Antiepileptic Drugs, 5th Edition

Phenytoin and Other Hydantoins


Interactions with Other Drugs

Isabelle Ragueneau-Majlessi MD*

Manoj Bajpai PhD**

René H. Levy PhD***

* Research Associate, Department of Pharmaceutics, University of Washington, Seattle, Washington

** Department of Pharmaceutics and Drug Metabolism, Amgen Incorporated, Thousand Oaks, California

*** Professor and Chair, Department of Pharmaceutics, Professor of Neurological Surgery, University of Washington School of Pharmacy and Medicine, Seattle, Washington

Numerous interactions between phenytoin (PHT) and other drugs have been reported, involving different therapeutic classes, and resulting in signs of intoxication or lack of effectiveness of PHT or the other drug(s). Most of the drug interactions observed with PHT involve inhibition of its biotransformation or alteration of its protein binding. In addition, PHT is a potent inducer of the metabolism of various compounds.

This chapter is divided as follows: Alteration of PHT Kinetics by Antiepileptic Drugs (AEDs); Alteration of PHT Kinetics by Other Drugs; Effects of PHT on Kinetics of Other AEDs; and Effects of PHT on Kinetics of Other Drugs. In each section, drugs or drug classes are presented in alphabetical order.



PHT is slowly but almost completely absorbed. In clinical studies using low dosages of antacids (10 mL every 6 hours), little or no effect was seen (70). Higher doses (15 to 45 mL), however, were found to reduce PHT bioavailability (14,19). The effect usually is more noticeable if the antacid is given at the same (or nearly the same) time as PHT; therefore, it is advisable to keep a minimum interval of about 2 hours between the administration of PHT and the ingestion of antiacids.

Food has been found to have variable but modest, usually enhancing, effects on PHT absorption (14). Lipid meals were found to increase PHT bioavailability (101). A protein-rich diet had the same effect on PHT acid but not on the sodium salt (41). A constant relationship in time between food intake and ingestion of PHT is recommended (41,59). Low levels of PHT have been found in some patients receiving liquid food concentrates given either by nasogastric tube or orally (108).

Activated charcoal delays and reduces absorption of PHT and influences the enterohepatic recirculation; therefore, it is beneficial to give large doses of charcoal in the early phases of massive PHT overdose (115).

Protein Binding

Approximately 90% of the total PHT in the plasma is protein bound. Other strongly bound drugs, such as tolbutamide (116), salicylates (27), valproate (63), and phenylbutazone (104), can displace PHT from its binding sites. Plasma protein binding interactions per se are not expected to modify the pharmacologic effect of PHT, but they should be taken into account when interpreting total serum PHT concentrations. In fact, in the presence of a displacing agent, therapeutic and toxic effects are expected to occur at total serum PHT concentrations lower than usual.


PHT undergoes extensive metabolism, with less than 5% of the dose excreted unchanged in urine. PHT is metabolized by cytochrome P450 (CYP) isoforms CYP2C9 and CYP2C19 to the two enantiomers of its primary metabolite, p-HPPH [5-(4-hydroxyphenyl)-5-phenylhydantoin] (6). CYP2C9 is the major contributor in the formation of the (S)-enantiomer of p-HPPH. Both CYP2C9 and


CYP2C19 are expressed polymorphically in the human population, with two functionally defective alleles of CYP2C9 and four null alleles of CYP2C19 currently recognized. Genetically determined defects in the expression of CYP2C9 and CYP2C19 could explain the occurrence of high serum PHT concentrations in some patients treated with normal doses of PHT.



The effect of carbamazepine on the plasma PHT level varies among patients. A lowering effect (120), no significant changes, and an upward trend has been observed (25,79,124). Prolongation of PHT half-life by carbamazepine in several but not all patients was seen using a stable isotope-labeled PHT test dose (13). What to expect in an individual patient is largely unpredictable and concurrent use should be monitored.


Chlordiazepoxide has caused elevated PHT concentrations in some patients (47,112).


Clobazam may have no marked effect on plasma PHT level in many patients (102), but it has caused an increase in PHT concentration and intoxication in some (125).


Clonazepam has been reported to lower the plasma PHT level in some patients (95), but in other studies, clonazepam has caused a rise in the PHT level (120) or no significant changes (35,38).


The effect of diazepam on the plasma PHT level varies among patients, with elevations (112) or decreases (35) of PHT levels. In most patients, the commonly used diazepam doses do not seem to cause significant changes in PHT level.


Felbamate has been shown to inhibit CYP2C19 in vitro with an inhibition constant in the therapeutic range (Ki, 225 µmol/L) (29). Recently, Sachdeo et al. showed that when 10 patients on PHT monotherapy received increasing dosages of felbamate (1,200, 1,800, 2,400 to 3,600 mg/day), PHT plasma concentrations increased and PHT dose reductions of at least 20% were required (96).


In several studies, the addition of flunarizine caused little change in PHT levels (111).


Gabapentin usually is not found to alter PHT levels (88).


Single and repeated doses of lamotrigine do not alter PHT kinetics significantly (74).


Levetiracetam has no effect in vitro on PHT metabolism (68). In most studies, levetiracetam did not modify plasma PHT levels in epileptic patients (72).


Comedication of epileptic patients with PHT and methsuximide caused varying degrees of elevation in the plasma PHT level (86).


Oxcarbazepine is an inhibitor of CYP2C19 and therefore may cause a moderate increase in plasma PHT concentration (7).


Phenobarbital induces CYP2C enzymes (46), but is also is a substrate for those enzymes (73). This dual effect leads to variable results in patients taking PHT and phenobarbital together, with an increase, a decrease, or no change in PHT levels having been reported.


Progabide given as add-on medication caused elevation of PHT levels to varying extents in most patients (52).


Stiripentol reduced the clearance of PHT in a dose-dependent manner up to 40% (51).


Tiagabine (90,91) does not cause significant alterations of plasma PHT levels.


Topiramate occasionally may cause an increase in plasma PHT concentration (76), probably by inhibiting CYP2C19.


The effect of valproate on PHT plasma level varies among patients and may vary in the same patient during the course of therapy. Thus, a persistent fall (54) or a transient fall (63) or even a rise (120) within days after the addition of valproate occurs in some patients. When a fall in plasma PHT concentration occurs, this can be ascribed to displacement of PHT from plasma protein binding sites (66), and the free plasma concentration is not reduced or even may be increased (54,75). Clinically, the need to adjust PHT dose is rare.


Vigabatrin may cause up to a 40% decline in PHT levels in some patients, sometimes as late as a few weeks after starting combined therapy (92). Comparing groups of patients taking PHT with and without vigabatrin revealed only small differences in PHT plasma levels (58).


The effect of zonisamide on blood PHT levels is modest and variable, and there was no need to adjust the PHT dose because of the interaction (34).




Activated Charcoal.

As discussed previously, activated charcoal effectively inhibits the absorption of PHT from the gastrointestinal tract (115).

Analgesics, Antipyretics, and Nonsteroidal Antiinflammatory Drugs


Prolongation of PHT half-life and PHT intoxication has occurred in some epileptic patients taking phenylbutazone (104). The major factors in this interaction are displacement of PHT from plasma binding sites and inhibition of PHT metabolism (inhibition of CYP2C9). Thus, an increase in the plasma concentration of free, pharmacologically active PHT also may occur in the absence of any change in total plasma PHT concentration. It may be necessary to adjust PHT dosage in some patients.


The PHT plasma level increased slightly in five patients after they received 65 mg of propoxyphene three times daily for 6 days (18). In another patient who took large amounts (650 mg/day) of propoxyphene for several days (47), PHT accumulated to the toxic range. These effects are consistent with inhibition of CYP2C9.


Salicylates can displace PHT from plasma protein binding sites in vitro and in vivo. In clinical studies, an increase in the unbound fraction of PHT from the usual 10% to near 16% and an increase in PHT clearance by acetylsalicylic acid was observed (27). This interaction is unlikely to be clinically relevant.

Anticoagulants and Inhibitors of Platelet Aggregation


Bishydroxycoumarin (104) and, to a lesser extent, phenprocoumon have been reported to cause elevations of PHT plasma levels in some patients.


Several cases of PHT toxicity during concomitant ticlopidine therapy have been reported (43,83). In a clinical study performed in six patients treated with PHT, 250 mg ticlopidine twice daily inhibited the clearance of PHT (20). These interactions are consistent with in vitro findings that ticlopidine is a potent inhibitor of CYP2C19.



Two case reports have described signs of PHT toxicity resulting from combined administration of fluoxetine and PHT (37). In both cases, PHT plasma levels increased significantly when fluoxetine was coadministered, and removal or gradual reduction of fluoxetine resulted in complete recovery. This interaction with PHT can be explained by inhibition of CYP2C19 by fluoxetine.


A recent report described the case of a patient with PHT plasma concentrations that increased from 16.6 to 49.1 µg/mL when fluvoxamine was coadministered, associated with clinical symptoms of PHT toxicity (53).


Imipramine caused an increase in PHT levels in some studies, but in other studies no significant alteration of PHT kinetics was seen. It appears that the tricyclic antidepressants rarely necessitate PHT dosage adjustments.


Sertraline, a known inhibitor of the CYP2C family, increased PHT plasma levels in two elderly patients, without symptoms of toxicity (32).


The PHT level increased from 17 to 46 µg/mL in a patient within a few weeks after trazodone administration. Clinical intoxication occurred and the PHT dose had to be reduced (23).


Viloxazine increased plasma PHT levels by 7% to 94% and caused intoxication in 4 of 10 epileptic patients (78).

Antifungal Agents


Several case reports have been published describing PHT toxicity in the presence of fluconazole (15,36,61), with significant increases in PHT plasma levels. In addition to these clinical reports, several controlled trials in healthy subjects have shown that fluconazole increases the serum concentration of PHT (10,49,110). Based on in vitro studies, the interaction between PHT and fluconazole can be attributed to inhibition of CYP2C9 and CYP2C19.


In one patient well controlled by PHT, miconazole in combination with flucytosine caused an elevation of PHT levels associated with symptoms of PHT toxicity (94). Miconazole is an inhibitor of CYP2C9.



A modest elevation of plasma PHT levels has occurred in some patients after the addition of chlorpheniramine, but without the need to change dosages (84).


Terfenadine caused essentially no changes in PHT pharmacokinetics (17).

Antimicrobial Agents


Chloramphenicol has caused modest elevations of PHT plasma levels in some patients and


marked elevations in others (44,66). The need to reduce the PHT dose has varied.


Isoniazid noncompetitively inhibits PHT metabolism in vitro and in vivo (46,121). In patients taking PHT and isoniazid, significant PHT accumulation and intoxication have been reported in 10% to 15% of the subjects (21,121), some of whom were identified as very slow acetylators (12,114).


Rifampin can lower PHT levels and increase its clearance by a factor of two. Furthermore, rifampin comedication minimizes the inhibitory effect of isoniazid even in the slow isoniazid acetylators (40).


A number of bacteriostatic sulfonamides, including sulfadiazine, sulfamethizole, sulfamethoxazole, and sulfaphenazole, can reduce PHT clearance and prolong its half-life (62). The mechanism appears to be inhibition of CYP2C enzymes, and sulfaphenazole is the strongest inhibitor (22,62) of PHT metabolism. Some sulfonamides also may displace PHT from plasma binding sites. Adjustment of PHT dosage may become necessary during sulfonamide therapy.

Antineoplastic Agents

Low PHT levels have been observed in several patients undergoing antineoplastic therapy with vinblastine, cisplatinum, or bleomycin and adriamycin (11,107).


High-dose tamoxifen therapy was associated with clinical signs of PHT toxicity and increased serum PHT levels (85).



Two case reports described PHT intoxication during concurrent administration of thioridazine (113). However, a retrospective study (99) in 27 adult patients treated with PHT showed no clinically important alterations in PHT serum concentration with thioridazine.

Antiulcer Agents


Antacids such as aluminum and magnesium hydroxides and calcium carbonate have been found to reduce or maintain low blood PHT levels in some patients but not in others. It appears that the total dose of antacid and the time of administration are determining factors.


Cimetidine has been found to increase PHT concentrations (50,77) by inhibition of metabolism (inhibition of CYP2C19). In one study (77), 300 mg of cimetidine given four times a day caused elevation of blood PHT levels in a few days in five of nine subjects. In another study (97), PHT levels increased in six patients, causing intoxication in two, after addition of cimetidine.


Gugler and Jensen (30) have shown that omeprazole, a weak inhibitor of CYP2C19, causes a small but consistent elevation of PHT levels in healthy subjects. Prichard et al. (82) also have shown significant increases in the plasma levels of PHT in healthy subjects receiving omeprazole.

Cardiovascular Agents


Amiodarone caused a twofold to threefold increase in PHT plasma levels in three patients (57) and increased the PHT half-life severalfold in healthy volunteers (69) by inhibition of PHT metabolism (inhibition of CYP2C9).

Calcium Channel Blockers.

Among calcium channel blockers, verapamil and nifedipine had little or no effect on PHT concentration, but diltiazem caused elevations and intoxication in 3 of 14 patients (5).


Diazoxide reduced the protein binding of PHT, with a consequent increase in the free fraction and a slight decrease in the total plasma PHT concentration (93).

Hypoglycemic Agents


Tolbutamide was found to displace PHT from plasma binding sites and to lower plasma PHT levels in patients (116).

Other Agents


Disulfiram noncompetitively inhibits PHT metabolism and causes an increase in plasma PHT concentrations and signs of PHT intoxication in most patients (71). A study by Svendsen et al. (106) with healthy volunteers demonstrated that disulfiram reduced PHT clearance from approximately 50 to 34 mL/min. Dosage adjustment of PHT is necessary when these two drugs are administered together.


Prolonged use of ethanol can reduce PHT plasma level (98), perhaps through enzyme induction. Elevation of the PHT plasma level, on the other hand, has been observed during occasional moderate or heavy intake of ethanol (47).



PHT is a potent inducer of carbamazepine biotransformation (25,48), probably through induction


of CYP3A4. The plasma concentration of 10,11-carbamazepine epoxide, which usually equals 10% to 20% of the parent compound in patients on monotherapy, may remain unchanged after the addition of PHT, or may undergo a small rise or fall (89).


PHT induces clobazam metabolism. The plasma levels of clobazam were lower, whereas those of the active metabolite norclobazam were higher during comedication (102).


PHT increased clonazepam clearance by 46% to 58% in healthy subjects (42).


Flunarizine levels were lower in patients receiving combined medication with enzyme inducers, including PHT (111).


Lamotrigine clearance is increased and plasma levels are lowered by comedication with PHT, suggesting induction of glucuronidation (74).


PHT does not appear to modify the plasma levels of levetiracetam to any significant extent (72).


PHT was found to increase the levels of the pharmacologically active metabolite N-desmethylmeth-suximide in epileptic patients (86).


PHT has been reported to cause an elevation of plasma phenobarbital levels in some patients (64,120). Also, in some patients stabilized on combination therapy, a decrease in phenobarbital plasma levels was noted after PHT was discontinued (25,64). In most patients, however, PHT does not cause significant changes in plasma phenobarbital levels, and the need to adjust dosages because of this interaction is expected to be rare.


PHT induces primidone biotransformation, but this interaction rarely leads to a need for dosage adjustments.


Induction of oxazepam metabolism has been demonstrated in epileptic patients treated with PHT alone or in combination with phenobarbitone (100).


PHT reduces to a moderate extent the plasma levels of 10-hydroxycarbazepine, the active metabolite of oxcarbazepine (4).


The plasma levels of tiagabine are reduced markedly by PHT (91).


PHT induces the metabolism of topiramate and reduces its concentration in plasma (76).


There is extensive evidence that plasma valproic acid levels are lower in patients who receive polytherapy with enzyme inducers. In particular, PHT was shown to have the strongest reducing effect (up to 50%) on plasma valproic acid levels (56).


PHT is a more effective inducer of zonisamide metabolism than is carbamazepine, and reduces plasma zonisamide levels to a considerable extent (34).


Analgesics and Antipyretics

Acetaminophen (Paracetamol).

The elimination of acetaminophen is accelerated by PHT, perhaps through induction of its biotransformation (66).

Meperidine (Pethidine).

Meperidine half-life declined from 6.4 to 4.3 hours, and the area under the concentration-time curve (AUC) of the primary metabolite of meperidine increased after the addition of PHT (81). Patients given PHT may need higher doses of meperidine.


Plasma methadone levels decreased by 50% in five patients on methadone maintenance who had received PHT for 3 weeks (109). Several of these patients started to have withdrawal signs and symptoms while receiving a previously adequate methadone maintenance dose.



Daily doses of 300 to 400 mg of PHT, producing blood levels of 10 to 20 µg/mL, reduced the half-life of intravenously administered theophylline by 40% and increased its clearance in 10 volunteers. It was suggested that patients receiving PHT may need higher or more frequent doses of theophylline (39,103).



A case was reported of an interaction between PHT and acenocoumarol, possibly potentiated by concomitant treatment with paroxetine, leading to a retroperitoneal hematoma (1). Monitoring of anticoagulant response is recommended in patients started on the combination of PHT and acenocoumarol, or when PHT is removed from combination therapy.


PHT can reduce the blood level of dicoumarol, leading to a need for increased dosage of that anticoagulant (31).


The effect of PHT on warfarin is variable. Although PHT is expected to reduce the effect of warfarin


through enzyme induction, an increased anticoagulant effect has been reported in some patients given this combination (65). Close monitoring of anticoagulant effect is recommended whenever PHT is added or removed from the therapeutic regimen of patients stabilized on warfarin.



In healthy volunteers given itraconazole (single dose of 200 mg orally) alone and after 15 days of 300 mg PHT once daily (24), PHT decreased the itraconazole AUC by more than 90%, from 3,203 to 224 ng/hr/mL, with a decrease in the itraconazole half-life from 22.3 to 3.8 hours. Similar changes were observed for hydroxyitraconazole. Given this marked reduction in itraconazole serum concentrations, it would be prudent to use an alternative antifungal agent in patients receiving PHT.



PHT was found to reduce chloramphenicol levels in patients (45).


The elimination of doxycycline was increased in patients receiving PHT (67).


The plasma levels of the anthelmintic praziquantel were reduced twofold to threefold during comedication with PHT, probably because of enzyme induction. Higher-than-average doses of praziquantel were recommended for comedicated patients with poor response in the treatment of neurocysticercosis (9).

Antineoplasic Agents


PHT increased the clearance of (R)-and (S)-cyclophosphamide by 100% and 150%, respectively, in three bone marrow transplant recipients (118).



PHT induced the metabolism of quetiapine, a newly introduced antipsychotic, in schizophrenic patients, resulting in a fivefold increase in quetiapine clearance (123). Dosage adjustment of quetiapine may be necessary when the two drugs are given concurrently.

Cardiovascular Agents


In some patients receiving PHT, digitoxin levels were reduced to a modest extent (105).


Coadministration of PHT caused a significant reduction in digoxin half-life and a 27% increase in its clearance in healthy subjects (87).


PHT can induce disopyramide metabolism but, because the dealkylated metabolite also is pharmacologically active, a loss of effectiveness may not occur (3).


The diuretic effect of furosemide is reduced by PHT to some degree. There is evidence that PHT reduces furosemide absorption, but interference with furosemide action in the kidney may occur as well (2,119).


PHT has been shown to enhance the metabolism of mexiletine and to reduce the AUC of mexiletine by 55% in healthy subjects (8). This interaction is likely to be clinically significant.


PHT increased the metabolism of nisoldipine to a clinically important extent in 12 epileptic patients (60), with a mean decrease in the nisoldipine AUC of 90%.


PHT has been found to reduce the half-life of quinidine by 50%. An increase in the dosage of quinidine may be required to maintain effective plasma quinidine levels. Conversely, if PHT is discontinued, the quinidine dosage may need to be reduced (66).



PHT reduced the maximal concentration, AUC, and half-life of cyclosporine. This may lead to a reduction in the clinical efficacy of cyclosporine (28).



PHT has been found to reduce the half-life of misonidazole and to accelerate its demethylation. This may diminish the toxicity of misonidazole while not reducing its effectiveness as an enhancer in radiation therapy (117).


Patients treated chronically with PHT needed higher and more frequent doses of vecuronium than average to obtain and maintain required muscle relaxation during neurosurgical procedures. This is likely to be induction related because newly started PHT had much smaller effect on vecuronium (80).


Repeated administration of PHT (100 to 200 mg three times daily for 7 days) increased the clearance of the antioxidant tirilazad (1.5 mg/kg intravenously every 6 hours) by 91.8% in healthy volunteers (26).



PHT induces the metabolism of dexamethasone considerably. The elimination half-life of the


steroid was reduced from 3.5 to 1.8 hours after the addition of PHT (16). In six patients, dexamethasone levels dropped by 50% with PHT comedication (122).

Oral Contraceptives.

Failure of oral contraceptives has been reported in some epileptic patients taking enzyme-inducing AEDs, including PHT (33). Higher-dose contraceptive pills may need to be given in patients comedicated with PHT (55).


Effectiveness of prednisone and prednisolone is reduced in patients taking enzyme-inducing AEDs, including PHT (66). Higher dosages of these steroids are needed in patients comedicated with PHT.


PHT is associated with a wide range of drug interactions, including enzyme induction and inhibition and protein binding displacement. PHT induction of extensively metabolized drugs (e.g., itraconazole, quetiapine, nisoldipine) or drugs with narrow therapeutic indices (e.g., theophylline) results in patient exposure to suboptimal levels of concurrent therapy if dosages are not adjusted by clinical or laboratory monitoring. On the other hand, interactions involving inhibition of PHT metabolism can result in clinical signs of PHT toxicity, and coprescription of known inhibitors of CYP2C9 and CYP2C19, the isoenzymes involved in PHT metabolism (e.g., amiodarone, ticlopidine, fluoxetine), requires careful monitoring. Interactions involving displacement from plasma protein binding sites need to be taken into account when interpreting total plasma PHT concentrations, but they are unlikely to be clinically significant unless additional mechanisms such as enzyme induction or inhibition also are present.

By understanding the different mechanisms involved in PHT interactions, clinicians can predict potential interactions and avoid clinical toxicity with careful monitoring and dosage adjustments.


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