Fosphenytoin

Fosphenytoin may be found in some form under the following brand names:

• Cerebyx

WARNING: CARDIOVASCULAR RISK ASSOCIATED WITH RAPID INFUSION RATES

The rate of intravenous fosphenytoin administration should not exceed 150 mg phenytoin sodium equivalents (PE) per minute because of the risk of severe hypotension and cardiac arrhythmias. Careful cardiac monitoring is needed during and after administering intravenous fosphenytoin. Although the risk of cardiovascular toxicity increases with infusion rates above the recommended infusion rate, these events have also been reported at or below the recommended infusion rate. Reduction in rate of administration or discontinuation of dosing may be needed

Fosphenytoin is an anticonvulsant that works by slowing down impulses in the brain that cause seizures.

Fosphenytoin is used to prevent or control seizures. Fosphenytoin is used only for a short time when other forms of phenytoin cannot be given.

Fosphenytoin may also be used for purposes not listed in this medication guide.

You should not use fosphenytoin if you also take delavirdine (Rescriptor), or if you have certain serious heart conditions such as slow heartbeats, heart block, AV block, or Adams-Stokes syndrome (a heart rhythm disorder).

Fosphenytoin is injected into a muscle, or into a vein through an IV. You may be shown how to use an IV at home. Do not self-inject this medicine if you do not understand how to give the injection and properly dispose of used needles, IV tubing, and other items used to inject the medicine.

Your breathing, blood pressure, oxygen levels, kidney function, and other vital signs will be watched closely while you are receiving fosphenytoin in a clinic or hospital setting. Your heart function may also need to be checked using an electrocardiograph or ECG (sometimes called an EKG). You will be watched closely for 10 or 20 minutes after receiving fosphenytoin, to be sure this medication is not causing harmful effects.

Use a disposable needle and syringe only once. Follow any state or local laws about throwing away used needles and syringes. Use a puncture-proof "sharps" disposal container (ask your pharmacist where to get one and how to throw it away). Keep this container out of the reach of children and pets.

Do not stop using fosphenytoin or your other seizure medications suddenly, even if you feel fine. Stopping suddenly may cause increased seizures. Follow your doctor's instructions about tapering your dose.

This medication can cause unusual results with certain medical tests. Tell any doctor who treats you that you are using fosphenytoin.

Store fosphenytoin in the refrigerator, do not freeze.

You may also store this medicine at room temperature, but only for up to 48 hours.

Do not use fosphenytoin if it has changed colors or has particles in it. Call your pharmacist for new medication.

• If you have an allergy to fosphenytoin, phenytoin, or any other part of this medicine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have a slow heartbeat, heart block, or other heartbeat that is not normal.
• If you have had liver problems in the past while taking fosphenytoin or phenytoin.
• If you are taking delavirdine.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take fosphenytoin with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

The more important adverse clinical events caused by the IV use of Fosphenytoin sodium injection or phenytoin are cardiovascular collapse and/or central nervous system depression. Hypotension can occur when either drug is administered rapidly by the IV route. The rate of administration is very important; for Fosphenytoin sodium injection, it should not exceed 150 mg PE/min. The adverse clinical events most commonly observed with the use of Fosphenytoin sodium injection in clinical trials were nystagmus, dizziness, pruritus, paresthesia, headache, somnolence, and ataxia. With two exceptions, these events are commonly associated with the administration of IV phenytoin. Paresthesia and pruritus, however, were seen much more often following Fosphenytoin sodium injection administration and occurred more often with IV Fosphenytoin sodium injection administration than with IM Fosphenytoin sodium injection administration. These events were dose and rate related; most alert patients (41 of 64; 64%) administered doses of ≥ 15 mg PE/kg at 150 mg PE/min experienced discomfort of some degree. These sensations, generally described as itching, burning, or tingling, were usually not at the infusion site. The location of the discomfort varied with the groin mentioned most frequently as a site of involvement. The paresthesia and pruritus were transient events that occurred within several minutes of the start of infusion and generally resolved within 10 minutes after completion of Fosphenytoin sodium injection infusion. Some patients experienced symptoms for hours. These events did not increase in severity with repeated administration. Concurrent adverse events or clinical laboratory change suggesting an allergic process were not seen (see PRECAUTIONS, Sensory Disturbances). Approximately 2% of the 859 individuals who received Fosphenytoin sodium injection in premarketing clinical trials discontinued treatment because of an adverse event. The adverse events most commonly associated with withdrawal were pruritus (0.5%), hypotension (0.3%), and bradycardia (0.2%).

Dose and Rate Dependency of Adverse Events Following IV Fosphenytoin Sodium Injection: The incidence of adverse events tended to increase as both dose and infusion rate increased. In particular, at doses of ≥ 15 mg PE/kg and rates ≥ 150 mg PE/min, transient pruritus, tinnitus, nystagmus, somnolence, and ataxia occurred 2 to 3 times more often than at lower doses or rates.

Incidence in Controlled Clinical Trials

All adverse events were recorded during the trials by the clinical investigators using terminology of their own choosing. Similar types of events were grouped into standardized categories using modified COSTART dictionary terminology. These categories are used in the tables and listings below with the frequencies representing the proportion of individuals exposed to Fosphenytoin sodium injection or comparative therapy. The prescriber should be aware that these figures cannot be used to predict the frequency of adverse events in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses or investigators. An inspection of these frequencies, however, does provide the prescribing physician with one basis to estimate the relative contribution of drug and nondrug factors to the adverse event incidences in the population studied.

Incidence in Controlled Clinical Trials - IV Administration To Patients With Epilepsy or Neurosurgical Patients: Table 2 lists treatment-emergent adverse events that occurred in at least 2% of patients treated with IV Fosphenytoin sodium injection at the maximum dose and rate in a randomized, double-blind, controlled clinical trial where the rates for phenytoin and Fosphenytoin sodium injection administration would have resulted in equivalent systemic exposure to phenytoin.

Incidence in Controlled Trials - IM Administration to Patients With Epilepsy: Table 3 lists treatment-emergent adverse events that occurred in at least 2% of Fosphenytoin sodium injection-treated patients in a double-blind, randomized, controlled clinical trial of adult epilepsy patients receiving either IM Fosphenytoin sodium injection substituted for oral Dilantin or continuing oral Dilantin. Both treatments were administered for 5 days.

Adverse Events During All Clinical Trials

Fosphenytoin sodium injection has been administered to 859 individuals during all clinical trials. All adverse events seen at least twice are listed in the following, except those already included in previous tables and listings. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in greater than 1/100 individuals; infrequent adverse events are those occurring in 1/100 to 1/1000 individuals.

Frequent: fever, injection-site reaction, infection, chills, face edema, injection-site pain; Infrequent: sepsis, injection-site inflammation, injection-site edema, injection-site hemorrhage, flu syndrome, malaise, generalized edema, shock, photosensitivity reaction, cachexia, cryptococcosis.

Frequent: hypertension; Infrequent: cardiac arrest, migraine, syncope, cerebral hemorrhage, palpitation, sinus bradycardia, atrial flutter, bundle branch block, cardiomegaly, cerebral infarct, postural hypotension, pulmonary embolus, QT interval prolongation, thrombophlebitis, ventricular extrasystoles, congestive heart failure.

Frequent: constipation; Infrequent: dyspepsia, diarrhea, anorexia, gastrointestinal hemorrhage, increased salivation, liver function tests abnormal, tenesmus, tongue edema, dysphagia, flatulence, gastritis, ileus.

Infrequent: diabetes insipidus.

Infrequent: thrombocytopenia, anemia, leukocytosis, cyanosis, hypochromic anemia, leukopenia, lymphadenopathy, petechia.

Frequent: hypokalemia; Infrequent: hyperglycemia, hypophosphatemia, alkalosis, acidosis, dehydration, hyperkalemia, ketosis.

Frequent: myasthenia; Infrequent: myopathy, leg cramps, arthralgia, myalgia.

Frequent: reflexes increased, speech disorder, dysarthria, intracranial hypertension, thinking abnormal, nervousness, hypesthesia; Infrequent: confusion, twitching, Babinski sign positive, circumoral paresthesia, hemiplegia, hypotonia, convulsion, extrapyramidal syndrome, insomnia, meningitis, depersonalization, CNS depression, depression, hypokinesia, hyperkinesia, brain edema, paralysis, psychosis, aphasia, emotional lability, coma, hyperesthesia, myoclonus, personality disorder, acute brain syndrome, encephalitis, subdural hematoma, encephalopathy, hostility, akathisia, amnesia, neurosis.

Frequent: pneumonia; Infrequent: pharyngitis, sinusitis, hyperventilation, rhinitis, apnea, aspiration pneumonia, asthma, dyspnea, atelectasis, cough increased, sputum increased, epistaxis, hypoxia, pneumothorax, hemoptysis, bronchitis.

Frequent: rash; Infrequent: maculopapular rash, urticaria, sweating, skin discoloration, contact dermatitis, pustular rash, skin nodule.

Frequent: taste perversion; Infrequent: deafness, visual field defect, eye pain, conjunctivitis, photophobia, hyperacusis, mydriasis, parosmia, ear pain, taste loss.

Infrequent: urinary retention, oliguria, dysuria, vaginitis, albuminuria, genital edema, kidney failure, polyuria, urethral pain, urinary incontinence, vaginal moniliasis.

Post-Marketing Experience

The following adverse reactions have been identified during postapproval use of Fosphenytoin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

There have been post-marketing reports of anaphylactoid reaction and anaphylaxis.

Other Phenytoin-Associated Adverse Events:

Dyskinesia.

To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-877-233-2001 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

• Cerebyx

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

Guideline recommendations: Status epilepticus: A benzodiazepine (eg, lorazepam, diazepam, midazolam) is the preferred initial treatment of status epilepticus according to clinical practice guidelines; IV fosphenytoin among other antiepileptics (eg, IV valproic acid or IV levetiracetam) is an option in patients failing first-line treatment (AES [Glauser 2016]; NCS [Glauser 2016]).

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

Status epilepticus: IV:

American Epilepsy Society recommendations: 20 mg PE/kg as a single dose (maximum dose: 1500 mg PE) (AES [Glauser 2016]).

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

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

Nonemergent loading and maintenance dosing: IM, IV: Note: After administration of a loading dose, start maintenance dose at next identified dosing interval (ie, if intended dose frequency is every 12 hours, start maintenance dosing 12 hours after loading dose). Due to the risks of cardiac and local toxicity, transition to oral phenytoin when possible.

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

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

Substitution for oral phenytoin therapy: IM, IV: May be substituted for oral phenytoin at the same total daily dose; however, Dilantin capsules are ~90% bioavailable by the oral route; phenytoin, supplied as fosphenytoin, is 100% bioavailable by both the IM and IV routes; for this reason, plasma phenytoin concentrations may modestly increase when IM or IV fosphenytoin is substituted for oral phenytoin; in clinical trials, IM fosphenytoin was administered as a single daily dose utilizing either 1 or 2 injection sites; some patients may require more frequent dosing

Phenytoin clearance is decreased in geriatric patients; lower doses may be required. In addition, older adults may have lower serum albumin which may increase the free fraction and, therefore, pharmacologic response including adverse events. Refer to adult dosing.

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

Acetaminophen: Fosphenytoin-Phenytoin may decrease the serum concentration of Acetaminophen. Specifically, serum concentrations of acetaminophen may be decreased (leading to decreased efficacy), but the formation of the toxic N-acetyl-p-benzoquinone imine (NAPQI) metabolite may be increased (leading to increased hepatotoxicity). Monitor therapy

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

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

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

Analgesics (Opioid): CNS Depressants may enhance the CNS depressant effect of Analgesics (Opioid). Management: Avoid concomitant use of opioid analgesics and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

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

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

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

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

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

ARIPiprazole: CYP3A4 Inducers (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. Consider therapy modification

ARIPiprazole Lauroxil: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of ARIPiprazole Lauroxil. Management: Patients taking the 441 mg dose of aripiprazole lauroxil increase their dose to 662 mg if used with a strong CYP3A4 inducer for more than 14 days. No dose adjustment is necessary for patients using the higher doses of aripiprazole lauroxil. Consider therapy modification

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Brexpiprazole: CYP3A4 Inducers (Strong) may decrease the serum concentration of Brexpiprazole. Management: If brexpiprazole is used together with a strong CYP3A4 inducer, the brexpiprazole dose should gradually be doubled over the course of 1 to 2 weeks. Consider therapy modification

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Consider therapy modification

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

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

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

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

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

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. Monitor therapy

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Dabrafenib: May decrease the serum concentration of CYP2C9 Substrates. 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). Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP2C19 Substrates. 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). Consider therapy modification

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Erlotinib: May increase the serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin 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. Avoid combination

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Gefitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Gefitinib. Management: In the absence of severe adverse reactions, increase gefitinib dose to 500 mg daily in patients receiving strong CYP3A4 inducers; resume 250 mg dose 7 days after discontinuation of the strong inducer. Carefully monitor clinical response. Consider therapy modification

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. Avoid combination

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

Glecaprevir and Pibrentasvir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Glecaprevir and Pibrentasvir. Monitor therapy

Glecaprevir and Pibrentasvir: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Glecaprevir and Pibrentasvir. Monitor therapy

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

GuanFACINE: CYP3A4 Inducers (Strong) may decrease the serum concentration of GuanFACINE. Management: Increase the guanfacine dose by up to double when initiating concomitant therapy with strong CYP3A4 inducers. Increase guanfacine dose gradually over 1-2 weeks if strong CYP3A4 inducer therapy is just beginning. Consider therapy modification

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

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

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

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

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

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

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

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

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

Imatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Imatinib. Management: Avoid concurrent use of imatinib with strong CYP3A4 inducers when possible. If such a combination must be used, increase imatinib dose by at least 50% and monitor the patient's clinical response closely. Consider therapy modification

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

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

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

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

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

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

Ixabepilone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ixabepilone. Management: Avoid this combination whenever possible. If this combination must be used, a gradual increase in ixabepilone dose from 40 mg/m2 to 60 mg/m2 (given as a 4-hour infusion), as tolerated, should be considered. Consider therapy modification

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

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

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

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

Lapatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lapatinib. Management: If therapy overlap cannot be avoided, consider titrating lapatinib gradually from 1,250 mg/day up to 4,500 mg/day (HER2 positive metastatic breast cancer) or 1,500 mg/day up to 5,500 mg/day (hormone receptor/HER2 positive breast cancer) as tolerated. Avoid combination

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

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

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

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

Linagliptin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Linagliptin. Management: Strongly consider using an alternative to any strong CYP3A4 inducer in patients who are being treated with linagliptin. If this combination is used, monitor patients closely for evidence of reduced linagliptin effectiveness. Consider therapy modification

Linagliptin: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Linagliptin. Management: Strongly consider using an alternative to any strong P-glycoprotein inducer in patients who are being treated with linagliptin. If this combination is used, monitor patients closely for evidence of reduced linagliptin effectiveness. Consider therapy modification

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

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

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

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

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

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

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

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

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

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

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. Consider therapy modification

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Mirodenafil: CYP3A4 Inducers (Strong) may decrease the serum concentration of Mirodenafil. Management: Consider avoiding the concomitant use of mirodenafil and strong CYP3A4 inducers. If combined, monitor for decreased mirodenafil effects. Mirodenafil dose increases may be required to achieve desired effects. Consider therapy modification

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Osimertinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Osimertinib. Consider therapy modification

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

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

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

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

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

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

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

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

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

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

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

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Monitor therapy

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

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

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

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

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

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

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

Propacetamol: Fosphenytoin-Phenytoin may decrease serum concentrations of the active metabolite(s) of Propacetamol. Specifically, serum concentrations of acetaminophen may be decreased (leading to decreased efficacy), but the formation of its toxic N-acetyl-p-benzoquinone imine (NAPQI) metabolite may be increased (leading to increased hepatotoxicity). Monitor therapy

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

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

QUEtiapine: CYP3A4 Inducers (Strong) may decrease the serum concentration of QUEtiapine. Management: 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. Consider therapy modification

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

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

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. Consider therapy modification

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Selexipag: CYP2C8 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Selexipag. Monitor therapy

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

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

Sirolimus: 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. Consider therapy modification

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

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

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

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

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

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

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

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

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

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

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

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

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

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

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

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

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

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

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

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

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

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

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. Consider therapy modification

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Valproate Products: May decrease the protein binding of Fosphenytoin-Phenytoin. This appears to lead to an initial increase in the percentage of unbound (free) phenytoin and to a decrease in total phenytoin concentrations. Whether concentrations of free phenytoin are increased is unclear. With long-term concurrent use, total phenytoin concentrations may increase. Fosphenytoin-Phenytoin may decrease the serum concentration of Valproate Products. Monitor therapy

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

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

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

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

Vemurafenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vemurafenib. 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. Consider therapy modification

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

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

Vilazodone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vilazodone. Management: Consider increasing vilazodone dose by as much as 2-fold (do not exceed 80 mg/day), based on response, in patients receiving strong CYP3A4 inducers for > 14 days. Reduce to the original vilazodone dose over 1-2 weeks after inducer discontinuation. Consider therapy modification

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

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

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

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

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

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

Vortioxetine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vortioxetine. Management: Consider increasing the vortioxetine dose to no more than 3 times the original dose when used with a strong drug metabolism inducer for more than 14 days. The vortioxetine dose should be returned to normal within 14 days of stopping the strong inducer. Consider therapy modification

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

Zaleplon: CYP3A4 Inducers (Strong) may decrease the serum concentration of Zaleplon. Management: Consider the use of an alternative hypnotic that is not metabolized by CYP3A4 in patients receiving strong CYP3A4 inducers. If zalephon is combined with a strong CYP3A4 inducer, monitor for decreased effectiveness of zaleplon. Consider therapy modification

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

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

15 to 20 mg PE/kg IV at 100 to 150 mg PE/min followed by maintenance doses of either fosphenytoin or phenytoin

Comments:
-The dose, concentration, and infusion rate of this drug should always be expressed as phenytoin sodium equivalents (PE).
-This drug should not ordinarily be given IM for the treatment of status epilepticus because therapeutic phenytoin concentrations may not be reached as quickly as with IV administration.
-Because the full antiepileptic effect of phenytoin is not immediate, other measures, including concomitant administration of an IV benzodiazepine, will usually be necessary for the control of status epilepticus.
-Because of the risk of hypotension, this drug should be administered no faster than 150 mg PE/min.
-Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is important and the patient should be observed throughout the period where maximal serum phenytoin concentrations occur, approximately 10 to 20 minutes after the end of the infusion.
-If this drug does not terminate seizures, the use of alternative anticonvulsants should be considered.

Use: For the control of generalized tonic-clonic status epilepticus

Data not available