Pharmacy Blog – Dr Vibore

Clinical evidence,mechanism, importance and management

Serum phenobarbital levels rose by about 30 % in 11 out of 27 children when given 0.5 mL of a whole virus influenza vaccine USP,types A and B, (Squibb). Levels remained elevated 28 days after vaccination (See reference number 1).

It was suggested that vaccine inhibits liver enzymes concerned with metabolism of phenobarbital, thereby reducing its loss from body. Information is very limited. Note that, a similar 30 % increase in phenobarbital levels with felbamate has eventually required a dosage adjustment; however with this interaction increase will eventually be self-limiting. Therefore it seems unlikely that this moderate increase in phenobarbital levels will be of clinical significance..

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

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)

1.

Toakley JG. Dilantin overdosage. Med J Aust (1968) 2,640.

2.

Leonard RF,Knott PJ, Rankin GO, Robinson DS, Melnick DE. Phenytoin-salicylate interaction. Clin Pharmacol Ther (1981) 29, 56–60.

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Ehrnebo M,Odar-Cederlöf I. Distribution of pentobarbital and diphenylhydantoin betweenplasma and cells in blood: effect of salicylic acid, temperature and total drug concentration.Eur J Clin Pharmacol (1977) 11, 37–42.

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Fraser DG,Ludden TM, Evens RP, Sutherland EW. Displacement of phenytoin from plasmabinding sites by salicylate. Clin Pharmacol Ther (1980) 27, 165–9.

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Paxton JW. Effects of aspirin on salivary and serum phenytoin kinetics in healthy subjects.Clin Pharmacol Ther (1980) 27,170–8.

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Olanow CW,Finn A, Prussak C. The effect of salicylate on phenytoin pharmacokinetics.Trans Am Neurol Assoc (1979) 104, 109–10.

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Inoue F,Walsh RJ. Folate supplements and phenytoin-salicylate interaction. Neurology (1983) 33, 115–16.

8.

Neuvonen PJ,Lehtovaara R, Bardy A, Elomaa E. Antipyretic analgesics in patients on antiepileptic drug therapy. Eur J Clin Pharmacol (1979) 15, 263–8.

9.

Geaney DP,Carver JG, Aronson JK, Warlow CP. Interaction of azapropazone with phenytoin. BMJ (1982) 284, 1373.

Aronson JK,Hardman M, Reynolds DJM. ABC of monitoring drug therapy. Phenytoin. BMJ (1992) 305, 1215–18.

Geaney DP,Carver JG, Davies CL, Aronson JK. Pharmacokinetic investigation of the interaction of azapropazone with phenytoin. Br J Clin Pharmacol (1983) 15, 727–34.

Roberts CJC,Daneshmend TK, Macfarlane D, Dieppe PA. Anticonvulsant intoxication precipitated by azapropazone. Postgrad Med J (1981) 57, 191–2.

Rheumox (Azapropazone dihydrate). Goldshield Pharmaceuticals Ltd. UK Summary of product characteristics,February 2000.

Gumbhir-Shah K,Cevallos WH, DeCleene SA, Korth-Bradley JM. Evaluation of pharmacokinetic interaction between bromfenac and phenytoin in healthy males. J Clin Pharmacol (1997) 37, 160–8.

Keeling KL,Jortani SA, Linder MW, Valdes R. Prolonged elimination half-life of phenytoinin an elderly patient also on celecoxib. Clin Chem (2002) 48 (Suppl.), A52–A53.

Zvaifler N. A review of the antiarthritic efficacy and safety of etodolac. Clin Rheumatol (1989) 8 (Suppl 1),43–53.

Bachmann KA,Schwartz JI, Forney RB, Jauregui L, Sullivan TJ. Inability of ibuprofen to alter single dose phenytoin disposition. Br J Clin Pharmacol (1986) 21, 165–9.

Townsend RJ,Fraser DG, Scavone JM, Cox SR. The effects of ibuprofen on phenytoin pharmacokinetics. Drug Intell Clin Pharm (1985) 19, 447–8.

Sandyk R. Phenytoin toxicity induced by interaction with ibuprofen. S Afr Med J (1982) 62,

592.

Andreasen PB,Frøland A, Skovsted L, Andersen SA, Hague M. Diphenylhydantoin half-lifein man and its inhibition by phenylbutazone: the role of genetic factors. Acta Med Scand (1973) 193, 561–4.

Lunde PKM,Rane A, Yaffe SJ, Lund L, Sjöqvist F. Plasma protein binding of diphenylhydantoin in man. Interaction with other drugs and the effect of temperature and plasma dilution. Clin Pharmacol Ther (1970) 11, 846–55.

Soda DM,Levy G. Inhibition of drug metabolism by hydroxylated metabolites: cross-inhibition and specificity. J Pharm Sci (1975) 64, 1928–31.

There is some evidence that enzyme-inducing antiepileptics(carbamazepine, phenobarbital, phenytoin and primidone) maymodestly reduce levetiracetam levels, but this is not thought to beclinically relevant. Levetiracetam does not usually alter levelsof these antiepileptics. However,some studies have found modestly raised phenytoin levels, and cases of possible carbamazepinetoxicity have also been reported. There appears to be no pharmacokinetic interaction between levetiracetam and gabapentin,lamotrigine,or valproate.

Clinical evidence,mechanism, importance and management

Evidence from clinical studies suggests that levetiracetam does not affect serum levels of carbamazepine (See reference number 1-3). There is also some evidence that patients taking levetiracetam and also receiving enzyme-inducing antiepileptics such as carbamazepine had modestly (24%) lower levetiracetam levels than those also receiving antiepileptics not considered to be enzyme-inducers,but this was not considered clinically relevant, see (d) below (See reference number 4). Similarly, another retrospective analysis of patient data found that serum levetiracetam level to dose ratio was modestly lower in patients also receiving carbamazepine than those receiving monotherapy (0.32 versus 0.52) (See reference number 5). suggesting that carbamazepine moderately lowers levetiracetam levels. One report describes 4 patients who experienced disabling symptoms compatible with carbamazepine toxicity when levetiracetam was added. The symptoms resolved after a decrease in carbamazepine dosage or withdrawal of levetiracetam. A pharmacodynamic interaction was suggested,because levels of carbamazepine and its metabolite, carbamazepine-10,11-epoxide, were not affected (See reference number 6).

In general, there is no need to modify dose of either carbamazepine or levetiracetam when used together. However, report of possible toxicity suggests that some caution is warranted.

There is some evidence that patients taking levetiracetam with enzyme-inducing antiepileptics such as phenytoin had modestly (24%) lower levetiracetam levels than those taking other antiepileptics not considered to be enzyme inducers,but this was not considered clinically relevant, see (d) below (See reference number 4). Similarly, another retrospective analysis of patient data found that serum levetiracetam level-to-dose ratio was modestly lower in patients also receiving phenytoin than those receiving monotherapy (0.32 versus 0.52),(See reference number 5) suggesting that phenytoin modestly lowers levetiracetam levels.

However, evidence from clinical studies suggests that levetiracetam does not affect serum levels of phenytoin (See reference number 1-3). Similarly,in another study, levetiracetam 1.5 g twice daily for 12 weeks had no effect on steady-state pharmacokinetics of phenytoin in 6 subjects with epilepsy who were taking stable doses of phenytoin (See reference number 7). In one clinical study addition of levetiracetam increased phenytoin levels by 27 % to 52 % in 4 patients. A further patient had a 75 % increase in phenytoin levels [estimated from figure] and experienced signs of toxicity (sedation,ataxia) and required a reduction in his phenytoin dose. Another patient with raised phenytoin levels [estimated increase of 47%] had dose of levetiracetam reduced (See reference number 8).

In general therefore, there is no need to modify dose of either phenytoin or levetiracetam when they are used together. However, report of raised phenytoin levels suggests that some caution is warranted.

There was no difference in pharmacokinetics of a single 1.5-g dose of levetiracetam given to healthy subjects before or after sodium valproate 500mg twice daily for 8 days. In addition, levetiracetam did not affect pharmacokinetics of valproate (See reference number 9). In an analysis of clinical study data, AUC of levetiracetam in 57 patients also taking valproic acid was slightly (11%) higher than in 28 patients also taking antiepileptics not thought to affect microsomal enzymes (gabapentin, lamotrigine, vigabatrin), but this was not thought to be clinically relevant (See reference number 4). In another retrospective analysis of patient data, serum levetiracetam level-to-dose ratio was same in patients also receiving valproic acid than those receiving monotherapy

(0.53 versus 0.52),(See reference number 5) suggesting that valproate does not alter levetiracetam levels. Furthermore, evidence from clinical studies suggests that levetiracetam does not affect serum levels of valproate (See reference number 1,3). There appears to be no need to adjust doses of either sodium valproate or levetiracetam if these drugs are used together.

The AUC of levetiracetam tended to be lower in 436 patients also taking enzyme-inducing antiepileptics (carbamazepine, phenobarbital, phenytoin, primidone) than in 28 patients also taking antiepileptics not thought to affect microsomal enzymes (gabapentin, lamotrigine, vigabatrin), but difference was modest (24%) (See reference number 4). Another retrospective analysis of patient data found that serum levetiracetam level-to-dose ratio did not differ significantly between patients also taking lamotrigine and those taking levetiracetam alone (0.45 versus 0.52),but was modestly lower in those taking oxcarbazepine (0.34 versus 0.52) (See reference number 5).

Furthermore, evidence from clinical studies suggests that levetiracetam does not affect serum levels of gabapentin, lamotrigine, phenobarbital, or primidone (See reference number 1-3). In general therefore,no dosage adjustments would seem to be needed if levetiracetam is used as add-on therapy with any of these drugs.

Keppra (Levetiracetam). UCB Pharma Ltd. UK Summary of product characteristics,January2007.

Patsalos PN. Pharmacokinetic profile of levetiracetam: towards ideal characteristics. Pharmacol Ther (2000) 85,77–85.

Keppra (Levetiracetam). UCB Inc. US Prescribing information,March 2007.

Perucca E,Gidal BE, Baltès E. Effects of antiepileptic comedication on levetiracetam pharmacokinetics: a pooled analysis of data from randomized adjunctive therapy trials. Epilepsy Res (2003) 53, 47–56.

May TW,Rambeck B, Jürgens U. Serum concentrations of levetiracetam in epileptic patients:the influence of dose and co-medication. Ther Drug Monit (2003) 25, 690–9.

Sisodiya SM,Sander JWAS, Patsalos PN. Carbamazepine toxicity during combination therapywith levetiracetam: a pharmacodynamic interaction. Epilepsy Res (2002) 48, 217–19.

Browne TR,Szabo GK, Leppik IE, Josephs E, Paz J, Baltes E, Jensen CM. Absence of pharmacokinetic drug interaction of levetiracetam with phenytoin in patients with epilepsy determined by new technique. J Clin Pharmacol (2000) 40, 590–5.

Sharief MK,et al. Efficacy and tolerability study of ucb L059 in patients with refractory epilepsy. J Epilepsy (1996) 9, 106–12.

Coupez R,Nicolas J-M, Browne TR. Levetiracetam, a new antiepileptic agent: lack of in vitroand in vivo pharmacokinetic interaction with valproic acid. Epilepsia (2003) 44, 171–8.

A report describes two cases,which suggest that sertraline mayincrease lamotrigine levels and cause toxicity.

Clinical evidence,mechanism, importance and management

A patient’s lamotrigine levels were found to have doubled and symptoms of toxicity were noted (confusion,cognitive impairment) 6 weeks after sertraline 25mg daily was started (See reference number 1). The lamotrigine dose was halved, and sertraline dose titrated to 50mg daily. Symptoms of toxicity resolved, but lamotrigine levels were still 24 % higher than before sertraline was started. In another patient taking sertraline and lamotrigine with signs of lamotrigine toxicity, a 33 % reduction in sertraline dose resulted in a halving of lamotrigine level even though lamotrigine dose was increased by 33%.

The authors suggest that sertraline may competitively inhibit glucuronidation of lamotrigine. Evidence so far appears limited to this case report. In view of increased risk of rash with increased lamotrigine levels (see also Lamotrigine + Valproate interaction, below), it may be prudent to monitor combination. Further study is needed.

1. Kaufman KR,Gerner R. Lamotrigine toxicity secondary to sertraline. Seizure (1998) 7, 163–5.

Carbamazepine toxicity, attributed to use of terfenadine, hasbeen described in one case report but interaction is not established.

Clinical evidence,mechanism, importance and management

A 18-year-old woman taking carbamazepine after treatment for brain metastases,developed confusion, disorientation, visual hallucinations, nausea and ataxia shortly after starting terfenadine 60mg twice daily for rhinitis. The symptoms were interpreted as carbamazepine toxicity. However,her total carbamazepine serum levels of 8.9 mg/L were within normal range. An interaction due to protein binding displacement was suspected and measurement of free carbamazepine revealed levels of 6 mg/L, almost three times upper limit of normal. All symptoms disappeared when terfenadine was stopped. The authors speculate that terfenadine had displaced carbamazepine from its plasma protein binding sites, thereby increasing levels of free and active carbamazepine (See reference number 1). The report is very brief and does not say whether any other drugs were being taken concurrently,so that this interaction is not established.

1. Hirschfeld S,Jarosinski P. Drug interaction of terfenadine and carbamazepine. Ann Intern Med (1993) 118, 907–8.

Omeprazole markedly raised levels of a single dose of carbamazepine, but had no significant effect on carbamazepine taken long-term. Some anecdotal reports suggest that carbamazepine serum levels may possibly be reduced by lansoprazole. Pantoprazole did not affect pharmacokinetics of carbamazepine in one study.

In 2001 manufacturers of lansoprazole had on record 5 undetailed case reports of apparent interactions between lansoprazole and carbamazepine. One of them describes development of carbamazepine toxicity when lansoprazole was added, but there is some doubt about this case because it is thought that patient may have started to take higher doses of carbamazepine.

The other 4 cases are consistent, in that carbamazepine levels fell shortly after lansoprazole was added, and/or control of seizures suddenly worsened. One patient had a fall in carbamazepine serum levels from 11.5 to 7.7 mg/L. The carbamazepine levels of another patient returned to normal when lansoprazole was stopped (See reference number 1).

Omeprazole 20mg daily for 14 days was found to increase AUC of a single 400mg dose of carbamazepine in 7 patients by 75%. The clearance was reduced by 40 % and elimination half-life was more than doubled (from 17.2 to 37.3 hours) (See reference number 2). However, a retrospective study of records of 10 patients who had been taking omeprazole 20mg daily with long-term carbamazepine (rather than a single dose) found a non-significant reduction in carbamazepine serum levels (See reference number 3).

Pantoprazole 40mg daily for 5 days had no effect on AUC of carbamazepine or carbamazepine-10,11-epoxide after a single 400mg dose of carbamazepine in healthy subjects (See reference number 4)

Omeprazole may inhibit oxidative metabolism of single doses of carbamazepine. However, when carbamazepine is taken continuously it induces its own metabolism by cytochrome P450 isoenzyme CYP3A4, thereby possibly opposing effects of this interaction (See reference number 3).

It seems that in practice no clinically relevant interaction is likely to occur between omeprazole and carbamazepine. For lansoprazole,information seems to be limited to this handful of reports from which no broad general conclusions can be drawn, but they do suggest that this interaction should be considered if lansoprazole is added to established treatment with carbamazepine. Pantoprazole appears not to affect pharmacokinetics of carbamazepine.

Wyeth (UK). Personal communication,September 2001.

Naidu MUR,Shoba J, Dixit VK, Kumar A, Kumar TR, Sekhar KR, Sekhar EC. Effect of multiple dose omeprazole on the pharmacokinetics of carbamazepine. Drug Invest (1994) 7, 8–12.

Böttiger Y,Bertilsson L. No effect on plasma carbamazepine concentration with concomitantomeprazole treatment. Drug Invest (1995) 9, 180–1.

Huber R,Bliesath H, Hartmann M, Steinijans VW, Koch H, Mascher H, Wurst W. Pantoprazole does not interact with the pharmacokinetics of carbamazepine. Int J Clin Pharmacol Ther (1998) 36, 521–4.

Clinical evidence,mechanism, importance and management

The carbamazepine AUC in an epileptic patient taking carbamazepine 600mg daily was reduced by 11 % when isotretinoin 500 micrograms/kg daily,was taken, and by 24 % when 1 mg/kg daily was taken. The AUC of carbamazepine-10,11-epoxide (the active metabolite of carbamazepine) was reduced by 21 and 44 % by small and large doses of isotretinoin, respectively. The patient had no adverse effects (See reference number 1). Although author of report suggests that monitoring may be necessary in patients given both drugs changes of this magnitude, especially those seen with lower dose, are not usually clinically significant.

1. Marsden JR. Effect of isotretinoin on carbamazepine pharmacokinetics. Br J Dermatol (1988) 119,403–4.

Colestyramine 8 g did not affect absorption of carbamazepine400 mg in 6 healthy subjects, whereas colestipol 10 g reduced it by10%. Both colestyramine and colestipol were given as a singledose 5 minutes after carbamazepine.(See reference number 1) This small reduction is unlikely to be clinically important.

1. Neuvonen PJ,Kivistö K, Hirvisalo EL. Effects of resins and activated charcoal on the absorption of digoxin, carbamazepine and frusemide. Br J Clin Pharmacol (1988) 25, 229–33.

Ketoconazole causes a small to moderate rise in serum carbamazepine levels. A marked rise in carbamazepine levels hasbeen seen in two patients taking fluconazole,with toxicity in one.Adverse effects were seen in another patient when carbamazepinewas given with miconazole. Carbamazepine may markedly reduce levels of itraconazole and possibly voriconazole, and ispredicted to lower levels of posaconazole.

24.5 micrograms/mL. Symptoms resolved when both drugs were stopped,and carbamazepine was later re-introduced without problem (See reference number 1). Another well-documented case report describes a threefold increase in carbamazepine levels (without any signs of toxicity) 10 days after fluconazole 400mg daily was started (See reference number 2).

About 14 days after starting carbamazepine 400mg daily,a patient taking itraconazole 200mg daily was noted to have low itraconazole levels

(0.15 mg/L),and about 2 months later they were undetectable. About 3 weeks after stopping carbamazepine, itraconazole levels had reached therapeutic range (0.36 mg/L) (See reference number 3). For mention of 2 patients taking carbamazepine with phenytoin,who had undetectable or very low itraconazole levels, and who relapsed or did not respond to itraconazole therapy, see Phenytoin + Azoles interaction.

When ketoconazole was stopped serum carbamazepine levels returned to their former levels (See reference number 4)

A patient receiving long-term treatment with carbamazepine 400mg daily developed malaise,myoclonia and tremor within 3 days of being given oral miconazole 1.125 g. The same reaction occurred on each subsequent occasion that miconazole was given. These toxic effects disappeared when miconazole was withdrawn (See reference number 5).

Carbamazepine levels are thought to rise because azole antifungals inhibit cytochrome P450 isoenzyme CYP3A4, which is concerned with metabolism of carbamazepine. Different azoles affect CYP3A4 to varying degrees,see azole antifungals, . Carbamazepine is an enzyme inducer, and appears to decrease levels of azole antifungals by increasing their metabolism.

Evidence for these interactions is limited and in some cases effects are only modest. Nevertheless, it would seem prudent to monitor outcome of adding azole antifungals to established carbamazepine treatment, being alert for any evidence of increased carbamazepine adverse effects.

Note also that carbamazepine may reduce levels of azole antifungals: a marked reduction in itraconazole levels has been reported, and some manufacturers of itraconazole consequently say that concurrent use of potent enzyme inducers such as carbamazepine is not recommended (See reference number 6,7). Based on interaction with phenytoin, , which results in reduced posaconazole levels, manufacturer of posaconazole suggests that concurrent use of posaconazole and carbamazepine should be avoided, unless benefits outweigh risks (See reference number 8). If both drugs are given it would seem sensible to consider increasing posaconazole dose, and increase monitoring of carbamazepine levels. Based on interaction with phenytoin, , manufacturers of voriconazole also contraindicate concurrent use of carbamazepine and voriconazole (See reference number 9,10).

Nair DR,Morris HH. Potential fluconazole-induced carbamazepine toxicity. Ann Pharmacother (1999) 33, 790–2.

Finch CK,Green CA, Self TH. Fluconazole-carbamazepine interaction. South Med J (2002) 95, 1099–1100.

Bonay M,Jonville-Bera AP, Diot P, Lemarie E, Lavandier M, Autret E. Possible interactionbetween phenobarbital, carbamazepine and itraconazole. Drug Safety (1993) 9, 309–11.

Spina E,Arena D, Scordo MG, Fazio A, Pisani F, Perucca E. Elevation of plasma carbamazepine concentrations by ketoconazole in patients with epilepsy. Ther Drug Monit (1997) 19, 535–8.

Loupi E,Descotes J, Lery N, Evreux JC. Interactions médicamenteuses et miconazole. A propos de 10 observations. Therapie (1982) 37, 437–41.

Sporanox Capsules (Itraconazole). Janssen-Cilag Ltd. UK Summary of product characteristics,March 2004.

Sporanox Capsules (Itraconazole). Janssen. US Prescribing information,June 2006.

Noxafil (Posaconazole). Schering-Plough Ltd. UK Summary of product characteristics,October 2006.

VFEND (Voriconazole). Pfizer Ltd. UK Summary of product characteristics,July 2007.

VFEND (Voriconazole). Pfizer Inc. US Prescribing information,November 2006.

Clinical evidence,mechanism, importance and management

Tolfenamic acid 300 mg for 3 days had no significant effect on serum levels of carbamazepine in 11 patients (See reference number 1)

1. Neuvonen PJ,Lehtovaara R, Bardy A, Elomaa E. Antipyretic analgesics in patients on anti-epileptic drug therapy. Eur J Clin Pharmacol (1979) 15, 263–8.