Phenytoin (Dilantin) - Uses, Dose, Side effects, MOA, Brands

A drug called phenytoin (Dilantin) is used to treat people who have seizures (fits). Both partial and generalised tonic-clonic seizures are treated with it. Patients with status epilepticus are treated with the intravenous formulation. For people with absence seizures, it is ineffective.

Phenytoin (Dilantin) Uses:

  • Focal (partial) onset seizures and generalized onset seizures:
    • Used to prevent seizures after a craniotomy and treat individuals with focal and generalised onset seizures. may be used for different seizure types off-label.
  • Status epilepticus:
    • Used to treat both convulsive and nonconvulsive status epilepticus patients.
  • Off Label Use of Phenytoin in Adults:
    • Used in the prevention of posttraumatic seizures

Phenytoin (Dilantin) Dose in  Adults

Note: Safety:

  • Consider conducting an HLA-B*1502 allele test before giving phenytoin in patients who are more likely to experience severe cutaneous adverse effects. (ie, those of Asian ancestry, including South Asian Indians).
  • Patients should still be watched for cutaneous reactions and other signs of hypersensitivity because a negative HLA-B*1502 genetic test does not completely rule out the possibility of severe hypersensitivity.
  • Therapeutic drug monitoring recommended:
    • Phenytoin has a narrow therapeutic index, displays nonlinear kinetics (ie, small dose increases may result in large increases in serum concentrations), is highly protein-bound, and has clinically significant drug interactions that affect phenytoin serum concentrations.
    • Trough levels are typically measured more than 2 hours after completion of an IV loading dose, 24 hours after an oral loading dose, and 1 to 3 weeks after dose adjustments with goal concentration of 10 to 20 mg/L.
    • In the presence of renal failure, low serum albumin, or other high protein-bound drugs (eg, valproate), free levels should be followed with a goal of 1 to 2 mg/L.
    • IV administration:
      • The maximum rate of administrations is 50 mg per minute under continuous cardiac, blood pressure, and respiratory monitoring; fosphenytoin is typically recommended when fast IV delivery is required due to the danger of cardiovascular side effects and local tissue harm.
      • Refer to the institutional procedure for details on required monitoring.
    • Dosage forms:
      • The phenytoin sodium salt is used to express dosages for injection and extended-release capsules.
      • Doses for chewable tablets and oral solution are expressed as phenytoin base (see Dosage form conversions for equivalence).
      • Individual oral doses shouldn't exceed 400 mg to ensure adequate absorption.

Phenytoin (Dilantin) dose to treat Seizures:

  • Dose as an alternative agent in the treatment of Craniotomy, seizure prophylaxis:
    • Loading dose: IV: 15 mg per kg at a rate of ≤50 mg per minute prior to incision;
    • maximum dose: 2 g.
    • Postoperative prophylaxis: IV, Oral:
      • 5 to 6 mg per kg per day in 2 to 3 divided doses;
      • usual daily dose: 300 to 400 mg; adjust dose based on response and serum concentrations.

Note: Duration individualized based on underlying intracranial pathology and other clinical considerations.

Phenytoin (Dilantin) Dose in the Focal (partial) onset seizures and generalized onset seizures:

Note:

  • FDA-approved for complicated partial and generalised tonic-clonic seizures; may also be used off-label for other seizure types.
  • Patients who need to reach a therapeutic blood level quickly should consider using a loading dosage; otherwise, the full impact will normally be felt after 1 to 3 weeks (ie, when steady-state serum concentrations are reached).
  • Fixed (non-weight-based) dosing (manufacturer's labeling):
    • Loading dose (optional) (phenytoin naive): Oral (capsule [extended release]):
      • 1 g split into 3 doses (for example, 300 mg, 300 mg, and 400 mg) and given at 2-hour intervals; maintenance dose should be started 24 hours following the first loading dose.
    • Maintenance dose: Oral (capsule [extended release]):
      • Initial: 100 mg three to four times daily; change dosage in accordance with reaction and serum concentrations.
  • Weight-based dosing (off-label):

Note: Depending on body weight, it is possible to predict the initial maintenance dose requirements and customise the loading dose.

  • Loading dose (optional) (phenytoin naive): IV, Oral:
    • The usual total loading dose is 1 to 1.5 g, and the maintenance dose should be started 8 to 12 hours following the loading dose.
  • Maintenance dose: IV, Oral:
    • Initial:  Given in two to four divided doses, 4 to 7 mg per kilogramme per day (often 300 to 400 mg/day); dose is adjusted in accordance with response and serum concentrations
    • Some specialists advise beginning maintenance medication with 5 mg per kilogramme administered twice daily.
    • There is no recognised maximum dose, thus care should be taken when prescribing maintenance doses greater than 600 mg daily.

Phenytoin (Dilantin) Dose as an alternative agent in the prevention of early posttraumatic seizure Traumatic brain injury (off-label):

Note: For usage in a small number of patients with a high risk of developing early seizures and possible side effects. Consult the institutional protocols if the dosing is center-specific.

  • Loading dose:
    • IV: 17 to 20 mg per kg at a rate of ≤50 mg per minute;
    • maximum dose: 2 g.
  • Maintenance dose: IV, Oral:
    • 100 mg every eight hours or 5 mg per kilogramme per day (rounded up to the nearest hundredth of a milligramme).
    • Note: 8 to 12 hours following the loading dose, start the maintenance dose. Prophylaxis is often used for a brief period of time, such as seven days or less

Phenytoin (Dilantin) Dose as an alternative agent in the treatment of Status epilepticus (convulsive and non-convulsive):

Note: If fosphenytoin is available, it should be used instead of phenytoin because it is more quickly delivered and better tolerated.

  • Under continuous cardiac and blood pressure monitoring, provide 20 mg per kg at a rate of 25 to 50 mg per minute along with a parenteral benzodiazepine (such as lorazepam); decrease infusion rate if substantial adverse effects happen.
  • Administer 20 minutes after initial therapy for convulsive status epilepticus or immediately after initial therapy for nonconvulsive status epilepticus.
  • Loading dose (phenytoin naive):
    • 10 minutes following the loading dose, if necessary, you could provide an extra dose of 5 to 10 mg per kg.;
    • maximum total loading dose: 30 mg per kg.
    • 8 to 12 hours after the loading dosage, start the maintenance dose (see Focal (partial) onset seizures and generalised onset seizures).
  • Discontinuation of therapy:
    • To reduce the risk of increasing seizure frequency in chronic therapy, phenytoin should be tapered off gradually over 2 to 6 months or progressively switched to another antiepileptic drug, unless safety considerations call for a more faster withdrawal.
  • Dosage form conversions:
    • Between IV and oral capsule formulations:
      • Use the same overall daily dose when converting.
      • The bioavailability of oral capsules is around 10% lower than that of injectable formulation; dosage modifications and more frequent serum monitoring may be necessary.
    • Conversion:
      • Phenytoin sodium 100 mg is comparable to 92 mg of phenytoin base.
    • Between phenytoin base (oral suspension, chewable tablets) and phenytoin sodium (capsule):
      • When changing formulations, dosage changes and closer serum monitoring may be required.

Phenytoin (Dilantin) Dose in  Childrens

Note: Clinical response and serum concentrations should be taken into account when determining the appropriate dosage; changes to maintenance therapy dosage are normally not made more frequently than once every seven days.

  • In comparison to phenytoin sodium, phenytoin base (such as chewable tablets and oral solution) contains around 8% more of the active ingredient (92 mg base is the same as 100 mg sodium).
  • When changing dose forms, dosage modifications and more frequent serum monitoring may be required.

Phenytoin (Dilantin) Dose in the treatment of Status epilepticus:

  • Infants, Children, and Adolescents:
    • Manufacturer labeling:
      • Loading dose: IV: 15 to 20 mg per kg in a single or divided dose;
      • afterwards, typically 12 hours following the dose, start maintenance therapy
    • Alternate dosing: AAP, NCS recommendations:
      • Loading dose: IV: 20 mg per kg in a single or divided doses;
      • maximum dose: 1000 mg, followed by the start of maintenance therapy, usually 12 hours later.
      • Some experts advise switching to a different medication once a total loading dose of 20 mg/kg has been administered; nevertheless, an extra load of 5 to 10 mg per kg has been utilised if status epilepticus is not controlled.

Phenytoin (Dilantin) Dose in the Seizures:

  • Infants, Children, and Adolescents:
    • Loading dose (if not previously on phenytoin):
      • IV, Oral: To reduce GI side effects and achieve complete oral absorption, an oral loading dose should be divided into three doses and given every 2-4 hours if the patient is already taking phenytoin. This dosage should be between 15 and 20 mg per kg.;
    • Maintenance therapy: IV, Oral:
      • Initial: 5 mg per kg per day in divided doses (based upon dosage form, see below);
      • usual range: 4 to 8 mg per kg per day;
      • maximum daily dose: 300 mg per day.
      •  
      • Dosing should be based upon ideal body weight (IBW).
    • Usual dosing range:
      • 6 months to 3 years:
        • 8 to 10 mg per kg per day
      • 4 to 6 years:
        • 5 to 9 mg per kg per day
      • 7 to 9 years:
        • 7 to 8 mg per kg per day
      • 10 to 16 years:
        • 6 to 7 mg per kg per day
    • Dosing interval (product specific):
      • Immediate-release preparations (including injection, suspension, and chewable tablets):
        • Divide daily dose into 2 to 3 doses every day.
      • Extended-release preparations:
        • A double-blind, placebo-controlled trial of 102 paediatric patients (n=46 treatment group; median age: 6.4 years) showed no significant difference in seizure

Phenytoin (Dilantin) Dose in the Seizure prophylaxis, traumatic brain injury:

  • Infants, Children, and Adolescents:
    • IV: Initial: 18 mg/kg over 20 minutes;
    • frequency between groups, but the trial was terminated early due to a very low seizure rate in the treatment group. In the majority of paediatric patients, usually dosed every 12 hours; however, in adolescent patients with sufficiently long half-life, may be dosed every 24 hours.
    • In a retrospective study, preventive phenytoin treatment was shown to minimise the frequency of seizures.

Note: According to current recommendations, preventive phenytoin may be used in paediatric patients with severe traumatic brain injuries to minimise the incidence of early post-traumatic seizures, but it does not lower the risk of long-term seizures or enhance neurologic outcomes.

 

Phenytoin (Dilantin) Pregnancy Risk Category: D

  • The placenta is crossed by Phenytoin
  • Following birth, there have been a few sporadic incidences of malignancies, such as neuroblastoma, and newborn coagulation abnormalities (which could be fatal). They also include mental retardation, heart problems, hypoplastic nails and digits, aberrant growth patterns, including microcephaly.
  • To reduce the chance of developing cleft palate or poor cognitive outcomes, it is best to avoid maternal phenytoin use.
  • In utero exposure to phenytoin may increase the risk of congenital malformations or other adverse outcomes.
  • Orofacial clefts and dysmorphic facial features are some of the reported malformations.
  • It is advised to provide mothers and newborns vitamin K.
  • Monotherapy is preferred as it reduces the chance of congenital malformations.
  • Folic acid is best used during pregnancy by mothers to lower the chance of major congenital malformations.
  • A decreased concentration of vitamin K-dependent factors may cause potentially life-threatening bleeding disorders in newborns after phenytoin treatment in utero.
  • During pregnancy, the mother's total plasma phenytoin concentrations fall.
  • Plasma clearance rises as unbound plasma (free) concentrations fall.
  • Women who become pregnant due to pregnancy-induced physiological changes may need dose adjustments of Phenytoin to maintain their clinical response.
  • Monitoring during pregnancy is recommended.
  • When seizure management is at its best, women with epilepsy who intend to become pregnant should assess baseline serum concentrations at least once or twice before conception.
  • The monitoring might continue at a rate of one per month both during pregnancy and after delivery. Some patients might need to be monitored more frequently.
  • Hormonal contraceptives can become less effective when taken with phenytoin. Consult our Drug Interactions Database for additional details.
  • It is recommended to monitor unbound plasma concentrations.
  • For females with reproductive potential and not planning to have a baby, effective contraception is recommended.
  • Additional information can be found at http://aedpregnancyregistry.org.

Use of phenytoin while breastfeeding

  • Breast milk contains phenytoin.
  • According to the manufacturer breastfeeding during therapy is a decision that should be made after considering the risks to infants and the benefits to mothers.

Phenytoin (Dilantin) Dose in Kidney Disease:

  • Manufacturer's labels don't include any dosage adjustments.
  • Less than 5 percent of the drug is considered unchanged.
  • In renal failure, it may be difficult for you to read the serum concentration.
  • It is recommended to monitor concentrations free of bound or adjust for interpretation.

Hemodialysis

  • High-efficiency dialyzers may require dose supplementation; monitor serum levels.
  • In renal failure, it may be difficult for you to read the serum concentration.

Phenytoin (Dilantin) Dose in Liver disease:

  • The manufacturer's labeling doesn't provide any dosage adjustments; undergoes hepatic metabolism and clearance may be decreased.
  • Monitor free phenytoin levels closely.
  • Dosage adjustments may be necessary.   

Side effects of Phenytoin (Dilantin):

  • Cardiovascular:
    • Cardiac Conduction Disturbance (Depression)
    • Hypotension
    • Circulatory Shock
    • Ventricular Fibrillation
    • Cardiac Arrhythmia
  • Central Nervous System:
    • Suicidal Tendencies
    • Cerebral Dysfunction (Elevated Serum Levels And/Or Long-Term Use)
    • Peripheral Neuropathy (Associated With Chronic Treatment)
    • Dizziness
    • Slurred Speech
    • Headache
    • Nervousness
    • Ataxia
    • Drowsiness
    • Insomnia
    • Suicidal Ideation
    • Paresthesia
    • Twitching
    • Confusion
    • Vertigo
    • Cerebral Atrophy (Elevated Serum Levels And/Or Long-Term Use)
  • Dermatologic:
    • Bullous Dermatitis
    • Scarlatiniform Rash
    • Skin Rash
    • Exfoliative Dermatitis
    • Skin Or Other Tissue Necrosis
    • Morbilliform Rash
  • Endocrine & Metabolic:
    • Vitamin D Deficiency (Associated With Chronic Treatment)
    • Increased Gamma-Glutamyl Transferase
    • Decreased T4
  • Gastrointestinal:
    • Vomiting
  • Genitourinary:
    • Peyronie's Disease
  • Hematologic & Oncologic:
    • Pseudolymphoma
    • Megaloblastic Anemia
    • Purpuric Dermatitis
    • Macrocytosis
  • Hepatic:
    • Hepatic Injury
    • Increased Serum Alkaline Phosphatase
    • Hepatitis
    • Toxic Hepatitis
    • Acute Hepatic Failure
  • Local:
    • Discoloration
    • Local Inflammation
    • Localized Tenderness
    • Injection Site Reaction ("Purple Glove Syndrome;" Edema
    • Local Tissue Necrosis
    • And Pain Distal To Injection Site)
  • Neuromuscular & Skeletal:
    • Osteomalacia
  • Ophthalmic:
    • Nystagmus
  • Miscellaneous:
    • Tissue Sloughing
    • Fever

Contraindications to Phenytoin (Dilantin):

  • History of acute hepatotoxicity due to phenytoin in the past
  • Intolerance to phenytoin, other hydantoins, or any ingredient in this formulation
  • Concurrent use of delavirdine

Injection: Other contraindications

  • Sinoatrial block
  • Adams-Stokes syndrome
  • Second- and third-degree heart blocks,
  • Sinus bradycardia

Canadian labeling (oral formulation). Additional contraindications not in US labeling

  • Second- and third-degree block of the heart;
  • Sinusitis is a serious condition.
  • Longer QT interval
  • Adams-Stokes syndrome or other disorders of the heart rhythm
  • Sinoatrial block
  • Sinus bradycardia

Warnings and precautions

  • Blood dyscrasias
    • There have been reports of a variety of hematologic reactions, including granulocytopenia and thrombocytopenia as well as agranulocytosis and leukopenia. These effects can be fatal.
    • Patients with a history of adverse hematologic reactions may be at higher risk.
    • It is important to detect hematologic changes early. Patients should be advised of symptoms such as fever, sore throats, mouth ulcers, infections and petechial hemorhage.
  • Bone effects
    • The stimulation of liver enzymes may result in lower vitamin D levels. Hypophosphatemia, hypocalcemia, and vitamin D deficiency could result from this.Inspect as necessary, and think about taking calcium and vitamin D supplements.
      Phenytoin use for an extended period of time can cause osteoporosis,
    • osteomalacia, decreased bone mineral density, and even bone fractures.
  • Cardiovascular events: [US Boxed Warn]
    • Phenytoin should be taken slowly.
    • Adult patients should not receive more than 50 mg/minute intravenous.
    • Pediatric patients should be administered intravenously at a rate of 1 to 3 mg/kg/minute, or 50 mg/minute, whichever is faster.
    • It is important to monitor your heart during and after intravenous phenytoin administration.
    • Rapid administration may lead to hypotension or severe cardiac arrhythmias, such as heart block, ventricular fibrillation, and ventricular tachycardia.
    • Injecting phenytoin intravenously should be done slowly for non-emergency purposes. If this is not possible, oral phenytoin should always be used.
    • Patients with underlying heart disease have reported cardiac arrest and Bradycardia. These cases were usually at the recommended dosages and levels.
  • Dermatologic reactions
    • There have been reports of severe cutaneous adverse effects, some fatal, including Stevens-Johnson Syndrome, toxic epidermal necrolysis, and acute generalised exanthematous putulosis (AGEP). Although they can happen later, symptoms often start to show around 28 days after therapy.
    • Information points to a genetic predisposition to severe cutaneous responses in patients of Asian ancestry (see "Special Populations" below).
    • If you have a rash, or any other symptoms that indicate a severe cutaneous reaction to phenytoin, stop taking it.
  • Extravasation
    • Vesicant (intravenous injection); make sure the catheter or needle is in the correct position before and during infusion.
    • This syndrome could be related to drug extravasation.
    • Although symptoms may disappear on their own, there may be skin necrosis or limb ischemia.
    • Interventions including fasciotomies, skin transplants, and (rarely) amputation may be required in these circumstances.
    • Avoid excessive use.
    • The IV formulation can result in skin necrosis, soft tissue irritation, and inflammation when it is injected. Avoid using tiny veins for IV administration.
    • After peripheral IV administration of Phenytoin, the "purple glove syndrome" may develop. This is a discoloration with edema or pain in the distal limb.
    • This will lessen the likelihood of this syndrome emerging. To do this, slowly inject phenytoin using a large gauge needle into a large vein. NS flushes with the same needle come next.
  • Hepatotoxicity
    • There have been a few reports of acute liver toxicity as well as sporadic instances of acute hepatic dysfunction.
    • Jaundice, an increased blood transaminase, leukocytosis, and hepatomegaly are other symptoms.
    • Acute phenytoin livertoxicity can lead to rapid recovery or even fatal results.
    • Stop taking phenytoin immediately in patients with acute hepatotoxicity. Do not re-administer.
  • Hypersensitivity
    • Reports of hypersensitivity and angioedema have been made
    • If you experience hypersensitivity reactions, stop immediately.
    • Patients who are hypersensitive to certain drugs, such as succinimides, barbiturates, and carboxamides (eg carbamazepine) should consider alternative treatment.
  • Lymphadenopathy
    • It can occur locally or globally, including benign lymphoma pseudolymphoma and lymphoma.
    • It is not clear if there is a cause-and-effect relationship.
  • Multiorgan hypersensitivity reactions
    • Some antiepileptic drugs, including phenytoin, have been linked to potentially fatal and sometimes deadly multiorgan hypersensitivity reactions.
    • Monitor for possible manifestations of lymphatic, hepatic and renal organ systems.
    • It may be necessary to gradually discontinue and convert to alternative therapy.
  • Suicidal thoughts:
    • Regardless of the studies' indication, a pooled review of antiepileptic trials revealed an increase in suicide ideation and behaviour.
    • The incidence rate was 0.43 percent for patients who were treated with the drug and 0.24 percent for patients who received placebo.
    • This risk was first observed one week after the medication was administered. It continued throughout the trial duration (most trials took less than 24 weeks).
    • Watch out for any changes in behavior or thoughts that could indicate depression or suicidal thoughts.
    • Notify your healthcare provider immediately if you notice these symptoms.
  • Cardiovascular disease
    • Patients with underlying heart disease should be cautious.
    • Patients with sinus bradycardia, sinoatrial blockage, second- and third-degree block are not advised to receive IV treatment.
  • Diabetes:
    • Patients with diabetes mellitus should be cautious when using phenytoin.
    • In persons with diabetes, phenytoin can impede insulin release and raise serum sugar levels.
  • Hepatic impairment
    • Patients with hepatic impairment should be cautious; monitor serum concentrations at a free (unbound).
  • Hypoalbuminemia
    • Patients with low serum albumin levels should be cautious. This will increase the free fraction and, consequently, the pharmacologic response.
    • Monitor with serum concentrations that are unbound.
  • Hypothyroidism
    • Hypothyroidism patients should be treated with caution
    • With chronic administration, phenytoin can alter the thyroid hormone serum levels.
  • Porphyria
    • Exacerbation may occur in cases of porphyria.
  • Renal impairment
    • Patients with impaired renal function should be cautious; monitor serum concentrations at a free (unbound).

Phenytoin: Drug Interaction

Risk Factor C (Monitor therapy)

Acemetacin

May raise the serum level of phenytoin-fosphenytoin.

Acetaminophen

Acetaminophen serum levels may be reduced by fosphenytoin-phenytoin. In particular, serum acetaminophen levels may drop (resulting in lower efficacy), but the production of the hazardous N-acetyl-p-benzoquinone imine (NAPQI) metabolite may rise (leading to increased hepatotoxicity).

Albendazole

The active metabolite(s) of albendazole's serum concentrations may be lowered by phenytoin.

Alcohol (Ethyl)

May intensify phenytoin's CNS depressive effects. Phenytoin serum levels may rise by drinking alcohol (Ethyl). This might be especially true for people who drink alcohol heavily and acutely. Alcohol (Ethyl) may lower phenytoin levels in the blood. This can be especially true for people who consume alcohol heavily and continuously.

Amiodarone

Amiodarone's serum levels may drop if you take phenytoin. Amiodarone may raise the level of phenytoin in the blood.

Amphetamines

May lower the level of phenytoin in the serum.

Bazedoxifene

Bazedoxifene's serum levels may drop when used with phenytoin. This could result in diminished effectiveness or, if bazedoxifene and oestrogen therapy are combined, a higher risk of endometrial hyperplasia.

Benperidol

The serum concentration of benperidol may fall in response to CYP3A4 Inducers (Strong).

Benzhydrocodone

CYP3A4 Inducers (Strong) may lower the level of benzhydrocodone in the blood. More specifically, hydrocodone serum concentrations might be decreased.

Benzodiazepines

Phenytoin serum levels can rise. There may not be as much risk from short-term use of benzodiazepines as there is from long-term treatment. ALPRAZolam is an exception.

Bleomycin

May lower the level of phenytoin in the serum.

Brentuximab Vedotin

The serum concentration of Brentuximab Vedotin may decrease when CYP3A4 Inducers (Strong) are present. Particularly, levels of the active monomethyl auristatin E (MMAE) constituent could drop.

Brentuximab Vedotin

The serum concentration of Brentuximab Vedotin may drop in response to P-glycoprotein/ABCB1 Inducers. Particularly, levels of the active monomethyl auristatin E (MMAE) constituent could drop.

Brivaracetam

Brivaracetam's serum levels may be reduced by phenytoin. Brivaracetam may raise the level of phenytoin in the blood.

Buprenorphine

The serum concentration of buprenorphine may decrease after taking CYP3A4 Inducers (Strong).

Busulfan

The serum concentration of Busulfan may be lowered by phenytoin.

Calcifediol

The serum concentration of calcifediol may drop in response to CYP3A4 Inducers (Strong).

Cannabidiol

The serum concentration of cannabidiol may drop in response to CYP3A4 Inducers (Strong).

Cannabis

Cannabis serum concentrations may be reduced by strong CYP3A4 inducers. Serum concentrations of tetrahydrocannabinol and cannabidiol may fall, to be more precise.

Carbonic Anhydrase Inhibitors

May intensify the hazardous or harmful effects of phenytoin-fosphenytoin. In particular, there may be a higher risk for rickets or osteomalacia. Brinzolamide and dorzolamide are exceptions.

CeFAZolin

Phenytoin's affinity for proteins might be reduced.

Celiprolol

The serum concentration of celiprolol may drop in response to P-glycoprotein/ABCB1 Inducers.

Chloramphenicol (Systemic)

Chloramphenicol serum levels may be reduced by phenytoin (Systemic).

Chlorpheniramine

Chloramphenicol serum levels may rise in response to phenytoin (Systemic). The serum levels of phenytoin may rise when using chloramphenicol (Systemic).May raise the serum level of phenytoin-fosphenytoin.

ChlorproPAMIDE

ChlorproPAMIDE's serum levels may be reduced by CYP3A4 Inducers (Strong).
may reduce Phenytoin's therapeutic impact. 

Ciprofloxacin (Systemic)

The serum levels of phenytoin may be reduced by the antibiotic systemic ciprofloxacin.

Cladribine:

P-glycoprotein/ABCB1 Inducers may lower the level of Cladribine in the serum.

Clindamycin (Systemic)

It's possible that CYP3A4 Inducers (Strong) will lower the level of Clindamycin in your blood (Systemic). For details on that combination, consult the particular clindamycin (systemic) - rifampin medication interaction monograph.

ClonazePAM

ClonazePAM serum levels may be reduced by phenytoin. Phenytoin concentrations may also change in response to clonazepam.

Codeine

The serum concentrations of the active metabolite(s) of codeine may be lowered by CYP3A4 Inducers (Strong).

Corticosteroids (Systemic)

Strong CYP3A4 Inducers may lower the level of corticosteroids in the blood (Systemic). Hydrocortisone (Systemic), PrednisoLONE (Systemic), and PredniSONE are exceptions.

Cosyntropin

May intensify phenytoin's hepatotoxic effects.

CYP2C19 Inducers (Moderate)

May decrease the serum concentration of CYP2C19 Substrates (High risk with Inducers).

CYP2C19 Inhibitors (Moderate)

May decrease the metabolism of CYP2C19 Substrates (High risk with Inhibitors).

CYP2C9 Inhibitors (Moderate)

May decrease the metabolism of CYP2C9 Substrates (High risk with Inhibitors).

Dapsone (Topical)

May intensify the harmful/toxic effects of agents associated with methemoglobinemia.

Darunavir

May lower the level of phenytoin in the serum.

Dexketoprofen

May intensify the hazardous or harmful effects of phenytoin-fosphenytoin.

Dexmethylphenidate

Phenytoin serum levels can rise.

Diazoxide

May lower the level of phenytoin in the serum. More so than free phenytoin concentrations, total phenytoin concentrations may be impacted.

Diethylstilbestrol

Diethylstilbestrol levels in the serum may be reduced by CYP3A4 Inducers (Strong).

Disopyramide

Disopyramide's serum levels may drop when phenytoin is taken.

Doxercalciferol

The active metabolite(s) of doxercalciferol may be present in higher serum concentrations when CYP3A4 Inducers (Strong) are present.

Doxofylline

The serum concentration of doxofylline may be reduced by the drug fosphenytoin-phenytoin.

Dronabinol

The serum concentration ofdronabinol may drop in response to CYP3A4 Inducers (Strong).

Edoxaban

The serum concentration of Edoxaban may be lowered by P-glycoprotein/ABCB1 Inducers.

Elagolix

Elagolix's serum levels may be reduced by CYP3A4 Inducers (Strong).

Eslicarbazepine

Eslicarbazepine's serum levels may drop when phenytoin is taken. Eslicarbazepine may raise the level of phenytoin in the blood.

Estriol (Systemic)

Strong CYP3A4 Inducers may lower serum estriol concentrations (Systemic).

Estriol (Topical)

Strong CYP3A4 Inducers may lower serum estriol concentrations (Topical).

Ethosuximide

May intensify phenytoin's CNS depressive effects. Ethosuximide's serum levels may drop if you take phenytoin. Ethosuximide may raise the level of phenytoin in the blood.

Etizolam

It's possible that CYP3A4 Inducers (Strong) will lower the level of etizolam in your blood.

Evogliptin

Evogliptin's serum levels may be reduced by CYP3A4 Inducers (Strong).

FentaNYL

The blood concentration of FentaNYL may drop when CYP3A4 Inducers (Strong) are taken.

Flunarizine

 Flunarizine's serum levels may be lowered by phenytoin.

Fluorouracil (Topical)

Phenytoin serum levels can rise.

FLUoxetine

Phenytoin serum levels can rise.

FluvoxaMINE

Phenytoin serum levels can rise.

Folic Acid

Phenytoin serum levels can rise.

Fosamprenavir

May lower the level of phenytoin in the serum. This effect is probably caused by the active metabolite of amprenavir. The serum levels of fosamprenavir may rise in response to phenytoin. Particularly, phenytoin may raise the level of amprenavir's active metabolite.

Gestrinone

The serum concentration of Gestrinone may drop when taking Fosphenytoin-Phenytoin.

Halothane

Phenytoin serum levels can rise.

HYDROcodone

CYP3A4 Inducers (Strong) may lower the level of HYDROcodone in the blood.

Hydrocortisone (Systemic)

CYP3A4 Inducers (Strong) may lower the level of hydrocortisone in the blood (Systemic).

Ifosfamide

The active metabolite(s) of ifosfamide may be present in lower serum quantities when CYP3A4 Inducers (Strong) are present. The blood concentrations of the active metabolite(s) of ifosfamide may rise in response to CYP3A4 Inducers (Strong).

Lacosamide

Antiepileptic drugs (Sodium Channel Blockers) may make lacosamide more harmful or poisonous. Particularly, there may be an increased risk for bradycardia, ventricular tachyarrhythmias, or a longer PR interval.

Letermovir

May lower the serum level of phenytoin-fosphenytoin.

Leucovorin Calcium-Levoleucovorin

May lower the level of phenytoin in the serum.

LevETIRAceta

LevETIRAcetam's serum concentration may be reduced by fosphenytoin-phenytoin.

Levodopa-Containing Products

Levodopa-Containing Products' therapeutic effects may be lessened by the use of fosphenytoin-phenytoin.

Levomefolate

May lower the level of phenytoin in the serum.

Levomethadone

Levomethadone's serum levels may drop when phenytoin is taken.

Lithium

Phenytoin may intensify Lithium's harmful or hazardous effects.

Local Anesthetics

Methemoglobinemia Local anaesthetics can have a negative or toxic effect that is amplified by associated agents. In particular, there may be an elevated risk for methemoglobinemia.

Loop Diuretics

The diuretic action of loop diuretics may be lessened by phenytoin.

Lumacaftor

May decrease the serum concentration of CYP2C9 Substrates (High Risk with Inhibitors or Inducers). Lumacaftor may increase the serum concentration of CYP2C9 Substrates (High Risk with Inhibitors or Inducers).

Lumacaftor

May decrease the serum concentration of CYP2C19 Substrates (High risk with Inducers).

Mebendazole

Phenytoin may decrease the serum concentration of Mebendazole.

Meperidine

Meperidine's serum levels may drop if you take phenytoin.Methadone serum levels may be reduced by phenytoin.

Methadone

Methadone serum levels may be reduced by phenytoin.

Methotrexate

May lower the serum level of phenytoin-fosphenytoin. FosphenytoinPhenytoin

Methylfolate

May make methotrexate more concentrated in the blood. In particular,

Methylphenidate

Mmethotrexate may be displaced from serum proteins by fosphenytoin phenytoin, raising the concentration of free, unbound medication.

MetroNIDAZOLE (Systemic)

May lower the level of phenytoin in the serum.

Mexiletine

May lower the level of phenytoin in the serum.

Mianserin

Phenytoin may lower MetroNIDAZOLE's serum levels (Systemic). Phenytoin serum levels may rise in response to MetroNIDAZOLE (Systemic).Mexiletine's serum levels may drop when taken with phenytoin.

Miconazole (Oral)

M]ay lower the level of phenytoin in the serum.

Multivitamins/Minerals (with ADEK, Folate, Iron)

May lower the serum level of phenytoin-fosphenytoin.

Nelfinavir

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

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 NeuromuscularBlocking Agents (Nondepolarizing). Fosphenytoin-Phenytoin may decrease the serum concentration of Neuromuscular-Blocking Agents (Nondepolarizing).

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.

Omeprazole

Phenytoin may decrease the serum concentration of Omeprazole. Omeprazole may increase the serum concentration of Phenytoin.

Orlistat

May decrease the serum concentration of Anticonvulsants.

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.). Exceptions: Betrixaban; Edoxaban.

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.

Phenylbutazone

May increase the serum concentration of Fosphenytoin-Phenytoin.

Platinum Derivatives

May decrease the serum concentration of Fosphenytoin-Phenytoin.

Polatuzumab Vedotin

CYP3A4 Inducers (Strong) may decrease the serum concentration of Polatuzumab Vedotin. Exposure to unconjugated MMAE, the cytotoxic small molecule component of polatuzumab vedotin, may be decreased.

PrednisoLONE (Systemic)

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

PredniSONE

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

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.

Primidone

Phenytoin may increase the metabolism of Primidone. The ratio of primidone:phenobarbital is thus changed.

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).

Propafenone

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

Pyridoxine

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

QuiNIDine

Phenytoin may decrease the serum concentration of QuiNIDine.

Ramelteon

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

Reboxetine

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

Rifapentine

May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers).

Rufinamide

May increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Rufinamide.

Ruxolitinib

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

SAXagliptin

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

Sertraline

May increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Sertraline.

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.

SUFentanil

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

SulfADIAZINE

May increase the serum concentration of Fosphenytoin-Phenytoin.

Sulfinpyrazone

May increase the serum concentration of Fosphenytoin-Phenytoin.

Sulthiame

May increase the serum concentration of Fosphenytoin-Phenytoin.

Tacrolimus (Systemic)

Phenytoin may decrease the serum concentration of Tacrolimus (Systemic). Tacrolimus (Systemic) may increase the serum concentration of Phenytoin.

Tetrahydrocannabinol

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

Tetrahydrocannabinol and Cannabidiol

CYP3A4 Inducers (Strong) may decrease the serum concentration of Tetrahydrocannabinol and Cannabidiol.

Thiothixene

Fosphenytoin-Phenytoin may decrease the serum concentration of Thiothixene.

Thyroid Products

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

Ticlopidine

May increase the serum concentration of Phenytoin.

TOLBUTamide

May decrease the protein binding of Fosphenytoin-Phenytoin. Specifically concentrations of free phenytoin may be increased.

Topiramate

May increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Topiramate.

TraMADol

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

TraZODone

Phenytoin may decrease the serum concentration of TraZODone. TraZODone may increase the serum concentration of Phenytoin.

Tropisetron

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

Udenafil

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

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.

Vigabatrin

May decrease the serum concentration of Phenytoin.

VinCRIStine

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

Vindesine

May decrease the serum concentration of Phenytoin.

Zolpidem

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

Zonisamide

Phenytoin may decrease the serum concentration of Zonisamide.

Zuclopenthixol

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

Risk Factor D (Consider therapy modification)

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.

Acalabrutinib

CYP3A4 Inducers (Strong) may decrease the serum concentration of Acalabrutinib. Management: Avoid co-administration of strong CYP3A inducers in patients taking acalabrutinib. If strong CYP3A inducers cannot be avoided, increase the dose of acalabrutinib to 200 mg twice daily.

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.

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.

ARIPiprazole

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

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 higher doses of aripiprazole lauroxil.

Bictegravir

Fosphenytoin-Phenytoin may decrease the serum concentration of Bictegravir. Management: When possible consider using an alternative anticonvulsant with concurrent bictegravir, emtricitabine, and tenofovir alafenamide. If the combination must be used, monitor closely for evidence of reduced antiviral effectiveness.

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.

BusPIRone

CYP3A4 Inducers (Strong) may decrease the serum concentration of BusPIRone. Management: Consider alternatives to this combination. If coadministration of these agents is deemed necessary, monitor patients for reduced buspirone effects and increase buspirone doses as needed.

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.

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.

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.

Capecitabine

May increase the serum concentration of Phenytoin.

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.

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/m , up to a maximum of 70 mg, daily in pediatric patients) when coadministered with known inducers of drug clearance.

Cimetidine

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

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 14hydroxyclarithromycin may alter the clinical activity of clarithromycin and may impair clarithromycin efficacy.

Colesevelam

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

CycloSPORINE (Systemic)

Phenytoin may increase the metabolism of CycloSPORINE (Systemic).

CYP2C19 Inducers (Strong)

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

CYP3A4 Substrates (High risk with Inducers)

CYP3A4 Inducers (Strong) may increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Exceptions: Benzhydrocodone; Buprenorphine; CarBAMazepine; Etizolam; HYDROcodone; TraMADol; Zolpidem.

Dabrafenib

May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP2C9 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects).

Dabrafenib

May decrease the serum concentration of CYP2C19 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP2C19 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects).

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.

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.

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.

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.

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.

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.

Doxycycline

Phenytoin may decrease the serum concentration of Doxycycline.

Efavirenz

Phenytoin may decrease the serum concentration of Efavirenz. Efavirenz may increase the serum concentration of Phenytoin.

Eravacycline

CYP3A4 Inducers (Strong) may decrease the serum concentration of Eravacycline. Management: Increase the eravacycline dose to 1.5 mg/kg every 12 hours when combined with strong CYP3A4 inducers.

Estrogen Derivatives (Contraceptive)

Phenytoin may diminish the therapeutic effect of Estrogen Derivatives (Contraceptive). Contraceptive failure is possible. Management: Use of an alternative, nonhormonal means of contraception is recommended.

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 combined, monitor patients closely for diminished etoposide response and need for etoposide dose increases.

Etoposide Phosphate

CYP3A4 Inducers (Strong) may decrease the serum concentration of Etoposide Phosphate. Management: When possible, seek alternatives to strong CYP3A4inducing medications in patients receiving etoposide phosphate. If these combinations cannot be avoided, monitor patients closely for diminished etoposide phosphate response.

Everolimus

CYP3A4 Inducers (Strong) may decrease the serum concentration of Everolimus. Management: Avoid concurrent use of strong CYP3A4 inducers if possible. If coadministration cannot be avoided, double the daily dose of everolimus using increments of 5 mg or less. Monitor everolimus serum concentrations closely when indicated.

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.

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.

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.

Floxuridine

May increase the serum concentration of Phenytoin.

Fluconazole

May increase the serum concentration of Phenytoin.

Fluorouracil (Systemic)

May increase the serum concentration of Phenytoin.

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.

GuanFACINE

CYP3A4 Inducers (Strong) may decrease the serum concentration of GuanFACINE. Management: Increase the guanfacine dose by up to double when initiating guanfacine in a patient taking a strong CYP3A4 inducer. Increase guanfacine dose gradually over 1 to 2 weeks if initiating strong CYP3A4 inducer therapy in a patient already taking guanfacine.

HMG-CoA Reductase Inhibitors (Statins)

Phenytoin may decrease the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Exceptions: Pitavastatin; Rosuvastatin.

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.

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.

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/m to 60 mg/m (given as a 4-hour infusion), as tolerated, should be considered.

LamoTRIgine

Phenytoin may decrease the serum concentration of LamoTRIgine.

Larotrectinib

CYP3A4 Inducers (Strong) may decrease the serum concentration of Larotrectinib. Management: Avoid use of strong CYP3A4 inducers with larotrectinib. If this combination cannot be avoided, double the larotrectinib dose. Reduced to previous dose after stopping the inducer after a period of 3 to 5 times the inducer half-life.

Lefamulin

CYP3A4 Inducers (Strong) may decrease the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin with strong CYP3A4 inducers unless the benefits outweigh the risks.

Lefamulin

P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin with P-glycoprotein/ABCB1 inducers unless the benefits outweigh the risks.

Lefamulin (Intravenous)

CYP3A4 Inducers (Strong) may decrease the serum concentration of Lefamulin (Intravenous). Management: Avoid concomitant use of lefamulin intravenous infusion with strong CYP3A4 inducers unless the benefits outweigh the risks.

Lefamulin (Intravenous)

P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Lefamulin (Intravenous). Management: Avoid concomitant use of lefamulin (intravenous) with P-glycoprotein/ABCB1 inducers unless the benefits outweigh the risks.

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.

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.

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.

Manidipine

CYP3A4 Inducers (Strong) may decrease the serum concentration of Manidipine. Management: Consider avoiding concomitant use of manidipine and strong CYP3A4 inducers. If combined, monitor closely for decreased manidipine effects and loss of efficacy. Increased manidipine doses may be required.

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.

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.

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.

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).

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.

Osimertinib

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

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.

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 extendedrelease tablets.

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.

Pitolisant

CYP3A4 Inducers (Strong) may decrease the serum concentration of Pitolisant. Management: For patients who are stable on pitolisant doses of 8.9 mg or 17.8 mg/day and who are also taking a strong CYP3A4 inducer, increase the pitolisant dose over 7 days to double the original dose (ie, to either 17.8 mg/day or 35.6 mg/day, respectively).

Progestins (Contraceptive)

Phenytoin may diminish the therapeutic effect of Progestins (Contraceptive). Contraceptive failure is possible. Management: Contraceptive failure is possible. Use of an alternative, nonhormonal contraceptive is recommended.

QUEtiapine

CYP3A4 Inducers (Strong) may decrease the serum concentration of QUEtiapine. Management: An increase in quetiapine dose (as much as 5 times the regular dose) may be required to maintain therapeutic benefit. Reduce the quetiapine dose back to the previous/regular dose within 7-14 days of discontinuing the inducer.

QuiNINE

Phenytoin may decrease the serum concentration of QuiNINE.

Radotinib

CYP3A4 Inducers (Strong) may decrease the serum concentration of Radotinib. Management: Consider alternatives to this combination when possible as the risk of radotinib treatment failure may be increased.

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.

RisperiDONE

CYP3A4 Inducers (Strong) may decrease the serum concentration of RisperiDONE. Management: Consider increasing the dose of oral risperidone (to no more than double the original dose) if a strong CYP3A4 inducer is initiated. For patients on IM risperidone, consider an increased IM dose or supplemental doses of oral risperidone.

Ritonavir

Phenytoin may decrease the serum concentration of Ritonavir. Ritonavir may decrease the serum concentration of Phenytoin.

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.

Sirolimus

CYP3A4 Inducers (Strong) may decrease the serum concentration of Sirolimus. Management: Avoid concomitant use of strong CYP3A4 inducers and sirolimus if possible. If combined, monitor for reduced serum sirolimus concentrations. Sirolimus dose increases will likely be necessary to prevent subtherapeutic sirolimus levels.

Sulfamethoxazole

May increase the serum concentration of Phenytoin.

SUNItinib

CYP3A4 Inducers (Strong) may decrease the serum concentration of SUNItinib. Management: Avoid when possible. If such a combination cannot be avoided, sunitinib dose increases are recommended, and vary by indication. See full monograph for details.

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.

Tamoxifen

CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Tamoxifen. CYP3A4 Inducers (Strong) may decrease the serum concentration of Tamoxifen. Management: Consider alternatives to concomitant use of strong CYP3A4 inducers and tamoxifen. If the combination cannot be avoided, monitor for reduced therapeutic effects of tamoxifen.

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.

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.

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.

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.

Thiotepa

CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Thiotepa. CYP3A4 Inducers (Strong) may decrease the serum concentration of Thiotepa. Management: Thiotepa prescribing information recommends avoiding concomitant use of thiotepa and strong CYP3A4 inducers. If concomitant use is unavoidable, monitor for adverse effects.

TiaGABine

CYP3A4 Inducers (Strong) may decrease the serum concentration of TiaGABine. Management: Approximately 2-fold higher tiagabine doses and a more rapid dose titration will likely be required in patients concomitantly taking a strong CYP3A4 inducer.

Tipranavir

Phenytoin may decrease the serum concentration of Tipranavir. Tipranavir may decrease the serum concentration of Phenytoin.

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.

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.

Vemurafenib

CYP3A4 Inducers (Strong) may decrease the serum concentration of Vemurafenib. Management: Avoid concurrent use of vemurafenib with a strong CYP3A4 inducer and replace with another agent when possible. If a strong CYP3A4 inducer is indicated and unavoidable, the dose of vemurafenib may be increased by 240 mg (1 tablet) as tolerated.

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.

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.

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.

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.

Risk Factor X (Avoid combination)

Abemaciclib

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

Alpelisib

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

Antihepaciviral Combination Products

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

Apixaban

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

Apremilast

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

Aprepitant

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

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.

Asunaprevir

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

Axitinib

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

Bedaquiline

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

Benznidazole

May enhance the adverse/toxic effect of Products Containing Propylene Glycol.

Betrixaban

P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Betrixaban.

Bortezomib

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

Bosutinib

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

Brigatinib

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

Cariprazine

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

Ceritinib

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

CloZAPine

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

Cobicistat

Fosphenytoin-Phenytoin may decrease the serum concentration of Cobicistat.

Cobimetinib

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

Copanlisib

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

Crizotinib

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

Dabigatran Etexilate

P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Dabigatran Etexilate. Management: Avoid concurrent use of dabigatran with P-glycoprotein inducers whenever possible.

Daclatasvir

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

Darolutamide

Inducers of CYP3A4 (Strong) and P-glycoprotein may decrease the serum concentration of Darolutamide.

Dasabuvir

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

Deflazacort

CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Deflazacort.

Delamanid

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

Delavirdine

Phenytoin may decrease the serum concentration of Delavirdine. Delavirdine may increase the serum concentration of Phenytoin.

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.

Dolutegravir

Fosphenytoin-Phenytoin may decrease the serum concentration of Dolutegravir.

Doravirine

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

Dronedarone

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

Duvelisib

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

Elbasvir

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

Eliglustat

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

Elvitegravir

Fosphenytoin-Phenytoin may decrease the serum concentration of Elvitegravir.

Encorafenib

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

Entrectinib

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

Enzalutamide

May decrease the serum concentration of Fosphenytoin-Phenytoin.

Erdafitinib

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

Erlotinib

May increase the serum concentration of Fosphenytoin-Phenytoin. FosphenytoinPhenytoin may decrease the serum concentration of Erlotinib. Management: Avoid use of erlotinib with phenytoin when possible. If required, increase erlotinib dose by 50 mg increments at 2 week intervals, as tolerated, to a max of 450 mg/day.

Etravirine

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

Fedratinib

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

Flibanserin

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

Fosaprepitant

CYP3A4 Inducers (Strong) may decrease the serum concentration of Fosaprepitant. Specifically, CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite aprepitant.

Fosnetupitant

CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Fosnetupitant.

Fostamatinib

CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Fostamatinib.

Fotemustine

Fosphenytoin-Phenytoin may decrease the serum concentration of Fotemustine. Fotemustine may decrease the serum concentration of Fosphenytoin-Phenytoin. Specifically, fotemustine may decrease concentrations of orally administered phenytoin.

Gemigliptin

CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Gemigliptin. CYP3A4 Inducers (Strong) may decrease the serum concentration of Gemigliptin.

Gilteritinib

Combined Inducers of CYP3A4 and P-glycoprotein may decrease the serum concentration of Gilteritinib.

Glasdegib

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

Glecaprevir and Pibrentasvir

Fosphenytoin-Phenytoin may decrease the serum concentration of Glecaprevir and Pibrentasvir.

Grazoprevir

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

Ibrutinib

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

Idelalisib

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

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.

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.

Itraconazole

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

Ivabradine

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

Ivacaftor

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

Ivosidenib

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

Ixazomib

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

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.

Ledipasvir

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

Lorlatinib

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

Lumefantrine

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

Lurasidone

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

Macimorelin

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

Macitentan

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

Midostaurin

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

MiFEPRIStone

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

Naldemedine

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

Naloxegol

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

Neratinib

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

Netupitant

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

NIFEdipine

May increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of NIFEdipine.

Nilotinib

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

NiMODipine

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

Nintedanib

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

Nisoldipine

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

Olaparib

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

Palbociclib

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

Panobinostat

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

PAZOPanib

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

Pexidartinib

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

Pimavanserin

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

Piperaquine

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

PONATinib

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

Praziquantel

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

Pretomanid

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

Ranolazine

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

Regorafenib

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

Ribociclib

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

Rilpivirine

Phenytoin may decrease the serum concentration of Rilpivirine.

Rivaroxaban

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

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.

RomiDEPsin

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

Simeprevir

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

Sofosbuvir

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

Sonidegib

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

SORAfenib

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

Stiripentol

May decrease the serum concentration of Phenytoin.

Tasimelteon

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

Tenofovir Alafenamide

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

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.

Tofacitinib

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

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.

Toremifene

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

Trabectedin

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

Ulipristal

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

Upadacitinib

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

Valbenazine

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

Vandetanib

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

Velpatasvir

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

Velpatasvir

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

Venetoclax

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

VinCRIStine (Liposomal)

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

VinCRIStine (Liposomal)

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

Vinflunine

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

Vorapaxar

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

Voxilaprevir

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

Monitoring parameters:

  • CBC,
  • liver function;
  • vitamin D status (chronic use);
  • suicidality (eg, depression, behavioral changessuicidal thoughts );
  • 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;
  • infusion site reactions

Consult individual institutional policies and procedures.   

How to administer Phenytoin (Dilantin)?

Oral:

  • Release immediately:
    • Divide the daily dose into two to three doses daily; if it is not possible to divide equally, you can take the higher dose before retiring.
  • Tablets with Chewable:
    • You may chew well before swallowing, or swallow whole.
  • Suspension
    • Before using, shake well
    • Use a calibrated oral dosing device (or other accurate dose-measuring device) to measure and administer dosage.
    • Patients who receive continuous nasogastric feeds will have their phenytoin suspension administered concurrently can experience impaired absorption.
    • This interaction can be resolved by dividing each day's dose of phenytoin, and withholding the administration of nutritional supplement for up to 2 hours prior to and after each dose.
    • Manufacturers recommend not to give enteral feeding preparations concurrently.
  • Extended-release
    • Dose is usually every 12 hours. However, patients with a prolonged half-life may need to be administered every 24 hours.

IM:

  • Avoid intramuscular administration (IM) due to the severe risk of tissue destruction and necrosis. If IM is required, use fosphenytoin.
  • Although the manufacturer's labeling may include IM administration, it should not be used.NOTcan be used to treat status epilepticus.

IV:

  • Fosphenytoin can be used instead for patients in hemodynamically unstable or status epilepticus.
  • Phenytoin can be administered directly via IV injection.
  • However, it is preferred that the phenytoin be administered via an infusion pump undiluted or diluted with NS as an IV Piggyback (IVPB).
  • This will prevent excess infusion rates (monitor for extravasation during infusion).
  • Use a large-gauge catheter to administer directly into large central or peripheral veins.
  • After NS dilution, infusion must be completed within four hours.
  • Maximum IV dose is 50 mg/minute
  • Patients with high levels of sensitivities (e.g. elderly patients or patients with preexisting heart conditions) should be given phenytoin at a slower rate (20 mg per minute).
  • If you are using IV for oral replacement, it is important to administer the dose at a slower rate.
  • Due to the possibility of precipitation, an in-line filter of 0.22- to 0.55 micron is recommended for IVPB solutions.
  • To avoid irritation, NS should always be injected via the same IV catheter or needle that was used for IV administration.

SubQ

  • Because of the potential for tissue damage due to high pH, SubQ administration should not be done.
  • Use Vesicant to ensure that the catheter or needle is correctly placed before and during IV Infusions. Avoid extravasation.

Extravasation management

  • Extravasation can be prevented by stopping infusion immediately.
  • Extravasated solution should be gently aspirated (do not flush the line).
  • Remove needle/cannula
  • Elevate extremities and apply dry heat
  • Closely monitor tissue sloughing and compartment syndrome.
  • Information regarding antidotes is inconsistent. Some sources suggest not using an antidote, others recommend hyaluronidase for refractory cases.

If appropriate, Hyaluronidase

  • Four separate injections of 0.2 mL of a 15 unit/mL solution (using an 25-gauge needle), should be administered to the extravasation area.

Mechanism of action of Phenytoin (Dilantin):

  • Stabilizes neuronal cells and decreases seizure activity through increasing efflux or decreasing the amount of sodium ions across cell membranes in motor cortex during the generation nerve impulses.
  • This prolongs the effective refractory time and suppresses ventricular ratemaker automaticity.
  • It also reduces heart action potential.

The onset of action:

  • IV: ~0.5 to 1 hour

Absorption:

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

Protein binding:

  • Neonates: ≥80 percent (≤20 percent free)
  • Infants: ≥85 percent (≤15 percent free)
  • Adults: 87.8 percent to 91.9 percent.
  • Others:
  • Disease states resulting in a decrease in serum albumin concentration:
    • pregnancy,
    • cystic fibrosis,
    • burns,
    • hepatic cirrhosis,
    • nephrotic syndrome

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 per minute (unbound fraction is increased two- to threefold in uremia)

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 V (metabolic capacity) and K (constant equal to the concentration at which the rate of metabolism is / of V );
  • V is increased in infants more than 6 months and children compared to adults;
  • major metabolite (via oxidation) HPPA undergoes enterohepatic recycling and elimination in urine as glucuronides

Bioavailability: Formulation dependent

  • IM: 83 percent to ~100 percent  (single dose)
  • IV: 100 percent
  • Oral (dependent on the product and/or salt): 70 percent  to 95 percent.

Half-life elimination:

  • Range: 7 to 42 hours;
  • newborns (PNA <weak ): 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 V and K.

Time to peak, serum (formulation dependent):

  • Oral: Extended-release capsule: 4 to 12 hours;
  • Immediate-release preparation: 1.5 to 3 hours

Excretion:

  • Urine (<5 percent  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

International Brand Names of Phenytoin:

  • Dilantin
  • Tremytoine
  • Aleviatin
  • Antisacer
  • Clerin
  • Clerin LR
  • Cumatil
  • Decatona
  • DiHydan
  • Difetoin
  • Dilantin
  • Dintoina
  • Diphedan
  • Ditoin
  • Dilantin Infatabs
  • Phenytek
  • Phenytoin Infatabs
  • APO-Phenytoin Sodium
  • Dilantin
  • Dilantin Infatabs
  • Dilantin-125
  • Dilantin-30
  • NOVO-Phenytoin
  • TARO-Phenytoin
  • Epamin
  • Epanutin
  • Epilan-D
  • Epilax
  • Epinat
  • Epinotid
  • Epinotin
  • Epitoin
  • Eptoin
  • Felantin
  • Fenatoin NM
  • Fenevit
  • Fenidantoin S
  • Fenitin
  • Fenitron
  • Fenytoin
  • Fomiken
  • Hidanil
  • Hidantin
  • Hidantoína
  • Hydantin
  • Hydantoin
  • Hydantol
  • Ikaphen
  • Ipanten
  • Kutoin
  • Lantidin
  • Lehydan
  • Pepsytoin-100
  • Phenhydan
  • Phenilep
  • Phenlin
  • Phentolep
  • Pyoredol
  • Sinergina
  • Sizatoin
  • Utoin
  • Xentoin

Phenytoin Brand Names in Pakistan:

Phenytoin Injection 250 mg in Pakistan

Epigran

Atco Laboratories Limited

Phenytoin Injection 30 mg/ml in Pakistan

Fentin

Geofman Pharmaceuticals

Phenytoin Suspension 30 mg/5ml in Pakistan

Dilantin

Pfizer Laboratories Ltd.

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Pharmedic (Pvt) Ltd.

Epitoin

Adamjee Pharmaceuticals (Pvt) Ltd.

Phenytoin Tablets 100 mg in Pakistan

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French Pharmaceutical Group

Epilantin

Pharmedic (Pvt) Ltd.

Epitoin

Adamjee Pharmaceuticals (Pvt) Ltd.

Phenytoin Sodium Capsules 100 mg in Pakistan

Dilantin

Pfizer Laboratories Ltd.

Phenton-S

Swiss Pharmaceuticals (Pvt) Ltd.

Shalentin

Shifa Laboratories.(Pvt) Ltd.

 

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