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Phenytoin

Pronunciation

Pronunciation

(FEN i toyn)

Index Terms

  • Dilantin
  • Diphenylhydantoin
  • DPH
  • Phenytoin Sodium
  • Phenytoin Sodium, Extended
  • Phenytoin Sodium, Prompt

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral, as sodium:

Dilantin: 30 mg [contains fd&c yellow #10 (quinoline yellow)]

Dilantin: 100 mg

Phenytek: 200 mg, 300 mg [contains brilliant blue fcf (fd&c blue #1), fd&c blue #1 aluminum lake, fd&c blue #2 aluminum lake, fd&c red #40 aluminum lake, fd&c yellow #10 aluminum lake]

Generic: 100 mg, 200 mg, 300 mg

Solution, Injection, as sodium:

Generic: 50 mg/mL (2 mL, 5 mL)

Suspension, Oral:

Dilantin: 125 mg/5 mL (237 mL) [orange-vanilla flavor]

Generic: 125 mg/5 mL (4 mL, 237 mL)

Tablet Chewable, Oral:

Dilantin Infatabs: 50 mg [scored]

Phenytoin Infatabs: 50 mg [scored; contains fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake, saccharin sodium]

Generic: 50 mg

Brand Names: U.S.

  • Dilantin
  • Dilantin Infatabs
  • Phenytek
  • Phenytoin Infatabs

Pharmacologic Category

  • Anticonvulsant, Hydantoin

Pharmacology

Stabilizes neuronal membranes and decreases seizure activity by increasing efflux or decreasing influx of sodium ions across cell membranes in the motor cortex during generation of nerve impulses; prolongs effective refractory period and suppresses ventricular pacemaker automaticity, shortens action potential in the heart

Absorption

Oral: Slow, variable; dependent on product formulation; decreased in neonates

Distribution

Vd:

Neonates: Premature: 1 to 1.2 L/kg; Full-term: 0.8 to 0.9 L/kg

Infants: 0.7 to 0.8 L/kg

Children: 0.7 L/kg

Adults: 0.6 to 0.7 L/kg

Metabolism

Follows dose-dependent (Michaelis-Menten) pharmacokinetics; “apparent” or calculated half-life is dependent upon serum concentration, therefore, metabolism is best described in terms of Km and Vmax; Vmax is increased in infants >6 months and children compared to adults; major metabolite (via oxidation) HPPA undergoes enterohepatic recycling and elimination in urine as glucuronides

Excretion

Urine (<5% as unchanged drug); as glucuronides

Clearance: Highly variable, dependent upon intrinsic hepatic function and dose administered; increased clearance and decreased serum concentrations with febrile illness

Onset of Action

IV: ~0.5 to 1 hour

Time to Peak

Serum (formulation dependent): Oral: Extended-release capsule: 4 to 12 hours; Immediate release preparation: 1.5 to 3 hours

Half-Life Elimination

Range: 7 to 42 hours; newborns (PNA <7 days): Apparent half-life greatly prolonged (clearance decreased) and then rapidly accelerates to infant levels by 5 weeks of 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).

Protein Binding

Neonates: ≥80% (≤20% free)

Infants: ≥85% (≤15% free)

Adults: 90% to 95%

Others: Decreased protein binding

Disease states resulting in a decrease in serum albumin concentration: Burns, hepatic cirrhosis, nephrotic syndrome, pregnancy, cystic fibrosis

Disease states resulting in an apparent decrease in affinity of phenytoin for serum albumin: Renal failure, jaundice (severe), other drugs (displacers), hyperbilirubinemia (total bilirubin >15 mg/dL), CrCl <25 mL/minute (unbound fraction is increased two- to threefold in uremia)

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

Clearance decreases ~20% in patients >70 years of age.

Use: Labeled Indications

Seizures: Control of generalized tonic-clonic and complex partial (psychomotor, temporal lobe) seizures; prevention and treatment of seizures occurring during or following neurosurgery

Use: Unlabeled

Prevention of early (within 1 week) post-traumatic seizures (PTS) following traumatic brain injury

Contraindications

Hypersensitivity to phenytoin, other hydantoins, or any component of the formulation; concurrent use of delavirdine

IV: Sinus bradycardia, sinoatrial block, second- and third-degree heart block, Adams-Stokes syndrome

Dosing: Adult

Note: Phenytoin base (eg, oral suspension, chewable tablets) contains ~8% more drug than phenytoin sodium (~92 mg base is equivalent to 100 mg phenytoin sodium). Dosage adjustments and closer serum monitoring may be necessary when switching dosage forms.

Status epilepticus: IV:

Neurocritical Care Society recommendation: Loading dose: 20 mg/kg at a maximum rate of 50 mg/minute; if necessary, may give an additional dose of 5 to 10 mg/kg 10 minutes after the loading dose (NCS [Brophy 2012])

Manufacturer recommendation: Loading dose: 10 to 15 mg/kg at a maximum rate of 50 mg/minute; initial maintenance dose: IV or Oral: 100 mg every 6 to 8 hours

Anticonvulsant: Oral:

Immediate release:

Tablet: Initial: 100 mg 3 times daily, individualize dosage with dosage adjustments at no less than 7- to 10-day intervals; maintenance dose: 300 to 400 mg/day; an increase to 600 mg/day may be necessary

Suspension: Initial: 125 mg 3 times daily, individualize dosage with dosage adjustments at no less than 7- to 10-day intervals; an increase to 625 mg/day may be necessary

Extended release:

Loading dose: 1 g divided into 3 doses (400, 300, 300 mg) administered at 2-hour intervals; begin maintenance dosage 24 hours after loading dose. Note: Do not use loading dose regimen in patients with a history of renal or hepatic disease. Reserve for patients who require rapid steady state serum levels, when IV administration is not desirable, and for patients in a clinic or hospital setting where phenytoin levels can be closely monitored.

Initial dosage (treatment naïve): 100 mg 3 times daily; adjust dosage at no less than 7- to 10-day intervals

Maintenance dose: 100 mg 3 to 4 times daily, doses up to 200 mg 3 times a day may be necessary. May consider converting patients established on 100 mg 3 times daily to 300 mg once daily

Dosing: Geriatric

Clearance is decreased in geriatric patients; lower doses or less frequent dosing may be required.

Dosing: Pediatric

Note: Phenytoin base (eg, oral suspension, chewable tablets) contains ~8% more drug than phenytoin sodium (~92 mg base is equivalent to 100 mg phenytoin sodium). Dosage adjustments and closer serum monitoring may be necessary when switching dosage forms.

Status epilepticus: Infants, Children, Adolescents: IV:

Neurocritical Care Society recommendation: Loading dose: 20 mg/kg at a maximum rate of 1 mg/kg/minute; if necessary, may give an additional dose of 5 to 10 mg/kg 10 minutes after the loading dose (NCS [Brophy 2012])

Manufacturer recommendation: Loading dose: 15 to 20 mg/kg, followed by maintenance therapy

Anticonvulsant (nonemergent use): Oral:

Immediate release: Children and Adolescents: Tablet and suspension: Initial: 5 mg/kg/day in 2 to 3 equally divided doses, individualize dosage with dosage adjustments at no less than 7- to 10-day intervals; maintenance dose: 4 to 8 mg/kg/day (maximum: 300 mg/day). Some experts suggest higher maintenance doses may be necessary in infant and young children (range: 8 to 10 mg/kg/day in divided doses) (Guerrini 2006).

Extended release: Children and Adolescents: Initial: 5 mg/kg/day in 2 or 3 equally divided doses, individualize dosage with dosage adjustments at no less than 7- to 10-day intervals; maintenance dose: 4 to 8 mg/kg/day (maximum: 300 mg/day)

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling; <5% excreted as unchanged drug. Serum concentration may be difficult to interpret in renal failure. Monitoring of free (unbound) concentrations or adjustment to allow interpretation is recommended.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling; undergoes hepatic metabolism and clearance may be decreased. Monitor free phenytoin levels closely. Dosage adjustments may be necessary.

Dosing: Obesity

Adults: Evidence from one small study in adult patients (N=24) with obesity (range: 71 to 197 kg) demonstrated that the volume of distribution (Vd) was 0.68 ± 0.03 L/kg (range: 0.53 to 0.85 L/kg) and distribution into weight in excess of IBW is disproportionately greater (by a factor of 1.33) (Abernethy 1985). Based on this evidence, the following dosing strategies have been suggested:

Loading dose:

14 mg/kg (IBW) + 19 mg/kg (weight in excess of IBW); maximum dose: 2 g (Abernethy 1985; Erstad 2004)

For example: For a patient with a total body weight (TBW) of 300 lb (136 kg) and an IBW of 73 kg

Loading dose = 14 mg/kg (73 kg) + 19 mg/kg (136 kg minus 73 kg) = 2219 mg; administer the maximum dose of 2,000 mg

OR

May also target a specific concentration (eg, 15 to 20 mg/L) by using the Vd obtained from patients with obesity (Abernethy 1985; Burton 2006). Therefore, the concentration desired (in mg/L) may be multiplied by this Vd (obesity) (in L) which is determined using the patient’s total and ideal body weights.

Vd (obesity) = 0.65 L/kg (IBW) + 1.33 (TBW – IBW)

Loading dose = Calculated Vd (obesity) (target concentration)

For example: For a patient with a total body weight (TBW) of 300 lb (136 kg) and an IBW of 73 kg

Vd (obesity) = 0.65 L/kg (73 kg) + 1.33 (136 kg – 73 kg) = 131 L; then,

Loading dose = 131 L x 15 mg/L = 1,965 mg

Maintenance dose: Base on ideal body weight if using weight-based regimens or use conventional daily doses with adjustments based upon therapeutic drug monitoring and clinical effectiveness. (Abernethy 1985; Erstad 2002; Erstad 2004)

Note: Additional data are necessary to further define dosing strategies in the obese patient.

Reconstitution

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

IV: May be further diluted in NS to a final concentration ≥5 mg/mL; infusion must be completed within 4 hours after preparation. Do not refrigerate.

Administration

Oral:

Immediate release: Divide daily dose into 2 to 3 doses per day; if the daily dosage cannot be divided equally, take the larger dose before retiring.

Chewable tablets: May chew thoroughly before being swallowing or swallow whole.

Suspension: Shake well prior to use; measure and administer dose using a calibrated oral dosing syringe (or other accurate dose-measuring device). Absorption is impaired when phenytoin suspension is given concurrently to patients who are receiving continuous nasogastric feedings. A method to resolve this interaction is to divide the daily dose of phenytoin and withhold the administration of nutritional supplements for 1 to 2 hours before and after each phenytoin dose. The manufacturer recommends not to administer concomitantly with an enteral feeding preparation.

Extended release: Usually dosed every 12 hours; however, in patients with sufficiently long half-life, may be dosed every 24 hours.

IM: Avoid IM administration due to severe risk of local tissue destruction and necrosis; use fosphenytoin if IM administration necessary (Boucher 1996; Meek 1999). The manufacturer’s labeling includes IM administration; however, in general the IM route should be avoided and should NOT be used for status epilepticus.

IV: Fosphenytoin may be considered for loading in patients who are in status epilepticus, hemodynamically unstable, or develop hypotension/bradycardia with IV administration of phenytoin. Although, phenytoin may be administered by direct IV injection, it is preferable that phenytoin be administered via infusion pump either undiluted or diluted in normal saline as an IV piggyback (IVPB) to prevent exceeding the maximum infusion rate (monitor closely for extravasation during infusion). The maximum rate of IV administration is 50 mg/minute in adults. Highly sensitive patients (eg, elderly, patients with preexisting cardiovascular conditions) should receive phenytoin more slowly (eg, 20 mg/minute) (Meek 1999). In neonates, the manufacturer recommends a maximum rate of 1 to 3 mg/kg/minute; however, a lower maximum rate of 0.5 to 1 mg/kg/minute is used clinically (Sankar 2010; Shields 1989). An in-line 0.22 to 0.55 micron filter is recommended for IVPB solutions due to the potential for precipitation of the solution. Following IV administration, NS should be injected through the same needle or IV catheter to prevent irritation.

SubQ: SubQ administration is not recommended because of the possibility of local tissue damage (due to high pH).

Vesicant; ensure proper needle or catheter placement prior to and during IV infusion. Avoid extravasation.

Extravasation management: If extravasation occurs, stop infusion immediately and disconnect (leave needle/cannula in place); gently aspirate extravasated solution (do NOT flush the line); remove needle/cannula; elevate extremity. There is conflicting information regarding an antidote; some sources recommend not to use an antidote (Montgomery 1999 [pediatric reference]), while other sources recommend hyaluronidase.

Hyaluronidase (if appropriate): SubQ: Administer four separate 0.2 mL injections of a 15 units/mL solution (using a 25-gauge needle) into area of extravasation (Sokol 1998)

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

Dietary Considerations

Folic acid: Phenytoin may decrease mucosal uptake of folic acid; to avoid folic acid deficiency and megaloblastic anemia, some clinicians recommend giving patients on anticonvulsants prophylactic doses of folic acid and cyanocobalamin. Folic acid 0.5 mg/day has been shown to reduce the incidence of phenytoin-induced gingival overgrowth in children (Arya 2011). However, folate supplementation may increase seizures in some patients (dose dependent). Discuss with healthcare provider prior to using any supplements.

Calcium: Hypocalcemia has been reported in patients taking prolonged high-dose therapy with an anticonvulsant. Some clinicians have given an additional 4000 units/week of vitamin D (especially in those receiving poor nutrition and getting no sun exposure) to prevent hypocalcemia.

Vitamin D: Phenytoin interferes with vitamin D metabolism and osteomalacia may result; may need to supplement with vitamin D

Tube feedings: Tube feedings decrease phenytoin absorption. To avoid decreased serum levels with continuous NG feeds, hold feedings for 1-2 hours prior to and 1-2 hours after phenytoin administration, if possible. The manufacturer recommends not to administer concomitantly with an enteral feeding preparation. There is a variety of opinions on how to administer phenytoin with enteral feedings. Be consistent throughout therapy.

Injection may contain sodium.

Compatibility

Y-site administration: Incompatible with amphotericin B cholesteryl sulfate complex, cefepime, ceftazidime, cimetidine, ciprofloxacin, diltiazem, enalaprilat, fenoldopam, fentanyl, heparin, heparin with hydrocortisone sodium succinate, hydromorphone, linezolid, methadone, micafungin, morphine, potassium chloride, propofol, sufentanil, theophylline, vasopressin, vitamin B complex with C.

Compatibility in syringe: Incompatible with hydromorphone, ondansetron, pantoprazole, sufentanil.

Storage

Capsule, tablet: Store at 20°C to 25°C (68°F to 77°F). Protect capsules from light. Protect capsules and tablets from moisture.

Oral suspension: Store at 20°C to 25°C (68°F to 77°F); do not freeze. Protect from light.

Solution for injection: Store at 15°C to 30°C (59°F to 86°F). Use only clear solutions free of precipitate and haziness; slightly yellow solutions may be used. Precipitation may occur if solution is refrigerated and may dissolve at room temperature.

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

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

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

Amiodarone: Phenytoin may decrease the serum concentration of Amiodarone. Amiodarone may increase the serum concentration of Phenytoin. Monitor therapy

Amphetamines: May decrease the serum concentration of Phenytoin. Monitor therapy

Antifungal Agents (Azole Derivatives, Systemic): May increase the serum concentration of Phenytoin. Applicable Isavuconazonium considerations are addressed in separate monographs. Phenytoin may decrease the serum concentration of Antifungal Agents (Azole Derivatives, Systemic). Management: Concomitant therapy with itraconazole, voriconazole, or ketoconazole and phenytoin should probably be avoided, as antifungal failure is likely. Consider selecting alternative antifungal therapy. 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: Phenytoin 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 Phenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy. Exceptions: ALPRAZolam. Monitor therapy

Bleomycin: May decrease the serum concentration of Phenytoin. Monitor therapy

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

Boceprevir: Phenytoin 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

Brivaracetam: Phenytoin may decrease the serum concentration of Brivaracetam. Brivaracetam may increase the serum concentration of Phenytoin. 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: Phenytoin 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 Phenytoin. Phenytoin may decrease the serum concentration of Calcium Channel Blockers. Management: Avoid use of nimodipine or nifedipine with phenytoin. Monitor for phenytoin toxicity and/or decreased calcium channel blocker effects with any concurrent use. Exceptions: Clevidipine. Consider therapy modification

Canagliflozin: Phenytoin 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 Phenytoin. Consider therapy modification

CarBAMazepine: May decrease the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of CarBAMazepine. CarBAMazepine may increase the serum concentration of Phenytoin. 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

Caspofungin: Inducers of Drug Clearance may decrease the serum concentration of Caspofungin. Management: Consider using an increased caspofungin dose of 70 mg daily in adults (or 70 mg/m2, up to a maximum of 70 mg, daily in pediatric patients) when coadministered with known inducers of drug clearance. Consider therapy modification

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

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

Chloramphenicol: Phenytoin may decrease the serum concentration of Chloramphenicol. Phenytoin may increase the serum concentration of Chloramphenicol. Chloramphenicol may increase the serum concentration of Phenytoin. 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): May diminish the therapeutic effect of Phenytoin. Ciprofloxacin (Systemic) may decrease the serum concentration of Phenytoin. 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

Colesevelam: May decrease the serum concentration of Phenytoin. Management: Administer phenytoin at least 4 hours prior to colesevelam. Consider therapy modification

Contraceptives (Estrogens): Phenytoin 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): Phenytoin 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

Cosyntropin: May enhance the hepatotoxic effect of Phenytoin. Monitor therapy

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

CycloSPORINE (Systemic): Phenytoin may increase the metabolism of CycloSPORINE (Systemic). 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

Dapsone (Topical): May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Monitor therapy

Darunavir: May decrease the serum concentration of Phenytoin. Monitor therapy

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

Dexamethasone (Systemic): Phenytoin may decrease the serum concentration of Dexamethasone (Systemic). Dexamethasone (Systemic) may decrease the serum concentration of Phenytoin. Dexamethasone (Systemic) may increase the serum concentration of Phenytoin. Management: Consider dexamethasone dose increases when combined with phenytoin and monitor closely for reduced steroid efficacy. Monitor phenytoin levels closely when combined with dexamethasone, 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 Phenytoin. Monitor therapy

Diazoxide: May decrease the serum concentration of Phenytoin. 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: Phenytoin may decrease the serum concentration of Disopyramide. Monitor therapy

Disulfiram: May increase the serum concentration of Phenytoin. 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

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

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: Phenytoin 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: Phenytoin may decrease the serum concentration of Efavirenz. Efavirenz may increase the serum concentration of Phenytoin. 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: Phenytoin may decrease the serum concentration of Eslicarbazepine. Eslicarbazepine may increase the serum concentration of 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 Phenytoin. Phenytoin may decrease the serum concentration of Ethosuximide. Ethosuximide may increase the serum concentration of Phenytoin. 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: Phenytoin may decrease the serum concentration of Etravirine. Management: The manufacturer of etravirine states these drugs should not be used in combination 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: May increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Felbamate. 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 Phenytoin. Consider therapy modification

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

Flunarizine: Phenytoin 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 Phenytoin. Consider therapy modification

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

FLUoxetine: May increase the serum concentration of Phenytoin. Monitor therapy

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

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

Fosamprenavir: May decrease the serum concentration of Phenytoin. The active amprenavir metabolite is likely responsible for this effect. Phenytoin may increase the serum concentration of Fosamprenavir. Specifically, phenytoin may increase the concentration of the active metabolite amprenavir. 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: Increase the guanfacine dose by up to double when initiating concomitant therapy with strong CYP3A4 inducers. Increase guanfacine dose gradually over 1-2 weeks if strong CYP3A4 inducer therapy is just beginning. Consider therapy modification

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

HMG-CoA Reductase Inhibitors: Phenytoin 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 Phenytoin. 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: Phenytoin may decrease the serum concentration of Lacosamide. Monitor therapy

LamoTRIgine: Phenytoin 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 Phenytoin. Monitor therapy

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

Levomefolate: May decrease the serum concentration of Phenytoin. 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: Phenytoin may enhance the adverse/toxic effect of Lithium. Monitor therapy

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

Lopinavir: Phenytoin may decrease the serum concentration of Lopinavir. Lopinavir may decrease the serum concentration of Phenytoin. 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: Phenytoin 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: Phenytoin may decrease the serum concentration of Meperidine. Monitor therapy

Methadone: Phenytoin 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 Phenytoin. Monitor therapy

Methylphenidate: May increase the serum concentration of Phenytoin. 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): Phenytoin may decrease the serum concentration of MetroNIDAZOLE (Systemic). MetroNIDAZOLE (Systemic) may increase the serum concentration of Phenytoin. Monitor therapy

MetyraPONE: Phenytoin 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: Phenytoin may decrease the serum concentration of Mexiletine. Monitor therapy

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

Miconazole (Oral): May increase the serum concentration of Phenytoin. 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

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: May decrease the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Nelfinavir. 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: May increase the serum concentration of Phenytoin. Phenytoin 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

Nitric Oxide: May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when nitric oxide is used in combination with other agents associated with development of methemoglobinemia. Avoid lidocaine/prilocaine. Monitor therapy

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

Orlistat: May decrease the serum concentration of Anticonvulsants. 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: Phenytoin 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: Phenytoin may enhance the CNS depressant effect of PHENobarbital. PHENobarbital may decrease the serum concentration of Phenytoin. Phenytoin may increase the serum concentration of PHENobarbital. Monitor therapy

Pimavanserin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Pimavanserin. 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

Prilocaine: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Prilocaine. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when prilocaine is used in combination with other agents associated with development of methemoglobinemia. Avoid lidocaine/prilocaine in infants receiving such agents. Monitor therapy

Primidone: Phenytoin 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 Phenytoin. 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: Phenytoin may decrease the serum concentration of QuiNIDine. Monitor therapy

QuiNINE: Phenytoin 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 Phenytoin. 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: Phenytoin may decrease the serum concentration of Rilpivirine. Avoid combination

Ritonavir: Phenytoin may decrease the serum concentration of Ritonavir. Ritonavir may decrease the serum concentration of Phenytoin. 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: May increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Rufinamide. 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: May increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Sertraline. Monitor therapy

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

Sirolimus: Phenytoin may decrease the serum concentration of Sirolimus. Management: Monitor for decreased sirolimus serum concentrations if 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 Nitrite: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Sodium Nitrite. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Monitor therapy

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

Stiripentol: May decrease the serum concentration of Phenytoin. Avoid combination

Sulfamethoxazole: May increase the serum concentration of Phenytoin. Consider therapy modification

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): Phenytoin may decrease the serum concentration of Tacrolimus (Systemic). Tacrolimus (Systemic) may increase the serum concentration of Phenytoin. 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 Phenytoin. Phenytoin may decrease the serum concentration of Telaprevir. Avoid combination

Temsirolimus: Phenytoin 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: Phenytoin 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

Tetracaine (Topical): May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Monitor therapy

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: Phenytoin may decrease the serum concentration of Theophylline Derivatives. Theophylline Derivatives may decrease the serum concentration of Phenytoin. 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: Phenytoin 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 Phenytoin. Monitor therapy

Tipranavir: Phenytoin may decrease the serum concentration of Tipranavir. Tipranavir may decrease the serum concentration of Phenytoin. 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: May increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Topiramate. 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: Phenytoin may decrease the serum concentration of TraZODone. TraZODone may increase the serum concentration of Phenytoin. 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: May increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Trimethoprim. 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

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

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

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 Phenytoin. 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: Phenytoin may decrease the serum concentration of VinCRIStine. VinCRIStine may decrease the serum concentration of Phenytoin. 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

Vindesine: May decrease the serum concentration of Phenytoin. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Phenytoin may enhance the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists may increase the serum concentration of Phenytoin. 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: Phenytoin may decrease the serum concentration of Zonisamide. Monitor therapy

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

Test Interactions

Falsely high plasma phenytoin concentrations may occur when measured by immunoanalytical techniques (eg, TDX, TDXFLX, Emit 2000). Phenytoin may produce falsely low results for serum concentrations of T4, and dexamethasone or metyrapone tests. Phenytoin may cause increased serum levels of glucose, alkaline phosphatase, and gamma glutamyl transpeptidase (GGT).

Adverse Reactions

Frequency not defined.

Cardiovascular: Atrial conduction depression (IV administration), bradycardia (IV administration), cardiac arrhythmia (IV administration), circulatory shock (IV administration), hypotension (IV administration), periarteritis nodosa, ventricular conduction depression (IV administration), ventricular fibrillation (IV administration)

Central nervous system: Ataxia, cerebral atrophy (elevated serum levels and/or long-term use), cerebral dysfunction (elevated serum levels and/or long-term use), confusion, dizziness, drowsiness, headache, insomnia, mood changes, nervousness, paresthesia, peripheral neuropathy (associated with chronic treatment), slurred speech, twitching, vertigo

Dermatologic: Bullous dermatitis, exfoliative dermatitis, hypertrichosis, morbilliform rash (most common), scarlatiniform rash, skin or other tissue necrosis (IV administration), skin rash, toxic epidermal necrolysis

Endocrine & metabolic: Hyperglycemia, vitamin D deficiency (associated with chronic treatment)

Gastrointestinal: Constipation, dysgeusia (metallic taste), enlargement of facial features (lips), gingival hyperplasia, nausea, vomiting

Genitourinary: Peyronie disease

Hematologic & oncologic: Agranulocytosis, granulocytopenia, Hodgkin lymphoma, immunoglobulin abnormality, leukopenia, lymphadenopathy, macrocytosis, malignant lymphoma, megaloblastic anemia, pancytopenia, pseudolymphoma, purpuric dermatitis, thrombocytopenia

Hepatic: Acute hepatic failure, hepatic injury, hepatitis, toxic hepatitis

Hypersensitivity: Anaphylaxis

Immunologic: DRESS syndrome

Local: Injection site reaction ("purple glove syndrome"; edema, discoloration, and pain distal to injection site), local inflammation (IV administration), local irritation (IV administration), localized tenderness (IV administration), local tissue necrosis (IV administration)

Neuromuscular & skeletal: Coarsening of facial features, osteomalacia, systemic lupus erythematosus, tremor

Ophthalmic: Nystagmus

Miscellaneous: Fever, tissue sloughing (IV administration)

<1% (Limited to important or life-threatening): Dyskinesia, hepatotoxicity (idiosyncratic) (Chalasani 2014)

ALERT: U.S. Boxed Warning

Cardiovascular risk associated with rapid infusion (injection):

The rate of intravenous phenytoin administration should not exceed 50 mg/minute in adults and 1-3 mg/kg/minute (or 50 mg/minute, whichever is slower) in pediatric patients because of the risk of severe hypotension and cardiac arrhythmias. Careful cardiac monitoring is needed during and after administering intravenous phenytoin. 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 (eg, agranulocytosis, leukopenia, granulocytopenia, 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.

• Bone effects: Chronic use of phenytoin has been associated with decreased bone mineral density (osteopenia, osteoporosis, and osteomalacia) and bone fractures. Chronic use may result in decreased vitamin D concentrations due to hepatic enzyme induction and may lead to vitamin D deficiency, hypocalcemia, and hypophosphatemia; monitor as appropriate and consider implementing vitamin D and calcium supplementation.

• Cardiovascular events: [US Boxed Warning]: Phenytoin must be administered slowly. Intravenous administration should not exceed 50 mg/minute in adult patients. In pediatric patients, intravenous administration rate should not exceed 1-3 mg/kg/minute or 50 mg/minute whichever is slower. Hypotension and severe cardiac arrhythmias (eg, heart block, ventricular tachycardia, ventricular fibrillation) may occur with rapid administration; adverse cardiac events have been reported at or below the recommended infusion rate. Cardiac monitoring is necessary during and after administration of intravenous phenytoin; reduction in rate of administration or discontinuation of infusion may be necessary. For nonemergency use, intravenous phenytoin should be administered more slowly; the use of oral phenytoin should be used whenever possible.

• Dermatologic reactions: Severe reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (some fatal) have been reported; the onset of symptoms is usually within 28 days of treatment, but can occur later. Discontinue phenytoin if there are any signs of rash and evaluate for signs and symptoms of drug reaction with eosinophilia and systemic symptoms (DRESS). Data suggests a genetic susceptibility for serious skin reactions in patients of Asian descent (see "Special populations" below).

• Extravasation: Vesicant (intravenous administration); ensure proper catheter or needle position prior to and during infusion. Avoid extravasation. IV formulation may cause soft tissue irritation and inflammation, and skin necrosis at IV site; avoid IV administration in small veins. The "purple glove syndrome" (ie, discoloration with edema and pain of distal limb) may occur following peripheral IV administration of phenytoin. This syndrome may or may not be associated with drug extravasation. Symptoms may resolve spontaneously; however, skin necrosis and limb ischemia may occur; interventions such as fasciotomies, skin grafts, and amputation (rare) may be required. To decrease the risk of this syndrome, inject phenytoin slowly and directly into a large vein through a large gauge needle or IV catheter; follow with NS flushes through the same needle or IV catheter.

• Hepatotoxicity: Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported. 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 phenytoin in patients who develop acute hepatotoxicity and do not readminister.

• Hypersensitivity: Consider alternative therapy in patients who have experienced hypersensitivity to structurally similar drugs such as carboxamides (eg, carbamazepine), barbiturates, succinimides, and oxazolidinediones (eg, trimethadione).

• Lymphadenopathy: May occur (local or generalized), including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin disease; cause and effect relationship has not been established.

• Multiorgan hypersensitivity reactions: Potentially serious, sometimes fatal multiorgan hypersensitivity reactions (also known as drug reaction with eosinophilia and systemic symptoms [DRESS]) have been reported with some antiepileptic drugs; including phenytoin; 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.

• Suicidal ideation: Pooled analysis of trials involving various antiepileptics (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% treated patients compared to 0.24% of patients receiving placebo); risk observed as early as 1 week after initiation and continued through duration of trials (most trials ≤24 weeks). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression; notify healthcare provider immediately if symptoms occur.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with underlying cardiac disease; IV use is contraindicated in patients with sinus bradycardia, sinoatrial block, or second and third degree heart block.

• Diabetes: Use with caution in patients with diabetes mellitus; phenytoin may inhibit insulin release and 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: May cause exacerbation of porphyria; use with caution in patients with porphyria.

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. Note: Carbamazepine, another antiepileptic with a chemical structure similar to phenytoin, includes in the manufacturer labeling a recommendation to screen patients of Asian descent for the HLA-B*1502 allele prior to initiating therapy; this is not a current recommendation in the phenytoin manufacturer labeling. Patients with a positive result should avoid phenytoin.

• 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:

• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer’s labeling.

• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures and respiratory depression; use caution (AAP 1997; Zar 2007).

Special handling:

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

Other warnings/precautions:

• Appropriate use: 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 cerebellar 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: 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

CBC, liver function; suicidality (eg, suicidal thoughts, depression, behavioral changes); plasma phenytoin concentrations (if available, free 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.

Additional monitoring with IV use: Continuous cardiac monitoring (rate, rhythm, blood pressure) and observation during administration recommended; blood pressure and pulse should be monitored every 15 minutes for 1 hour after administration (Meek, 1999); infusion site reactions

Consult individual institutional policies and procedures.

Pregnancy Risk Factor

D

Pregnancy Considerations

Phenytoin crosses the placenta (Harden and Pennell 2009). 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. Maternal use of phenytoin should be avoided when possible to decrease the risk of cleft palate and poor cognitive outcomes. Polytherapy may also increase the risk of congenital malformations; monotherapy is recommended (Harden and Meader 2009). The maternal use of folic acid throughout pregnancy is recommended to reduce the risk of major congenital malformations (Harden and Pennell 2009).

Total plasma concentrations of phenytoin are decreased in the mother during pregnancy; unbound plasma (free) concentrations are also decreased and plasma clearance is increased. Due to pregnancy-induced physiologic changes, women who are pregnant may require dose adjustments of phenytoin in order to maintain clinical response; monitoring during pregnancy should be considered (Harden and Pennell 2009). For women with epilepsy who are planning a pregnancy in advance, baseline serum concentrations should be measured once or twice prior to pregnancy during a period when seizure control is optimal. Monitoring can then be continued once each trimester during pregnancy and postpartum; more frequent monitoring may be needed in some patients. Monitoring of unbound plasma concentrations is recommended (Patsalos 2008). In women taking phenytoin who are trying to avoid pregnancy, potentially significant interactions may exist with hormone-containing contraceptives; consult drug interactions database for more detailed information.

Patients exposed to phenytoin 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 https:\\aedpregnancyregistry.org.

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 dizziness, fatigue, headache, insomnia, constipation, vomiting, or nausea. Have patient report immediately to prescriber signs of infection, 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 high blood sugar (confusion, feeling sleepy, more thirst, hunger, passing urine more often, flushing, fast breathing, or breath that smells like fruit), change in balance, abnormal gait, illogical thinking, slurred speech, gingival pain or edema, severe muscle pain, abnormal movements, loss of strength and energy, seizures, burning or numbness feeling, bruising, bleeding, weak bones, bone pain, involuntary eye movements, tremors, enlarged lymph nodes, fever, rash, angina, urinary retention, change in amount of urine passed, signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), bradycardia, tachycardia, arrhythmia, severe injection site pain or irritation, or skin discoloration (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 healthcare 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.

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