Pharmacy Blog – Dr Vibore

In some patients plasma levels of phenytoin are slightly raisedby topiramate, and topiramate plasma levels may be reduced byphenytoin.

Topiramate,titrated to a maximum of 400mg twice daily, was given to 12 epileptic patients taking phenytoin 260 to 600mg daily. When maximum tolerated dose of topiramate was reached, phenytoin dose was then reduced, and in some cases phenytoin was subsequently discontinued. Topiramate clearance was assessed in 2 patients and was found to be increased two to threefold by phenytoin (See reference number 1). Similarly,a population pharmacokinetic study reported that patients taking phenytoin and topiramate had 50 % lower morning topiramate levels than patients not taking enzyme-inducing antiepileptics (See reference number 2).

In first study above, 3 of 12 patients had a decrease in phenytoin clearance and an increase of 25 to 55 % in AUC of phenytoin when taking topiramate: other 9 had no changes (See reference number 1). This slight increase is said not to be clinically significant based on analyses from six add-on studies (See reference number 3).

An in vitro study using human liver microsomes found that topiramate does not inhibit most hepatic cytochrome P450 isoenzymes,except for CYP2C19 at high concentrations (See reference number 1). This isoenzyme plays a minor role in phenytoin metabolism,but it has been suggested this may become important at high doses of topiramate in patients who are poor CYP2C9 metabolisers,(See reference number 1) (see genetic factors in drug metabolism, , for more information). Phenytoin appears to induce metabolism of topiramate.

The interaction between topiramate and phenytoin appears to be established,and topiramate dose adjustments may be required if phenytoin is added or discontinued. No reduction in phenytoin dosage seems necessary in majority of patients, but be aware that a few patients may have increased phenytoin levels, particularly at high topiramate doses. Monitor phenytoin levels.

Sachdeo RC,Sachdeo SK, Levy RH, Streeter AJ, Bishop FE, Kunze KL, Mather GG, RoskosLK, Shen DD, Thummel KE, Trager WF, Curtin CR, Doose DR, Gisclon LG, Bialer M.Topiramate and phenytoin pharmacokinetics during repetitive monotherapy and combinationtherapy to epileptic patients. Epilepsia (2002) 43: 691–6.

May TW,Jürges U. Serum concentrations of topiramate in epileptic patients: the influence ofdose and comedication. Epilepsia (1999) 40 (Suppl, 2), 249.

Johannessen SI. Pharmacokinetics and interaction profile of topiramate: review and comparison with other newer antiepileptic drugs. Epilepsia (1997) 38 (Suppl 1),S18–S23.

Clinical evidence,mechanism, importance and management

A patient taking primidone had raised serum primidone levels and reduced serum phenobarbital levels. This was attributed to concurrent use of isoniazid, which inhibited metabolism of primidone by liver. The half-life of primidone rose from 8.7 to 14 hrs while taking isoniazid and steady-state primidone levels rose by 83 % (See reference number 1). The importance of this interaction is uncertain but prescribers should bear this interaction in mind in case of an unexpected response to primidone.

1. Sutton G,Kupferberg HJ. Isoniazid as an inhibitor of primidone metabolism. Neurology (1975) 25, 1179–81.

Ticlopidine reduces metabolism of phenytoin

A 65-year-old man taking phenytoin 200mg daily and clobazam developed signs of phenytoin toxicity (vertigo,ataxia, somnolence) within a week of starting ticlopidine 250mg daily. His serum phenytoin levels had risen from 18 mg/L to 34 mg/L. When phenytoin dosage was reduced to 200mg daily toxic symptoms disappeared within a few days and his serum phenytoin levels fell to 18 mg/L. To test whether an interaction had occurred, ticlopidine was stopped, whereupon serum phenytoin levels fell, within about 3 weeks, to 8 mg/L, during which time patient

experienced his first seizure in 2 years. When ticlopidine was restarted, his serum phenytoin levels rose again, within a month, to 19 mg/L (See reference number 1). A number of other case reports describe phenytoin toxicity,which occurred within 2 to 6 weeks of starting ticlopidine 250mg once or twice daily (See reference number 2-7). These were usually managed by reducing phenytoin dose. One patient then experienced breakthrough seizures after ticlopidine was stopped without re-adjusting phenytoin dose (See reference number 6). One case in a patient also taking phenobarbital reported that no change in phenobarbital levels occurred (See reference number 4).

A study in 6 patients taking phenytoin alone found that ticlopidine 250mg twice daily approximately halved steady-state phenytoin clearance (See reference number 8)

The metabolism of phenytoin to 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH) by cytochrome P450 isoenzyme CYP2C19, and to a lesser extent by CYP2C9, in liver is inhibited by ticlopidine (See reference number 1,3,4,9). Further metabolism of HPPH to dihydroxylated products is mediated mainly by CYP2C19 and this may also be inhibited by ticlopidine (See reference number 9).

The interaction is established and clinically important,but its incidence is unknown. It would now be prudent to monitor serum phenytoin levels very closely in any patient if ticlopidine is added to established treatment, being alert for need to reduce phenytoin dosage. If ticlopidine is discontinued, phenytoin dose may need to be increased.

Riva R,Cerullo A, Albani F, Baruzzi A. Ticlopidine impairs phenytoin clearance: a case report. Neurology (1996) 46, 1172–3.

Rindone JP,Bryan G. Phenytoin toxicity associated with ticlopidine administration. Arch Intern Med (1996) 156, 1113.

Privitera M,Welty TE. Acute phenytoin toxicity followed by seizure breakthrough from aticlopidine-phenytoin interaction. Arch Neurol (1996) 53, 1191–2.

Donahue SR,Flockhart DA, Abernethy DR, Ko J-W. Ticlopidine inhibition of phenytoin metabolism mediated by potent inhibition of CYP2C19. Clin Pharmacol Ther (1997) 62, 572–7.

López-Ariztegui N,Ochoa M, Sánchez-Migallón, Nevado C, Martín M, Intoxicación agudapor fenitoína secundaria a interacción con ticlopidina. Rev Neurol (1998) 26, 1017–18.

Klaassen SL. Ticlopidine-induced phenytoin toxicity. Ann Pharmacother (1998) 32,1295–8.

Dahm AEA,Brørs O. Fenytoinforgiftning forårsaket av interaksjon med tiklopidin. Tidsskr Nor Laegeforen (2002) 122, 278–80.

Donahue S,Flockhart DA, Abernethy DR. Ticlopidine inhibits phenytoin clearance. Clin Pharmacol Ther (1999) 66, 563–8.

Giancarlo GM,Venkatakrishnan K, Granda BW, von Moltke LL, Greenblatt DJ. Relative contributions of CYP2C9 and 2C19 to phenytoin 4-hydroxylation in vitro: inhibition by sulfaphenazole, omeprazole, and ticlopidine. Eur J Clin Pharmacol (2001) 57, 31–36.

Clinical evidence,mechanism, importance and management

An isolated report describes a 59-year-old man whose phenytoin levels rose by one-third,from about 19 to 25.5 micrograms/mL,and who experienced drowsiness within a week of starting tizanidine 6mg daily. The phenytoin was stopped for 3 days and restarted at a reduced dose, but drowsiness recurred in 3 weeks (phenytoin level 20.5 micrograms/mL). Therefore, tizanidine was withdrawn (See reference number 1). The general importance of this interaction is unclear,but it would seem prudent to remain aware of this interaction in case of an unusual response to treatment.

1. Ueno K,Miyai K, Mitsuzane K. Phenytoin-tizanidine interaction. DICP Ann Pharmacother (1991) 25, 1273.

Note that tricyclics also lower convulsive threshold

The serum phenytoin levels of 2 patients rose over a 3-month period when they were given imipramine 75mg daily. One of them had an increase in phenytoin levels from about 7.6 to 15 micrograms/mL and developed mild toxicity (drowsiness and uncoordination). These signs disappeared and phenytoin serum levels of both patients fell when imipramine was withdrawn. One of them was also taking nitrazepam and clonazepam, and other sodium valproate and carbamazepine, but were stable on these combinations before addition of imipramine (See reference number 1).

Other studies have shown that nortriptyline 75 mg daily had an insignificant effect on serum phenytoin levels of 5 patients,(See reference number 2) and that amitriptyline had no effect on elimination of phenytoin in 3 subjects (See reference number 3)

A report describes 2 patients who had low serum desipramine levels,despite taking standard dosages, while they were also taking phenytoin (See reference number 4).

One suggestion is that imipramine inhibits metabolism of phenytoin by liver, which results in its accumulation in body. In vitro study(See reference number 5) has shown that tricyclics can inhibit cytochrome P450 isoenzyme CYP2C19, but this isoenzyme usually has only a minor role in phenytoin metabolism (see Antiepileptics,). The reduced desipramine levels may be a result of enzyme induction by phenytoin.

The documentation is very limited indeed and none of these interactions is adequately established. The results of in vitro study suggest that interaction may only assume importance in those who are deficient in CYP2C9, enzyme usually responsible for phenytoin metabolism (See reference number 5). The tricyclic antidepressants as a group lower seizure threshold,(See reference number 6) which suggests extra care should be taken if deciding to use them in epileptic patients. If concurrent use is undertaken effects should be very well monitored.

Perucca E,Richens A. Interaction between phenytoin and imipramine. Br J Clin Pharmacol (1977) 4, 485–6.

Houghton GW,Richens A. Inhibition of phenytoin metabolism by other drugs used in epilepsy.Int J Clin Pharmacol Biopharm (1975) 12, 210–16.

Pond SM,Graham GG, Birkett DJ, Wade DN. Effects of tricyclic antidepressants on drug metabolism. Clin Pharmacol Ther (1975) 18, 191–9.

Fogel BS,Haltzman S. Desipramine and phenytoin: a potential drug interaction of therapeuticrelevance. J Clin Psychiatry (1987) 48, 387–8.

Shin J-G,Park J-Y, Kim M-J, Shon J-H, Yoon Y-R, Cha I-J, Lee S-S, Oh S-W, Kim S-W, Flockhart DA. Inhibitory effects of tricyclic antidepressants (TCAs) on human cytochromeP450 enzymes in vitro: mechanism of drug interaction between TCAs and phenytoin. Drug Metab Dispos (2002) 30, 1102–7.

Dallos V,Heathfield K. Iatrogenic epilepsy due to antidepressant drugs. BMJ (1969) 4, 80–2.

A review of drug interactions of sulfinpyrazone identified two studies that found interactions with phenytoin (See reference number 1). In first, serum phenytoin levels of 2 out of 5 patients taking phenytoin 250 to 350mg daily were doubled from about 10 to 20 micrograms/mL within 11 days of starting to take sulfinpyrazone 800mg daily. One of remaining patients had a small increase in phenytoin levels, but other two had no changes at all. When sulfinpyrazone was withdrawn, serum phenytoin concentrations fell to their former levels. The second study was a clinical study in epileptic patients that found that sulfinpyrazone 800mg daily for a week increased phenytoin half-life from 10 to 16.5 hrs and reduced metabolic clearance from 59 to 32 mL/minute.

Uncertain. It seems probable that sulfinpyrazone inhibits metabolism of phenytoin by liver, thereby allowing it to accumulate in body and leading to a rise in its serum levels. Displacement of phenytoin from its plasma protein binding sites may also have a small part to play.

Information seems to be limited to these studies,which await confirmation. A similar interaction with phenytoin has been reported with phenylbutazone,which has a very close chemical relationship with sulfinpyrazone (see Phenytoin + Aspirin or NSAIDs interaction). Thus what is known suggests that concurrent use should be monitored and suitable phenytoin dosage reductions made where necessary.

1. Pedersen AK,Jacobsen P, Kampmann JP, Hansen JM. Clinical pharmacokinetics and potentially important drug interactions of sulphinpyrazone. Clin Pharmacokinet (1982) 7, 42–56.

Orlistat does not alter pharmacokinetics of phenytoin

Clinical evidence,mechanism, importance and management

In a placebo-controlled,randomised, crossover study, 12 healthy subjects were given a single 300mg dose of phenytoin on day 4 of a 7-day course of orlistat 120mg three times daily. The pharmacokinetics of phenytoin were unchanged by orlistat,(See reference number 1)and no special precautions are therefore thought to be needed if these two drugs are given concurrently.

1. Melia AT,Mulligan TE, Zhi J. The effect of orlistat on the pharmacokinetics of phenytoin inhealthy volunteers. J Clin Pharmacol (1996) 36, 654–8.

Although two small studies found that methylphenidate did notalter phenytoin levels,raised serum phenytoin levels and phenytoin toxicity have been seen in three patients given methylphenidate.

A 5-year-old hyperkinetic epileptic boy taking phenytoin 8.9 mg/kg andprimidone 17.7 mg/kg daily,developed ataxia without nystagmus when he was also given methylphenidate 40mg daily. Serum levels of both antiepileptics were found to be at toxic levels and only began to fall when methylphenidate dosage was reduced (See reference number 1).

A further case of phenytoin toxicity occurred in another child given methylphenidate (See reference number 2). Only one other case has been reported, but this patient was later rechallenged with two drugs and phenytoin toxicity was not seen (See reference number 3).

Furthermore,this interaction has not been seen in clinical studies and observations of 3 healthy subjects(See reference number 3) and more than 11 patients(See reference number 4) taking phenytoin and methylphenidate.

Not fully understood. The suggestion is that methylphenidate acts as an enzyme inhibitor, slowing metabolism of phenytoin by liver and leading to its accumulation in those individuals whose drug metabolising system is virtually saturated by phenytoin.

These appear to be only reports, and any interaction is not established. Concurrent use of phenytoin need not be avoided but be alert for any evi-

dence of toxicity, particularly if phenytoin dosage is high. It would seem prudent to monitor for symptoms of phenytoin toxicity (e.g. blurred vision,nystagmus, ataxia or drowsiness) and take levels if necessary.

Garrettson LK,Perel JM, Dayton PG. Methylphenidate interaction with both anticonvulsantsand ethyl biscoumacetate. A new action of methylphenidate. JAMA (1969) 207, 2053–6.

Ghofrani M. Possible phenytoin-methylphenidate interaction. Dev Med Child Neurol (1988) 30,267–8.

Mirkin BL,Wright F. Drug interactions: effect of methylphenidate on the disposition of diphenylhydantoin in man. Neurology (1971) 21, 1123–8.

Kupferberg HJ,Jeffery W, Hunninghake DB. Effect of methylphenidate on plasma anticonvulsant levels. Clin Pharmacol Ther (1972) 13, 201–4.

Influenza vaccine is reported to increase,decrease or to have noeffect on phenytoin serum levels. The efficacy of vaccine remains unchanged.

The serum phenytoin levels of 8 epileptic children were increased by about 50%,from 9.5 to 15.16 micrograms/mL,7 days after they were given 0.5 mL of an influenza virus vaccine USP,types A and B, whole virus (Squibb). The phenytoin levels returned to baseline over following 7days (See reference number 1). Temporary rises in serum phenytoin levels of 3 patients, apparently caused by influenza vaccination, are briefly described in another report (See reference number 2).

In contrast,another study in 16 patients given 0.5 mL of an inactivated whole-virion trivalent influenza vaccine found that 7 and 14 days later their mean serum phenytoin levels were not significantly altered,although 4 of them showed a trend towards raised levels. Subsequently,these 4 patients had serum phenytoin increases ranging from 46 to 170%, which returned to baseline between week 4 and 17 after immunisation.(See reference number 3)

In yet another study,within 4 days of receiving 0.5 mL of a subvirion, trivalent influenza vaccine, serum phenytoin levels of 7 patients were reduced by 11 to 14%, which is unlikely to have much clinical significance (See reference number 4). A further study(See reference number 5) measured both free and total phenytoin levels in 8 patients receiving phenytoin alone. Two days after receiving 0.5 mL of a trivalent influenza vaccine, total phenytoin level had increased by 10%, and this then returned to baseline levels by day 7. However, free phenytoin level gradually decreased after vaccination to a maximum of 25 % less at day 14.

Where an interaction occurs it is suggested that it may be due to inhibitory effect of vaccine on liver enzymes concerned with metabolism of phenytoin, resulting in a reduced clearance from body (See reference number 1).

Concurrent use need not be avoided but it would be prudent to monitor effects closely

Jann MW,Fidone GS. Effect of influenza vaccine on serum anticonvulsant concentrations. Clin Pharm (1986) 5, 817–20.

Mooradian AD,Hernandez L, Tamai IC, Marshall C. Variability of serum phenytoin concentrations in nursing home patients. Arch Intern Med (1989) 149, 890–2.

Levine M,Jones MW, Gribble M. Increased serum phenytoin concentration following influenza vaccination. Clin Pharm (1984) 3, 505–9.

Sawchuk RJ,Rector TS, Fordice JJ, Leppik IE. Case report. Effect of influenza vaccination onplasma phenytoin concentrations. Ther Drug Monit (1979) 1, 285–8.

Smith CD,Bledsoe MA, Curran R, Green L, Lewis J. Effect of influenza vaccine on serum concentrations of total and free phenytoin. Clin Pharm (1988) 7, 828–32.

Levine M,Beattie BL, McLean DM, Corman D. Phenytoin therapy and immune response toinfluenza vaccine. Clin Pharm (1985) 4, 191–4.

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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