Fosphenytoin - Uses, Dose, Side effects, Contraindictions

A prodrug of phenytoin is called fosphenytoin. It can only be obtained as a parenteral preparation to treat seizures.

Indications of Fosphenytoin:

  • Seizures:

    • It is effective in controlling generalized tonic-clonic status epilepticus and the prevention and treatment of seizures occurring during neurosurgery;
    • short-term parenteral administration when oral phenytoin is not possible.

  • Guideline recommendations:

    • Status epilepticus:
    • The first-line treatment is a benzodiazepine (eg, lorazepam, diazepam, midazolam).
    • In patients with failed first-line management, IV fosphenytoin among other antiepileptics (eg, IV valproic acid or IV levetiracetam) is an option.

Fosphenytoin dose in adults:

Note:

  • Fosphenytoin should always be given and administered in phenytoin equivalents (PE); fosphenytoin 1.5 mg is equivalent to phenytoin 1 mg and is referred to as 1 mg PE. The dose, concentration, and infusion rates for fosphenytoin are expressed as phenytoin equivalents (PE).

Fosphenytoin Dose in Status epilepticus: 

  • American Epilepsy Society recommendations:

    • 20 mg PE/kg I/V  as a single dose.
    • The maximum dose: 1500 mg PE

  • Neurocritical Care Society recommendations:

    • Loading dose:
      • A further 5 mg PE/kg may be administered if necessary 10 minutes following the loading dose (20 mg PE/kg I/V; maximum rate of administration: 150 mg PE/minute).

  • Manufacturer's labeling:

    • Current clinical practise might not be reflected in the dosing in the prescribed information.
    • Following a loading dosage of 15 to 20 mg PE/kg I/V at 100 to 150 mg PE/minute, either fosphenytoin or phenytoin maintenance doses are given.

  • Nonemergent loading and maintenance dosing: IM, IV:

Note:

  • Start the maintenance dose at the following determined dosing interval after administering the loading dose (ie, if intended dose frequency is every 12 hours, start maintenance dosing 12 hours after loading dose).
  • Due to cardiotoxicity and local toxicity, switching to oral phenytoin is necessary whenever it is practical.
    • Loading dose:
      • 10 to 20 mg PE/kg (maximum rate: 150 mg PE/minute; IV rate: Infuse more slowly, say over 30 minutes).
    • Initial daily maintenance dose:
      • Divided doses of 4 to 6 mg PE/kg/day.

  • Substitution for oral phenytoin therapy:

    • The same total daily dose of phenytoin may be administered intramuscularly or intravenously.
    • As opposed to phenytoin, which is supplied as fosphenytoin, which is 100% bioavailable by both the IM and IV routes, dilantin capsules are only about 90% bioavailable when taken orally. As a result, plasma phenytoin concentrations may slightly rise when IM or IV fosphenytoin is used in place of oral phenytoin.
    • One or two injection sites were used to provide IM fosphenytoin as a single daily dose during clinical trials; however, some patients might need to receive the medication more frequently.

Fosphenytoin dose in children:

Fosphenytoin dosage, solution concentration, and infusion rates are represented as PHENYTOIN SODIUM EQUIVALENTS (PE). If fosphenytoin is not recommended and administered in cases of PE, serious medication mistakes may ensue.

Note:

  • Children should receive it intravenously.
  • The dosage is determined by serum concentrations and clinical response.
  • Using doses in PE equal to the phenytoin doses (i.e., phenytoin 1 mg = fosphenytoin 1 mg PE), experts advise following the paediatric IV phenytoin dosing guidelines based on pharmacokinetic studies.
  • Due to the possibility of toxicity, switching to oral phenytoin should be done as soon as possible.

Fosphenytoin Dose in Status epilepticus:

  • Infants, Children, and Adolescents:

    • 15 to 20 mg PE/kg IV (recommended), IM loading dosage.
    • A loading dose of 20 mg PE/kg is advised by experts; the maximum dose is 1,500 mg PE.
    • The best course of treatment for refractory status epilepticus is not known; if the condition does not improve, several professional opinions exist.
    • Some experts advise adding a 5 mg PE/kg load 10 minutes after the initial dosage.

Fosphenytoin Dose in the Seizures (nonemergent):

  • Infants, Children, and Adolescents:

    • IM or IV: 10 to 15 mg PE/kg for a loading dose (if necessary); start maintenance doses 12 hours following the loading dose.

Fosphenytoin Dose in the maintenance therapy of Seizures (short-term when oral route not available or appropriate):

  • Infants, Children, and Adolescents:

    • IV (preferred), IM: Initial:

      • 2 separate doses of 4 to 8 mg PE/kg/day; the maintenance dose should be started 12 hours following the loading dose.
      • For infants and young children, greater maintenance dosages (8 to 10 mg PE/kg/day), according to some experts, may be required.
      • Treatment periods longer than five days have not been studied in adult patients.

Fosphenytoin Dose in Seizures, substitution for oral phenytoin therapy:

  • Infants, Children, and Adolescents:

    • IV (preferred), IM:

    • However, phenytoin, delivered as fosphenytoin, is 100% bioavailable by both the IM and IV routes, meaning that when IM or IV fosphenytoin is substituted for oral phenytoin sodium, plasma phenytoin concentrations can increase. Phenytoin capsules are only 90% accessible by the oral route.

Fosphenytoin dose in the prophylaxis of seizures in patients with Traumatic brain injury: Dosing based on experience with phenytoin:

  • Infants, Children, and Adolescents:

    • IV:

      • Initial dose of 18 mg PE/kg loading dose, then 6 mg PE/kg each day divided into eight-hour intervals for 48 hours.

Note:

  • Prophylactic phenytoin can be used to reduce the frequency of early posttraumatic seizures in children with severe traumatic brain injuries, but it does not lower the risk of long-term seizures or improve neurologic prognosis.

Fosphenytoin Pregnancy Risk Category: D

  • Fosphenytoin, the prodrug for phenytoin, is called Fosphenytoin.
  • Increased risk of congenital malformations in the womb from phenytoin-induced in utero exposure
  • After delivery, coagulation defects and malignancies like neuroblastoma or neonatal fibroblastoma are seen.
  • To lower the risk of deadly haemorrhage, vitamin K should be given to the mother before labour and to the newborn after birth.
  • This is because after phenytoin-induced clot formation, the levels of vitamin K dependent clotting factors in the uterus dropped.
  • Orofacial clefts, heart problems, and dysmorphic facial traits are among more deformities brought on by phenytoin.
  • A few examples are nail/digit hypoplasia, growth problems, microcephaly, and mental impairment.

Use fosphenytoin while breastfeeding

  • Fosphenytoin, the prodrug for phenytoin, is called Fosphenytoin.
  • It is unknown if fosphenytoin was secreted in breast milk before conversion to phenytoin.
  • The decision to continue or discontinue nursing during therapy is based on the hazards of baby exposure, the advantages to the mother, and the benefits to the infant, according to the manufacturer's instructions.
  • For more information, refer to the Phenytoin monograph

Fosphenytoin Dose adjustment in kidney disease:

  • The manufacturer's labeling does not include any dosage adjustments.
  • Patients with kidney disease or hypoalbuminemia need to be closely monitored for phenytoin levels.
  • Fosphenytoin clearance may increase in renal disease without an equal increase in phenytoin.
  • Adverse events may occur more frequently and with greater severity as a result.

Fosphenytoin Dose adjustment in liver disease:

  • The manufacturer's labeling does not include any dosage adjustments.
  • Patients with hepatic disease and those with hypoalbuminemia need to be closely monitored for phenytoin levels.
  • Fosphenytoin clearance may increase in the presence of hepatic disease.
  • However, phenytoin clearance may not be as high.
  • This can lead to an increase in severity and frequency of adverse events.

Common Side Effects of Fosphenytoin:

  • Central Nervous System:

    • Burning Sensation
    • Paresthesia
    • Dizziness
    • Drowsiness
    • Ataxia

  • Dermatologic:

    • Pruritus

  • Ophthalmic:

    • Nystagmus Disorder

Less common Side Effects Of Fosphenytoin:

  • Cardiovascular:

    • Hypotension
    • Vasodilatation
    • Tachycardia
    • Facial Edema
    • Hypertension
    • Atrial Flutter
    • Bundle Branch Block
    • Cardiac Failure
    • Cardiomegaly
    • Cerebral Infarction
    • Edema
    • Orthostatic Hypotension
    • Palpitations
    • Prolonged QT Interval On ECG
    • Pulmonary Embolism
    • Shock
    • Sinus Bradycardia
    • Subdural Hematoma
    • Syncope
    • Thrombophlebitis
    • Ventricular Premature Contractions

  • Central Nervous System:

    • Headache
    • Stupor
    • Paresthesia
    • Extrapyramidal Reaction
    • Absent Reflexes
    • Agitation
    • Vertigo
    • Cerebral Edema
    • Dysarthria
    • Hypoesthesia
    • Abnormality In Thinking
    • Chills
    • Hyperreflexia
    • Intracranial Hypertension
    • Myasthenia
    • Nervousness
    • Speech Disturbance
    • Akathisia
    • Altered Sense Of Smell
    • Amnesia
    • Aphasia
    • Brain Disease
    • Central Nervous System Depression
    • Cerebral Hemorrhage
    • Coma
    • Confusion
    • Delirium
    • Depersonalization
    • Depression
    • Emotional Lability
    • Encephalitis
    • Hemiplegia
    • Hostility
    • Hyperacusis
    • Hyperesthesia
    • Hypotonia
    • Insomnia
    • Malaise
    • Meningitis
    • Migraine
    • Myoclonus
    • Paralysis
    • Personality Disorder
    • Positive Babinski Sign
    • Psychoneurosis
    • Psychosis
    • Seizure
    • Twitching

  • Dermatologic:

    • Ecchymoses
    • Skin Rash
    • Contact Dermatitis
    • Cutaneous Nodule
    • Diaphoresis
    • Maculopapular Rash
    • Pustular Rash
    • Skin Discoloration
    • Skin Photosensitivity
    • Urticaria

  • Endocrine & Metabolic:

    • Hypokalemia
    • Acidosis
    • Albuminuria
    • Alkalosis
    • Cachexia
    • Dehydration
    • Diabetes Insipidus
    • Hyperglycemia
    • Hyperkalemia
    • Hypophosphatemia
    • Ketosis

  • Gastrointestinal:

    • Nausea
    • Tongue Disease
    • Xerostomia
    • Dysgeusia
    • Vomiting
    • Constipation
    • Ageusia
    • Anorexia
    • Diarrhea
    • Dyspepsia
    • Dysphagia
    • Flatulence
    • Gastritis
    • Gastrointestinal Hemorrhage
    • Intestinal Obstruction
    • Oral Paresthesia
    • Sialorrhea
    • Tenesmus

  • Genitourinary:

    • Pelvic Pain
    • Dysuria
    • Genital Edema
    • Oliguria
    • Urethral Pain
    • Urinary Incontinence
    • Urinary Retention
    • Vaginitis
    • Vulvovaginal Candidiasis

  • Hematologic & Oncologic:

    • Anemia
    • Hypochromic Anemia
    • Leukocytosis
    • Leukopenia
    • Lymphadenopathy
    • Petechia
    • Thrombocytopenia

  • Hepatic:

    • Abnormal Hepatic Function Tests

  • Hypersensitivity:

    • Tongue Edema

  • Infection:

    • Infection
    • Cryptococcosis
    • Sepsis

  • Local:

    • Injection Site Reaction
    • Pain At Injection Site
    • Bleeding At Injection Site
    • Inflammation At Injection Site
    • Swelling At Injection Site

  • Neuromuscular & Skeletal:

    • Tremor
    • Asthenia
    • Back Pain
    • Arthralgia
    • Hyperkinetic Muscle Activity
    • Hypokinesia
    • Lower Limb Cramp
    • Myalgia
    • Myopathy

  • Ophthalmic:

    • Diplopia
    • Amblyopia
    • Conjunctivitis
    • Eye Pain
    • Mydriasis
    • Photophobia
    • Visual Field Defect

  • Otic:

    • Tinnitus
    • Deafness
    • Otalgia

  • Renal:

    • Polyuria
    • Renal Failure Syndrome

  • Respiratory:

    • Pneumonia
    • Apnea
    • Aspiration Pneumonia
    • Asthma
    • Atelectasis
    • Bronchitis
    • Cyanosis
    • Dyspnea
    • Epistaxis
    • Flu-Like Symptoms
    • Hemoptysis
    • Hyperventilation
    • Hypoxia
    • Increased Bronchial Secretions
    • Increased Cough
    • Pharyngitis
    • Pneumothorax
    • Rhinitis
    • Sinusitis

  • Miscellaneous:

    • Fever

Rare Side effects of Fosphenytoin :

  • Cardiovascular:

    • Cardiac arrhythmia
    • Severe hypotension

Contraindications to Fosphenytoin:

  • Intolerance to phenytoin, fosphenytoin, any other hydantoins, or any other ingredient in this formulation
  • Stokes Adams syndrome
  • Sinus bradycardia
  • Sinoatrial block, second and third-degree AV blocks
  • Fosphenytoin and phenytoin have been linked to acute livertoxicity in the past
  • Combination therapy with delavirdine

Warnings and precautions

  • Blood dyscrasias

    • With or without inhibition of the bone marrow, phenytoin can cause fatal haematological toxicities. This comprises leukopenia, granulocytopenia, and thrombocytopenia.
    • Patients who have previously experienced a negative hematologic reaction to any medication are more vulnerable.
    • Management, early evaluation and close monitoring are essential.

  • Cardiovascular events: [US Boxed Warn]

    • Severe hypotension and cardiac arrhythmias, such as bradycardia or heart block, QT prolongation, bradycardia, or ventricular fibrillation, might result from rapid delivery.
    • This risk is higher in the elderly, hypotension, critically ill patients and severe myocardial impairment.
    • Close monitoring of the heart and respiratory system is essential during and after IV fosphenytoin treatment.
    • It may be necessary to stop therapy or reduce the rate of administration.
    • Adults should not consume more than 150 mg of fosphenytoin IV equivalents (PE) per minute.
    • A maximal IV rate of 2 mg/kg/minute (up to 150 mg PE/minute) should be maintained while treating epilepticus in youngsters.
    • Less than one to two mg/kg/minute (up to 100 mg PE/minute) of maintenance doses should be avoided.
    • They have been observed to occur at or below the approved infusion rates, despite the fact that cardiovascular toxicity is more common when infusion rates are higher.

  • Dermatologic reactions

    • Steven Johnson's syndrome, toxic epidermal necrolysis (TEN), drug reaction eosinophilia systemic symptoms (DRESS), and exanthematous pustulosis are only a few of the severe dermatological reactions that phenytoin can induce. Although it normally happens within 28 days, it could happen sooner.
    • Research suggests that patients of Asian descent are more susceptible to serious skin reactions.
    • If you notice any of these symptoms, it is important to stop all therapy immediately.

  • Hepatotoxicity

    • Acute hepatic failure, jaundice and hepatomegaly can all be caused by phenytoin.
    • Acute phenytoin livertoxicity can lead to life-threatening complications.
    • If acute hepatotoxicity is suspected, treatment should be stopped immediately.

  • Hypersensitivity

    • Hypersensitivity reactions like angioedema can be caused by Phenytoin.
    • In such cases, therapy should be stopped.
    • Patients who are hypersensitive to medications with similar structural makeup, such as carbamazepine, barbiturates, and succinimides, should receive alternative care (eg trimethadione).

  • Toxicity local:

    • Fosphenytoin IV can cause "purple gloves syndrome", i.e. discoloration with edema, and pain in the distal limb. This may be caused by drug extravasation.
    • Although the condition is usually resolved spontaneously, it can lead to skin necrosis or limb ischemia.
    • Fosphenytoin causes less venous irritation than a comparable dose of phenytoin and causes less phlebitis.

  • Lymphadenopathy

    • A benign lymph node hyperplasia, pseudolymphoma, lymphoma, or Hodgkin's disease could exist. This should be taken into account while ending therapy.

  • Multiorgan hypersensitivity reactions

    • Drugs used to treat epilepsy may result in catastrophic multiorgan hypersensitivity responses (also called drug reaction with eosinophilia systemic symptoms [DRESS]).
    • You should monitor your symptoms and signs for possible manifestations of lymphatic, hepatic and renal organ systems.
    • You should consider therapy withdrawal and alternative agents.

  • Sensory disturbances

    • Maximum administration can cause extreme burning, itching, or paresthesias, most commonly perineal, lasting for minutes to hours.
    • Milder sensory disturbances can last up to 24 hours.
    • The ability to slow down or temporarily stop infusions can reduce their frequency and intensity.

  • Cardiovascular disease

    • Hypotension and severe myocardial dysfunction should not be treated with phenytoin.
    • Contraindications include sinus bradycardia, sinoatrial, second-degree block, and Adam-Stokes syndrome.

  • Diabetes:

    • Patients with diabetes mellitus should be cautious.
    • Phenytoin may cause diabetes or inhibit insulin production in patients with hyperglycemia.

  • Hepatic impairment

    • Patients with hepatic impairment should be cautious.
    • Patients with hypoalbuminemia may have a higher level of unbound Phenytoin.
    • As a result, it's crucial to evaluate total plasma phenytoin levels carefully.
    • Concentrations of unbound phenytoin may be more beneficial.

  • Hyperbilirubinemia

    • Patients with hyperbilirubinemia have a higher free fraction and pharmacologic response.
    • It should therefore be used with caution when dealing with such situations.
    • Patients with hyperbilirubinemia may have a higher fraction of unbound Phenytoin.
    • As a result, it's crucial to evaluate total plasma phenytoin levels carefully. Concentrations of unbound phenytoin may be more beneficial.

  • Hypoalbuminemia

    • The free fraction and pharmacologic response of phenytoin are both enhanced by hypoalbuminemia. As a result, the medicine should only be used with care.
    • Unbound phenytoin levels may be higher in hypoalbuminemic patients.
    • As a result, it's crucial to evaluate total plasma phenytoin levels carefully. Concentrations of unbound phenytoin may be more beneficial.

  • Hypothyroidism

    • Hypothyroidism patients should be treated with caution.
    • Long-term phenytoin therapy can cause a decrease in thyroid hormone serum levels.

  • Porphyria

    • Patients with porphyria should be treated with caution.

  • Renal impairment

    • Patients with impaired renal function should be cautious.
    • The phosphate load for fosphenytoin should be checked (0.0037 mg phosphate/mgPE fosphenytoin).
    • Total plasma concentrations should be read with caution since the fraction of phenytoin that is unbound is higher with renal impairment.
    • Concentrations of unbound phenytoin may be more effective.

Fosphenytoin: Drug Interaction

Risk Factor C (Monitor therapy)

Acemetacin

May increase the serum concentration of Fosphenytoin-Phenytoin.

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).

Alcohol (Ethyl)

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

Bazedoxifene

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

Benperidol

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

Benzhydrocodone

CYP3A4 Inducers (Strong) may decrease the serum concentration of Benzhydrocodone. Specifically, the serum concentrations of hydrocodone may be reduced.

Benzodiazepines

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

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.

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.

Buprenorphine

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

Busulfan

Fosphenytoin may decrease the serum concentration of Busulfan.

Calcifediol

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

Cannabidiol

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

Cannabis

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

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.

CeFAZolin

May decrease the protein binding of Fosphenytoin.

Celiprolol

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

Chloramphenicol (Systemic)

Fosphenytoin may decrease the serum concentration of Chloramphenicol (Systemic). Fosphenytoin may increase the serum concentration of Chloramphenicol (Systemic). Chloramphenicol (Systemic) may increase the serum concentration of Fosphenytoin.

Chlorpheniramine

May increase the serum concentration of Fosphenytoin-Phenytoin.

ChlorproPAMIDE

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

Ciprofloxacin (Systemic)

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

Cladribine

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

Clindamycin (Systemic)

CYP3A4 Inducers (Strong) may decrease the serum concentration of Clindamycin (Systemic). Refer to the specific clindamycin (systemic) - rifampin drug interaction monograph for information concerning that combination.

ClonazePAM

Fosphenytoin may decrease the serum concentration of ClonazePAM. Clonazepam may also alter concentrations of Phenytoin (active metabolite of Fosphenytoin).

Codeine

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

Corticosteroids (Systemic)

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

CYP2C19 Inducers (Moderate)

May lower the serum level of CYP2C19 substrates (High risk with Inducers).

CYP2C19 Inhibitors (Moderate)

slows down the metabolism of CYP2C19 substrates (High risk with Inhibitors).

Dexketoprofen

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

Dexmethylphenidate

Fosphenytoin serum levels might rise.

Diazoxide

May lower the level of fosphenytoin 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).

Doxercalciferol

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

Doxofylline

Fosphenytoin-Phenytoin may decrease the serum concentration of Doxofylline.

Dronabinol

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

Elagolix

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

Eslicarbazepine

Eslicarbazepine's serum levels may drop when fosphenytoin is used. (based on phenytoin research) Eslicarbazepine may raise the level of fosphenytoin in the blood. (based on phenytoin research)

Estriol (Systemic)

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

Estriol (Topical)

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

Ethosuximide

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

Etizolam

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

Evogliptin

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

FentaNYL

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

Flunarizine

Fosphenytoin may decrease the serum concentration of Flunarizine.

Fluorouracil (Topical)

May increase the serum concentration of Fosphenytoin.

FluvoxaMINE

May increase the serum concentration of Fosphenytoin.

Folic Acid

May decrease the serum concentration of Fosphenytoin.

Fosamprenavir

Fosphenytoin may increase the serum concentration of Fosamprenavir. Fosamprenavir may decrease the serum concentration of Fosphenytoin.

Gestrinone

Fosphenytoin-Phenytoin may decrease the serum concentration of Gestrinone.

Halothane

May increase the serum concentration of Fosphenytoin.

HYDROcodone

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

Hydrocortisone (Systemic)

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

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.

Lacosamide

Antiepileptic Agents (Sodium Channel Blockers) may enhance the adverse/toxic effect of Lacosamide. Specifically the risk for bradycardia, ventricular tachyarrhythmias, or a prolonged PR interval may be increased.

Letermovir

May decrease the serum concentration of Fosphenytoin-Phenytoin.

Leucovorin Calcium-Levoleucovorin

May decrease the serum concentration of Fosphenytoin.

LevETIRAcetam

Fosphenytoin-Phenytoin may decrease the serum concentration of LevETIRAcetam.

Levodopa-Containing Products

Fosphenytoin-Phenytoin may diminish the therapeutic effect of Levodopa-Containing Products.

Levomefolate

May decrease the serum concentration of Fosphenytoin.

Levomethadone

Fosphenytoin may decrease the serum concentration of Levomethadone.

Lithium

Fosphenytoin may enhance the adverse/toxic effect of Lithium.

Loop Diuretics

Fosphenytoin may diminish the diuretic effect of Loop Diuretics.

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

Fosphenytoin may decrease the serum concentration of Mebendazole.

Meperidine

Fosphenytoin may decrease the serum concentration of Meperidine.

Methadone

Fosphenytoin may decrease the serum concentration of Methadone.

Methotrexate

May decrease the serum concentration of Fosphenytoin-Phenytoin. FosphenytoinPhenytoin may increase the serum concentration of Methotrexate. Specifically, fosphenytoinphenytoin may displace methotrexate from serum proteins, increasing the concentration of free, unbound drug.

Methylfolate

May decrease the serum concentration of Fosphenytoin.

Methylphenidate

May increase the serum concentration of Fosphenytoin.

MetroNIDAZOLE (Systemic)

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

Mexiletine

Fosphenytoin may decrease the serum concentration of Mexiletine.

Mianserin

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

Miconazole (Oral)

May increase the serum concentration of Fosphenytoin.

Multivitamins/Minerals (with ADEK, Folate, Iron)

May decrease the serum concentration of Fosphenytoin-Phenytoin.

Nelfinavir

Fosphenytoin may decrease the serum concentration of Nelfinavir. Nelfinavir may decrease the serum concentration of Fosphenytoin.

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).

Omeprazole

May increase the serum concentration of Fosphenytoin. Fosphenytoin may decrease the serum concentration of Omeprazole.

glycoprotein/ABCB1 Substrates

The serum concentration of P-glycoprotein/ABCB1 Substrates may be reduced by P-P-glycoprotein/ABCB1 Inducers. P-glycoprotein inducers may also further restrict the distribution of p-glycoprotein substrates to particular cells, tissues, and organs that have high levels of p-glycoprotein (e.g., brain, T-lymphocytes, testes, etc.).

PHENobarbital

PHENobarbital's CNS depressive impact may be strengthened by fosphenytoin. PHENobarbital's serum levels may rise in response to fosphenytoin. PHENobarbital may lower the level of fosphenytoin in the blood.

Phenylbutazone

May raise the serum level of phenytoin-fosphenytoin.

Pimavanserin

The serum concentration of pimavanserin may be reduced by CYP3A4 Inducers (Strong).

Pitolisant

Pitolisant's serum levels may drop if you take CYP3A4 Inducers (Strong).

Platinum Derivatives

May lower the serum level of phenytoin-fosphenytoin.

PrednisoLONE (Systemic)

PrednisoLONE serum levels may be decreased by CYP3A4 Inducers (Strong) (Systemic).

PredniSONE

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

Primidone

Primidone's metabolism may be accelerated by fosphenytoin. This alters the primidone:phenobarbital ratio.

Propacetamol

The serum concentrations of the active metabolite(s) of propacetamol may be reduced by fosphenytoin-phenytoin. In particular, acetaminophen serum concentrations may drop (resulting in lower efficacy), but the production of its dangerous N-acetyl-p-benzoquinone imine (NAPQI) metabolite may rise (leading to increased hepatotoxicity).

Propafenone

Propafenone's serum levels may drop if you take CYP3A4 Inducers (Strong)

Pyridoxine

Fosphenytoin's metabolism might be accelerated. This is particularly noticeable at high pyridoxine doses (e.g., 80 mg to 200 mg daily)

Ramelteon

Ramelteon's serum levels may drop when taken with CYP3A4 Inducers (Strong).

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

Fosphenytoin may decrease the serum concentration of Rufinamide. Rufinamide may increase the serum concentration of Fosphenytoin.

Ruxolitinib

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

SAXagliptin

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

Sertraline

Fosphenytoin may decrease the serum concentration of Sertraline. Sertraline may increase the serum concentration of Fosphenytoin.

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)

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

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

Fosphenytoin 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 Fosphenytoin.

TOLBUTamide

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

Topiramate

Fosphenytoin may decrease the serum concentration of Topiramate. Topiramate may increase the serum concentration of Fosphenytoin.

TraMADol

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

TraZODone

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

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 Fosphenytoin.

VinCRIStine

Fosphenytoin may decrease the serum concentration of VinCRIStine. VinCRIStine may decrease the serum concentration of Fosphenytoin.

Zolpidem

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

Zonisamide

Fosphenytoin 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.

Amiodarone

Fosphenytoin may increase Amiodarone's ability to extend QTc. Amiodarone's serum concentration may drop when used with fosphenytoin. Fosphenytoin's serum levels may rise in response to amiodarone. Management: When possible, look for alternatives. Patients receiving this combination should be watched for QT prolongation, changes in heart rhythm, decreased serum amiodarone concentrations/effects, and increased serum phenytoin concentrations/effects.

Antifungal Agents (Azole Derivatives, Systemic)

Fosphenytoin may lower the level of antifungal agents in the serum (Azole Derivatives, Systemic). The serum concentration of fosphenytoin may rise in response to antifungal agents (systemic azole derivatives). In separate monographs, relevant Isavuconazonium concerns are covered. Exceptions: Sulfate of isavuconazonium.

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

Fosphenytoin serum levels might rise. Monitoring for phenytoin toxicity while using a calcium channel blocker (CCB) at the same time or reduced phenytoin effects while stopping the CCB are the two management options. Check for diminished therapeutic effects of CCB. The Canadian labelling for nimodipine specifically forbids the use of phenytoin. Clevidipine is an exception.

Canagliflozin

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

Capecitabine

May increase the serum concentration of Fosphenytoin.

CarBAMazepine

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

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.

CycloSPORINE (Systemic)

Fosphenytoin may decrease the serum concentration 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

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

Dexamethasone (Systemic)

Fosphenytoin may decrease the serum concentration of Dexamethasone (Systemic). Dexamethasone (Systemic) may decrease the serum concentration of Fosphenytoin. Dexamethasone (Systemic) may increase the serum concentration of Fosphenytoin. Management: Consider dexamethasone dose increases when combined with fosphenytoin and monitor closely for reduced steroid efficacy. Monitor phenytoin levels closely, both increased and decreased phenytoin levels have been reported.

Disopyramide

Could increase the QTc-extension effect of phenytoin. Disopyramide's serum concentration may drop when used with fosphenytoin. Management: When possible, look for alternatives. For signs of QT interval prolongation or changes in heart rhythm, as well as for lower serum concentrations/therapeutic effects of disopyramide, closely monitor patients receiving this combination.

Disulfiram

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

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

Fosphenytoin may decrease the serum concentration of Doxycycline.

Efavirenz

May increase the serum concentration of Fosphenytoin. Fosphenytoin may decrease the serum concentration of Efavirenz.

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)

Fosphenytoin 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

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

Floxuridine

May increase the serum concentration of Fosphenytoin.

Fluconazole

May increase the serum concentration of Fosphenytoin.

Fluorouracil (Systemic)

May increase the serum concentration of Fosphenytoin.

FLUoxetine

Fosphenytoin may enhance the QTc-prolonging effect of FLUoxetine. FLUoxetine may increase the serum concentration of Fosphenytoin.

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)

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

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

Fosphenytoin 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.

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

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

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

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

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

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

Progestins (Contraceptive)

Fosphenytoin 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 lower the level of quetiapine in the serum. Management: To sustain therapeutic benefit, a dose increase of quetiapine (up to five times the usual dose) may be necessary. Within 7–14 days of stopping the inducer, lower the quetiapine dosage to the previous/regular level.

QuiNIDine

QuiNIDine's ability to extend QTc may be enhanced by fosphenytoin.

QuiNINE

QuiNIDine's serum concentration may drop when used with fosphenytoin. Management: When feasible, take into account alternatives. Watch attentively for signs and symptoms of severe QTc interval prolongation and arrhythmia in patients receiving this combination, as well as for dropping quinidine serum concentrations and therapeutic effects.

Radotinib

QuiNINE serum levels may drop when taking fosphenytoin.
The serum concentration of Radotinib may drop when CYP3A4 Inducers (Strong) are taken. 

RifAMPin

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

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

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

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.

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

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

Teniposide

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

Theophylline Derivatives

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

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

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

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

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

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)

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

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.

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.

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.

Darunavir

Fosphenytoin may decrease the serum concentration of Darunavir.

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

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

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.

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.

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

CYP3A4 Inducers (Strong) 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.

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.

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

Fosphenytoin 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.

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.

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:

  • Vital signs
  • Blood pressure
  • ECG
  • Respiratory function 
  • CBC
  • LFTS
  • Monitoring the level of plasma phenytoin (plasma concentrations shouldn't be checked until the conversion to phenytoin is complete, which takes around 2 hours for an IV infusion and 4 hours for an IM injection).

Note:

  • In patients with hepatic/renal impairment, hypoalbuminemia, or hyperbilirubinemia, free (unbound) phenytoin concentrations should be checked if possible.
  • The adjusted total phenytoin concentration in adult patients can be calculated using formulae if free (unbound) phenytoin concentrations are not available.
  • Because these patients have a higher fraction of unbound phenytoin, it is advisable to evaluate total phenytoin levels with caution.
  • In general, trough concentrations are advised for routine monitoring.
  • Consult the regulations and procedures of each specific institution.

How to administer Fosphenytoin?

IM:

  • You can administer it using one to four injection sites (up 20 mL per site that is well tolerated by adults).

IV:

  • The maximum infusion rate should be 150 mg PE/minute. The loading dose shouldn't be given as quickly in non-emergent situations (for instance, over 30 mins [33 mg PE/minute to 1,000 mg PE or 50 to 100m PE/minute]).
  • Fosphenytoin should be administered slowly to patients who are extremely sensitive (eg elderly patients, patients with preexisting heart conditions).
  • Slow delivery lessens the degree of paresthesias or urticaria as well as the risk of cardiovascular problems including hypotension and arrhythmia.

Mechanism of action of Fosphenytoin:

  • Diphosphate ester salt is phenytoin's water-soluble prodrug.
  • Fosphenytoin can be converted to formaldehyde, phosphate (not expected to have clinically significant consequences), and phenytoin by plasma esterases.
  • When nerve impulses are being produced in the motor cortex, phenytoin controls the integrity of neuronal membranes and the reduced efflux or influx of sodium ions across cell membranes.
  • This reduces seizure activity. For more information, see the Phenytoin monograph.

Notification

  • Patients with hypoalbuminemia and renal impairment may have a higher fraction of unbound Phenytoin.

Protein binding:

  • Fosphenytoin: 95 to 99% (mainly to Albumin); saturable fosphenytoin-protein binding (the percentage bound decreases with increasing total concentration).
  • Phenytoin can be replaced by fosphenytoin in the protein binding sites, and during this time, the unbound percentage can increase by up to 30%.

Metabolism:

  • Fosphenytoin soon becomes phenytoin by hydrolysis. The liver then breaks down phenytoin to create metabolites.

Bioavailability:

  • Fosphenytoin: IM: 100%.

Half-life elimination:

  • Pediatric patients (ages: 1 day to 16.7 years):
    • 8.3 minutes (range: 2.5 to 18.5 minutes).
  • Adults:
    • Fosphenytoin: IV 15 minutes; IM: 30 minutes.
    • Phenytoin: Variable (mean: 12 to 29 hours);
    • pharmacokinetics of phenytoin are saturable

Time to peak:

  • Conversion to phenytoin:
    • IV:
      • Adults: Following IV administration (maximum rate of administration): 15 minutes
    • IM:
      • In a case series (n=3; PNA: 15 to 47 days), neonates and infants under 6 months were reported to experience symptoms for 1-3 hours.
      • Children older than 7 months: Therapeutic concentrations are reached in under 30 minutes; the time to the peak serum concentration is unknown.
      • Adults: 3 hours; after IM (gluteal) injection, therapeutic phenytoin concentrations may be reached as soon as 5 to 20 minutes later.

Excretion:

  • Phenytoin: Urine (as inactive metabolites).

International Brands of Fosphenytoin:

  • Cerebyx
  • Cereneu
  • Epanutin
  • Fosolin
  • Fostoin
  • Pro-Epanutin
  • ProDilantin

Fosphenytoin Brand Names in Pakistan:

No Brands Available in Pakistan.

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