Skip to Content
Find MS events and support groups near you! Get started >>

Fosphenytoin

Pronunciation

(FOS fen i toyn)

Index Terms

  • Cerebyx
  • Fosphenytoin Sodium

Dosage Forms

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/10ML (2 mL, 10 mL); 500 mg PE/10 mL (10 mL)

Generic: 100 mg PE/2 mL (2 mL); 500 mg PE/10 mL (10 mL)

Brand Names: U.S.

  • Cerebyx

Pharmacologic Category

  • Anticonvulsant, Hydantoin

Pharmacology

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

Distribution

Fosphenytoin: Vd: 4.3 to 10.8 L; Vd of fosphenytoin increases with dose and rate of administration (Fischer 2003)

Metabolism

Fosphenytoin is rapidly converted via hydrolysis to phenytoin; phenytoin is metabolized in the liver and forms metabolites

Excretion

Phenytoin: Urine (as inactive metabolites)

Time to Peak

Conversion to phenytoin:

IV: Adults: Following IV administration (maximum rate of administration): ~15 minutes

IM:

Neonates and Infants ≤6 months: 1-3 hours was reported in a case series (n=3; PNA: 15 to 47 days) (Fischer 2003)

Pediatric patients >7 months: Therapeutic concentrations within 30 minutes; time to maximum serum concentration not reported (Fischer 2003)

Adults: ~3 hours; Therapeutic phenytoin concentrations may be achieved as early as 5 to 20 minutes following IM (gluteal) administration (Pryor 2001)

Half-Life Elimination

Pediatric patients (ages: 1 day to 16.7 years): 8.3 minutes (range: 2.5 to 18.5 minutes) (Fischer 2003)

Adults:

Fosphenytoin: IV: ~15 minutes; IM: ~ 30 minutes.

Phenytoin: Variable (mean: 12 to 29 hours); pharmacokinetics of phenytoin are saturable

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.

Special Populations: Renal Function Impairment

Increased fraction of unbound phenytoin may occur.

Special Populations: Hepatic Function Impairment

Increased fraction of unbound phenytoin may occur.

Special Populations: Elderly

Phenytoin clearance decreases ~20% in patients >70 years of age

Special Populations Note

Hypoalbuminemia: Increased fraction of unbound phenytoin may occur.

Use: Labeled Indications

Seizures: Control of generalized tonic-clonic status epilepticus and the prevention and treatment of seizures occurring during neurosurgery; short-term parenteral administration when oral phenytoin is not possible.

Contraindications

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; concurrent use with delavirdine

Dosing: Adult

Note: The dose, concentration, and infusion rates for fosphenytoin are expressed as phenytoin equivalents (PE); fosphenytoin should always be prescribed and dispensed in phenytoin equivalents (PE); fosphenytoin 1.5 mg is equivalent to phenytoin 1 mg and is referred to as 1 mg PE.

Status epilepticus: IV: Note: Because the full antiepileptic effect is not immediate, other measures, including concomitant administration of an IV benzodiazepine, will usually be necessary for the control of status epilepticus.

Neurocritical Care Society recommendations: Loading dose: 20 mg PE/kg (maximum rate of administration: 150 mg PE/minute); if necessary, may give an additional 5 mg PE/kg 10 minutes after the loading dose (NCS [Brophy 2012]).

Manufacturer's labeling: Loading dose: 15 to 20 mg PE/kg administered at 100 to 150 mg PE/minute. Follow loading dose with maintenance doses of either fosphenytoin or phenytoin.

Nonemergent loading and maintenance dosing: IV or IM:

Loading dose: 10 to 20 mg PE/kg (IV rate: Infuse more slowly [eg, over 30 minutes]; maximum rate: 150 mg PE/minute)

Initial daily maintenance dose: 4 to 6 mg PE/kg/day in divided doses

Substitution for oral phenytoin therapy: IM or IV: May be substituted for oral phenytoin at the same total daily dose; however, Dilantin 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 modestly increase when IM or IV fosphenytoin is substituted for oral phenytoin; in 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

Dosing: Geriatric

Phenytoin clearance is decreased in geriatric patients; lower doses 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. Refer to adult dosing.

Dosing: Pediatric

Note: The dose, concentration, and infusion rates for fosphenytoin are expressed as phenytoin equivalents (PE); fosphenytoin should always be prescribed and dispensed in phenytoin equivalents (PE); fosphenytoin 1.5 mg is equivalent to phenytoin 1 mg and is referred to as 1 mg PE.

Infants, Children, and Adolescents (off-label use): IV: Note: A limited number of clinical studies have been conducted in pediatric patients; based on pharmacokinetic studies, experts recommend the following (Fischer 2003): 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). Further pediatric studies are needed.

Status epilepticus (off-label use): IV: Loading dose: 20 mg PE/kg (maximum rate of administration: 3 mg PE/kg/minute); if necessary, may give an additional 5 mg PE/kg 10 minutes after the loading dose (NCS [Brophy 2012]).

Dosing: Renal Impairment

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.

Dosing: Hepatic Impairment

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; 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.

Reconstitution

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

Must be diluted to concentrations of 1.5 to 25 mg PE/mL, in NS or D5W (maximum concentration: 25 mg PE/mL).

Administration

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) (Meek 1999; Pryor 2001).

IV: Rates of infusion:

Children and Adolescents: 1 to 3 mg PE/kg/minute (maximum rate: 150 mg PE/minute) (Pellock 1996)

Adults: 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 [Fischer 2003]). Highly sensitive patients (eg, elderly, patients with preexisting cardiovascular conditions) should receive fosphenytoin more slowly (eg, 25 to 50 mg PE/minute) (Meek 1999).

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

Dietary Considerations

Provides phosphate 0.0037 mmol/mg PE fosphenytoin

Compatibility

Stable in D5LR, D51/2NS, D5W, D10W, hetastarch 6% in NS, mannitol 20%, LR, NS.

Y-site administration: Incompatible with fenoldopam, midazolam.

Storage

Store intact vials refrigerated at 2°C to 8°C (36°F to 46°F). Do not store at room temperature for more than 48 hours. After opening, discard any unused solution in vials.

Has been shown to be stable at 1, 8, and 20 mg PE/mL in normal saline or D5W at 25°C (77°F) for 30 days in glass container and at 4°C to 20°C (39°F to 68°F) for 30 days in PVC bag. Undiluted fosphenytoin injection (50 mg PE/mL) is stable in polypropylene syringes for 30 days at 25°C, 4°C, or frozen at -20°C. Fosphenytoin at concentrations of 1, 8, and 20 mg PE/mL prepared in D51/2NS, D51/2NS with KCl 20 mEq/L, D51/2NS with 40 mEq/L, LR, D5LR, D10W, amino acid 10%, mannitol 20%, hetastarch 6% in NS or Plasma-Lyte A injection is stable in polyvinyl chloride bags for 7 days when stored at 25°C (room temperature) (Fischer 1997).

Drug Interactions

Abiraterone Acetate: CYP3A4 Inducers (Strong) may decrease the serum concentration of Abiraterone Acetate. Management: Avoid whenever possible. If such a combination cannot be avoided, increase abiraterone acetate dosing frequency from once daily to twice daily during concomitant use. Avoid combination

Acetaminophen: Fosphenytoin-Phenytoin may decrease the 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). Monitor therapy

Afatinib: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Afatinib. Management: Per US labeling: if requiring chronic use of P-gp inducers, increase afatinib dose by 10mg as tolerated; reduce to original afatinib dose 2-3 days after stopping P-gp inducers. Per Canadian labeling: avoid combination if possible. Consider therapy modification

Alcohol (Ethyl): May enhance the CNS depressant effect of Fosphenytoin. Alcohol (Ethyl) may decrease the serum concentration of Fosphenytoin. This may be particularly applicable with chronic, heavy alcohol consumption. Alcohol (Ethyl) may increase the serum concentration of Fosphenytoin. This may be particularly applicable with acute, heavy alcohol consumption. Monitor therapy

Amiodarone: Fosphenytoin may enhance the QTc-prolonging effect of Amiodarone. Fosphenytoin may decrease the serum concentration of Amiodarone. Amiodarone may increase the serum concentration of Fosphenytoin. Management: Seek alternatives when possible. Monitor patients receiving this combination for QT interval prolongation or changes in cardiac rhythm, and for decreased serum concentrations/effects of amiodarone and increased concentrations/effects of phenytoin. Consider therapy modification

Antifungal Agents (Azole Derivatives, Systemic): Fosphenytoin may decrease the serum concentration of Antifungal Agents (Azole Derivatives, Systemic). Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Fosphenytoin. Applicable Isavuconazonium considerations are addressed in separate monographs. Exceptions: Isavuconazonium Sulfate. Consider therapy modification

Antihepaciviral Combination Products: CYP3A4 Inducers (Strong) may decrease the serum concentration of Antihepaciviral Combination Products. Avoid combination

Apixaban: CYP3A4 Inducers (Strong) may decrease the serum concentration of Apixaban. Avoid combination

Apremilast: CYP3A4 Inducers (Strong) may decrease the serum concentration of Apremilast. Avoid combination

Aprepitant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Aprepitant. Avoid combination

ARIPiprazole: CYP3A4 Inducers may decrease the serum concentration of ARIPiprazole. Management: Double the oral aripiprazole dose and closely monitor response. Reduce oral aripiprazole dose to 10-15 mg/day (for adults) if the inducer is discontinued. Avoid use of CYP3A4 inducers for more than 14 days with extended-release injectable aripiprazole. Consider therapy modification

ARIPiprazole Lauroxil: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) 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 662 mg or 882 mg doses of aripiprazole lauroxil. Consider therapy modification

Artemether: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Artemether. Specifically, dihydroartemisinin concentrations may be reduced. CYP3A4 Inducers (Strong) may decrease the serum concentration of Artemether. Avoid combination

Asunaprevir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Asunaprevir. Avoid combination

Axitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Axitinib. Avoid combination

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Bazedoxifene: Fosphenytoin may decrease the serum concentration of Bazedoxifene. This may lead to loss of efficacy or, if bazedoxifene is combined with estrogen therapy, an increased risk of endometrial hyperplasia. Monitor therapy

Bedaquiline: CYP3A4 Inducers (Strong) may decrease the serum concentration of Bedaquiline. Avoid combination

Benzodiazepines: May increase the serum concentration of Fosphenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy. Exceptions: ALPRAZolam. Monitor therapy

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Boceprevir: Fosphenytoin may decrease the serum concentration of Boceprevir. Avoid combination

Bortezomib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Bortezomib. Avoid combination

Bosutinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Bosutinib. Avoid combination

Brentuximab Vedotin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be decreased. Monitor therapy

Brentuximab Vedotin: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be decreased. Monitor therapy

Brexpiprazole: CYP3A4 Inducers (Strong) may decrease the 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. Consider therapy modification

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Consider therapy modification

Busulfan: Fosphenytoin may decrease the serum concentration of Busulfan. Monitor therapy

Cabozantinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Cabozantinib. Management: Avoid use of strong CYP3A4 inducers with cabozantinib if possible. If combined, cabozantinib dose adjustments are recommended and vary based on the cabozantinib product used and the indication for use. See monograph for details. Consider therapy modification

Calcifediol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Calcifediol. Monitor therapy

Calcium Channel Blockers: May increase the serum concentration of Fosphenytoin. Management: Monitor for phenytoin toxicity with concomitant use of a calcium channel blocker (CCB) or decreased phenytoin effects with CCB discontinuation. Monitor for decreased CCB therapeutic effects. Nimodipine Canadian labeling contraindicates use with phenytoin. Exceptions: Clevidipine. Consider therapy modification

Canagliflozin: Fosphenytoin may decrease the serum concentration of Canagliflozin. Management: Consider increasing canagliflozin dose to 300 mg/day in patients with estimated GFR >60 mL/min/1.73 m2 who tolerate canagliflozin 100 mg/day and require greater glycemic control. Consider alternatives in patients with estimated GFR 45-60 mL/min/1.73 m2. Consider therapy modification

Cannabidiol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Cannabidiol. Monitor therapy

Cannabis: CYP3A4 Inducers (Strong) may decrease the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be decreased. Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Capecitabine: May increase the serum concentration of Fosphenytoin. Consider therapy modification

CarBAMazepine: Fosphenytoin may decrease the serum concentration of CarBAMazepine. CarBAMazepine may decrease the serum concentration of Fosphenytoin. CarBAMazepine may increase the serum concentration of Fosphenytoin. Possibly by competitive inhibition at sites of metabolism. Consider therapy modification

Carbonic Anhydrase Inhibitors: May enhance the adverse/toxic effect of Fosphenytoin-Phenytoin. Specifically, the risk for osteomalacia or rickets may be increased. Exceptions: Brinzolamide; Dorzolamide. Monitor therapy

Cariprazine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Cariprazine. Avoid combination

CeFAZolin: May decrease the protein binding of Fosphenytoin. Monitor therapy

Ceritinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ceritinib. Avoid combination

Chloramphenicol: Fosphenytoin may decrease the serum concentration of Chloramphenicol. Fosphenytoin may increase the serum concentration of Chloramphenicol. Chloramphenicol may increase the serum concentration of Fosphenytoin. Monitor therapy

Chlorpheniramine: May increase the serum concentration of Fosphenytoin-Phenytoin. Monitor therapy

Cimetidine: May enhance the adverse/toxic effect of Fosphenytoin-Phenytoin. Cimetidine may increase the serum concentration of Fosphenytoin-Phenytoin. Management: Consider using an alternative H2-antagonist to avoid this interaction. Monitor for toxic effects of hydantoin anticonvulsants if cimetidine is initiated/dose increased. Consider therapy modification

Ciprofloxacin (Systemic): Fosphenytoin may enhance the QTc-prolonging effect of Ciprofloxacin (Systemic). Ciprofloxacin (Systemic) may diminish the therapeutic effect of Fosphenytoin. Ciprofloxacin (Systemic) may decrease the serum concentration of Fosphenytoin. Monitor therapy

Clarithromycin: CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Clarithromycin. Clarithromycin may increase the serum concentration of CYP3A4 Inducers (Strong). CYP3A4 Inducers (Strong) may decrease the serum concentration of Clarithromycin. Management: Consider alternative antimicrobial therapy for patients receiving a CYP3A inducer. Drugs that enhance the metabolism of clarithromycin into 14-hydroxyclarithromycin may alter the clinical activity of clarithromycin and may impair clarithromycin efficacy. Consider therapy modification

CloZAPine: CYP3A4 Inducers (Strong) may decrease the serum concentration of CloZAPine. Avoid combination

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy

Cobicistat: Fosphenytoin-Phenytoin may decrease the serum concentration of Cobicistat. Avoid combination

Cobimetinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Cobimetinib. Avoid combination

Contraceptives (Estrogens): Fosphenytoin may diminish the therapeutic effect of Contraceptives (Estrogens). Contraceptive failure is possible. Management: Use of an alternative, nonhormonal means of contraception is recommended. Consider therapy modification

Contraceptives (Progestins): Fosphenytoin may diminish the therapeutic effect of Contraceptives (Progestins). Contraceptive failure is possible. Management: Contraceptive failure is possible. Use of an alternative, nonhormonal contraceptive is recommended. Consider therapy modification

Corticosteroids (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of Corticosteroids (Systemic). Exceptions: Hydrocortisone (Systemic); PrednisoLONE (Systemic); PredniSONE. Monitor therapy

Crizotinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Crizotinib. Avoid combination

CycloSPORINE (Systemic): Fosphenytoin may decrease the serum concentration of CycloSPORINE (Systemic). Consider therapy modification

CYP2C19 Inducers (Strong): May increase the metabolism of CYP2C19 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP2C19 Inhibitors (Moderate): May decrease the metabolism of CYP2C19 Substrates. Monitor therapy

CYP2C19 Inhibitors (Strong): May decrease the metabolism of CYP2C19 Substrates. Consider therapy modification

CYP2C19 Substrates: CYP2C19 Inducers (Strong) may increase the metabolism of CYP2C19 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP2C8 Substrates: CYP2C8 Inducers (Strong) may increase the metabolism of CYP2C8 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP2C9 Inducers (Strong): May increase the metabolism of CYP2C9 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP2C9 Inhibitors (Moderate): May decrease the metabolism of CYP2C9 Substrates. Monitor therapy

CYP2C9 Inhibitors (Strong): May decrease the metabolism of CYP2C9 Substrates. Consider therapy modification

CYP2C9 Substrates: CYP2C9 Inducers (Strong) may increase the metabolism of CYP2C9 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Substrates: CYP3A4 Inducers (Strong) may increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Exceptions: Buprenorphine; Etizolam; HYDROcodone. Consider therapy modification

Dabigatran Etexilate: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Dabigatran Etexilate. Management: Avoid concurrent use of dabigatran with p-glycoprotein inducers when possible. Closely monitor for decreased levels/effects of dabigatran if concomitantly administering p-glycoprotein inducers, particularly strong inducers. Avoid combination

Dabrafenib: CYP2C8 Inducers (Strong) may decrease the serum concentration of Dabrafenib. Avoid combination

Dabrafenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dabrafenib. Avoid combination

Daclatasvir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Daclatasvir. Avoid combination

Darunavir: Fosphenytoin may decrease the serum concentration of Darunavir. Avoid combination

Dasatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dasatinib. Management: Avoid when possible. If such a combination cannot be avoided, consider increasing dasatinib dose and monitor clinical response and toxicity closely. Consider therapy modification

Deferasirox: Fosphenytoin may decrease the serum concentration of Deferasirox. Management: Avoid combination when possible; if the combination must be used, consider a 50% increase in initial deferasirox dose, with monitoring of serum ferritin concentrations and clinical responses to guide further dosing. Consider therapy modification

Delavirdine: Fosphenytoin may decrease the serum concentration of Delavirdine. Delavirdine may increase the serum concentration of Fosphenytoin. Avoid combination

Dexamethasone (Systemic): Fosphenytoin may decrease the serum concentration of Dexamethasone (Systemic). Dexamethasone (Systemic) may decrease the serum concentration of Fosphenytoin. Dexamethasone (Systemic) may increase the 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. Consider therapy modification

Dexketoprofen: May enhance the adverse/toxic effect of Fosphenytoin-Phenytoin. Monitor therapy

Dexmethylphenidate: May increase the serum concentration of Fosphenytoin. Monitor therapy

Diazoxide: May decrease the serum concentration of Fosphenytoin. Total phenytoin concentrations may be affected more than free phenytoin concentrations. Monitor therapy

Diclofenac (Systemic): CYP2C9 Inducers (Strong) may decrease the serum concentration of Diclofenac (Systemic). Monitor therapy

Dienogest: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dienogest. Management: Avoid use of dienogest for contraception when using medications that induce CYP3A4 and for at least 28 days after discontinuation of a CYP3A4 inducer. An alternative form of contraception should be used during this time. Avoid combination

Dimethindene: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Disopyramide: May enhance the QTc-prolonging effect of Fosphenytoin. Fosphenytoin may decrease the serum concentration of Disopyramide. Management: Seek alternatives when possible. Monitor patients receiving this combination closely for evidence of QT interval prolongation or changes in cardiac rhythm, as well as for decreased serum concentrations/therapeutic effects of disopyramide. Consider therapy modification

Disulfiram: May increase the serum concentration of Fosphenytoin. Management: Avoid concomitant use of disulfiram and phenytoin when possible. Phenytoin dose adjustment will likely be necessary when starting and/or stopping concurrent disulfiram. Monitor phenytoin response and concentrations closely. Consider therapy modification

Dolutegravir: Fosphenytoin-Phenytoin may decrease the serum concentration of Dolutegravir. Avoid combination

Doxofylline: Fosphenytoin-Phenytoin may decrease the serum concentration of Doxofylline. Monitor therapy

DOXOrubicin (Conventional): CYP3A4 Inducers (Strong) may decrease the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to strong CYP3A4 inducers in patients treated with doxorubicin. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inducers in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Doxycycline: Fosphenytoin may decrease the serum concentration of Doxycycline. Consider therapy modification

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

Dronabinol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dronabinol. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Dronedarone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dronedarone. Avoid combination

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Consider therapy modification

Efavirenz: Fosphenytoin may decrease the serum concentration of Efavirenz. Efavirenz may increase the serum concentration of Fosphenytoin. Consider therapy modification

Eliglustat: CYP3A4 Inducers (Strong) may decrease the serum concentration of Eliglustat. Avoid combination

Elvitegravir: Fosphenytoin-Phenytoin may decrease the serum concentration of Elvitegravir. Avoid combination

Enzalutamide: CYP2C8 Inducers (Strong) may decrease the serum concentration of Enzalutamide. Avoid combination

Enzalutamide: CYP3A4 Inducers (Strong) may decrease the serum concentration of Enzalutamide. Management: Consider using an alternative agent that has no or minimal CYP3A4 induction potential when possible. If this combination cannot be avoided, increase the dose of enzalutamide from 160 mg daily to 240 mg daily. Avoid combination

Enzalutamide: May decrease the serum concentration of Fosphenytoin-Phenytoin. Avoid combination

Erlotinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Erlotinib. Management: Avoid combination if possible. If combination must be used, increase erlotinib dose by 50 mg increments every 2 weeks as tolerated, to a maximum of 450 mg/day. Consider therapy modification

Eslicarbazepine: Fosphenytoin may decrease the serum concentration of Eslicarbazepine. (based on studies with phenytoin) Eslicarbazepine may increase the serum concentration of Fosphenytoin. (based on studies with phenytoin) Monitor therapy

Estriol (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of Estriol (Systemic). Monitor therapy

Estriol (Topical): CYP3A4 Inducers (Strong) may decrease the serum concentration of Estriol (Topical). Monitor therapy

Ethosuximide: May enhance the CNS depressant effect of Fosphenytoin. Fosphenytoin may decrease the serum concentration of Ethosuximide. Ethosuximide may increase the serum concentration of Fosphenytoin. Monitor therapy

Etoposide: CYP3A4 Inducers (Strong) may decrease the serum concentration of Etoposide. Management: When possible, seek alternatives to strong CYP3A4-inducing medications in patients receiving etoposide. If these combinations cannot be avoided, monitor patients closely for diminished etoposide response. Consider therapy modification

Etoposide Phosphate: CYP3A4 Inducers (Strong) may decrease the 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. Consider therapy modification

Etravirine: Fosphenytoin may decrease the serum concentration of Etravirine. Avoid combination

Everolimus: CYP3A4 Inducers (Strong) may decrease the serum concentration of Everolimus. Management: Avoid concurrent use of strong CYP3A4 inducers, but if strong CYP3A4 inducers cannot be avoided, consider gradually (in 5 mg increments) increasing the everolimus dose from 10 mg/day to 20 mg/day (adult doses). Avoid combination

Exemestane: CYP3A4 Inducers (Strong) may decrease the serum concentration of Exemestane. Management: Exemestane U.S. product labeling recommends using an increased dose (50 mg/day) in patients receiving concurrent strong CYP3A4 inducers. The Canadian product labeling does not recommend a dose adjustment with concurrent use of strong CYP3A4 inducers. Consider therapy modification

Ezogabine: Fosphenytoin-Phenytoin may decrease the serum concentration of Ezogabine. Management: Consider increasing the ezogabine dose when adding phenytoin. Patients using this combination should be monitored closely for evidence of adequate ezogabine therapy. Consider therapy modification

Felbamate: Fosphenytoin may decrease the serum concentration of Felbamate. Felbamate may increase the serum concentration of Fosphenytoin. Management: Decreased phenytoin dose will likely be needed when adding felbamate; some reports suggest an empiric 20% decrease in phenytoin dose. Additional reductions may be needed if felbamate dose is increased or as otherwise guided by monitoring. Consider therapy modification

FentaNYL: CYP3A4 Inducers (Strong) may decrease the serum concentration of FentaNYL. Monitor therapy

Flibanserin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Flibanserin. Avoid combination

Floxuridine: May increase the serum concentration of Fosphenytoin. Consider therapy modification

Fluconazole: May increase the serum concentration of Fosphenytoin. Consider therapy modification

Flunarizine: Fosphenytoin may decrease the serum concentration of Flunarizine. Monitor therapy

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

Fluorouracil (Systemic): May increase the serum concentration of Fosphenytoin. Consider therapy modification

Fluorouracil (Topical): May increase the serum concentration of Fosphenytoin. Monitor therapy

FLUoxetine: Fosphenytoin may enhance the QTc-prolonging effect of FLUoxetine. FLUoxetine may increase the serum concentration of Fosphenytoin. Consider therapy modification

FluvoxaMINE: May increase the serum concentration of Fosphenytoin. Monitor therapy

Folic Acid: May decrease the serum concentration of Fosphenytoin. Monitor therapy

Fosamprenavir: Fosphenytoin may increase the serum concentration of Fosamprenavir. Fosamprenavir may decrease the serum concentration of Fosphenytoin. Monitor therapy

Gefitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Gefitinib. Management: In the absence of severe adverse reactions, increase 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. Consider therapy modification

Gestrinone: Fosphenytoin-Phenytoin may decrease the serum concentration of Gestrinone. Monitor therapy

Grazoprevir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Grazoprevir. Avoid combination

GuanFACINE: CYP3A4 Inducers (Strong) may decrease the serum concentration of GuanFACINE. Management: Consider increasing the guanfacine dose by 2-fold when adding a strong CYP3A4 inducer. Consider therapy modification

Halothane: May increase the serum concentration of Fosphenytoin. Monitor therapy

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

HMG-CoA Reductase Inhibitors: Fosphenytoin may decrease the serum concentration of HMG-CoA Reductase Inhibitors. Exceptions: Pitavastatin; Rosuvastatin. Consider therapy modification

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Consider starting with a 20% to 30% lower hydrocodone dose when using together with any other CNS depressant. Dose reductions in the other CNS depressant may also be warranted. Consider therapy modification

Hydrocortisone (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of Hydrocortisone (Systemic). Monitor therapy

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Ibrutinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ibrutinib. Avoid combination

Idelalisib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Idelalisib. Avoid combination

Ifosfamide: CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Ifosfamide. CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. Monitor therapy

Imatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Imatinib. Management: Avoid concurrent use of imatinib with 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. Consider therapy modification

Irinotecan Products: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, serum concentrations of SN-38 may be reduced. CYP3A4 Inducers (Strong) may decrease the serum concentration of Irinotecan Products. Avoid combination

Isavuconazonium Sulfate: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Isavuconazonium Sulfate. Specifically, CYP3A4 Inducers (Strong) may decrease isavuconazole serum concentrations. Avoid combination

Isoniazid: May increase the serum concentration of Fosphenytoin. Management: Consider alternatives. If concomitant therapy cannot be avoided, monitor for increased phenytoin concentrations/effects with isoniazid initiation/dose increase, or decreased concentrations/effects with isoniazid discontinuation/dose decrease. Consider therapy modification

Itraconazole: CYP3A4 Inducers (Strong) may decrease the serum concentration of Itraconazole. Avoid combination

Ivabradine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ivabradine. Avoid combination

Ivacaftor: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ivacaftor. Avoid combination

Ixabepilone: CYP3A4 Inducers (Strong) may decrease the 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. Consider therapy modification

Ixazomib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ixazomib. Avoid combination

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Lacosamide: Fosphenytoin may decrease the serum concentration of Lacosamide. Monitor therapy

LamoTRIgine: Fosphenytoin may decrease the serum concentration of LamoTRIgine. Consider therapy modification

Lapatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lapatinib. Management: If therapy overlap cannot be avoided, consider titrating 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. Avoid combination

Ledipasvir: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Ledipasvir. Avoid combination

Leucovorin Calcium-Levoleucovorin: May decrease the serum concentration of Fosphenytoin. Monitor therapy

Levodopa: Fosphenytoin may diminish the therapeutic effect of Levodopa. Monitor therapy

Levomefolate: May decrease the serum concentration of Fosphenytoin. Monitor therapy

Linagliptin: CYP3A4 Inducers (Strong) may decrease the 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. Consider therapy modification

Linagliptin: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Linagliptin. Management: Strongly consider using an alternative to any strong 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. Consider therapy modification

Lithium: Fosphenytoin may enhance the adverse/toxic effect of Lithium. Monitor therapy

Loop Diuretics: Fosphenytoin may diminish the diuretic effect of Loop Diuretics. Monitor therapy

Lopinavir: Fosphenytoin may decrease the serum concentration of Lopinavir. Lopinavir may decrease the serum concentration of Fosphenytoin. Management: The manufacturer of lopinavir/ritonavir recommends avoiding once-daily administration if used together with phenytoin. Consider therapy modification

Luliconazole: May increase the serum concentration of CYP2C19 Substrates. Monitor therapy

Lumacaftor: May decrease the serum concentration of CYP2C9 Substrates. Lumacaftor may increase the serum concentration of CYP2C9 Substrates. Monitor therapy

Lumacaftor: May decrease the serum concentration of CYP2C19 Substrates. Monitor therapy

Lumefantrine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lumefantrine. Avoid combination

Lurasidone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lurasidone. Avoid combination

Macitentan: CYP3A4 Inducers (Strong) may decrease the serum concentration of Macitentan. Avoid combination

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Maraviroc: CYP3A4 Inducers (Strong) may decrease the serum concentration of Maraviroc. Management: Increase maraviroc adult dose to 600 mg twice daily when used with strong CYP3A4 inducers. This does not apply to patients also receiving strong CYP3A4 inhibitors. Do not use maraviroc with strong CYP3A4 inducers in patients with CrCl less than 30 mL/min. Consider therapy modification

Mebendazole: Fosphenytoin may decrease the serum concentration of Mebendazole. Monitor therapy

Mefloquine: May diminish the therapeutic effect of Anticonvulsants. Mefloquine may decrease the serum concentration of Anticonvulsants. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of convulsions. Monitor anticonvulsant concentrations and treatment response closely with concurrent use. Consider therapy modification

Meperidine: Fosphenytoin may decrease the serum concentration of Meperidine. Monitor therapy

Methadone: Fosphenytoin may decrease the serum concentration of Methadone. Monitor therapy

Methotrexate: May decrease the serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may increase the serum concentration of Methotrexate. Specifically, fosphenytoin-phenytoin may displace methotrexate from serum proteins, increasing the concentration of free, unbound drug. Monitor therapy

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

Methylfolate: May decrease the serum concentration of Fosphenytoin. Monitor therapy

Methylphenidate: May increase the serum concentration of Fosphenytoin. Monitor therapy

MethylPREDNISolone: CYP3A4 Inducers (Strong) may decrease the serum concentration of MethylPREDNISolone. Management: Consider methylprednisolone dose increases in patients receiving strong CYP3A4 inducers and monitor closely for reduced steroid efficacy. Consider therapy modification

MetroNIDAZOLE (Systemic): Fosphenytoin may decrease the serum concentration of MetroNIDAZOLE (Systemic). MetroNIDAZOLE (Systemic) may increase the serum concentration of Fosphenytoin. Monitor therapy

MetyraPONE: Fosphenytoin may decrease the serum concentration of MetyraPONE. The oral metyrapone test would thus be unreliable unless the metapyrone dosage was substantially increased (e.g., 750 mg every 2 hours). Consider therapy modification

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

Mexiletine: Fosphenytoin may decrease the serum concentration of Mexiletine. Monitor therapy

Mianserin: May diminish the therapeutic effect of Fosphenytoin. Fosphenytoin may decrease the serum concentration of Mianserin. Monitor therapy

Miconazole (Oral): May increase the serum concentration of Fosphenytoin. Monitor therapy

MiFEPRIStone: CYP3A4 Inducers (Strong) may decrease the serum concentration of MiFEPRIStone. Avoid combination

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mirodenafil: CYP3A4 Inducers (Strong) may decrease the 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. Consider therapy modification

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Multivitamins/Minerals (with ADEK, Folate, Iron): May decrease the serum concentration of Fosphenytoin-Phenytoin. Monitor therapy

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Naloxegol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Naloxegol. Avoid combination

Nelfinavir: Fosphenytoin may decrease the serum concentration of Nelfinavir. Nelfinavir may decrease the serum concentration of Fosphenytoin. Monitor therapy

Netupitant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Netupitant. Avoid combination

Neuromuscular-Blocking Agents (Nondepolarizing): Fosphenytoin-Phenytoin may diminish the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing). Fosphenytoin-Phenytoin may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing). Fosphenytoin-Phenytoin may decrease the serum concentration of Neuromuscular-Blocking Agents (Nondepolarizing). Monitor therapy

NIFEdipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of NIFEdipine. Avoid combination

Nilotinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Nilotinib. Avoid combination

NiMODipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of NiMODipine. Avoid combination

Nintedanib: Combined Inducers of CYP3A4 and P-glycoprotein may decrease the serum concentration of Nintedanib. Avoid combination

Nisoldipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Nisoldipine. Avoid combination

Olaparib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Olaparib. Avoid combination

Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: CYP2C8 Inducers (Strong) may decrease the serum concentration of Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir. Specifically, the serum concentrations of dasabuvir may decrease significantly. Avoid combination

Omeprazole: May increase the serum concentration of Fosphenytoin. Fosphenytoin may decrease the serum concentration of Omeprazole. Monitor therapy

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Osimertinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Osimertinib. Avoid combination

OXcarbazepine: Fosphenytoin-Phenytoin may decrease serum concentrations of the active metabolite(s) of OXcarbazepine. Specifically, concentrations of the major active 10-monohydroxy metabolite may be reduced. OXcarbazepine may increase the serum concentration of Fosphenytoin-Phenytoin. Management: Consider increasing the initial adult oxcarbazepine extended release tablet (Oxtellar XR) dose to 900 mg/day. No specific recommendations are available for other oxcarbazepine formulations. Consider therapy modification

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: When oxycodone is combined with another CNS depressant, a dose reduction of one or both agents should be considered. The extended release oxycodone starting dose should be reduced 50% to 67% when initiated in patients already receiving CNS depressants. Consider therapy modification

Palbociclib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Palbociclib. Avoid combination

Paliperidone: Inducers of CYP3A4 (Strong) and P-glycoprotein may decrease the serum concentration of Paliperidone. Management: Avoid using the 3-month extended-release injectable suspension (Invega Trinza) with inducers of both CYP3A4 and P-glycoprotein during the 3-month dosing interval if possible. If combination is necessary, consider using extended-release tablets. Consider therapy modification

Panobinostat: CYP3A4 Inducers (Strong) may decrease the serum concentration of Panobinostat. Avoid combination

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

PAZOPanib: CYP3A4 Inducers (Strong) may decrease the serum concentration of PAZOPanib. Avoid combination

Perampanel: Fosphenytoin may decrease the serum concentration of Perampanel. Management: Increase the perampanel starting dose to 4 mg/day when perampanel is used with phenytoin/fosphenytoin. Patients receiving this combination should be followed closely for response, especially with any changes to phenytoin/fosphenytoin therapy. Consider therapy modification

P-glycoprotein/ABCB1 Substrates: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

PHENobarbital: Fosphenytoin may enhance the CNS depressant effect of PHENobarbital. Fosphenytoin may increase the serum concentration of PHENobarbital. PHENobarbital may decrease the serum concentration of Fosphenytoin. Monitor therapy

Platinum Derivatives: May decrease the serum concentration of Fosphenytoin-Phenytoin. Monitor therapy

PONATinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of PONATinib. Avoid combination

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

Praziquantel: CYP3A4 Inducers (Strong) may decrease the serum concentration of Praziquantel. Management: Avoid concomitant use of praziquantel with strong CYP3A4 inducers. Discontinue rifampin 4 weeks prior to initiation of praziquantel therapy. Rifampin may be resumed the day following praziquantel completion. Avoid combination

PrednisoLONE (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of PrednisoLONE (Systemic). Monitor therapy

PredniSONE: CYP3A4 Inducers (Strong) may decrease the serum concentration of PredniSONE. Monitor therapy

Primidone: Fosphenytoin may increase the metabolism of Primidone. The ratio of primidone:phenobarbital is thus changed. Monitor therapy

Propacetamol: Fosphenytoin-Phenytoin may decrease serum concentrations of the active metabolite(s) 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). Monitor therapy

Propafenone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Propafenone. Monitor therapy

Pyridoxine: May increase the metabolism of Fosphenytoin. This is most apparent in high pyridoxine doses (e.g., 80 mg to 200 mg daily) Monitor therapy

QUEtiapine: CYP3A4 Inducers (Strong) may decrease the serum concentration of QUEtiapine. Management: Quetiapine dose increases to 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 7-14 days of discontinuing the inducer. Consider therapy modification

QuiNIDine: Fosphenytoin may enhance the QTc-prolonging effect of QuiNIDine. Fosphenytoin may decrease the serum concentration of QuiNIDine. Management: Consider alternatives when possible. Monitor patients receiving this combination closely forsigns and symptoms of excessive QTc interval prolongation and arrhythmia, as well as for decreased serum concentrations/therapeutic effects of quinidine. Consider therapy modification

QuiNINE: Fosphenytoin may decrease the serum concentration of QuiNINE. Consider therapy modification

Ranolazine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ranolazine. Avoid combination

Reboxetine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Reboxetine. Monitor therapy

Regorafenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Regorafenib. Avoid combination

RifAMPin: May decrease the serum concentration of Fosphenytoin. Management: Seek alternatives when possible. If used together, monitor closely for decreased serum phenytoin concentrations following rifampin initiation/dose increase, or increased concentrations and toxic effects following rifampin discontinuation/dose decrease. Consider therapy modification

Rilpivirine: Fosphenytoin may decrease the serum concentration of Rilpivirine. Avoid combination

Ritonavir: Fosphenytoin may decrease the serum concentration of Ritonavir. Ritonavir may decrease the serum concentration of Fosphenytoin. Consider therapy modification

Rivaroxaban: CYP3A4 Inducers (Strong) may decrease the serum concentration of Rivaroxaban. Avoid combination

Roflumilast: CYP3A4 Inducers (Strong) may decrease the serum concentration of Roflumilast. Management: Roflumilast U.S. prescribing information recommends against combining strong CYP3A4 inducers with roflumilast. The Canadian product monograph makes no such recommendation but notes that such agents may reduce roflumilast therapeutic effects. Avoid combination

Rolapitant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Rolapitant. Management: Avoid rolapitant use in patients requiring chronic administration of strong CYP3A4 inducers. Monitor for reduced rolapitant response and the need for alternative or additional antiemetic therapy even with shorter-term use of such inducers. Consider therapy modification

RomiDEPsin: CYP3A4 Inducers (Strong) may decrease the serum concentration of RomiDEPsin. Avoid combination

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: Fosphenytoin may decrease the serum concentration of Rufinamide. Rufinamide may increase the serum concentration of Fosphenytoin. Monitor therapy

SAXagliptin: CYP3A4 Inducers may decrease the serum concentration of SAXagliptin. Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Sertraline: Fosphenytoin may decrease the serum concentration of Sertraline. Sertraline may increase the serum concentration of Fosphenytoin. Monitor therapy

Simeprevir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Simeprevir. Avoid combination

Sirolimus: Fosphenytoin may decrease the serum concentration of Sirolimus. Management: Monitor for decreased sirolimus concentrations if fosphenytoin/phenytoin is initiated/dose increased. Monitor for increased sirolimus concentrations with phenytoin discontinuation/dose decrease. Sirolimus dose adjustments may be necessary. Consider therapy modification

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

Sofosbuvir: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Sofosbuvir. Avoid combination

Sonidegib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Sonidegib. Avoid combination

SORAfenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of SORAfenib. Avoid combination

Sulthiame: May increase the serum concentration of Fosphenytoin-Phenytoin. Monitor therapy

SUNItinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of SUNItinib. Management: Avoid when possible. If such a combination cannot be avoided, consider increasing sunitinib dose and monitor clinical response and toxicity closely. Consider therapy modification

Suvorexant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Suvorexant. Avoid combination

Tacrolimus (Systemic): Fosphenytoin may decrease the serum concentration of Tacrolimus (Systemic). Tacrolimus (Systemic) may increase the serum concentration of Fosphenytoin. Monitor therapy

Tadalafil: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tadalafil. Management: Erectile dysfunction: monitor for decreased effectiveness - no standard dose adjustments recommended. Avoid use of tadalafil for pulmonary arterial hypertension in patients receiving a strong CYP3A4 inducer. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Start tapentadol at a dose of one-third to one-half of the normal dose if being initiated in a patient who is taking another drug with CNS depressant effects. Monitor closely for evidence of excessive CNS depression. Consider therapy modification

Tasimelteon: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tasimelteon. Avoid combination

Tegafur: May increase the serum concentration of Fosphenytoin-Phenytoin. Management: Phenytoin dose reductions may be necessary when used together with fluorouracil, which is the active metabolite of tegafur. Consider therapy modification

Telaprevir: May increase the serum concentration of Fosphenytoin. Fosphenytoin may decrease the serum concentration of Telaprevir. Avoid combination

Temsirolimus: Fosphenytoin may decrease the serum concentration of Temsirolimus. Concentrations of the active metabolite, sirolimus, are also likely to be decreased (and maybe to an even greater degree). Management: Temsirolimus prescribing information recommends against coadministration with strong CYP3A4 inducers such as phenytoin; however, if concurrent therapy is necessary, an increase in temsirolimus adult dose to 50 mg/week should be considered. Consider therapy modification

Teniposide: Fosphenytoin may decrease the serum concentration of Teniposide. Management: Consider alternatives to combined treatment with phenytoin and teniposide due to the potential for decreased teniposide concentrations. If the combination cannot be avoided, monitor teniposide response closely. Consider therapy modification

Tenofovir Alafenamide: Fosphenytoin-Phenytoin may decrease the serum concentration of Tenofovir Alafenamide. Avoid combination

Tetrahydrocannabinol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tetrahydrocannabinol. Monitor therapy

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Theophylline Derivatives: Fosphenytoin may decrease the serum concentration of Theophylline Derivatives. Theophylline Derivatives may decrease the serum concentration of Fosphenytoin. Management: Seek alternatives when possible. If used together, monitor for decreased concentrations/effects of phenytoin or theophylline if the other agent is initiated/dose increased, or increased concentrations/effects if the other is discontinued/dose decreased. Exceptions: Dyphylline. Consider therapy modification

Thyroid Products: Fosphenytoin may decrease the serum concentration of Thyroid Products. Phenytoin may also displace thyroid hormones from protein binding sites. Monitor therapy

Ticagrelor: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Ticagrelor. CYP3A4 Inducers (Strong) may decrease the serum concentration of Ticagrelor. Avoid combination

Ticlopidine: May increase the serum concentration of Fosphenytoin. Monitor therapy

Tipranavir: Fosphenytoin may decrease the serum concentration of Tipranavir. Tipranavir may decrease the serum concentration of Fosphenytoin. Consider therapy modification

Tofacitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tofacitinib. Avoid combination

Tolvaptan: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tolvaptan. Management: If concurrent use is necessary, increased doses of tolvaptan (with close monitoring for toxicity and clinical response) may be needed. Avoid combination

Topiramate: Fosphenytoin may decrease the serum concentration of Topiramate. Topiramate may increase the serum concentration of Fosphenytoin. Monitor therapy

Topotecan: Fosphenytoin-Phenytoin may decrease the serum concentration of Topotecan. Management: Monitor topotecan response closely, and consider alternatives to phenytoin when possible. No specific guidelines for topotecan dose adjustment are available. Consider therapy modification

Toremifene: CYP3A4 Inducers (Strong) may decrease the serum concentration of Toremifene. Avoid combination

Trabectedin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Trabectedin. Avoid combination

TraZODone: Fosphenytoin may decrease the serum concentration of TraZODone. TraZODone may increase the serum concentration of Fosphenytoin. Monitor therapy

Treprostinil: CYP2C8 Inducers (Strong) may decrease the serum concentration of Treprostinil. Monitor therapy

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Trimethoprim: Fosphenytoin may decrease the serum concentration of Trimethoprim. Trimethoprim may increase the serum concentration of Fosphenytoin. Management: Consider alternatives to this combination when possible, to avoid potential decreased trimethoprim efficacy and increased phenytoin concentrations/effects. Monitor patients receiving this combination closely for both of these possible effects. Consider therapy modification

Ulipristal: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ulipristal. Avoid combination

Valproate Products: May decrease the 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 the serum concentration of Valproate Products. Monitor therapy

Vandetanib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vandetanib. Avoid combination

Velpatasvir: CYP2C8 Inducers (Strong) may decrease the serum concentration of Velpatasvir. Avoid combination

Velpatasvir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Velpatasvir. Avoid combination

Velpatasvir: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Velpatasvir. Avoid combination

Vemurafenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vemurafenib. Avoid combination

Venetoclax: CYP3A4 Inducers (Strong) may decrease the serum concentration of Venetoclax. Avoid combination

Vigabatrin: May decrease the serum concentration of Fosphenytoin. Monitor therapy

Vilazodone: CYP3A4 Inducers (Strong) may decrease the 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 1-2 weeks after inducer discontinuation. Consider therapy modification

VinCRIStine: Fosphenytoin may decrease the serum concentration of VinCRIStine. VinCRIStine may decrease the serum concentration of Fosphenytoin. Monitor therapy

VinCRIStine (Liposomal): CYP3A4 Inducers (Strong) may decrease the serum concentration of VinCRIStine (Liposomal). Avoid combination

VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of VinCRIStine (Liposomal). Avoid combination

Vitamin K Antagonists (eg, warfarin): Fosphenytoin may enhance the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists may increase the serum concentration of Fosphenytoin. Management: Anticoagulant dose adjustment will likely be necessary when phenytoin is initiated or discontinued. Monitor patients extra closely (INR and signs/symptoms of bleeding) when using this combination. Consider therapy modification

Vorapaxar: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vorapaxar. Avoid combination

Vortioxetine: CYP3A4 Inducers (Strong) may decrease the 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. Consider therapy modification

Zaleplon: CYP3A4 Inducers (Strong) may decrease the 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 zalephon is combined with a strong CYP3A4 inducer, monitor for decreased effectiveness of zaleplon. Consider therapy modification

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Zonisamide: Fosphenytoin may decrease the serum concentration of Zonisamide. Monitor therapy

Test Interactions

Falsely high plasma phenytoin concentrations (due to cross-reactivity with fosphenytoin) when measured by immunoanalytical techniques (eg, TDX, TDXFLX, Emit 2000) prior to complete conversion of fosphenytoin to phenytoin. Phenytoin may produce falsely low results for dexamethasone or metyrapone tests. Phenytoin has the potential to lower serum folate levels.

Adverse Reactions

The following adverse reactions occurred with IV and IM administration unless otherwise specified. The more important adverse clinical events caused by the IV use of fosphenytoin are cardiovascular collapse and/or central nervous system depression. Hypotension can occur when the drug is administered rapidly by the IV route.

Paresthesia and pruritus were dose- and rate-related (adult doses ≥15 mg/kg at a rate of 150 mg PE/minute). Transient pruritus, tinnitus, nystagmus, somnolence, and ataxia occurred 2 to 3 times more often at adult doses ≥15 mg/kg and rates ≥150 mg PE/minute. Adverse events specified as IV were as reported at the maximum dose/rate. Adverse events specified as IM were reported when fosphenytoin was used as a substitute for oral phenytoin. Other adverse events were reported in clinical trials.

Also refer to the phenytoin monograph for additional adverse reactions.

>10%:

Central nervous system: Paresthesia (IV: 4% to 64%; IM: 4%; transient; occurred within several minutes of start of infusion and generally resolved within 10 minutes after completion of infusion; generally described as itching, burning or tingling, usually not at the infusion site; location varied, with the groin mentioned most frequently), dizziness (IV: 31%; IM: 5%), drowsiness (IV: 20%; IM: 7%), ataxia (IV: 4% to 11%; IM: 8%)

Dermatologic: Pruritus (IV: 49% to 64%; IM: 3%; transient; occurred within several minutes of start of infusion and generally resolved within 10 minutes after completion of infusion; generally described as itching, burning or tingling, usually not at the infusion site; location varied, with the groin mentioned most frequently)

Ophthalmic: Nystagmus (IV: 44%; IM: 15%)

1% to 10%:

Cardiovascular: Hypotension (IV: 7%), vasodilatation (IV: 6%), tachycardia (IV: 2%), facial edema, hypertension

Central nervous system: Headache (IM: 9%; IV: 2%), stupor (IV: 7%), extrapyramidal reaction (IV: 4%), agitation (IV: 3%), hyporeflexia (IM: 3%), cerebral edema (IV: 2%), dysarthria (IV: 2%), hypoesthesia (IV: 2%), vertigo (IV: 2%), chills, hyperreflexia, intracranial hypertension, myasthenia, nervousness

Endocrine & metabolic: Hypokalemia

Gastrointestinal: Nausea (IV: 9%; IM: 5%), tongue disease (IV: 4%), xerostomia (IV: 4%), dysgeusia (IV: 3%), vomiting (IM: 3%; IV: 2%)

Genitourinary: Pelvic pain (IV: 4%)

Hematologic & oncologic: Bruise (IM: 7%)

Neuromuscular & skeletal: Tremor (IM: 10%; IV: 3%), weakness (IM: 4%; IV: 2%), back pain (IV: 2%)

Ophthalmic: Diplopia (IV: 3%), amblyopia (IV: 2%)

Otic: Tinnitus (IV: 9%), deafness (IV: 2%)

Miscellaneous: Fever

<1% (Limited to important or life-threatening): Abnormal hepatic function tests, acidosis, acute hepatic failure, acute hepatotoxicity, ageusia, alkalosis, altered sense of smell, akathisia, amnesia, anemia, anorexia, aphasia, apnea, arthralgia, asthma, atrial flutter, bleeding at injection site, brain disease, bundle branch block, cachexia, cardiac failure, cardiomegaly, central nervous system depression, cerebral hemorrhage, cerebral infarction, cyanosis, dehydration, diabetes insipidus, diarrhea, dyskinesia, dyspepsia, dysphagia, dyspnea, edema, emotional lability, epistaxis, gastritis, gastrointestinal hemorrhage, hemiplegia, hemoptysis, hostility, hyperacusis, hyperesthesia, hyperglycemia, hyperkalemia, hyperkinesia, hyperventilation, hypochromic anemia, hypokinesia, hypophosphatemia, hypotonia, hypoxia, inflammation at injection site, intestinal obstruction, ketosis, leg cramps, leukocytosis, leukopenia, lymphadenopathy, maculopapular rash, malaise, migraine, myalgia, mydriasis, myopathy, oral paresthesia, orthostatic hypotension, palpitations, paralysis, petechia, photophobia, positive Babinski sign, prolonged Q-T interval on ECG, psychoneurosis, psychosis, pulmonary embolism, pustular rash, renal failure, sinus bradycardia, shock, skin photosensitivity, Stevens-Johnson syndrome, subdural hematoma, swelling at injection site, syncope, tenesmus, thrombocytopenia, thrombophlebitis, tongue edema, toxic epidermal necrolysis, urinary retention, urticaria, ventricular premature contractions, visual field defect

ALERT: U.S. Boxed Warning

Cardiovascular risk associated with rapid infusion rates:

The rate of fosphenytoin intravenous (IV) administration should not exceed 150 mg phenytoin sodium equivalent (PE)/min 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.

Warnings/Precautions

Concerns related to adverse effects:

• 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 (off-label use), do not exceed a maximum IV administration rate of 1 to 3 PE/kg/minute (up to 150 mg PE/minute) (Hegenbarth 2008). 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 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 reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndromes, although rarely reported, have resulted in fatalities; drug should be discontinued if there are any signs of rash and patient should be evaluated for signs and symptoms of drug reaction with eosinophilia and systemic symptoms (DRESS). The onset of symptoms is usually within 28 days, but can occur later. Data suggests 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.

• 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.

• 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.

• 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.

• Hypothyroidism: Use with caution in patients with hypothyroidism; phenytoin may alter thyroid 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).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Asian ancestry: Asian patients with the variant HLA-B*1502 may be at an increased risk of developing Stevens-Johnson syndrome and/or TEN. Consider avoiding fosphenytoin as an alternative for carbamazepine patients positive for HLA-B*1502.

• Critically ill patients: Use with caution in critically ill patients.

• Debilitated patients: Use with caution in patients who are debilitated.

• Elderly: Use with caution in the elderly.

Dosage form specific issues:

• Phenytoin sodium equivalent (PE): 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.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

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. 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: Anticonvulsants 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.

Monitoring Parameters

Continuous blood pressure, ECG, and respiratory function monitoring with loading dose and for 10 to 20 minutes following infusion; vital signs, CBC, hepatic function tests, plasma phenytoin concentration monitoring (plasma concentrations should not be measured until conversion to phenytoin is complete, ~2 hours after an IV infusion or ~4 hours after an IM injection). Note: If available, free (unbound) phenytoin concentrations should be obtained in patients with renal impairment and/or hypoalbuminemia; if free phenytoin concentrations are unavailable, the adjusted total concentration may be determined based upon equations in adult patients. Trough concentrations are generally recommended for routine monitoring.

Consult individual institutional policies and procedures.

Pregnancy Risk Factor

D

Pregnancy Considerations

Fosphenytoin is the prodrug of phenytoin. Refer to Phenytoin monograph for additional information.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience dry mouth, nausea, vomiting, fatigue or headache. Have patient report immediately to prescriber signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes), signs of depression (suicidal ideation, anxiety, emotional instability, illogical thinking), signs of low potassium (muscle pain or weakness, muscle cramps, or an abnormal heartbeat), signs of infection, severe dizziness, passing out, tachycardia, bradycardia, arrhythmia, abnormal movements, twitching, change in balance, dysphagia, difficulty speaking, tinnitus, hearing loss, gingival pain or swelling, tremors, bruising, bleeding, involuntary eye movements, injection site irritation or skin discoloration, burning or numbness feeling, enlarged lymph nodes, angina, urinary retention, change in amount of urine passed, or signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Hide