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.
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.
| Interacting Agent | Examples |
|---|---|
| |
Drugs that may increase phenytoin serum levels | |
Antiepileptic drugs | Ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate |
Azoles | Fluconazole, ketoconazole, itraconazole, miconazole, voriconazole |
Antineoplastic agents | Capecitabine, fluorouracil |
Antidepressants | Fluoxetine, fluvoxamine, sertraline |
Gastric acid reducing agents | H2 antagonists (cimetidine), omeprazole |
Sulfonamides | Sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim |
Other | Acute 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 combination | Bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate |
Antiviral agents | Fosamprenavir, nelfinavir, ritonavir |
Antiepileptic drugs | Carbamazepine, vigabatrin |
Other | Chronic alcohol abuse, diazepam, diazoxide, folic acid, reserpine, rifampin, St. John's wort,* theophylline |
Drugs that may either increase or decrease phenytoin serum levels | |
Antiepileptic drugs | Phenobarbital, valproate sodium, valproic acid |
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.
| Interacting Agent | Examples |
|---|---|
| |
Drugs whose efficacy is impaired by phenytoin | |
Azoles | Fluconazole, ketoconazole, itraconazole, posaconazole, voriconazole |
Antineoplastic agents | Irinotecan, paclitaxel, teniposide |
Delavirdine | Phenytoin can substantially reduce the concentrations of delavirdine. This can lead to loss of virologic response and possible resistance [see Contraindications (4)]. |
Neuromuscular blocking agents | Cisatracurium, 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.
|
Warfarin | Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin. |
Other | Corticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D |
Drugs whose level is decreased by phenytoin | |
Anticoagulants | Apixaban, dabigatran, edoxaban, rivaroxaban |
Antiepileptic drugs* | Carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine, lacosamide |
Antiplatelets | Ticagrelor |
Antilipidemic agents | Atorvastatin, fluvastatin, simvastatin |
Antiviral agents | Efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir |
Calcium channel blockers | Nifedipine, nimodipine, nisoldipine, verapamil |
Other | Albendazole (decreases active metabolite), chlorpropamide, clozapine, cyclosporine, digoxin, disopyramide, folic acid, methadone, mexiletine, praziquantel, quetiapine |
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.
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.
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.
| Interacting Agent | Examples |
|---|---|
| |
Drugs that may increase phenytoin serum levels | |
Antiepileptic drugs | Ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate |
Azoles | Fluconazole, ketoconazole, itraconazole, miconazole, voriconazole |
Antineoplastic agents | Capecitabine, fluorouracil |
Antidepressants | Fluoxetine, fluvoxamine, sertraline |
Gastric acid reducing agents | H2 antagonists (cimetidine), omeprazole |
Sulfonamides | Sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim |
Other | Acute 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 combination | Bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate |
Antiviral agents | Fosamprenavir, nelfinavir, ritonavir |
Antiepileptic drugs | Carbamazepine, vigabatrin |
Other | Chronic alcohol abuse, diazepam, diazoxide, folic acid, reserpine, rifampin, St. John's wort,* theophylline |
Drugs that may either increase or decrease phenytoin serum levels | |
Antiepileptic drugs | Phenobarbital, valproate sodium, valproic acid |
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.
| Interacting Agent | Examples |
|---|---|
| |
Drugs whose efficacy is impaired by phenytoin | |
Azoles | Fluconazole, ketoconazole, itraconazole, posaconazole, voriconazole |
Antineoplastic agents | Irinotecan, paclitaxel, teniposide |
Delavirdine | Phenytoin can substantially reduce the concentrations of delavirdine. This can lead to loss of virologic response and possible resistance [see Contraindications (4)]. |
Neuromuscular blocking agents | Cisatracurium, 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.
|
Warfarin | Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin. |
Other | Corticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D |
Drugs whose level is decreased by phenytoin | |
Anticoagulants | Apixaban, dabigatran, edoxaban, rivaroxaban |
Antiepileptic drugs* | Carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine, lacosamide |
Antiplatelets | Ticagrelor |
Antilipidemic agents | Atorvastatin, fluvastatin, simvastatin |
Antiviral agents | Efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir |
Calcium channel blockers | Nifedipine, nimodipine, nisoldipine, verapamil |
Other | Albendazole (decreases active metabolite), chlorpropamide, clozapine, cyclosporine, digoxin, disopyramide, folic acid, methadone, mexiletine, praziquantel, quetiapine |
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.
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