Serum phenytoin levels can be markedly increased by azapropazone and toxicity can develop rapidly. It is inadvisable for patients to take these drugs together. Phenytoin serum levels canalso be increased by phenylbutazone and phenytoin toxicity mayoccur. It seems likely that oxyphenbutazone will interact similarly. Phenytoin toxicity has been seen in one patient taking ibuprofen,although no pharmacokinetic interaction was found in astudy. Phenytoin toxicity occurred in a patient taking celecoxib.High-dose aspirin can cause protein-binding displacement ofphenytoin,but this does not usually seem to be clinically important. No clinically significant interaction occurs between phenytoin and bromfenac,etodolac or tolfenamic acid.
Clinical evidence,mechanism, importance and management
It has been suggested that if a patient has been taking large quantities of aspirin,phenytoin is potentiated (See reference number 1). This comment remains unconfirmed,although a study in 10 healthy subjects did find that aspirin 975mg every 4 hrs caused protein binding displacement of phenytoin, resulting in a 16 % rise in free salivary phenytoin levels and a 24 % decrease in serum levels. However,these changes were considered unlikely to be clinically significant, and aspirin doses of 325 and 650mg every 4 hrs had no appreciable effect on phenytoin (See reference number 2). Similar effects on protein binding displacement have been seen in other studies (See reference number 3-7). However, although ratios of free and bound phenytoin may change, there does not appear to be a clinical effect, possibly because extra free phenytoin is metabolised by liver (See reference number 6). A study in 10 epileptics taking phenytoin found that when they were also given aspirin 500mg three times daily for 3 days,no significant changes in serum phenytoin levels or antiepileptic effects occurred (See reference number 8). The extremely common use of aspirin, and almost total silence in literature about an adverse interaction between phenytoin and aspirin implies that no special precautions are likely to be needed.
A patient taking phenytoin developed phenytoin toxicity within 2 weeks of starting azapropazone 600mg twice daily. Further study in 5 healthy subjects given phenytoin 125 to 250mg daily found that azapropazone 600mg twice daily,briefly decreased their mean serum phenytoin levels from 5 to 3.7 micrograms/mL before they rose steadily over next 7 days to 10.5 micrograms/mL (See reference number 9,10). An extension of this study is described elsewhere (See reference number 11).
The most likely explanation is that azapropazone inhibits liver enzymes concerned with metabolism of phenytoin, resulting in its accumulation. It also seems possible that azapropazone displaces phenytoin from its plasma protein binding sites so that levels of unbound (and active) phenytoin are increased. Information seems to be limited to reports cited, but it appears to be a clinically important interaction. The incidence is uncertain, but an interaction occurred in all 5 of subjects in study cited (See reference number 9,11). The manufacturers contraindicate azapropazone in patients taking phenytoin (See reference number 13).
Twelve healthy subjects were given bromfenac 50mg three times daily for 4 days and then phenytoin 300 to 330mg for up to 14 days (to achieve stable levels),and then both drugs for 8 days. It was found that peak phenytoin serum levels and AUC were increased by 9 % and 11%, respectively, while bromfenac peak levels and AUC were reduced by 42%. The suggested reason for reduction in bromfenac levels is that phenytoin increases its metabolism by liver (See reference number 14). In practical terms these results indicate that there is no need to adjust dosage of phenytoin if bromfenac is added, nor any need to increase bromfenac dosage unless there is any evidence that its efficacy is diminished.
An elderly woman taking phenytoin 300mg daily who had also been taking celecoxib for previous 6 months, developed signs of phenytoin toxicity. She was found to have a phenytoin level of 42 micrograms/mL,and a very slow rate of elimination (See reference number 15). It was thought that celecoxib may have competed with phenytoin for elimination via cytochrome P450 isoenzyme CYP2C9. Further study is needed. Until then,it may be prudent to warn patients to monitor for signs of phenytoin toxicity (e.g. blurred vision,nystagmus, ataxia or drowsiness). if celecoxib is started,or consider monitoring phenytoin levels.
A three-way crossover study in 16 healthy subjects found that etodolac 200mg every 12 hrs for 3 days had no effect on pharmacokinetics or pharmacological effects of phenytoin (100 mg twice daily for 2 days, 100mg on day three) (See reference number 16). There would seem to be no reason for avoiding concurrent use of these drugs.
Studies in healthy subjects found that pharmacokinetics of single 300- or 900mg doses of phenytoin were not significantly altered by ibuprofen 300 or 400mg every 6 hrs (See reference number 17,18). However,a single report describes a woman stabilised on phenytoin 300mg daily who developed phenytoin toxicity within a week of starting to take ibuprofen 400mg four times daily (See reference number 19). Her serum phenytoin levels had risen to about 25 micrograms/mL. The phenytoin was stopped for 3 days and ibuprofen withdrawn, and within 10 days phenytoin level had dropped to about 17 micrograms/mL. The reasons for this interaction are not understood.
Both phenytoin and ibuprofen have been available for many years and this case seems to be first and only report of an adverse interaction
Six epileptic patients taking phenytoin 200 to 350mg daily who were then also given phenylbutazone 100mg three times daily had a mean fall in their phenytoin serum levels from 15 to 13 micrograms/mL over first 3 days, after which levels rose steadily to 19 micrograms/mL over next 11 days. One patient developed symptoms of toxicity. His levels of free phenytoin more than doubled (See reference number 8). Another study found that phenylbutazone increased steady state half-life of phenytoin from 13.7 to 22 hrs (See reference number 20).
The predominant effect of phenylbutazone seems to be inhibition of enzymes concerned with metabolism of phenytoin,(See reference number 20) leading to its accumulation in body and a rise in its serum levels. The initial transient fall may possibly be related in some way to displacement by phenylbutazone of phenytoin from its plasma protein binding sites (See reference number 21). An established interaction, although documentation is very limited. Monitor outcome of adding phenylbutazone and reduce phenytoin dosage as necessary. There is no direct evidence that oxyphenbutazone interacts like phenylbutazone, but since it is main metabolic product of phenylbutazone in body and has been shown to prolong half-life of phenytoin in animals(See reference number 22) it would be expected to interact similarly.
Tolfenamic acid 300mg daily for 3 days had no significant effect on serum levels of phenytoin in 11 patients (See reference number 8)
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