Interactions : אינטראקציות

7        DRUG INTERACTIONS
Phenytoin is extensively bound to 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 is a potent inducer of hepatic drug-metabolizing enzymes.

7.1      Drugs that Affect Phenytoin Concentrations
Table 2 includes commonly occurring drug interactions that affect phenytoin 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 2: Drugs That Affect Phenytoin Concentrations
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
H2 antagonists (cimetidine), omeprazole agents
Sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-
Sulfonamides trimethoprim
Acute alcohol intake, amiodarone, chloramphenicol, chlordiazepoxide,
disulfiram, estrogen, fluvastatin, isoniazid, methylphenidate,
Other phenothiazines, salicylates, ticlopidine, tolbutamide, trazodone,
warfarin
Drugs that may decrease phenytoin serum levels
Calcium carbonate, aluminum hydroxide, magnesium hydroxide a
Antacids                     Prevention or Management: Phenytoin and antacids should not be taken at the same time of day


    Antineoplastic agents
Bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate
(usually in combination)
Antiviral agents            Fosamprenavir, nelfinavir, ritonavir
Antiepileptic drugs         Carbamazepine, vigabatrin
Chronic alcohol abuse, diazepam, diazoxide, folic acid, reserpine,
Other rifampin, St. John’s wortb, sucralfate, theophylline
Drugs that may either increase or decrease phenytoin serum levels
Antiepileptic drugs         Phenobarbital, valproate sodium, valproic acid a
Antacids may affect absorption of phenytoin.
b
The induction potency of St. John’s wort may vary widely based on preparation.
c Valproate sodium and valproic acid are similar medications. The term valproate has been used to represent these medications.

7.2         Drugs Affected by Phenytoin

Table 3 includes commonly occurring drug interactions affected by phenytoin. 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 3: Drugs Affected by Phenytoin
Interacting Agent               Examples
Drugs whose efficacy is impaired by phenytoin
Azoles                          Fluconazole, ketoconazole, itraconazole, posaconazole, voriconazole Antineoplastic agents           Irinotecan, paclitaxel, teniposide
Phenytoin can substantially reduce the concentrations of delavirdine.
Delavirdine                     This can lead to loss of virologic response and possible resistance [see Contraindications (4)].
Cisatracurium, pancuronium, rocuronium and vecuronium: resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents has occurred in patients chronically
Neuromuscular blocking          administered phenytoin. Whether or not phenytoin has the same effect agents                          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.
Increased and decreased PT/INR responses have been reported when
Warfarin phenytoin is coadministered with warfarin
Corticosteroids, doxycycline, estrogens, furosemide, oral
Other                           contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D
Drugs whose level is decreased by phenytoin

Anticoagulants                  Apixaban, dabigatran, edoxaban, rivaroxaban Carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine,
Antiepileptic drugs a lacosamide
Antilipidemic agents            Atorvastatin, fluvastatin, simvastatin Antiplatelets                   Ticagrelor
Efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir,
saquinavir
Antiviral agents                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 blockers        Nifedipine, nimodipine, nisoldipine, verapamil Albendazole (decreases active metabolite), chlorpropamide, clozapine, Other                           cyclosporine, digoxin, disopyramide, folic acid, methadone, mexiletine, praziquantel, quetiapine a
The effect of phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is unpredictable 
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 Enteral Feeding/Nutritional Preparations Interaction

Literature reports suggest that patients who have received enteral feeding preparations and/or related nutritional supplements have lower than expected phenytoin serum levels. It is therefore suggested that phenytoin not be administered concomitantly with an enteral feeding preparation. More frequent serum phenytoin level monitoring may be necessary in these patients.

7.5       Drug/Laboratory Test Interactions

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