensory disturbances: Severe burning or itching, and/or paresthesias, mostly perineal, may occur upon administration, usually at the maximum administration rate and last from minutes to hours; milder sensory disturbances may persist for as long as 24 hours; occurrence and intensity may be lessened by slowing or temporarily stopping the infusion.
Disease-related concerns:
• Cardiovascular disease: Use with caution in patients with hypotension and/or severe myocardial insufficiency; use is contraindicated in patients with sinus bradycardia, sinoatrial block, second- and third-degree heart block or Adam-Stokes syndrome.
• Diabetes: Use with caution in patients with diabetes mellitus. Phenytoin may inhibit insulin release; may increase serum glucose in patients with diabetes.
• Hepatic impairment: Use with caution in patients with hepatic impairment. Due to an increased fraction of unbound phenytoin in patients with hepatic impairment, interpret total plasma phenytoin concentrations with caution; unbound phenytoin concentrations may be more useful.
• Hyperbilirubinemia: Use with caution in patients with any condition associated with elevated serum bilirubin levels, which will increase the free fraction of phenytoin in the serum and, therefore, the pharmacologic response. Due to an increased fraction of unbound phenytoin in patients with hyperbilirubinemia, interpret total plasma phenytoin concentrations with caution; unbound phenytoin concentrations may be more useful.
• Hypoalbuminemia: Use with caution in patients with any condition associated with low serum albumin levels, which will increase the free fraction of phenytoin in the serum and, therefore, the pharmacologic response. Due to an increased fraction of unbound phenytoin in patients with hypoalbuminemia, interpret total plasma phenytoin concentrations with caution; unbound phenytoin concentrations may be more useful.
• Hypothyroidism: Use with caution in patients with hypothyroidism; phenytoin may alter thyroid (T4) hormone serum concentrations (with chronic administration).
• Porphyria: Use with caution in patients with porphyria.
• Renal impairment: Use with caution in patients with renal impairment; also consider the phosphate load of fosphenytoin (0.0037 mmol phosphate/mg PE fosphenytoin). Due to an increased fraction of unbound phenytoin in patients with renal impairment, interpret total plasma phenytoin concentrations with caution; unbound phenytoin concentrations may be more useful.
Special populations:
• Asian ancestry: Asian patients with the variant HLA-B*1502 and/or patients who are carriers for the variant CYP2C9*3 (intermediate or poor metabolizers) may be at an increased risk of developing SJS and/or TEN.
• Critically ill patients: Use with caution in critically ill patients.
• Debilitated patients: Use with caution in patients who are debilitated.
• Older adult: Use with caution in the elderly.
Dosage form specific issues:
• Phenytoin sodium equivalent: Doses of fosphenytoin are always expressed as their phenytoin sodium equivalent (PE). Thus, 1 mg PE is equivalent to 1 mg phenytoin sodium. Do not change the recommended doses when substituting fosphenytoin for phenytoin or vice versa as they are not equivalent on a mg to mg basis. Dosing errors have also occurred due to misinterpretation of vial concentrations resulting in two- or tenfold overdoses (some fatal); ensure correct volume of fosphenytoin is withdrawn from vial.
Other warnings/precautions:
• Appropriate use: Administer only when oral phenytoin administration is not possible. If rapid phenytoin loading is a primary goal, IV administration of fosphenytoin is preferred. As non-emergency therapy, fosphenytoin IV should be administered more slowly. Fosphenytoin is not indicated for the treatment of absence seizures or seizures due to hypoglycemia or other metabolic causes.
• Sustained serum concentrations: Plasma 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 atrophy. Measure plasma phenytoin concentrations at the first sign of acute toxicity; dosage reduction is indicated if phenytoin concentrations are excessive; if symptoms persist, discontinue administration.
• Withdrawal: Antiseizure medications should not be discontinued abruptly because of the possibility of increasing seizure frequency; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal.
Pediatric patients may be at increased risk for vitamin D deficiency; with chronic therapy, phenytoin may cause catabolism of vitamin D; the daily vitamin D requirement may be increased in these patients (≥400 units/day); vitamin D status should be periodically monitored with laboratory data (Misra 2008; Wagner 2008).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Injection, as sodium:
Cerebyx: 100 mg PE/2 mL (2 mL); 500 mg PE/10 mL (10 mL)
Generic: 100 mg PE/2 mL (2 mL); 500 mg PE/10 mL (10 mL)
Solution, Injection, as sodium [preservative free]:
Generic: 100 mg PE/2 mL (2 mL); 500 mg PE/10 mL (10 mL)
Yes
Solution (Cerebyx Injection)
100 mg PE/2 mL (per mL): $16.39
500 mg PE/10 mL (per mL): $9.83
Solution (Fosphenytoin Sodium Injection)
100 mg PE/2 mL (per mL): $2.87 - $9.00
500 mg PE/10 mL (per mL): $2.40 - $5.76
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Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Injection:
Cerebyx: 75 mg/mL (2 mL, 10 mL)
IM: May be administered as a single daily dose using 1 to 4 injection sites (up to 20 mL per site well tolerated in adults) (Ref).
IV: Rates of infusion: Do not exceed 150 mg PE/minute. Slower administration reduces incidence of cardiovascular events (eg, hypotension, arrhythmia) as well as severity of paresthesias and pruritus. For nonemergent situations, may administer loading dose more slowly (eg, over 30 minutes [~33 mg PE/minute for 1,000 mg PE] or 50 to 100 mg PE/minute (Ref)). Highly sensitive patients (eg, elderly, patients with preexisting cardiovascular conditions) should receive fosphenytoin more slowly (eg, 25 to 50 mg PE/minute) (Ref).
Parenteral:
IV: Administer diluted solution as intermittent IV infusion; do not administer as a continuous infusion or IV push. Slower administration rates may reduce the incidence of cardiovascular events (eg, hypotension, arrhythmia), as well as severity of paresthesias and pruritus. In neonates, infusion over 10 to 30 minutes has been recommended (Ref); in older patients, administration varies by patient condition and type of dose (eg, loading or maintenance). Highly sensitive patients (eg, patients with preexisting cardiovascular conditions) should receive fosphenytoin more slowly (Ref).
Maximum rates of infusion:
Loading doses: Administer at 2 mg PE/kg/minute up to a maximum of 150 mg PE/minute.
Maintenance doses: Administer more slowly at 1 to 2 mg PE/kg/minute up to 100 mg PE/minute.
IM: Not the preferred route in neonatal and pediatric patients. May administer undiluted; the quadricep area has been recommended as an injection site; due to volume of dose, multiple injection sites may be necessary to administer a single dose; in adults, this has required 1 to 4 injection sites (Ref).
Hazardous agent (NIOSH 2024 [table 2]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2023; NIOSH 2024; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
Seizures: Control of generalized tonic-clonic status epilepticus and the prevention and treatment of seizures occurring during neurosurgery (eg, prophylaxis during craniotomy); may be used for short-term parenteral administration (eg, focal [partial] onset seizures or generalized onset seizures) when oral phenytoin is not possible.
Traumatic brain injury, prevention of early posttraumatic seizure; Trigeminal neuralgia, rescue therapy
Cerebyx may be confused with CeleBREX, CeleXA, Cerezyme, Cervarix
Fosphenytoin may be confused with fospropofol
Overdoses have occurred due to confusion between the mg per mL concentration of fosphenytoin (50 mg phenytoin equivalent (PE)/mL) and total drug content per vial (either 100 mg PE/2 mL vial or 500 mg PE/10 mL vial). ISMP recommends that the total drug content per container is identified instead of the concentration in mg per mL to avoid confusion and potential overdoses. Additionally, since most errors have occurred with overdoses in children, ISMP recommends that pediatric hospitals consider stocking only the 2 mL vial.
Substrate of CYP2C19 (Major), CYP2C9 (Major), CYP3A4 (Minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Induces CYP1A2 (Weak), CYP2B6 (Weak), CYP3A4 (Strong), P-glycoprotein, UGT1A1, UGT1A4;
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Abemaciclib: CYP3A4 Inducers (Strong) may decrease serum concentration of Abemaciclib. Risk X: Avoid
Abiraterone Acetate: CYP3A4 Inducers (Strong) may decrease serum concentration of Abiraterone Acetate. Management: Avoid coadministration with strong CYP3A4 inducers. For patients treated with single-agent abiraterone who require therapy with a strong CYP3A4 inducers, abiraterone frequency may increased to twice daily. See full mono for details. Risk D: Consider Therapy Modification
Acalabrutinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Acalabrutinib. Management: Avoid co-administration of strong CYP3A inducers in patients taking acalabrutinib. If strong CYP3A inducers cannot be avoided, increase the dose of acalabrutinib to 200 mg twice daily. Risk D: Consider Therapy Modification
Acemetacin: May increase serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor
Acetaminophen: Fosphenytoin-Phenytoin may decrease serum concentration of Acetaminophen. Specifically, serum concentrations of acetaminophen may be decreased (leading to decreased efficacy), but the formation of the toxic N-acetyl-p-benzoquinone imine (NAPQI) metabolite may be increased (leading to increased hepatotoxicity). Risk C: Monitor
AcetaZOLAMIDE: May increase adverse/toxic effects of Fosphenytoin-Phenytoin. Specifically, the risk for osteomalacia or rickets may be increased. Risk C: Monitor
Acoramidis: UGT1A1 Inducers may decrease serum concentration of Acoramidis. Risk X: Avoid
Adagrasib: May increase serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may decrease serum concentration of Adagrasib. Risk X: Avoid
Afatinib: P-glycoprotein/ABCB1 Inducers may decrease serum concentration of Afatinib. Management: Increase the afatinib dose by 10 mg as tolerated in patients requiring chronic coadministration of P-gp inducers with afatinib. Reduce afatinib dose back to the original afatinib dose 2 to 3 days after discontinuation of the P-gp inducer. Risk D: Consider Therapy Modification
Alcohol (Ethyl): May decrease serum concentration of Fosphenytoin-Phenytoin. Alcohol (Ethyl) may increase serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor
Aldesleukin: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Alfacalcidol: CYP3A4 Inducers (Strong) may decrease serum concentration of Alfacalcidol. Risk C: Monitor
ALfentanil: CYP3A4 Inducers (Strong) may decrease serum concentration of ALfentanil. Management: If concomitant use of alfentanil and strong CYP3A4 inducers is necessary, consider dosage increase of alfentanil until stable drug effects are achieved. Monitor patients for signs of opioid withdrawal. Risk D: Consider Therapy Modification
Aliskiren: P-glycoprotein/ABCB1 Inducers may decrease serum concentration of Aliskiren. Risk C: Monitor
Alpelisib: CYP3A4 Inducers (Strong) may decrease serum concentration of Alpelisib. Risk X: Avoid
ALPRAZolam: CYP3A4 Inducers (Strong) may decrease serum concentration of ALPRAZolam. Risk C: Monitor
Amiodarone: Fosphenytoin-Phenytoin may decrease serum concentration of Amiodarone. Amiodarone may increase serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor
AmLODIPine: CYP3A4 Inducers (Strong) may decrease serum concentration of AmLODIPine. Risk C: Monitor
Antihepaciviral Combination Products: CYP3A4 Inducers (Strong) may decrease serum concentration of Antihepaciviral Combination Products. Risk X: Avoid
Apixaban: Inducers of CYP3A4 (Strong) and P-glycoprotein may decrease serum concentration of Apixaban. Risk X: Avoid
Apremilast: CYP3A4 Inducers (Strong) may decrease serum concentration of Apremilast. Risk X: Avoid
Aprepitant: CYP3A4 Inducers (Strong) may decrease serum concentration of Aprepitant. Risk X: Avoid
ARIPiprazole Lauroxil: CYP3A4 Inducers (Strong) may decrease active metabolite exposure of ARIPiprazole Lauroxil. Management: Patients taking the 441 mg dose of aripiprazole lauroxil increase their dose to 662 mg if used with a strong CYP3A4 inducer for more than 14 days. No dose adjustment is necessary for patients using the higher doses of aripiprazole lauroxil. Risk D: Consider Therapy Modification
ARIPiprazole: CYP3A4 Inducers (Strong) may decrease serum concentration of ARIPiprazole. Management: For indications other than major depressive disorder: double the oral aripiprazole dose over 1 to 2 weeks and closely monitor. Avoid use of strong CYP3A4 inducers for more than 14 days with extended-release injectable aripiprazole. Risk D: Consider Therapy Modification
Artemether and Lumefantrine: CYP3A4 Inducers (Strong) may decrease serum concentration of Artemether and Lumefantrine. CYP3A4 Inducers (Strong) may decrease active metabolite exposure of Artemether and Lumefantrine. Specifically, concentrations of dihydroartemisinin (DHA), the active metabolite of artemether may be decreased. Risk X: Avoid
Artesunate: Fosphenytoin-Phenytoin may decrease active metabolite exposure of Artesunate. Risk C: Monitor
Atazanavir: May decrease serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may decrease serum concentration of Atazanavir. Risk X: Avoid
Atogepant: CYP3A4 Inducers (Strong) may decrease serum concentration of Atogepant. Management: For treatment of episodic migraine, the recommended dose of atogepant is 30 mg once daily or 60 mg once daily when combined with CYP3A4 inducers. When used for treatment of chronic migraine, use of atogepant with CYP3A4 inducers should be avoided. Risk D: Consider Therapy Modification
Atorvastatin: CYP3A4 Inducers (Strong) may decrease serum concentration of Atorvastatin. Risk C: Monitor
Atrasentan: CYP3A4 Inducers (Strong) may decrease serum concentration of Atrasentan. Risk X: Avoid
Avacopan: CYP3A4 Inducers (Strong) may decrease serum concentration of Avacopan. Risk X: Avoid
Avanafil: CYP3A4 Inducers (Strong) may decrease serum concentration of Avanafil. Risk X: Avoid
Avapritinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Avapritinib. Risk X: Avoid
Axitinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Axitinib. Risk X: Avoid
Barnidipine: CYP3A4 Inducers (Strong) may decrease serum concentration of Barnidipine. Risk C: Monitor
Bazedoxifene: Fosphenytoin-Phenytoin may decrease serum concentration of Bazedoxifene. Risk C: Monitor
Bedaquiline: CYP3A4 Inducers (Strong) may decrease serum concentration of Bedaquiline. CYP3A4 Inducers (Strong) may decrease active metabolite exposure of Bedaquiline. Risk X: Avoid
Belumosudil: CYP3A4 Inducers (Strong) may decrease serum concentration of Belumosudil. Management: Increase the dose of belumosudil to 200 mg twice daily when coadministered with strong CYP3A4 inducers. Risk D: Consider Therapy Modification
Benidipine: CYP3A4 Inducers (Strong) may decrease serum concentration of Benidipine. Risk C: Monitor
Benperidol: CYP3A4 Inducers (Strong) may decrease serum concentration of Benperidol. Risk C: Monitor
Benzhydrocodone: CYP3A4 Inducers (Strong) may decrease serum concentration of Benzhydrocodone. Specifically, the serum concentrations of hydrocodone may be reduced. Risk C: Monitor
Berotralstat: P-glycoprotein/ABCB1 Inducers may decrease serum concentration of Berotralstat. Risk X: Avoid
Beta-Acetyldigoxin: P-glycoprotein/ABCB1 Inducers may decrease serum concentration of Beta-Acetyldigoxin. Risk C: Monitor
Betamethasone (Systemic): CYP3A4 Inducers (Strong) may decrease serum concentration of Betamethasone (Systemic). Risk C: Monitor
Bictegravir: Fosphenytoin-Phenytoin may decrease serum concentration of Bictegravir. Management: When possible consider using an alternative antiseizure drug with concurrent bictegravir, emtricitabine, and tenofovir alafenamide. If the combination must be used, monitor closely for evidence of reduced antiviral effectiveness. Risk D: Consider Therapy Modification
Bisoprolol: CYP3A4 Inducers (Strong) may decrease serum concentration of Bisoprolol. Risk C: Monitor
Blonanserin: CYP3A4 Inducers (Strong) may decrease serum concentration of Blonanserin. Risk C: Monitor
Bortezomib: CYP3A4 Inducers (Strong) may decrease serum concentration of Bortezomib. Risk X: Avoid
Bosutinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Bosutinib. Risk X: Avoid
Brentuximab Vedotin: CYP3A4 Inducers (Strong) may decrease serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be decreased. Risk C: Monitor
Brexpiprazole: CYP3A4 Inducers (Strong) may decrease serum concentration of Brexpiprazole. Management: If brexpiprazole is used together with a strong CYP3A4 inducer, the brexpiprazole dose should gradually be doubled over the course of 1 to 2 weeks. Decrease brexpiprazole to original dose over 1 to 2 weeks if the strong CYP3A4 inducer is discontinued. Risk D: Consider Therapy Modification
Brigatinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Brigatinib. Risk X: Avoid
Brivaracetam: May increase serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may decrease serum concentration of Brivaracetam. Risk C: Monitor
Bromocriptine: CYP3A4 Inducers (Strong) may decrease serum concentration of Bromocriptine. Risk C: Monitor
Bromperidol: CYP3A4 Inducers (Strong) may decrease serum concentration of Bromperidol. Risk C: Monitor
Brotizolam: CYP3A4 Inducers (Strong) may decrease serum concentration of Brotizolam. Risk C: Monitor
Buprenorphine: CYP3A4 Inducers (Strong) may decrease serum concentration of Buprenorphine. Risk C: Monitor
BuPROPion: CYP2B6 Inducers (Weak) may decrease serum concentration of BuPROPion. Risk C: Monitor
BusPIRone: CYP3A4 Inducers (Strong) may decrease serum concentration of BusPIRone. Management: Consider alternatives to this combination. If coadministration of these agents is deemed necessary, monitor patients for reduced buspirone effects and increase buspirone doses as needed. Risk D: Consider Therapy Modification
Busulfan: Fosphenytoin-Phenytoin may decrease serum concentration of Busulfan. Risk C: Monitor
Butorphanol: CYP3A4 Inducers (Strong) may decrease serum concentration of Butorphanol. Risk C: Monitor
Cabazitaxel: CYP3A4 Inducers (Strong) may decrease serum concentration of Cabazitaxel. Risk C: Monitor
Cabotegravir: UGT1A1 Inducers may decrease serum concentration of Cabotegravir. Risk X: Avoid
Cabozantinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Cabozantinib. Management: Avoid use of strong CYP3A4 inducers with cabozantinib if possible. If combined, increase cabozantinib capsules (Cometriq) by 40 mg from previous dose, max 180 mg daily. Increase cabozantinib tablets (Cabometyx) by 20 mg from previous dose, max 80 mg daily Risk D: Consider Therapy Modification
Calcifediol: CYP3A4 Inducers (Strong) may increase serum concentration of Calcifediol. Risk C: Monitor
Calcitriol (Systemic): CYP3A4 Inducers (Strong) may decrease serum concentration of Calcitriol (Systemic). Risk C: Monitor
Calcium Channel Blockers (Nondihydropyridine): May increase serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may decrease serum concentration of Calcium Channel Blockers (Nondihydropyridine). Management: Consider alternatives to this combination when possible. If combined, monitor for increased phenytoin concentrations and toxicities and monitor for decreased calcium channel blocker efficacy. Risk D: Consider Therapy Modification
Canagliflozin: Fosphenytoin may decrease serum concentration of Canagliflozin. Management: Consider increasing canagliflozin dose to 200 mg/day in patients tolerating 100 mg/day. A further increase to 300 mg/day can be considered in patients with an estimated glomerular filtration rate (GFR) of 60 mL/min/1.73 m2 or greater. Risk D: Consider Therapy Modification
Cannabidiol: May increase serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may decrease serum concentration of Cannabidiol. Risk C: Monitor
Cannabis: CYP3A4 Inducers (Strong) may decrease serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be decreased. Risk C: Monitor
Capivasertib: CYP3A4 Inducers (Strong) may decrease serum concentration of Capivasertib. Risk X: Avoid
Capmatinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Capmatinib. Risk X: Avoid
CarBAMazepine: Fosphenytoin-Phenytoin may decrease serum concentration of CarBAMazepine. CarBAMazepine may decrease serum concentration of Fosphenytoin-Phenytoin. CarBAMazepine may increase serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor
Cariprazine: CYP3A4 Inducers (Strong) may decrease serum concentration of Cariprazine. Risk X: Avoid
Carmustine: May decrease serum concentration of Fosphenytoin-Phenytoin. Management: Consider alternatives to fosphenytoin-phenytoin in carmustine treated patients. If combined, monitor closely for reduced phenytoin concentrations and increase fosphenytoin-phenytoin doses as needed. Risk D: Consider Therapy Modification
CeFAZolin: May increase serum concentration of Fosphenytoin. Specifically, the ratio of free phenytoin to total phenytoin may be increased. Risk C: Monitor
Celiprolol: P-glycoprotein/ABCB1 Inducers may decrease serum concentration of Celiprolol. Risk C: Monitor
Cenobamate: Fosphenytoin-Phenytoin may decrease serum concentration of Cenobamate. Cenobamate may increase serum concentration of Fosphenytoin-Phenytoin. Management: Gradually reduce the dose of fosphenytoin/phenytoin by up to 50% as the dose of cenobamate is being titrated up. Monitor phenytoin levels closely; higher doses of cenobamate may be required. Risk D: Consider Therapy Modification
Ceritinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Ceritinib. Risk X: Avoid
Certoparin: May increase serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor
Chloramphenicol (Systemic): Fosphenytoin may decrease serum concentration of Chloramphenicol (Systemic). Fosphenytoin may increase serum concentration of Chloramphenicol (Systemic). Chloramphenicol (Systemic) may increase serum concentration of Fosphenytoin. Risk C: Monitor
ChlordiazePOXIDE: May increase serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor
Chlorpheniramine: May increase serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor
ChlorproPAMIDE: CYP3A4 Inducers (Strong) may decrease serum concentration of ChlorproPAMIDE. Risk C: Monitor
Cilnidipine: CYP3A4 Inducers (Strong) may decrease serum concentration of Cilnidipine. Risk C: Monitor
Cimetidine: May increase adverse/toxic effects of Fosphenytoin-Phenytoin. Cimetidine may increase serum concentration of Fosphenytoin-Phenytoin. Management: Consider using an alternative H2-antagonist to avoid this interaction. Monitor for toxic effects of hydantoin antiseizure drugs if cimetidine is initiated/dose increased. Risk D: Consider Therapy Modification
Ciprofloxacin (Systemic): May decrease therapeutic effects of Fosphenytoin. Ciprofloxacin (Systemic) may decrease serum concentration of Fosphenytoin. Risk C: Monitor
Citalopram: CYP3A4 Inducers (Strong) may decrease serum concentration of Citalopram. Risk C: Monitor
Cladribine: P-glycoprotein/ABCB1 Inducers may decrease serum concentration of Cladribine. Risk C: Monitor
Clarithromycin: CYP3A4 Inducers (Strong) may increase active metabolite exposure of Clarithromycin. CYP3A4 Inducers (Strong) may decrease serum concentration of Clarithromycin. Management: Consider alternative antimicrobial therapy for patients receiving a CYP3A4 inducer. Drugs that enhance the metabolism of clarithromycin into 14-hydroxyclarithromycin may alter the clinical activity of clarithromycin and may impair clarithromycin efficacy. Risk D: Consider Therapy Modification
Clindamycin (Systemic): CYP3A4 Inducers (Strong) may decrease serum concentration of Clindamycin (Systemic). Risk C: Monitor
ClonazePAM: CYP3A4 Inducers (Strong) may decrease serum concentration of ClonazePAM. Risk C: Monitor
CloZAPine: CYP3A4 Inducers (Strong) may decrease serum concentration of CloZAPine. Management: Avoid use with strong CYP3A4 inducers when possible. If combined, monitor patients closely and consider clozapine dose increases. Clozapine dose reduction and further monitoring may be required when strong CYP3A4 inducers are discontinued. Risk D: Consider Therapy Modification
Cobicistat: Fosphenytoin-Phenytoin may decrease serum concentration of Cobicistat. Risk X: Avoid
Cobimetinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Cobimetinib. Risk X: Avoid
Codeine: CYP3A4 Inducers (Strong) may decrease active metabolite exposure of Codeine. Risk C: Monitor
Colchicine: CYP3A4 Inducers (Strong) may decrease serum concentration of Colchicine. Risk C: Monitor
Copanlisib: CYP3A4 Inducers (Strong) may decrease serum concentration of Copanlisib. Risk X: Avoid
Crinecerfont: CYP3A4 Inducers (Strong) may decrease serum concentration of Crinecerfont. Management: Double the morning and evening doses of crinecerfont during coadministration with strong CYP3A4 inducers. See full interaction monograph for details. Risk D: Consider Therapy Modification
Crizotinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Crizotinib. Risk X: Avoid
CycloPHOSphamide: Fosphenytoin-Phenytoin may increase active metabolite exposure of CycloPHOSphamide. More specifically, phenytoin may increase the rate of cyclophosphamide conversion to its primary active metabolite, 4-hydroxycyclophosphamide. Fosphenytoin-Phenytoin may decrease serum concentration of CycloPHOSphamide. Risk C: Monitor
CycloSPORINE (Systemic): CYP3A4 Inducers (Strong) may decrease serum concentration of CycloSPORINE (Systemic). Management: Monitor closely for reduced cyclosporine concentrations when combined with strong CYP3A4 inducers. Cyclosporine dose increases will likely be required to maintain adequate serum concentrations. Risk D: Consider Therapy Modification
CYP2C19 Inducers (Moderate): May decrease serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor
CYP2C19 Inducers (Strong): May decrease serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor
CYP2C19 Inhibitors (Moderate): May increase serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor
CYP2C19 Inhibitors (Strong): May increase serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor
CYP2C19 Inhibitors (Weak): May increase serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor
CYP2C9 Inhibitors (Moderate): May increase serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor
CYP2C9 Inhibitors (Weak): May increase serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor
Cyproterone: CYP3A4 Inducers (Strong) may decrease serum concentration of Cyproterone. Risk C: Monitor
Dabigatran Etexilate: P-glycoprotein/ABCB1 Inducers may decrease serum concentration of Dabigatran Etexilate. Management: Avoid concurrent use of dabigatran with P-glycoprotein inducers whenever possible. Risk X: Avoid
Daclatasvir: CYP3A4 Inducers (Strong) may decrease serum concentration of Daclatasvir. Risk X: Avoid
Dapsone (Systemic): May increase adverse/toxic effects of CYP3A4 Inducers (Strong). CYP3A4 Inducers (Strong) may decrease serum concentration of Dapsone (Systemic). Management: Consider alternatives to this combination when possible. Monitor for decreased dapsone efficacy if combined with strong CYP3A4 inducers. Risk D: Consider Therapy Modification
Daridorexant: CYP3A4 Inducers (Strong) may decrease serum concentration of Daridorexant. Risk X: Avoid
Darolutamide: Inducers of CYP3A4 (Strong) and P-glycoprotein may decrease serum concentration of Darolutamide. Risk X: Avoid
Darunavir: May decrease serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor
Dasabuvir: CYP3A4 Inducers (Strong) may decrease serum concentration of Dasabuvir. Risk X: Avoid
Dasatinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Dasatinib. Management: Avoid concurrent use of dasatinib with strong CYP3A4 inducers when possible. If such a combination cannot be avoided, consider increasing dasatinib dose and monitor clinical response and toxicity closely. Risk D: Consider Therapy Modification
Deferasirox: UGT1A1 Inducers may decrease serum concentration of Deferasirox. Management: Avoid concomitant use of deferasirox and UGT1A1 inducers when possible. If combined, consider a 50% increase in the initial deferasirox dose, with monitoring of serum ferritin concentrations and clinical response to guide further dosing. Risk D: Consider Therapy Modification
Deflazacort: CYP3A4 Inducers (Strong) may decrease active metabolite exposure of Deflazacort. Risk X: Avoid
Delamanid: CYP3A4 Inducers (Strong) may decrease serum concentration of Delamanid. Risk X: Avoid
Desmopressin: Hyponatremia-Associated Agents may increase hyponatremic effects of Desmopressin. Risk C: Monitor
Deuruxolitinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Deuruxolitinib. Risk X: Avoid
DexAMETHasone (Systemic): Fosphenytoin may decrease serum concentration of DexAMETHasone (Systemic). DexAMETHasone (Systemic) may decrease serum concentration of Fosphenytoin. DexAMETHasone (Systemic) may increase serum concentration of Fosphenytoin. Management: Consider dexamethasone dose increases when combined with fosphenytoin and monitor closely for reduced steroid efficacy. Monitor phenytoin levels closely, both increased and decreased phenytoin levels have been reported. Risk D: Consider Therapy Modification
Dexketoprofen: May increase adverse/toxic effects of Fosphenytoin-Phenytoin. Risk X: Avoid
DiazePAM: Fosphenytoin-Phenytoin may decrease serum concentration of DiazePAM. DiazePAM may increase serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor
Diazoxide Choline: May increase serum concentration of Fosphenytoin-Phenytoin. Diazoxide Choline may decrease serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor
Diazoxide: May decrease serum concentration of Fosphenytoin-Phenytoin. Total phenytoin concentrations may be affected more than free phenytoin concentrations. Risk C: Monitor
Dienogest: CYP3A4 Inducers (Strong) may decrease serum concentration of Dienogest. Risk C: Monitor
Digitoxin: CYP3A4 Inducers (Strong) may decrease serum concentration of Digitoxin. Risk C: Monitor
Digitoxin: P-glycoprotein/ABCB1 Inducers may decrease serum concentration of Digitoxin. Risk C: Monitor
Digoxin: P-glycoprotein/ABCB1 Inducers may decrease serum concentration of Digoxin. Risk C: Monitor
Dinutuximab Beta: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Disopyramide: CYP3A4 Inducers (Strong) may decrease serum concentration of Disopyramide. Risk C: Monitor
Disulfiram: May increase serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor
DOCEtaxel: CYP3A4 Inducers (Strong) may decrease serum concentration of DOCEtaxel. Risk C: Monitor
Dolutegravir: Fosphenytoin-Phenytoin may decrease serum concentration of Dolutegravir. Risk X: Avoid
Domperidone: CYP3A4 Inducers (Strong) may decrease serum concentration of Domperidone. Risk C: Monitor
Doravirine: CYP3A4 Inducers (Strong) may decrease serum concentration of Doravirine. Risk X: Avoid
Doxercalciferol: CYP3A4 Inducers (Strong) may increase active metabolite exposure of Doxercalciferol. Risk C: Monitor
Doxofylline: Fosphenytoin-Phenytoin may decrease serum concentration of Doxofylline. Risk C: Monitor
DOXOrubicin (Conventional): CYP3A4 Inducers (Strong) may decrease serum concentration of DOXOrubicin (Conventional). Risk X: Avoid
DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inducers may decrease serum concentration of DOXOrubicin (Conventional). Risk X: Avoid
Doxycycline: Fosphenytoin may decrease serum concentration of Doxycycline. Risk C: Monitor
DroNABinol: CYP3A4 Inducers (Strong) may decrease serum concentration of DroNABinol. Risk C: Monitor
Dronedarone: CYP3A4 Inducers (Strong) may decrease serum concentration of Dronedarone. Risk X: Avoid
Duvelisib: CYP3A4 Inducers (Strong) may decrease serum concentration of Duvelisib. Risk X: Avoid
Dydrogesterone: CYP3A4 Inducers (Strong) may decrease serum concentration of Dydrogesterone. Risk C: Monitor
Ebastine: CYP3A4 Inducers (Strong) may decrease serum concentration of Ebastine. CYP3A4 Inducers (Strong) may decrease active metabolite exposure of Ebastine. Risk C: Monitor
Edoxaban: P-glycoprotein/ABCB1 Inducers may decrease serum concentration of Edoxaban. Management: Avoid coadministration of edoxaban and P-glycoprotein (P-gp) inducers if possible. If concomitant use is required, be aware the edoxaban efficacy may be decreased. Risk D: Consider Therapy Modification
Efavirenz: Fosphenytoin-Phenytoin may decrease serum concentration of Efavirenz. Efavirenz may decrease serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor
Elacestrant: CYP3A4 Inducers (Strong) may decrease serum concentration of Elacestrant. Risk X: Avoid
Elagolix, Estradiol, and Norethindrone: May increase serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may decrease serum concentration of Elagolix, Estradiol, and Norethindrone. Risk C: Monitor
Elagolix: Fosphenytoin-Phenytoin may decrease serum concentration of Elagolix. Elagolix may increase serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor
Elbasvir and Grazoprevir: CYP3A4 Inducers (Strong) may decrease serum concentration of Elbasvir and Grazoprevir. Risk X: Avoid
Elexacaftor, Tezacaftor, and Ivacaftor: CYP3A4 Inducers (Strong) may decrease serum concentration of Elexacaftor, Tezacaftor, and Ivacaftor. Risk X: Avoid
Eliglustat: CYP3A4 Inducers (Strong) may decrease serum concentration of Eliglustat. Risk X: Avoid
Elranatamab: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Encorafenib: CYP3A4 Inducers (Strong) may decrease serum concentration of Encorafenib. Risk X: Avoid
Enfortumab Vedotin: CYP3A4 Inducers (Strong) may decrease serum concentration of Enfortumab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be decreased. Risk C: Monitor
Ensartinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Ensartinib. Risk X: Avoid
Entrectinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Entrectinib. Risk X: Avoid
Enzalutamide: May decrease serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may decrease serum concentration of Enzalutamide. Management: Avoid concurrent use of phenytoin/fosphenytoin and enzalutamide whenever possible. If combined, increase enzalutamide dose to 240 mg daily. Additionally, monitor for reduced phenytoin serum concentrations and effects. Risk D: Consider Therapy Modification
Epcoritamab: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Eplerenone: CYP3A4 Inducers (Strong) may decrease serum concentration of Eplerenone. Risk C: Monitor
Eravacycline: CYP3A4 Inducers (Strong) may decrease serum concentration of Eravacycline. Management: Increase the eravacycline dose to 1.5 mg/kg every 12 hours when combined with strong CYP3A4 inducers. Risk D: Consider Therapy Modification
Erdafitinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Erdafitinib. Risk X: Avoid
Erlotinib: May increase serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may decrease serum concentration of Erlotinib. Management: Avoid use of erlotinib with phenytoin when possible. If required, increase erlotinib dose by 50 mg increments at 2 week intervals, as tolerated, to a max of 450 mg/day. Also monitor for increased phenytoin concentrations and toxicities. Risk D: Consider Therapy Modification
Escitalopram: CYP3A4 Inducers (Strong) may decrease serum concentration of Escitalopram. Risk C: Monitor
Esketamine (Injection): CYP3A4 Inducers (Strong) may decrease serum concentration of Esketamine (Injection). Risk C: Monitor
Eslicarbazepine: Fosphenytoin may decrease serum concentration of Eslicarbazepine. (based on studies with phenytoin) Eslicarbazepine may increase serum concentration of Fosphenytoin. (based on studies with phenytoin) Risk C: Monitor
Estazolam: CYP3A4 Inducers (Strong) may decrease serum concentration of Estazolam. Risk C: Monitor
Estrogen Derivatives: CYP3A4 Inducers (Strong) may decrease serum concentration of Estrogen Derivatives. Risk C: Monitor
Eszopiclone: CYP3A4 Inducers (Strong) may decrease serum concentration of Eszopiclone. Risk C: Monitor
Ethosuximide: May increase serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may decrease serum concentration of Ethosuximide. Risk C: Monitor
Etizolam: CYP3A4 Inducers (Strong) may decrease serum concentration of Etizolam. Risk C: Monitor
Etoposide Phosphate: CYP3A4 Inducers (Strong) may decrease serum concentration of Etoposide Phosphate. Management: When possible, seek alternatives to strong CYP3A4-inducing medications in patients receiving etoposide phosphate. If these combinations cannot be avoided, monitor patients closely for diminished etoposide phosphate response. Risk D: Consider Therapy Modification
Etoposide: CYP3A4 Inducers (Strong) may decrease serum concentration of Etoposide. Management: When possible, seek alternatives to strong CYP3A4-inducing medications in patients receiving etoposide. If combined, monitor patients closely for diminished etoposide response and need for etoposide dose increases. Risk D: Consider Therapy Modification
Etoricoxib: CYP3A4 Inducers (Strong) may decrease serum concentration of Etoricoxib. Risk C: Monitor
Etravirine: CYP3A4 Inducers (Strong) may decrease serum concentration of Etravirine. Risk X: Avoid
Everolimus: Inducers of CYP3A4 (Strong) and P-glycoprotein may decrease serum concentration of Everolimus. Management: Afinitor: Double the everolimus daily dose, using increments of 5 mg or less, with careful monitoring; multiple increments may be necessary. Zortress: Avoid if possible and monitor for decreased everolimus concentrations if combined. Risk D: Consider Therapy Modification
Evogliptin: CYP3A4 Inducers (Strong) may decrease serum concentration of Evogliptin. Risk C: Monitor
Exemestane: CYP3A4 Inducers (Strong) may decrease serum concentration of Exemestane. Management: Increase the exemestane dose to 50 mg once daily in patients receiving concurrent strong CYP3A4 inducers. Monitor patients closely for evidence of toxicity or inadequate clinical response. Risk D: Consider Therapy Modification
Fedratinib: May increase serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may decrease serum concentration of Fedratinib. Risk X: Avoid
Felbamate: Fosphenytoin may decrease serum concentration of Felbamate. Felbamate may increase serum concentration of Fosphenytoin. Management: Initiate felbamate at typical doses (1,200 mg/day in 3 or 4 divided doses for adults and children 14 years of age or older; 15 mg/kg/day in 3 or 4 divided doses in children 2 to 14 years of age) while reducing the fosphenytoin dose by 20%. Risk D: Consider Therapy Modification
Felodipine: CYP3A4 Inducers (Strong) may decrease serum concentration of Felodipine. Management: Consider alternatives to this combination when possible. If combined, monitor for reduced felodipine efficacy and the need for felodipine dose increases. Risk D: Consider Therapy Modification
Fenfluramine: CYP3A4 Inducers (Strong) may decrease serum concentration of Fenfluramine. Management: Avoid concurrent use of strong CYP3A4 inducers with fenfluramine when possible. If combined use cannot be avoided, consider increasing the fenfluramine dose, but do not exceed the fenfluramine maximum daily dose. Risk D: Consider Therapy Modification
Fenoprofen: May increase serum concentration of Fosphenytoin-Phenytoin. Specifically, concentrations of free phenytoin may be increased. Risk C: Monitor
FentaNYL: CYP3A4 Inducers (Strong) may decrease serum concentration of FentaNYL. Risk C: Monitor
Fesoterodine: CYP3A4 Inducers (Strong) may decrease active metabolite exposure of Fesoterodine. Risk C: Monitor
Fexinidazole: CYP3A4 Inducers (Strong) may increase active metabolite exposure of Fexinidazole. Risk X: Avoid
Fexofenadine: P-glycoprotein/ABCB1 Inducers may decrease serum concentration of Fexofenadine. Risk C: Monitor
Finerenone: CYP3A4 Inducers (Strong) may decrease serum concentration of Finerenone. Risk X: Avoid
Flibanserin: CYP3A4 Inducers (Strong) may decrease serum concentration of Flibanserin. Risk X: Avoid
Fludrocortisone: CYP3A4 Inducers (Strong) may decrease serum concentration of Fludrocortisone. Risk C: Monitor
Flunarizine: Fosphenytoin may decrease serum concentration of Flunarizine. Risk C: Monitor
Fluvastatin: May increase serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may increase serum concentration of Fluvastatin. Risk C: Monitor
Folic Acid: May decrease serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor
Fosamprenavir: Fosphenytoin may decrease serum concentration of Fosamprenavir. Fosamprenavir may decrease serum concentration of Fosphenytoin. Specifically, fosamprenavir boosted with ritonavir may decrease phenytoin concentrations. Risk C: Monitor
Fosaprepitant: CYP3A4 Inducers (Strong) may decrease serum concentration of Fosaprepitant. Specifically, CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite aprepitant. Risk X: Avoid
Fosnetupitant: CYP3A4 Inducers (Strong) may decrease active metabolite exposure of Fosnetupitant. Risk X: Avoid
Fostamatinib: CYP3A4 Inducers (Strong) may decrease active metabolite exposure of Fostamatinib. Risk X: Avoid
Fostemsavir: CYP3A4 Inducers (Strong) may decrease active metabolite exposure of Fostemsavir. Risk X: Avoid
Fotemustine: Fosphenytoin-Phenytoin may decrease serum concentration of Fotemustine. Fotemustine may decrease serum concentration of Fosphenytoin-Phenytoin. Specifically, fotemustine may decrease concentrations of orally administered phenytoin. Risk X: Avoid
Fruquintinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Fruquintinib. Risk X: Avoid
Furosemide: Fosphenytoin-Phenytoin may decrease diuretic effects of Furosemide. Risk C: Monitor
Futibatinib: Inducers of CYP3A4 (Strong) and P-glycoprotein may decrease serum concentration of Futibatinib. Risk X: Avoid
Ganaxolone: CYP3A4 Inducers (Strong) may decrease serum concentration of Ganaxolone. Management: Avoid concomitant use of ganaxolone and strong CYP3A4 inducers whenever possible. If combined, consider increasing the dose of ganaxolone, but do not exceed the maximum recommended daily dose. Risk D: Consider Therapy Modification
Gefitinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Gefitinib. Management: In the absence of severe adverse reactions, increase the gefitinib dose to 500 mg daily in patients receiving strong CYP3A4 inducers; resume 250 mg dose 7 days after discontinuation of the strong inducer. Carefully monitor clinical response. Risk D: Consider Therapy Modification
Gemigliptin: CYP3A4 Inducers (Strong) may decrease serum concentration of Gemigliptin. CYP3A4 Inducers (Strong) may decrease active metabolite exposure of Gemigliptin. Risk X: Avoid
Gepirone: CYP3A4 Inducers (Strong) may decrease serum concentration of Gepirone. Risk X: Avoid
Gepotidacin: CYP3A4 Inducers (Strong) may decrease serum concentration of Gepotidacin. Risk X: Avoid
Gestrinone: Fosphenytoin-Phenytoin may decrease serum concentration of Gestrinone. Risk C: Monitor
Gilteritinib: Inducers of CYP3A4 (Strong) and P-glycoprotein may decrease serum concentration of Gilteritinib. Risk X: Avoid
Glasdegib: CYP3A4 Inducers (Strong) may decrease serum concentration of Glasdegib. Risk X: Avoid
Glecaprevir and Pibrentasvir: Fosphenytoin-Phenytoin may decrease serum concentration of Glecaprevir and Pibrentasvir. Risk X: Avoid
Glofitamab: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
GuanFACINE: CYP3A4 Inducers (Strong) may decrease serum concentration of GuanFACINE. Management: Increase extended-release guanfacine dose by up to double when initiating guanfacine in patients taking CYP3A4 inducers or if initiating a CYP3A4 inducer in a patient already taking extended-release guanfacine. Monitor for reduced guanfacine efficacy. Risk D: Consider Therapy Modification
Haloperidol: CYP3A4 Inducers (Strong) may decrease serum concentration of Haloperidol. Risk C: Monitor
Hormonal Contraceptives: CYP3A4 Inducers (Strong) may decrease serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing a strong CYP3A4 inducer to ensure contraceptive reliability. Risk D: Consider Therapy Modification
HYDROcodone: CYP3A4 Inducers (Strong) may decrease serum concentration of HYDROcodone. Risk C: Monitor
Hydrocortisone (Systemic): CYP3A4 Inducers (Strong) may decrease serum concentration of Hydrocortisone (Systemic). Risk C: Monitor
Ibrexafungerp: CYP3A4 Inducers (Strong) may decrease serum concentration of Ibrexafungerp. Risk X: Avoid
Ibrutinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Ibrutinib. Risk X: Avoid
Idelalisib: CYP3A4 Inducers (Strong) may decrease serum concentration of Idelalisib. Risk X: Avoid
Ifosfamide: CYP3A4 Inducers (Strong) may increase active metabolite exposure of Ifosfamide. CYP3A4 Inducers (Strong) may decrease active metabolite exposure of Ifosfamide. Risk C: Monitor
Imatinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Imatinib. Management: Avoid use of imatinib and strong CYP3A4 inducers when possible. If such a combination must be used, increase imatinib dose by at least 50% and monitor the patient's clinical response closely. Doses up to 1200 mg/day (600 mg twice daily) have been used. Risk D: Consider Therapy Modification
Indinavir: CYP3A4 Inducers (Strong) may decrease serum concentration of Indinavir. Management: Consider avoiding the combination of indinavir and strong CYP3A4 inducers whenever possible due to the risk for decreased indinavir concentrations, reduced efficacy, and development of resistance. If combined, monitor for indinavir treatment failure Risk D: Consider Therapy Modification
Irinotecan Products: CYP3A4 Inducers (Strong) may decrease serum concentration of Irinotecan Products. CYP3A4 Inducers (Strong) may decrease active metabolite exposure of Irinotecan Products. Specifically, serum concentrations of SN-38 may be reduced. Management: Avoid administration of strong CYP3A4 inducers during irinotecan treatment, and substitute non-CYP3A4 inducing agents at least 2 weeks prior to irinotecan initiation, whenever possible. If combined, monitor for reduced irinotecan efficacy. Risk D: Consider Therapy Modification
Isavuconazonium Sulfate: CYP3A4 Inducers (Strong) may decrease active metabolite exposure of Isavuconazonium Sulfate. Specifically, CYP3A4 Inducers (Strong) may decrease isavuconazole serum concentrations. Risk X: Avoid
Isoniazid: May increase serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor
Isradipine: May increase serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may decrease serum concentration of Isradipine. Risk C: Monitor
Istradefylline: CYP3A4 Inducers (Strong) may decrease serum concentration of Istradefylline. Risk X: Avoid
Itraconazole: CYP3A4 Inducers (Strong) may decrease serum concentration of Itraconazole. CYP3A4 Inducers (Strong) may decrease active metabolite exposure of Itraconazole. Risk X: Avoid
Ivabradine: CYP3A4 Inducers (Strong) may decrease serum concentration of Ivabradine. Risk X: Avoid
Ivacaftor: CYP3A4 Inducers (Strong) may decrease serum concentration of Ivacaftor. Risk X: Avoid
Ivosidenib: CYP3A4 Inducers (Strong) may decrease serum concentration of Ivosidenib. Risk X: Avoid
Ixabepilone: CYP3A4 Inducers (Strong) may decrease serum concentration of Ixabepilone. Management: Avoid this combination whenever possible. If this combination must be used, a gradual increase in ixabepilone dose from 40 mg/m2 to 60 mg/m2 (given as a 4-hour infusion), as tolerated, should be considered. Risk D: Consider Therapy Modification
Ixazomib: CYP3A4 Inducers (Strong) may decrease serum concentration of Ixazomib. Risk X: Avoid
Ketamine: CYP3A4 Inducers (Strong) may decrease serum concentration of Ketamine. Risk C: Monitor
Ketoconazole (Systemic): CYP3A4 Inducers (Strong) may decrease serum concentration of Ketoconazole (Systemic). Management: The use of ketoconazole concurrently with or within 2 weeks of a strong CYP3A4 inducer is not recommended. If such a combination cannot be avoided, monitor patients closely for evidence of diminished clinical response to ketoconazole. Risk D: Consider Therapy Modification
Lacidipine: CYP3A4 Inducers (Strong) may decrease serum concentration of Lacidipine. Risk C: Monitor
Lacosamide: Antiseizure Agents (Sodium Channel Blockers) may increase adverse/toxic effects of Lacosamide. Specifically the risk for bradycardia, ventricular tachyarrhythmias, or a prolonged PR interval may be increased. Risk C: Monitor
LamoTRIgine: Fosphenytoin may increase arrhythmogenic effects of LamoTRIgine. Fosphenytoin may decrease serum concentration of LamoTRIgine. Management: Consider the risk of serious arrhythmias or death versus benefit of this combination. For patients taking fosphenytoin without valproate, lamotrigine dose adjustments are recommended for lamotrigine initiation. See full interact monograph for details. Risk D: Consider Therapy Modification
Lapatinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Lapatinib. Management: If concomitant use cannot be avoided, titrate lapatinib gradually from 1,250 mg/day up to 4,500 mg/day (HER2 positive metastatic breast cancer) or 1,500 mg/day up to 5,500 mg/day (hormone receptor/HER2 positive breast cancer) as tolerated. Risk D: Consider Therapy Modification
Larotrectinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Larotrectinib. Management: Avoid use of strong CYP3A4 inducers with larotrectinib. If this combination cannot be avoided, double the larotrectinib dose. Reduced to previous dose after stopping the inducer after a period of 3 to 5 times the inducer's half-life. Risk D: Consider Therapy Modification
Lazertinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Lazertinib. Risk X: Avoid
Ledipasvir: P-glycoprotein/ABCB1 Inducers may decrease serum concentration of Ledipasvir. Risk X: Avoid
Lefamulin (Intravenous): CYP3A4 Inducers (Strong) may decrease serum concentration of Lefamulin (Intravenous). Management: Avoid concomitant use of lefamulin intravenous infusion with strong CYP3A4 inducers unless the benefits outweigh the risks. Risk D: Consider Therapy Modification
Lefamulin (Intravenous): P-glycoprotein/ABCB1 Inducers may decrease serum concentration of Lefamulin (Intravenous). Management: Avoid concomitant use of lefamulin (intravenous) with P-glycoprotein/ABCB1 inducers unless the benefits outweigh the risks. Risk D: Consider Therapy Modification
Lefamulin: CYP3A4 Inducers (Strong) may decrease serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin with strong CYP3A4 inducers unless the benefits outweigh the risks. Risk D: Consider Therapy Modification
Lefamulin: P-glycoprotein/ABCB1 Inducers may decrease serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin with P-glycoprotein/ABCB1 inducers unless the benefits outweigh the risks. Risk D: Consider Therapy Modification
Lemborexant: CYP3A4 Inducers (Strong) may decrease serum concentration of Lemborexant. Risk X: Avoid
Lenacapavir: CYP3A4 Inducers (Strong) may decrease serum concentration of Lenacapavir. Risk X: Avoid
Leniolisib: CYP3A4 Inducers (Strong) may decrease serum concentration of Leniolisib. Risk X: Avoid
Lercanidipine: CYP3A4 Inducers (Strong) may decrease serum concentration of Lercanidipine. Risk C: Monitor
Letermovir: P-glycoprotein/ABCB1 Inducers may decrease serum concentration of Letermovir. Risk X: Avoid
Letermovir: UGT1A1 Inducers may decrease serum concentration of Letermovir. Risk X: Avoid
Leucovorin Calcium-Levoleucovorin: May decrease serum concentration of Fosphenytoin. Risk C: Monitor
Leuprolide and Norethindrone: CYP3A4 Inducers (Strong) may decrease serum concentration of Leuprolide and Norethindrone. Specifically, norethindrone concentrations may be decreased. Risk C: Monitor
Levamlodipine: CYP3A4 Inducers (Strong) may decrease serum concentration of Levamlodipine. Risk C: Monitor
LevETIRAcetam: Fosphenytoin-Phenytoin may decrease serum concentration of LevETIRAcetam. Risk C: Monitor
Levodopa-Foslevodopa: Fosphenytoin-Phenytoin may decrease therapeutic effects of Levodopa-Foslevodopa. Risk C: Monitor
Levoketoconazole: CYP3A4 Inducers (Strong) may decrease serum concentration of Levoketoconazole. Risk X: Avoid
Levomethadone: CYP3A4 Inducers (Strong) may decrease serum concentration of Levomethadone. Risk C: Monitor
Levonorgestrel (IUD): CYP3A4 Inducers (Strong) may decrease therapeutic effects of Levonorgestrel (IUD). CYP3A4 Inducers (Strong) may decrease serum concentration of Levonorgestrel (IUD). Risk C: Monitor
Lidocaine (Systemic): CYP3A4 Inducers (Strong) may decrease serum concentration of Lidocaine (Systemic). Risk C: Monitor
LinaGLIPtin: CYP3A4 Inducers (Strong) may decrease serum concentration of LinaGLIPtin. Management: Strongly consider using an alternative to any strong CYP3A4 inducer in patients who are being treated with linagliptin. If this combination is used, monitor patients closely for evidence of reduced linagliptin effectiveness. Risk D: Consider Therapy Modification
LinaGLIPtin: P-glycoprotein/ABCB1 Inducers may decrease serum concentration of LinaGLIPtin. Management: Strongly consider using an alternative to any P-glycoprotein inducer in patients who are being treated with linagliptin. If this combination is used, monitor patients closely for evidence of reduced linagliptin effectiveness. Risk D: Consider Therapy Modification
Lithium: Fosphenytoin-Phenytoin may increase adverse/toxic effects of Lithium. Risk C: Monitor
Lonafarnib: CYP3A4 Inducers (Strong) may decrease serum concentration of Lonafarnib. Risk X: Avoid
Lopinavir: Fosphenytoin may decrease serum concentration of Lopinavir. Lopinavir may decrease serum concentration of Fosphenytoin. Management: Avoid once-daily administration of lopinavir/ritonavir if used together with phenytoin. If twice daily lopinavir/ritonavir is coadministered with phenytoin, monitor phenytoin levels and response to both agents. Risk D: Consider Therapy Modification
Lorlatinib: CYP3A4 Inducers (Strong) may increase hepatotoxic effects of Lorlatinib. CYP3A4 Inducers (Strong) may decrease serum concentration of Lorlatinib. Risk X: Avoid
Lovastatin: CYP3A4 Inducers (Strong) may decrease serum concentration of Lovastatin. Risk C: Monitor
Lumacaftor and Ivacaftor: CYP3A4 Inducers (Strong) may decrease serum concentration of Lumacaftor and Ivacaftor. Specifically, the serum concentration of ivacaftor may be decreased. Risk X: Avoid
Lumateperone: CYP3A4 Inducers (Strong) may decrease serum concentration of Lumateperone. Risk X: Avoid
Lurasidone: CYP3A4 Inducers (Strong) may decrease serum concentration of Lurasidone. Risk X: Avoid
Lurbinectedin: CYP3A4 Inducers (Strong) may decrease serum concentration of Lurbinectedin. Risk X: Avoid
Macimorelin: CYP3A4 Inducers (Strong) may decrease serum concentration of Macimorelin. Risk X: Avoid
Macitentan: CYP3A4 Inducers (Strong) may decrease serum concentration of Macitentan. Risk X: Avoid
Manidipine: CYP3A4 Inducers (Strong) may decrease serum concentration of Manidipine. Management: Consider avoiding concomitant use of manidipine and strong CYP3A4 inducers. If combined, monitor closely for decreased manidipine effects and loss of efficacy. Increased manidipine doses may be required. Risk D: Consider Therapy Modification
Maraviroc: CYP3A4 Inducers (Strong) may decrease serum concentration of Maraviroc. Management: Increase maraviroc adult dose to 600 mg twice/day, but only if not receiving a strong CYP3A4 inhibitor. Not recommended for pediatric patients not also receiving a strong CYP3A4 inhibitor. Contraindicated in patients with CrCl less than 30 mL/min. Risk D: Consider Therapy Modification
Maribavir: Fosphenytoin-Phenytoin may decrease serum concentration of Maribavir. Management: Increase the dose of maribavir to 1,200 mg twice daily with concomitant use of fosphenytoin or phenytoin. Risk D: Consider Therapy Modification
Mavacamten: CYP3A4 Inducers (Strong) may decrease serum concentration of Mavacamten. Risk X: Avoid
Mavorixafor: CYP3A4 Inducers (Strong) may decrease serum concentration of Mavorixafor. Risk X: Avoid
Mebendazole: Fosphenytoin-Phenytoin may decrease serum concentration of Mebendazole. Risk C: Monitor
Mefloquine: May decrease therapeutic effects of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may decrease serum concentration of Mefloquine. Mefloquine may decrease serum concentration of Fosphenytoin-Phenytoin. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of seizures. If fosphenytoin/phenytoin is being used for another indication, monitor for decreased concentrations and efficacy of both phenytoin and mefloquine. Risk D: Consider Therapy Modification
Meperidine: CYP3A4 Inducers (Strong) may decrease serum concentration of Meperidine. CYP3A4 Inducers (Strong) may increase active metabolite exposure of Meperidine. Specifically, concentrations of normeperidine, the CNS stimulating metabolite, may be increased. Risk C: Monitor
Methadone: CYP3A4 Inducers (Strong) may decrease serum concentration of Methadone. Risk C: Monitor
Methotrexate: May decrease serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may increase serum concentration of Methotrexate. Specifically, fosphenytoin-phenytoin may displace methotrexate from serum proteins, increasing the concentration of free, unbound drug. Risk C: Monitor
Methylergonovine: CYP3A4 Inducers (Strong) may decrease serum concentration of Methylergonovine. Risk C: Monitor
MethylPREDNISolone: CYP3A4 Inducers (Strong) may decrease serum concentration of MethylPREDNISolone. Management: Consider methylprednisolone dose increases in patients receiving strong CYP3A4 inducers and monitor closely for reduced steroid efficacy. Risk D: Consider Therapy Modification
MetroNIDAZOLE (Systemic): Fosphenytoin may decrease serum concentration of MetroNIDAZOLE (Systemic). MetroNIDAZOLE (Systemic) may increase serum concentration of Fosphenytoin. Risk C: Monitor
MetyraPONE: Coadministration of Antiseizure Agents and MetyraPONE may alter diagnostic results. Management: Consider alternatives to the use of the metyrapone test in patients taking antiseizure agents. Risk D: Consider Therapy Modification
Mexiletine: Fosphenytoin-Phenytoin may decrease serum concentration of Mexiletine. Risk C: Monitor
Mianserin: May decrease therapeutic effects of Fosphenytoin. Fosphenytoin may decrease serum concentration of Mianserin. Risk C: Monitor
Miconazole (Oral): May increase serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor
Midazolam: CYP3A4 Inducers (Strong) may decrease serum concentration of Midazolam. Risk C: Monitor
Midostaurin: CYP3A4 Inducers (Strong) may decrease serum concentration of Midostaurin. Risk X: Avoid
MiFEPRIStone: CYP3A4 Inducers (Strong) may decrease serum concentration of MiFEPRIStone. Management: Avoid combined use in patients treated for Cushing's disease. When used for pregnancy termination, mifepristone efficacy may be reduced and an alternative pregnancy termination procedure may be warranted. Ensure a follow-up assessment after combined use. Risk D: Consider Therapy Modification
Mirabegron: CYP3A4 Inducers (Strong) may decrease serum concentration of Mirabegron. Risk C: Monitor
Mirodenafil: CYP3A4 Inducers (Strong) may decrease serum concentration of Mirodenafil. Management: Consider avoiding the concomitant use of mirodenafil and strong CYP3A4 inducers. If combined, monitor for decreased mirodenafil effects. Mirodenafil dose increases may be required to achieve desired effects. Risk D: Consider Therapy Modification
Mirtazapine: CYP3A4 Inducers (Strong) may decrease serum concentration of Mirtazapine. Risk C: Monitor
Mitapivat: CYP3A4 Inducers (Strong) may decrease serum concentration of Mitapivat. Risk X: Avoid
Mobocertinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Mobocertinib. CYP3A4 Inducers (Strong) may decrease active metabolite exposure of Mobocertinib. Risk X: Avoid
Montelukast: CYP3A4 Inducers (Strong) may decrease serum concentration of Montelukast. Risk C: Monitor
Mosunetuzumab: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Multivitamins/Minerals (with ADEK, Folate, Iron): May decrease serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor
Naldemedine: CYP3A4 Inducers (Strong) may decrease serum concentration of Naldemedine. Risk X: Avoid
Naloxegol: CYP3A4 Inducers (Strong) may decrease serum concentration of Naloxegol. Risk X: Avoid
Nateglinide: CYP3A4 Inducers (Strong) may decrease serum concentration of Nateglinide. Risk C: Monitor
Nelfinavir: Fosphenytoin-Phenytoin may decrease serum concentration of Nelfinavir. Nelfinavir may decrease serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor
Neratinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Neratinib. Risk X: Avoid
Netupitant: CYP3A4 Inducers (Strong) may decrease serum concentration of Netupitant. Risk X: Avoid
Neuromuscular-Blocking Agents (Nondepolarizing): Fosphenytoin-Phenytoin may decrease neuromuscular-blocking effects of Neuromuscular-Blocking Agents (Nondepolarizing). Specifically, this effect is observed with chronic phenytoin administration. Fosphenytoin-Phenytoin may increase neuromuscular-blocking effects of Neuromuscular-Blocking Agents (Nondepolarizing). Specifically, this effects is observed with acute/short term phenytoin administration. Risk C: Monitor
Nevirapine: CYP3A4 Inducers (Strong) may decrease serum concentration of Nevirapine. Management: Consider alternatives to this combination when possible. If combined, monitor for reduced nevirapine efficacy. Risk D: Consider Therapy Modification
NiCARdipine: CYP3A4 Inducers (Strong) may decrease serum concentration of NiCARdipine. Risk C: Monitor
NIFEdipine (Topical): CYP3A4 Inducers (Strong) may decrease serum concentration of NIFEdipine (Topical). Risk C: Monitor
NIFEdipine: CYP3A4 Inducers (Strong) may decrease serum concentration of NIFEdipine. Management: Avoid coadministration of nifedipine with strong CYP3A4 inducers when possible and if combined, monitor patients closely for clinical signs of diminished nifedipine response. Risk D: Consider Therapy Modification
Nilotinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Nilotinib. Risk X: Avoid
Nilvadipine: CYP3A4 Inducers (Strong) may decrease serum concentration of Nilvadipine. Risk C: Monitor
NiMODipine: CYP3A4 Inducers (Strong) may decrease serum concentration of NiMODipine. Risk X: Avoid
Nintedanib: Inducers of CYP3A4 (Strong) and P-glycoprotein may decrease serum concentration of Nintedanib. Risk X: Avoid
Nirmatrelvir and Ritonavir: Fosphenytoin-Phenytoin may decrease serum concentration of Nirmatrelvir and Ritonavir. Nirmatrelvir and Ritonavir may decrease serum concentration of Fosphenytoin-Phenytoin. Risk X: Avoid
Nirogacestat: CYP3A4 Inducers (Strong) may decrease serum concentration of Nirogacestat. Risk X: Avoid
Nisoldipine: CYP3A4 Inducers (Strong) may decrease serum concentration of Nisoldipine. Risk X: Avoid
Nitrazepam: CYP3A4 Inducers (Strong) may decrease serum concentration of Nitrazepam. Risk C: Monitor
Noscapine: May increase serum concentration of CYP2C9 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
OLANZapine: CYP1A2 Inducers (Weak) may decrease serum concentration of OLANZapine. Risk C: Monitor
Olaparib: CYP3A4 Inducers (Strong) may decrease serum concentration of Olaparib. Risk X: Avoid
Oliceridine: CYP3A4 Inducers (Strong) may decrease serum concentration of Oliceridine. Risk C: Monitor
Olmutinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Olmutinib. Risk C: Monitor
Olutasidenib: CYP3A4 Inducers (Strong) may decrease serum concentration of Olutasidenib. Risk X: Avoid
Omaveloxolone: CYP3A4 Inducers (Strong) may decrease serum concentration of Omaveloxolone. Risk X: Avoid
Ondansetron: CYP3A4 Inducers (Strong) may decrease serum concentration of Ondansetron. Risk C: Monitor
Opipramol: Antiseizure Agents may decrease serum concentration of Opipramol. Risk C: Monitor
Ornidazole: Fosphenytoin-Phenytoin may decrease serum concentration of Ornidazole. Risk C: Monitor
Osilodrostat: CYP3A4 Inducers (Strong) may decrease serum concentration of Osilodrostat. Risk C: Monitor
Osimertinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Osimertinib. Management: Avoid coadministration of osimertinib and strong CYP3A4 inducers if possible. If coadministration is unavoidable, increase osimertinib to 160 mg daily. Reduce osimertinib to 80 mg daily 3 weeks after discontinuation of the strong CYP3A4 inducer. Risk D: Consider Therapy Modification
OXcarbazepine: Fosphenytoin-Phenytoin may decrease active metabolite exposure of OXcarbazepine. Specifically, concentrations of the major active 10-monohydroxy metabolite may be reduced. OXcarbazepine may increase serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor
OxyCODONE: CYP3A4 Inducers (Strong) may decrease serum concentration of OxyCODONE. Risk C: Monitor
PACLitaxel (Conventional): CYP3A4 Inducers (Strong) may decrease serum concentration of PACLitaxel (Conventional). Risk C: Monitor
PACLitaxel (Protein Bound): CYP3A4 Inducers (Strong) may decrease serum concentration of PACLitaxel (Protein Bound). Risk C: Monitor
Pacritinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Pacritinib. Risk X: Avoid
Palbociclib: CYP3A4 Inducers (Strong) may decrease serum concentration of Palbociclib. Risk X: Avoid
Paliperidone: P-glycoprotein/ABCB1 Inducers may decrease serum concentration of Paliperidone. Management: Avoid coadministration of extended-release injectable paliperidone and P-gp inducers. If coadministration is required, consider use of paliperidone extended-release tablets, monitor for reduced paliperidone effects, and increase the dose as needed. Risk D: Consider Therapy Modification
Palovarotene: CYP3A4 Inducers (Strong) may decrease serum concentration of Palovarotene. Risk X: Avoid
Panobinostat: CYP3A4 Inducers (Strong) may decrease serum concentration of Panobinostat. Risk X: Avoid
PAZOPanib: CYP3A4 Inducers (Strong) may decrease serum concentration of PAZOPanib. Risk X: Avoid
Pemigatinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Pemigatinib. Risk X: Avoid
Perampanel: Fosphenytoin may decrease serum concentration of Perampanel. Management: Increase perampanel starting dose to 4 mg/day if used with fosphenytoin. Increase perampanel dose by 2 mg/day no more than once weekly based on response and tolerability. Dose adjustments may be needed if fosphenytoin is discontinued. Risk D: Consider Therapy Modification
Perazine: CYP3A4 Inducers (Strong) may decrease serum concentration of Perazine. Risk C: Monitor
Pexidartinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Pexidartinib. Risk X: Avoid
Phenobarbital-Primidone: Fosphenytoin-Phenytoin may increase CNS depressant effects of Phenobarbital-Primidone. Phenobarbital-Primidone may decrease serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may increase serum concentration of Phenobarbital-Primidone. Risk C: Monitor
Phenylbutazone: May increase serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor
Pimavanserin: CYP3A4 Inducers (Strong) may decrease serum concentration of Pimavanserin. Risk X: Avoid
Piperaquine: CYP3A4 Inducers (Strong) may decrease serum concentration of Piperaquine. Risk X: Avoid
Pirtobrutinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Pirtobrutinib. Risk X: Avoid
Pitolisant: CYP3A4 Inducers (Strong) may decrease serum concentration of Pitolisant. Management: If on a stable pitolisant dose of 8.9 mg or 17.8 mg/day and starting a strong CYP3A4 inducer, double the pitolisant dose over 7 days (ie, to either 17.8 mg/day or 35.6 mg/day, respectively). Reduce pitolisant dose by 50% when the inducer is discontinued. Risk D: Consider Therapy Modification
Platinum Derivatives: May decrease serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor
Polatuzumab Vedotin: CYP3A4 Inducers (Strong) may decrease serum concentration of Polatuzumab Vedotin. Exposure to unconjugated MMAE, the cytotoxic small molecule component of polatuzumab vedotin, may be decreased. Risk C: Monitor
PONATinib: CYP3A4 Inducers (Strong) may decrease serum concentration of PONATinib. Management: Avoid coadministration of ponatinib with strong CYP3A4 inducers unless the potential benefit of concomitant treatment outweighs the risk of reduced ponatinib exposure. Monitor patients for reduced ponatinib efficacy if combined. Risk D: Consider Therapy Modification
Posaconazole: Fosphenytoin-Phenytoin may decrease serum concentration of Posaconazole. Management: Concomitant use of posaconazole and fosphenytoin/phenytoin should be avoided unless the benefit to the patient outweighs the risk. If concomitant administration is required, close monitoring for breakthrough fungal infections is recommended. Risk D: Consider Therapy Modification
Pralsetinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Pralsetinib. Management: Avoid concomitant use of pralsetinib with strong CYP3A4 inducers when possible. If combined, increase the starting dose of pralsetinib to double the current pralsetinib dosage starting on day 7 of coadministration. Risk D: Consider Therapy Modification
Praziquantel: CYP3A4 Inducers (Strong) may decrease serum concentration of Praziquantel. Risk X: Avoid
PrednisoLONE (Systemic): CYP3A4 Inducers (Strong) may decrease serum concentration of PrednisoLONE (Systemic). Risk C: Monitor
PredniSONE: CYP3A4 Inducers (Strong) may decrease serum concentration of PredniSONE. Risk C: Monitor
Pretomanid: CYP3A4 Inducers (Strong) may decrease serum concentration of Pretomanid. Risk X: Avoid
Propacetamol: Fosphenytoin-Phenytoin may decrease active metabolite exposure of Propacetamol. Specifically, serum concentrations of acetaminophen may be decreased (leading to decreased efficacy), but the formation of its toxic N-acetyl-p-benzoquinone imine (NAPQI) metabolite may be increased (leading to increased hepatotoxicity). Risk C: Monitor
Propafenone: CYP3A4 Inducers (Strong) may decrease serum concentration of Propafenone. Risk C: Monitor
Pyridoxine: May decrease serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor
Pyrimethamine: CYP3A4 Inducers (Strong) may decrease serum concentration of Pyrimethamine. Risk C: Monitor
QUEtiapine: CYP3A4 Inducers (Strong) may decrease serum concentration of QUEtiapine. Management: An increase in quetiapine dose (as much as 5 times the regular dose) may be required to maintain therapeutic benefit. Reduce the quetiapine dose back to the previous/regular dose within 7 to 14 days of discontinuing the inducer. Risk D: Consider Therapy Modification
QuiNIDine: CYP3A4 Inducers (Strong) may decrease serum concentration of QuiNIDine. Risk C: Monitor
QuiNINE: CYP3A4 Inducers (Strong) may decrease serum concentration of QuiNINE. Management: Consider alternatives to this combination when possible. If combined, monitor for reduced quinine efficacy and treatment failure. Risk D: Consider Therapy Modification
Quizartinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Quizartinib. Risk X: Avoid
Radotinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Radotinib. Management: Consider alternatives to this combination when possible as the risk of radotinib treatment failure may be increased. Risk D: Consider Therapy Modification
Ramelteon: CYP3A4 Inducers (Strong) may decrease serum concentration of Ramelteon. Risk C: Monitor
Ranolazine: CYP3A4 Inducers (Strong) may decrease serum concentration of Ranolazine. Risk X: Avoid
Reboxetine: CYP3A4 Inducers (Strong) may decrease serum concentration of Reboxetine. Risk C: Monitor
Regorafenib: CYP3A4 Inducers (Strong) may decrease serum concentration of Regorafenib. CYP3A4 Inducers (Strong) may increase active metabolite exposure of Regorafenib. Risk X: Avoid
Relugolix, Estradiol, and Norethindrone: Inducers of CYP3A4 (Strong) and P-glycoprotein may decrease serum concentration of Relugolix, Estradiol, and Norethindrone. Risk X: Avoid
Relugolix: Inducers of CYP3A4 (Strong) and P-glycoprotein may decrease serum concentration of Relugolix. Management: Avoid use of relugolix with drugs that are both strong CYP3A4 and P-glycoprotein (P-gp) inducer. If combined, increase the dose of relugolix to 240 mg once daily. Reduce back to 120 mg daily once the combined inducer is discontinued. Risk D: Consider Therapy Modification
Repaglinide: CYP3A4 Inducers (Strong) may decrease serum concentration of Repaglinide. Risk C: Monitor
Repotrectinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Repotrectinib. Risk X: Avoid
Revumenib: CYP3A4 Inducers (Strong) may decrease serum concentration of Revumenib. Risk X: Avoid
Ribociclib: CYP3A4 Inducers (Strong) may decrease serum concentration of Ribociclib. Risk X: Avoid
Rifabutin: CYP3A4 Inducers (Strong) may decrease serum concentration of Rifabutin. Risk C: Monitor
Rifapentine: May decrease serum concentration of CYP2C9 Substrates (High risk with Inducers). Risk C: Monitor
Rilpivirine: Fosphenytoin may decrease serum concentration of Rilpivirine. Risk X: Avoid
Rimegepant: CYP3A4 Inducers (Strong) may decrease serum concentration of Rimegepant. Risk X: Avoid
Riociguat: CYP3A4 Inducers (Strong) may decrease serum concentration of Riociguat. Risk C: Monitor
Ripretinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Ripretinib. Risk X: Avoid
RisperiDONE: CYP3A4 Inducers (Strong) may decrease serum concentration of RisperiDONE. CYP3A4 Inducers (Strong) may decrease active metabolite exposure of RisperiDONE. Management: Careful monitoring for reduced risperidone efficacy and possible dose adjustment are recommended when combined with strong CYP3A4 inducers. See full interaction monograph for details. Risk D: Consider Therapy Modification
Ritlecitinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Ritlecitinib. Risk X: Avoid
Ritonavir: Fosphenytoin may decrease serum concentration of Ritonavir. Ritonavir may decrease serum concentration of Fosphenytoin. Management: Consider avoiding when possible. Dose adjustments may be required. Monitor phenytoin concentrations, and for therapeutic response to fosphenytoin and ritonavir, particularly with any dose adjustments. Risk D: Consider Therapy Modification
Rivaroxaban: Inducers of CYP3A4 (Strong) and P-glycoprotein may decrease serum concentration of Rivaroxaban. Risk X: Avoid
Roflumilast (Systemic): CYP3A4 Inducers (Strong) may decrease serum concentration of Roflumilast (Systemic). CYP3A4 Inducers (Strong) may decrease active metabolite exposure of Roflumilast (Systemic). Risk X: Avoid
Rolapitant: CYP3A4 Inducers (Strong) may decrease serum concentration of Rolapitant. Risk X: Avoid
RomiDEPsin: CYP3A4 Inducers (Strong) may decrease serum concentration of RomiDEPsin. Risk X: Avoid
Rufinamide: Fosphenytoin may decrease serum concentration of Rufinamide. Rufinamide may increase serum concentration of Fosphenytoin. Risk C: Monitor
Ruxolitinib (Systemic): CYP3A4 Inducers (Strong) may decrease serum concentration of Ruxolitinib (Systemic). CYP3A4 Inducers (Strong) may increase active metabolite exposure of Ruxolitinib (Systemic). Risk C: Monitor
Sacituzumab Govitecan: UGT1A1 Inducers may decrease active metabolite exposure of Sacituzumab Govitecan. Specifically, concentrations of SN-38 may be decreased. Risk X: Avoid
Samidorphan: CYP3A4 Inducers (Strong) may decrease serum concentration of Samidorphan. Risk X: Avoid
Saquinavir: Fosphenytoin-Phenytoin may decrease serum concentration of Saquinavir. Risk X: Avoid
SAXagliptin: CYP3A4 Inducers (Strong) may decrease serum concentration of SAXagliptin. Risk C: Monitor
Selpercatinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Selpercatinib. Risk X: Avoid
Selumetinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Selumetinib. Risk X: Avoid
Sertindole: CYP3A4 Inducers (Strong) may decrease serum concentration of Sertindole. Risk C: Monitor
Sertraline: May increase serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may decrease serum concentration of Sertraline. Risk C: Monitor
Sildenafil: CYP3A4 Inducers (Strong) may decrease serum concentration of Sildenafil. Risk C: Monitor
Simeprevir: CYP3A4 Inducers (Strong) may decrease serum concentration of Simeprevir. Risk X: Avoid
Simvastatin: CYP3A4 Inducers (Strong) may decrease serum concentration of Simvastatin. Risk C: Monitor
Sirolimus (Conventional): CYP3A4 Inducers (Strong) may decrease serum concentration of Sirolimus (Conventional). Management: Avoid concomitant use of strong CYP3A4 inducers and sirolimus if possible. If combined, monitor for reduced serum sirolimus concentrations. Sirolimus dose increases will likely be necessary to prevent subtherapeutic sirolimus levels. Risk D: Consider Therapy Modification
Sirolimus (Protein Bound): CYP3A4 Inducers (Strong) may decrease serum concentration of Sirolimus (Protein Bound). Risk X: Avoid
Sofosbuvir: P-glycoprotein/ABCB1 Inducers may decrease serum concentration of Sofosbuvir. Risk X: Avoid
Solifenacin: CYP3A4 Inducers (Strong) may decrease serum concentration of Solifenacin. Risk C: Monitor
Sonidegib: CYP3A4 Inducers (Strong) may decrease serum concentration of Sonidegib. Risk X: Avoid
SORAfenib: CYP3A4 Inducers (Strong) may decrease serum concentration of SORAfenib. Risk X: Avoid
Sotorasib: CYP3A4 Inducers (Strong) may decrease serum concentration of Sotorasib. Risk X: Avoid
Sparsentan: CYP3A4 Inducers (Strong) may decrease serum concentration of Sparsentan. Risk X: Avoid
Stiripentol: Fosphenytoin-Phenytoin may decrease serum concentration of Stiripentol. Stiripentol may increase serum concentration of Fosphenytoin-Phenytoin. Management: Avoid this combination when possible. If combined, monitor for decreased stiripentol concentrations and effects and monitor for increased phenytoin concentrations and effects. Dose adjustments of either medication may be needed. Risk D: Consider Therapy Modification
SUFentanil: CYP3A4 Inducers (Strong) may decrease serum concentration of SUFentanil. Management: If a strong CYP3A4 inducer is initiated in a patient on sufentanil, consider a sufentanil dose increase and monitor for decreased sufentanil effects and opioid withdrawal symptoms. Risk D: Consider Therapy Modification
SulfADIAZINE: May increase serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor
Sulthiame: May increase serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor
SUNItinib: CYP3A4 Inducers (Strong) may decrease serum concentration of SUNItinib. Management: Avoid when possible. If combined, increase sunitinib dose to a max of 87.5 mg daily when treating GIST or RCC. Increase sunitinib dose to a max of 62.5 mg daily when treating PNET. Monitor patients for both reduced efficacy and increased toxicities. Risk D: Consider Therapy Modification
Suvorexant: CYP3A4 Inducers (Strong) may decrease serum concentration of Suvorexant. Risk C: Monitor
Suzetrigine: CYP3A4 Inducers (Strong) may decrease serum concentration of Suzetrigine. Risk X: Avoid
Tacrolimus (Systemic): CYP3A4 Inducers (Strong) may decrease serum concentration of Tacrolimus (Systemic). Management: Tacrolimus dose increases will likely be needed during concomitant use with strong CYP3A4 inducers. Monitor more closely and frequently for decreased tacrolimus concentrations and effects when combined. Risk D: Consider Therapy Modification
Tadalafil: CYP3A4 Inducers (Strong) may decrease serum concentration of Tadalafil. Management: Erectile dysfunction or benign prostatic hypertrophy: monitor for decreased effectiveness - no standard dose adjustment is recommended. Avoid use of tadalafil for pulmonary arterial hypertension in patients receiving a strong CYP3A4 inducer. Risk D: Consider Therapy Modification
Talquetamab: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Tamoxifen: CYP3A4 Inducers (Strong) may decrease serum concentration of Tamoxifen. CYP3A4 Inducers (Strong) may decrease active metabolite exposure of Tamoxifen. Risk X: Avoid
Tarlatamab: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Tasimelteon: CYP3A4 Inducers (Strong) may decrease serum concentration of Tasimelteon. Risk X: Avoid
Taurursodiol: CYP3A4 Inducers (Strong) may decrease serum concentration of Taurursodiol. Specifically, the concentrations of phenylbutyrate may be decreased. Risk C: Monitor
Tazemetostat: CYP3A4 Inducers (Strong) may decrease serum concentration of Tazemetostat. Risk X: Avoid
Teclistamab: May increase serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Temsirolimus: CYP3A4 Inducers (Strong) may decrease serum concentration of Temsirolimus. CYP3A4 Inducers (Strong) may decrease active metabolite exposure of Temsirolimus. Specifically, concentrations of sirolimus may be decreased. Management: Avoid concomitant use of temsirolimus and strong CYP3A4 inducers. If coadministration is unavoidable, increase temsirolimus dose to 50 mg per week. Resume previous temsirolimus dose after discontinuation of the strong CYP3A4 inducer. Risk D: Consider Therapy Modification
Teniposide: CYP3A4 Inducers (Strong) may decrease serum concentration of Teniposide. Risk C: Monitor
Tenofovir Alafenamide: Fosphenytoin-Phenytoin may decrease serum concentration of Tenofovir Alafenamide. Risk X: Avoid
Tetrahydrocannabinol and Cannabidiol: CYP3A4 Inducers (Strong) may decrease serum concentration of Tetrahydrocannabinol and Cannabidiol. Management: Avoid use of the tetrahydrocannabinol/cannabidiol oromucosal spray and strong CYP3A4 inducers when possible. If combined use is necessary, careful titration is recommended, notably within the two weeks following discontinuation of the inducer. Risk D: Consider Therapy Modification
Tetrahydrocannabinol: CYP3A4 Inducers (Strong) may decrease serum concentration of Tetrahydrocannabinol. Risk C: Monitor
Tezacaftor and Ivacaftor: CYP3A4 Inducers (Strong) may decrease serum concentration of Tezacaftor and Ivacaftor. Risk X: Avoid
Theophylline Derivatives: Fosphenytoin-Phenytoin may decrease serum concentration of Theophylline Derivatives. Risk C: Monitor
Thiotepa: CYP3A4 Inducers (Strong) may increase active metabolite exposure of Thiotepa. CYP3A4 Inducers (Strong) may decrease serum concentration of Thiotepa. Management: Thiotepa prescribing information recommends avoiding concomitant use of thiotepa and strong CYP3A4 inducers. If concomitant use is unavoidable, monitor for adverse effects. Risk D: Consider Therapy Modification
Thiothixene: Fosphenytoin-Phenytoin may decrease serum concentration of Thiothixene. Risk C: Monitor
Thyroid Products: Fosphenytoin may decrease serum concentration of Thyroid Products. Phenytoin may also displace thyroid hormones from protein binding sites. Risk C: Monitor
TiaGABine: CYP3A4 Inducers (Strong) may decrease serum concentration of TiaGABine. Risk C: Monitor
Ticagrelor: CYP3A4 Inducers (Strong) may decrease serum concentration of Ticagrelor. CYP3A4 Inducers (Strong) may decrease active metabolite exposure of Ticagrelor. Risk X: Avoid
Tipranavir: CYP3A4 Inducers (Strong) may decrease serum concentration of Tipranavir. Risk C: Monitor
Tivozanib: CYP3A4 Inducers (Strong) may decrease serum concentration of Tivozanib. Risk X: Avoid
Tofacitinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Tofacitinib. Risk X: Avoid
TOLBUTamide: May decrease protein binding of Fosphenytoin-Phenytoin. Specifically concentrations of free phenytoin may be increased. Risk C: Monitor
Tolvaptan: CYP3A4 Inducers (Strong) may decrease serum concentration of Tolvaptan. Risk X: Avoid
Topiramate: Fosphenytoin-Phenytoin may decrease serum concentration of Topiramate. Topiramate may increase serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor
Topotecan: Fosphenytoin-Phenytoin may decrease serum concentration of Topotecan. Management: Monitor topotecan response closely, and consider alternatives to phenytoin when possible. Systemic concentrations and effects of topotecan may be reduced. No specific guidelines for topotecan dose adjustment are available. Risk D: Consider Therapy Modification
Toremifene: CYP3A4 Inducers (Strong) may decrease serum concentration of Toremifene. CYP3A4 Inducers (Strong) may decrease active metabolite exposure of Toremifene. Risk X: Avoid
Torsemide: May increase adverse/toxic effects of Fosphenytoin-Phenytoin. Risk C: Monitor
Trabectedin: CYP3A4 Inducers (Strong) may decrease serum concentration of Trabectedin. Risk X: Avoid
TraMADol: CYP3A4 Inducers (Strong) may decrease serum concentration of TraMADol. Risk C: Monitor
TraZODone: Fosphenytoin may decrease serum concentration of TraZODone. TraZODone may increase serum concentration of Fosphenytoin. Management: Consider increasing the trazodone dose during coadministration with strong CYP3A4 inducers, such as fosphenytoin. In addition, monitor for increased phenytoin concentrations and effects during coadministration with trazodone. Risk D: Consider Therapy Modification
Treosulfan: May increase serum concentration of CYP2C19 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor
Tretinoin (Systemic): CYP3A4 Inducers (Strong) may decrease serum concentration of Tretinoin (Systemic). Management: Avoid use of tretinoin and strong CYP3A4 inducers when possible. If combined, monitor for reduced tretinoin concentrations and efficacy. Risk D: Consider Therapy Modification
Triamcinolone (Systemic): CYP3A4 Inducers (Strong) may decrease serum concentration of Triamcinolone (Systemic). Risk C: Monitor
Triazolam: CYP3A4 Inducers (Strong) may decrease serum concentration of Triazolam. Management: Consider alternatives to this combination when possible. If combined, monitor for reduced triazolam efficacy. Substantial triazolam dose increases will likely be required. Risk D: Consider Therapy Modification
Trimethoprim: May increase serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor
Tropisetron: CYP3A4 Inducers (Strong) may decrease serum concentration of Tropisetron. Risk C: Monitor
Tucatinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Tucatinib. Risk X: Avoid
Ubrogepant: CYP3A4 Inducers (Strong) may decrease serum concentration of Ubrogepant. Risk X: Avoid
Udenafil: CYP3A4 Inducers (Strong) may decrease serum concentration of Udenafil. Risk C: Monitor
Ulipristal: CYP3A4 Inducers (Strong) may decrease serum concentration of Ulipristal. Risk X: Avoid
Upadacitinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Upadacitinib. Risk X: Avoid
Valbenazine: CYP3A4 Inducers (Strong) may decrease serum concentration of Valbenazine. CYP3A4 Inducers (Strong) may decrease active metabolite exposure of Valbenazine. Risk X: Avoid
Valproic Acid and Derivatives: Fosphenytoin-Phenytoin may increase adverse/toxic effects of Valproic Acid and Derivatives. Specifically, the risk of hepatotoxicity or hyperammonemia may be increased. Valproic Acid and Derivatives may decrease protein binding of Fosphenytoin-Phenytoin. This appears to lead to an initial increase in the percentage of unbound (free) phenytoin and to a decrease in total phenytoin concentrations. Whether concentrations of free phenytoin are increased is unclear. With long-term concurrent use, total phenytoin concentrations may increase. Fosphenytoin-Phenytoin may decrease serum concentration of Valproic Acid and Derivatives. Risk C: Monitor
Vandetanib: CYP3A4 Inducers (Strong) may decrease serum concentration of Vandetanib. CYP3A4 Inducers (Strong) may increase active metabolite exposure of Vandetanib. Risk X: Avoid
Vanzacaftor, Tezacaftor, and Deutivacaftor: CYP3A4 Inducers (Strong) may decrease serum concentration of Vanzacaftor, Tezacaftor, and Deutivacaftor. Risk X: Avoid
Velpatasvir: CYP3A4 Inducers (Strong) may decrease serum concentration of Velpatasvir. Risk X: Avoid
Vemurafenib: CYP3A4 Inducers (Strong) may decrease serum concentration of Vemurafenib. Management: Avoid coadministration of vemurafenib and strong CYP3A4 inducers if possible. If coadministration is unavoidable, increase the vemurafenib dose by 240 mg as tolerated. Resume prior vemurafenib dose 2 weeks after discontinuation of strong CYP3A4 inducer. Risk D: Consider Therapy Modification
Venetoclax: CYP3A4 Inducers (Strong) may decrease serum concentration of Venetoclax. Risk X: Avoid
Vigabatrin: May decrease serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor
Vilazodone: CYP3A4 Inducers (Strong) may decrease serum concentration of Vilazodone. Management: Consider increasing vilazodone dose by as much as 2-fold (do not exceed 80 mg/day), based on response, in patients receiving strong CYP3A4 inducers for > 14 days. Reduce to the original vilazodone dose over 1 to 2 weeks after inducer discontinuation. Risk D: Consider Therapy Modification
Viloxazine: May increase serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor
VinCRIStine: May decrease serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may decrease serum concentration of VinCRIStine. Risk X: Avoid
Vinflunine: CYP3A4 Inducers (Strong) may decrease serum concentration of Vinflunine. Risk X: Avoid
Vinorelbine: CYP3A4 Inducers (Strong) may decrease serum concentration of Vinorelbine. Risk C: Monitor
Vitamin K Antagonists: Fosphenytoin-Phenytoin may increase anticoagulant effects of Vitamin K Antagonists. Fosphenytoin-Phenytoin may decrease anticoagulant effects of Vitamin K Antagonists. Vitamin K Antagonists may increase serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor
Voclosporin: CYP3A4 Inducers (Strong) may decrease serum concentration of Voclosporin. Risk X: Avoid
Vonoprazan: CYP3A4 Inducers (Strong) may decrease serum concentration of Vonoprazan. Risk X: Avoid
Vorapaxar: CYP3A4 Inducers (Strong) may decrease serum concentration of Vorapaxar. Risk X: Avoid
Vorasidenib: Fosphenytoin-Phenytoin may decrease serum concentration of Vorasidenib. Risk X: Avoid
Voriconazole: Fosphenytoin-Phenytoin may decrease serum concentration of Voriconazole. Voriconazole may increase serum concentration of Fosphenytoin-Phenytoin. Management: Increase maintenance dose of voriconazole from 4 mg/kg to 5 mg/kg IV every 12 hours or from 200 mg to 400 mg orally every 12 hours in patients who weigh 40 kg or more or from 100 mg to 200 mg orally every 12 hours for patients who weigh less than 40 kg. Risk D: Consider Therapy Modification
Vortioxetine: CYP3A4 Inducers (Strong) may decrease serum concentration of Vortioxetine. Management: Consider increasing the vortioxetine dose to no more than 3 times the original dose when used with a strong drug metabolism inducer for more than 14 days. The vortioxetine dose should be returned to normal within 14 days of stopping the strong inducer. Risk D: Consider Therapy Modification
Voxelotor: CYP3A4 Inducers (Strong) may decrease serum concentration of Voxelotor. Management: Avoid concomitant use of voxelotor and strong CYP3A4 inducers. If unavoidable, increase the voxelotor dose to 2,500 mg once daily. For children ages 4 to less than 12 years, weight-based dose adjustments are required. See full monograph for details. Risk D: Consider Therapy Modification
Voxilaprevir: CYP3A4 Inducers (Strong) may decrease serum concentration of Voxilaprevir. Risk X: Avoid
Zaleplon: CYP3A4 Inducers (Strong) may decrease serum concentration of Zaleplon. Management: Consider the use of an alternative hypnotic that is not metabolized by CYP3A4 in patients receiving strong CYP3A4 inducers. If zaleplon is combined with a strong CYP3A4 inducer, monitor for decreased effectiveness of zaleplon. Risk D: Consider Therapy Modification
Zanubrutinib: CYP3A4 Inducers (Strong) may decrease serum concentration of Zanubrutinib. Risk X: Avoid
Ziprasidone: CYP3A4 Inducers (Strong) may decrease serum concentration of Ziprasidone. Risk C: Monitor
Zolpidem: CYP3A4 Inducers (Strong) may decrease serum concentration of Zolpidem. Risk C: Monitor
Zonisamide: CYP3A4 Inducers (Strong) may decrease serum concentration of Zonisamide. Risk C: Monitor
Zopiclone: CYP3A4 Inducers (Strong) may decrease serum concentration of Zopiclone. Risk C: Monitor
Zuclopenthixol: CYP3A4 Inducers (Strong) may decrease serum concentration of Zuclopenthixol. Risk C: Monitor
Zuranolone: CYP3A4 Inducers (Strong) may decrease serum concentration of Zuranolone. Risk X: Avoid
Ethanol:
Acute use: Ethanol inhibits metabolism of phenytoin and may also increase CNS depression. Management: Monitor patients. Caution patients about effects.
Chronic use: Ethanol stimulates metabolism of phenytoin. Management: Monitor patients.
Females of reproductive potential who are not planning a pregnancy should use effective contraception; hormonal contraceptives may be less effective.
Fosphenytoin is the prodrug of phenytoin. An increased risk of congenital malformations and adverse outcomes may occur following in utero phenytoin exposure. Reported malformations include orofacial clefts, cardiac defects, dysmorphic facial features, nail/digit hypoplasia, growth abnormalities including microcephaly, and mental deficiency. Isolated cases of malignancies (including neuroblastoma) and coagulation defects in the neonate (may be life threatening) following delivery have also been reported. Potentially life-threatening bleeding disorders in the newborn may also occur due to decreased concentrations of vitamin K-dependent clotting factors following phenytoin exposure in utero; vitamin K administration to the mother prior to delivery and the newborn after birth is recommended.
Due to pregnancy-induced physiologic changes, the pharmacokinetics may be changed; additional monitoring is needed.
Also refer to the Phenytoin monograph for additional information.
Patients exposed to fosphenytoin during pregnancy are encouraged to enroll themselves into the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334. Additional information is available at http://www.aedpregnancyregistry.org/.
Fosphenytoin is the prodrug of phenytoin. It is not known if fosphenytoin is present in breast milk prior to conversion to phenytoin. According to the manufacturer, the decision to continue or discontinue breastfeeding during therapy should take into account the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother. Refer to Phenytoin monograph for additional information.
Provides 0.0037 mmol phosphate/mg PE fosphenytoin
Continuous blood pressure, heart rate, ECG, and respiratory function monitoring with loading dose and for ~10 to 20 minutes following infusion; CBC, hepatic function tests, plasma phenytoin concentration monitoring (plasma concentrations should not be measured until conversion to phenytoin is complete, ~2 hours after the end of an IV infusion or ~4 hours after an IM injection).
Note: If available, free (unbound) phenytoin concentrations should be obtained in patients with renal or hepatic impairment, and/or hypoalbuminemia or hyperbilirubinemia. If free (unbound) phenytoin concentrations are unavailable, the adjusted total phenytoin concentration may be determined based upon equations in adult patients; however, due to an increased fraction of unbound phenytoin in these patients, interpret total phenytoin concentrations with caution. Trough concentrations are generally recommended for routine monitoring.
Consult individual institutional policies and procedures.
Adults: Due to narrow safety margin and nonlinear pharmacokinetics (small dose increases can result in disproportionately large increases in serum concentrations), serum phenytoin concentration monitoring recommended.
Therapeutic range:
Total phenytoin: 10 to 20 mg/L (SI: 39.6 to 79.2 micromole/L) (Winter 2010).
Concentrations of 5 to 10 mg/L (SI: 19.8 to 39.6 micromole/L) may be therapeutic for some patients, but concentrations <5 mg/L (SI: <19.8 micromole/L) are not likely to be effective.
Free (unbound) phenytoin: 1 to 2.5 mg/L (SI: 4 to 9.9 micromole/L).
Total phenytoin:
Toxic: >30 mg/L (SI: >118.8 micromole/L).
Lethal: >100 mg/L (SI: >396 micromole/L).
Toxicity is measured clinically, and some patients require levels outside the suggested therapeutic range (refer to phenytoin monograph for additional information).
When to draw levels (Winter 2010):
Key points: Time of sampling is dependent on the disease state being treated and the clinical condition of the patient. Trough concentrations are generally recommended for routine monitoring.
After a loading dose:
First concentration: It is recommended that phenytoin concentrations NOT be monitored until conversion to phenytoin is complete. It is prudent to draw within 2 to 3 days of therapy initiation to ensure that the patient's metabolism is not remarkably altered. Alternatively, if rapid therapeutic levels are needed, a level may be drawn 2 hours after completion of an IV loading dose (Meek 1999; manufacturer's labeling) or 4 hours after an IM injection to aid in determining maintenance dose or need to reload (manufacturer's labeling).
Second concentration: Draw within 5 to 8 days of therapy initiation with subsequent doses of phenytoin adjusted accordingly.
If plasma concentrations have not changed over a 3- to 5-day period, monitoring interval may be increased to once weekly in the acute clinical setting.
Diphosphate ester salt of phenytoin that acts as a water-soluble prodrug of phenytoin; after administration, plasma esterases convert fosphenytoin to phosphate, formaldehyde (not expected to be clinically consequential [Fierro 1996]), and phenytoin as the active moiety. Phenytoin works by stabilizing neuronal membranes and decreasing seizure activity by increasing efflux or decreasing influx of sodium ions across cell membranes in the motor cortex during generation of nerve impulses
The pharmacokinetics of intravenous fosphenytoin in pediatric patients have been evaluated in 2 studies (n=49, age range: 1 day to 16.7 years; n=8, age range: 5 to 18 years) and found to be similar to the pharmacokinetics observed in young adults; the conversion rate of fosphenytoin to phenytoin was consistent throughout childhood (Fischer 2003; Pellock 1996). Also refer to Phenytoin monograph for additional information.
Distribution:
Fosphenytoin: Vd: 4.3 to 10.8 L; Vd of fosphenytoin increases with dose and rate of administration (Fischer 2003).
Phenytoin: Vd: Neonates (Painter 1978):
GA 27 to 30 weeks: 1.2 ± 0.11 L/kg.
GA 31 to 36 weeks: 1.17 ± 0.21 L/kg.
GA ≥37 weeks: 1.22 ± 0.22 L/kg.
Protein binding:
Fosphenytoin: 95% to 99% (primarily to albumin); binding of fosphenytoin to protein is saturable (the percent bound decreases as total concentration increases); fosphenytoin displaces phenytoin from protein binding sites; can displace phenytoin and increase free fraction (up to 30% unbound) during the period required for conversion of fosphenytoin to phenytoin. Note: In patients with renal and/or hepatic impairment or hypoalbuminemia, the fraction of unbound phenytoin may be increased.
Phenytoin: Neonates: GA 25 to 43 weeks: 61% to 91% (Painter 1994).
Metabolism: Fosphenytoin is rapidly converted via hydrolysis to phenytoin; phenytoin is metabolized in the liver following dose-dependent (Michaelis-Menten) pharmacokinetics and forms metabolites.
Bioavailability: Fosphenytoin: IM: 100%.
Half-life elimination:
Fosphenytoin: Conversion half-life to Phenytoin:
Pediatric patients (ages: 1 day to 16.7 years): 8.3 minutes (range: 2.5 to 18.5 minutes) (Fischer 2003; Morton 1998).
Adults: IV: ~15 minutes; IM: ~30 minutes.
Phenytoin half-life: Note: Elimination is not first-order (ie, follows Michaelis-Menten pharmacokinetics); half-life increases with increasing phenytoin concentrations; best described using parameters such as Vmax (metabolic capacity) and Km (constant equal to the concentration at which the rate of metabolism is 1/2 of Vmax) (Patsalos 2008).
Neonates: Prolonged and highly variable particularly during the first week of life and in premature neonates; reported range varies from 6.9 to 194 hours (Bourgeois 1983; Loughnan 1977; Painter 1978; Painter 1981).
Preterm neonates: 75.4 ± 64.5 hours (Loughnan 1977).
Term neonates: PNA ≤1 week: 20.7 ± 11.6 hours; PNA >2 weeks: 7.6 ± 3.5 hours (Loughnan 1977).
Adults: Variable (mean: 12 to 29 hours); pharmacokinetics of phenytoin are saturable.
Time to peak, serum concentration: Phenytoin:
IV: Adults: ~30 to 60 minutes from start of IV infusion (Fischer 2003).
IM:
Neonates and infants ≤47 days: 1 to 2.4 hours was reported in a case series (n=3; GA 32 to 38 weeks; postnatal age: 15 to 47 days) (Hatzopoulos 1998).
Pediatric patients >7 months: Therapeutic concentrations within 30 minutes; time to maximum serum concentration not reported (Fischer 2003).
Adults: ~3 hours (manufacturer's labeling); therapeutic phenytoin concentrations may be achieved as early as 5 to 20 minutes following IM (gluteal) administration (Pryor 2001).
Excretion: Phenytoin: Urine (as inactive metabolites).
Altered kidney function: Increased fraction of unbound phenytoin may occur.
Hepatic function impairment: Increased fraction of unbound phenytoin may occur.
Older adult: Phenytoin clearance decreases ~20% in patients >70 years of age
Hyperbilirubinemia: Increased fraction of unbound phenytoin may occur.
Hypoalbuminemia: Increased fraction of unbound phenytoin may occur.
