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CEREBYX® Drug Interactions (fosphenytoin sodium)


Fosphenytoin is extensively bound to human plasma proteins. Drugs highly bound to albumin could increase the unbound fraction of fosphenytoin. Although, it is unknown whether this could result in clinically significant effects, caution is advised when administering CEREBYX with other drugs that significantly bind to serum albumin. The most significant drug interactions following administration of CEREBYX are expected to occur with drugs that interact with phenytoin. Phenytoin is extensively bound to serum plasma proteins and is prone to competitive displacement. Phenytoin is primarily metabolized by the hepatic cytochrome P450 enzyme CYP2C9 and to a lesser extent by CYP2C19 and is particularly susceptible to inhibitory drug interactions because it is subject to saturable metabolism. Inhibition of metabolism may produce significant increases in circulating phenytoin concentrations and enhance the risk of drug toxicity. Monitoring of phenytoin serum levels is recommended when a drug interaction is suspected.

Phenytoin or CEREBYX is a potent inducer of hepatic drug-metabolizing enzymes.

7.1 Drugs that Affect Phenytoin or CEREBYX

Table 6 includes commonly occurring drug interactions that affect phenytoin (the active metabolite of CEREBYX) concentrations. However, this list is not intended to be inclusive or comprehensive. Individual prescribing information from relevant drugs should be consulted.

The addition or withdrawal of these agents in patients on phenytoin therapy may require an adjustment of the phenytoin dose to achieve optimal clinical outcome.

Table 6. Drugs That Affect Phenytoin Concentrations
Interacting AgentExamples
The induction potency of St. John's wort may vary widely based on preparation.
Drugs that may increase phenytoin serum levels
  Antiepileptic drugsEthosuximide, felbamate, oxcarbazepine, methsuximide, topiramate
  AzolesFluconazole, ketoconazole, itraconazole, miconazole, voriconazole
  Antineoplastic agentsCapecitabine, fluorouracil
  AntidepressantsFluoxetine, fluvoxamine, sertraline
  Gastric acid reducing agentsH2 antagonists (cimetidine), omeprazole
  SulfonamidesSulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim
  OtherAcute alcohol intake, amiodarone, chloramphenicol, chlordiazepoxide, disulfiram, estrogen, fluvastatin, isoniazid, methylphenidate, phenothiazines, salicylates, ticlopidine, tolbutamide, trazodone, warfarin
Drugs that may decrease phenytoin serum levels
  Antineoplastic agents usually in combinationBleomycin, carboplatin, cisplatin, doxorubicin, methotrexate
  Antiviral agentsFosamprenavir, nelfinavir, ritonavir
  Antiepileptic drugsCarbamazepine, vigabatrin
  OtherChronic alcohol abuse, diazepam, diazoxide, folic acid, reserpine, rifampin, St. John's wort,* theophylline
Drugs that may either increase or decrease phenytoin serum levels
  Antiepileptic drugsPhenobarbital, valproate sodium, valproic acid

7.2 Drugs Affected by Phenytoin or CEREBYX

Table 7 includes commonly occurring drug interactions affected by phenytoin (the active metabolite of CEREBYX). However, this list is not intended to be inclusive or comprehensive. Individual drug package inserts should be consulted. The addition or withdrawal of phenytoin during concomitant therapy with these agents may require adjustment of the dose of these agents to achieve optimal clinical outcome.

Table 7: Drugs Affected by Phenytoin
Interacting AgentExamples
The effect of phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is unpredictable.
Drugs whose efficacy is impaired by phenytoin
  AzolesFluconazole, ketoconazole, itraconazole, posaconazole, voriconazole
  Antineoplastic agentsIrinotecan, paclitaxel, teniposide
  DelavirdinePhenytoin can substantially reduce the concentrations of delavirdine. This can lead to loss of virologic response and possible resistance [see Contraindications (4)].
  Neuromuscular blocking agentsCisatracurium, pancuronium, rocuronium and vecuronium: resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents has occurred in patients chronically administered phenytoin. Whether or not phenytoin has the same effect on other non-depolarizing agents is unknown.
Prevention or Management: Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.
  WarfarinIncreased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin.
  OtherCorticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D
Drugs whose level is decreased by phenytoin
  AnticoagulantsApixaban, dabigatran, edoxaban, rivaroxaban
  Antiepileptic drugs*Carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine, lacosamide
  Antilipidemic agentsAtorvastatin, fluvastatin, simvastatin
  Antiviral agentsEfavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir
Fosamprenavir: phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir
  Calcium channel blockersNifedipine, nimodipine, nisoldipine, verapamil
  OtherAlbendazole (decreases active metabolite), chlorpropamide, clozapine, cyclosporine, digoxin, disopyramide, folic acid, methadone, mexiletine, praziquantel, quetiapine

7.3 Hyperammonemia with Concomitant Use of Valproate

Concomitant administration of phenytoin and valproate has been associated with an increased risk of valproate-associated hyperammonemia. Patients treated concomitantly with these two drugs should be monitored for signs and symptoms of hyperammonemia.

7.4 Drug/Laboratory Test Interactions

Care should be taken when using immunoanalytical methods to measure serum phenytoin concentrations following CEREBYX administration.

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