Epilepsiu, 33(6):1145-1148, 1992 Raven Press, Ltd., New York 0 International League Against Epilepsy

Oxcarbazepine Does Not Affect the Anticoagulant Activity of Warfarin G. Kramer, B. Tettenborn, *P. Klosterskov Jensen, *G. P. Menge, and tK. D. Stoll Johannes Cutenberg University, Mainz, Germany; *Ciba-Geigy AG, Basel, Switzerland; and tCiba-Geigy AG, Frankfurt, Germany

Summary: The possible interaction of the antiepileptic drug oxcarbazepine (OCBZ) on the anticoagulant effect of warfarin was investigated in 10 healthy male volunteers. After reaching steady-state conditions by repeated administration of warfarin, the prothrombin time (Quick value) was assessed before and after single (600 mg) and multiple dosing (450 mg twice daily in 1 week) of OCBZ. In 7 of the 10 volunteers with evaluable data, the pro-

thrombin time was not significantly different (paired t test) from baseline either after single (p = 0.299) or repeated dosing (p = 0.333), indicating that OCBZ does not interact to any relevant extent with the hypothrombinemic effect of warfarin. Key Words: Epilepsy-Anticonvulsant s-Oxcarbazepine-Warfarin-Prothrombin time-Drug interactions.

higher and/or more frequent dosing to maintain adequate therapeutic levels. Conversely, the increase in the anticoagulant effect of warfarin when CBZ therapy is decreased or discontinued is potentially dangerous (Ross and Beeley, 1980). The major metabolic pathway for OCBZ in humans is reduction in the keto group leading to formation of the monohydroxy derivative (MHD), 10,l l-dihydro-10-hydroxy-5H-dibenz[bflazepine5-carboxamide, racemic reference compound GP 47 779 (Rai et al., 1979; Feldmann et al., 1977,1981). This compound (MHD), which is responsible for the anticonvulsant effect of OCBZ in humans, is mainly eliminated in urine as the glucuronide conjugate (Schutz et al., 1986). A small amount of MHD is further transformed to the dihydroxy derivative (DHD) (Feldmann et al., 1977; Schutz et al., 1986), which is pharmacologically inactive (Faigle and Feldmann, 1989). OCBZ is less expected to cause drug interactions than CBZ, because the reductive metabolism of OCBZ requires noninducible hepatic cytosolic reductases (Bachur, 1976; Nakayama et al., 1985). In the case of coadministration of warfarin, this would be an advantage because OCBZ is believed not to induce the cytochrome P-450 oxygenases. Therefore, we investigated the influence of OCBZ on the steady-state anticoagulant effect of warfarin, as measured by prothrombin time.

Oxcarbazepine (OCBZ) 10,ll-dihydro-10-0x0-

SH-dibenz[bflazepine-5-carboxamide),or GP 47 680, is a new antiepileptic drug (AED) structurally related to carbamazepine (CBZ). It is approved for marketing in Denmark, Finland, Holland, Argentina, and Mexico under the trade name Trileptal and awaits marketing authorization in other countries. OCBZ is effective in preventing both electrically and chemically induced seizures in animals (Baltzer and Schmutz, 1977). In double-blind clinical trials, OCBZ is consistently as efficacious and at least as well tolerated as CBZ in treatment of generalized tonic-clonic or partial seizures (Houtkooper et al., 1987; Reinikainen et al., 1987; Dam et al., 1989). Despite similar chemical structure, the metabolic profiles of OCBZ and CBZ in humans are different. CBZ is mainly eliminated through oxidative metabolism, and repeated administration leads to induction of hepatic oxygenases of the cytochrome P-450 family (Faigle and Feldmann, 1989). This effect not only accelerates metabolism of CBZ and other AEDs (Pitlick and Levy, 1989), but also that of other drugs metabolized by the same class of liver enzymes, such as warfarin (Hansen et al., 1971). This leads to faster clearances and the need for Received September 1991; revision accepted March 1992. Address correspondence and reprint requests to Dr. G. Kramer at Department of Neurology, University Hospital, Langenbeckstralje 1 , Postfach 3960, 6500 Mainz, Germany.

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G. KRAMER E T A L .

METHODS Ten healthy men with a mean age of 26.6 years (range 22-30 years) and a mean weight of 74.7 kg (range 64-89 kg) volunteered for the study at the Department of Neurology, Johannes Gutenberg University, Mainz, Germany. The study was performed in accordance with the guidelines of the Declaration of Helsinki, and informed consent was obtained from each subject. None of the subjects demonstrated any clinically significant biochemical or hematologic abnormalities or had histories of intolerance to CBZ or tricyclic antidepressants, or any hepatic, renal, or hematologic disorder. Furthermore, none of the subjects abused drugs or alcohol. To avoid hepatic enzyme induction by uncontrolled factors, concomitant medications and alcohol consumption were not allowed throughout the study. The subjects were required to maintain a constant diet (both in type and amount) throughout the study, and green vegetables and liver were to be avoided. During the first 3 weeks of the trial, each volunteer received daily titrating doses of sodium warfarin (Coumadin, Merrell Dow, Russelsheim, Germany) 5-mg tablets at 6 p.m. Prothrombin times were monitored by Quick value (Duckert, 1983), the target level for which was 3545% (normal value 100%). Quick values of 3545% correspond to an international normalized ratio (LNR) of 2.15-1.75 according to the ISI-index 1.11 of the used thromboplastin (Thromborel S, Ch.-B./lot no. 505678, Behringwerke AG, Marburg, Germany). From day 21 to day 35 of study, the warfarin dose was kept constant. On day 29, a single 600-mg oral dose of OCBZ (Trileptal, Ciba Geigy AG, Basel, Switzerland) was administered at 8 a.m. in 300-mg divisible tablets. From day 30, OCBZ 450 mg was given orally twice daily at 8 a.m. and 8 p.m., the last dose being given on the morning of day 36. The effect of OCBZ on the pharmacodynamic action of warfarin was assessed by comparing the Quick values on day 28 (before OCBZ dosing) with those on day 29 (after a single dose of OCBZ) and those on day 36 (after repeated doses of OCBZ) by paired t tests. RESULTS The mean Quick value observed in 7 subjects on the last day before the start of OCBZ dosing (day 28) was 36.6%. The mean value after a single dose of OCBZ (day 29) was 38.6%, and the mean value after repeated dosing of OCBZ (day 36) was 38.1%. Neither of these values was significantly different Epilepsia, Vol. 33, No. 6 , 1992

from the baseline (day 28) value. lndividual values are shown in Table 1. One volunteer had to be excluded because of a rash on the right foot on day 32 of the study. The subject had no history of allergic rashes, and whether this reaction was related to either of the study drugs was not clear. All medications were discontinued, and the rash resolved in 2 days. Owing to protocol violations, the results from 2 other volunteers were not included in statistical analysis of Quick values: 1 subject who was not maintained on a constant dose of warfarin during the week before OCBZ administration, as required by the protocol, and 1 subject who took alcohol during the study and whose Quick value returned to normal before the end of the study, suggesting noncompliance with warfarin dosing. All other adverse events reported during warfarin and OCBZ coadministration were mild; the most common was tiredness (Table 2). DISCUSSION Our results indicate that single and repeated doses of OCBZ do not influence the pharmacodynamic action of warfarin therapy, as measured by prothrombin time. The adverse events reported during the coadministration phase of the study were mild apart from an unexplained foot rash. Tiredness was reported by 6 volunteers. Tiredness with or without dizziness is also the most common side effect reported by patients independent of the medication used for antiepileptic therapy. No significant difference in the incidence of this symptom was obTABLE 1. Quick values of 7 healthy men determined on day 28 under steady-state conditions of warfarin dosing (baseline), on day 29 after a single, oral 600-mg dose of OCBZ and on day 36 aj’ter repeated oral h.i.d. dosing of 450 mg OCBZ Quick values (%)

Subject

Day 28 baseline

Day 29 single dose

Day 36 repeated dose

2 4 6 7 8 9 10 Mean SD

33 37 37 41 46 38 24 36.6 6.9

45 37 36 43 47 36 26 38.6 +- 7.1

33 40 42 45 52 35 20

*

*

38.1

?

10.2

OCBZ, oxycarbazepine; b.i.d., twice daily. The individual Quick values after single and repeated dosing with OCBZ were not significantly different from the baseline values: Day 29 (p = 0.299), day 36 (p = 0.333), evaluated by paired f test.

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OCBZ-WARFARIN COADMINISTRATION TABLE 2. Adverse events reported by 7 subjects during OCBZ administration Event Tiredness Dizziness Headache Bleeding of gums Parasthesias of hands Flatulence Rash on right foot

Causal relationship to OCBZ dosing

Total

Mild Mild Mild Mild

Probable Definite, probable Possible Possible

6 2 2 1

Mild Mild

Probable Unlikely

1 1

Severe

Not assessable

1

Severity

served when patients were switched from CBZ to therapy with OCBZ (Dam et al., 1989). In many instances, drug interactions based on cytochrome P-450 induction may be of little clinical significance. However, in the case of drugs with a narrow therapeutic index, induction may compromise efficacy severely and can lead to potentially fatal outcomes. A well-known example is the interaction between phenobarbital and warfarin (Goldberg, 1980; Park and Breckenridge, 1981). CBZ is known to accelerate metabolism of warfarin (Hansen et al., 1971) and consequently to reduce its hypothrombinemic effect. On the other hand, discontinuation and/or dose reduction of CBZ therapy has resulted in a potentially dangerous increase in prothrombin time (Ross and Beeley, 1980). Investigation of possible drug interactions between warfarin and AEDs is important because it is clear that clinically significant interactions may occur with current first-line AEDs. We conclude that antiepileptic therapy with OCBZ offers a clinical advantage over CBZ, especially when coadministration of warfarin is required. Acknowledgment: We thank F. Sayles for help in manu-

script preparation.

REFERENCES Baltzer V, Schmutz M. Experimental anti-convulsive properties of GP 47 680 and of GP 47 779, its main metabolite; compounds related to carbamazepine. In: Meinardi H, Rowan AJ, eds. Advances in epileptology. Amsterdam/Lisse: Swets & Zeitlinger, 1977:295-9. Bachur NR. Cytoplasmic aldo-keto reductases: a class of drugmetabolizing enzymes. Science 1976;193:595-7. Dam M, Ekberg R, Loyning Y, Waltimo 0, Jacobsen K. A double-blind study comparing oxcarbazepine and carbamazepine in patients with newly diagnosed previously untreated epilepsy. Epilepsy Res 1989;3:7(M. Duckert F. Analytische Methoden. 2. Die einzelnen Methoden. In: Koller F , Duckert F , eds. Thrombose und Embolie: Arterielle und veniise GefaJverschliisse in Innerer Medizin, Chirurgie, Frauenheilkunde und Neurologie. Stuttgart: F.K. Schattauer Verlag, 1983:761-78. Faigle JW, Feldmann KF. Carbamazepine: biotransformation. In: Levy R, Mattson R, Meldrum B, Penry JK, Dreifuss FE,

eds. Antiepileptic drugs, 3rd ed. New York: Raven Press, 1989:49 1-504. Feldmann KF, Brechbuhler S, Faigle JW, Imhof P. Pharmacokinetics and metabolism of GP 47 680, a compound related to carbamazepine in animals and man. In: Meinardi H, Rowan AJ, eds. Advnnces in epileptology. AmsterdamlLisse: Swets & Zeitlinger, 1977:290-4. Feldmann KF, Dorhofer G, Faigle JW, Imhof P. Pharmacokinetics and metabolism of GP 47 779, the main human metabolite of oxcarbazepine (GP 47 680) in animals and healthy volunteers. In: Dam M, Gram L , Penry JK, eds. Advances in epileptology: XIIth epilepsy international symposium. New York: Raven Press, 1981:89-96. Goldberg DM. The expanding role of microsomal enzyme induction, and its implications for clinical chemistry. Clin Chem 1980;26:69 1-9. Hansen JM, Siersbaek-Nielsen K, Skovsted L. Carbamazepineinduced acceleration of diphenylhydantoin and warfarin metabolism in man. Clin Pharmucol Ther 1971;12:53943. Houtkooper MA, Lammertsma A, Meyer J, et al. Oxcarbazepine (GP 47 680): a possible alternative to carbamazepine? Epilepsin 1987;28:693-8. Nakayama T, Hara A, Yashiro K, Sawada H. Reductases for carbonyl compounds in human liver. Pharmacology 1985;34: 107-17. Park BK, Breckenridge AM. Clinical implications of enzyme induction and enzyme inhibition. Clin Pharrnacokinet 1981; 6: 1-24. Pitlick WH, Levy RH. Carbamazepine: interaction with other drugs. In: Levy R, Mattson R , Meldrum B, Penry J K , Dreifuss FE, eds. Antiepileptic drugs, 3rd ed. New York: Raven Press, 1989521-31. Rai PV, Egli M, Wad N. Serum level studies of oxcarbazepine and its metabolites in clinically effective dosage [Abstract]. 1 l t h Epilepsy internationul symposium-abstracts. Florence, 1979:158. Reinikainen KJ, Keranen T, Halogen T, Komulainen H, Riekkinen PJ. Comparison of oxcarbazepine and carbamazepine: a double-blind study. Epilepsy Res 1987;1:284-9. Ross JRY, Beeley L. Interaction between carbamazepine and warfarin. Br Med J 1980;280:1415-6. Schiitz H, Feldmann KF, Faigle JW. The metabolism of 14Coxcarbazepine in man. Xenobioticu 1986;16:769-78.

RESUME L’interaction Cventuelle entre I’oxcarbazepine (OCBZ, antiepileptique) et la warfarine (anticoagulant), a Cte CtudiCe chez 10 volontaires sains de sexe masculin. Des doses rCpetCes de warfarine ont CtC administrees afin d’atteindre un Ctat d’Cquilibre. Le temps de prothrombine a CtC mesurC avant et apres I’administration d’une dose unique (600 mg) et apres doses rCpCtCes (450 mg, deux fois par jour, durant une semaine) d’OCBZ. Chez les 7 des 10 volontaires avec des resultas evaluable aucune diffCrence statistiquement significative antre les resultats obtenus avant et apr& administration d’une dose unique (p = 0.299) ou rCpCtCes (p = 0.333) d’OCBZ n’a 6tC mise en evidence lors d’un test t en strie appariCe. Ces rCsultats tendraient a indiquer que I’OCBZ n’a pas d’influence notable sur I’effet anticoagulant de la warfarine. (Translation supplied by authors)

RESUMEN En diez varones voluntarios sanos se investig6 la posible interaccion de la droga antiepilkptica Oxcarbacepina (OCBZ) con el efecto anticoagulante de la Warfarina. Luego de repetidas administraciones de Warfarina que llevaron a 10s pacientes a condiciones de equilibrio, se midi6 el tiempo de protrombina antes y Epilepsiu, Vol. 33, No. 6 , 1992

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despuCs de una dosis unica (600 mg), y de dosis multiples (450 mg dos veces por dia, durante una semana) de OCBZ. En siete de 10s diez voluntarios con datos evaluables, por lo que el tiempo de protrombina no diferia significativamente (test t apareado), de la linea de base ni de la d6sis unica (p = 0.299) como tampoco de las repetidas d6sis (p = 0.333), indicando que la OCBZ no interactua en medida relevante con el efecto hipo protrombinemico de la Warfarina. (Translution supplied by authors)

ZUSAMMENFASSUNG Die Auswirkungen des Antiepileptikums Oxcarbazepin (OCBZ) auf die antikoagulative Wirkung von Warfarin wurde bei

Epilepsiu. Vol. 33, N o . 6, 1992

zehn gesunden mannlichen Freiwilligen untersucht. Nach Erreichen von steady-state Bedingungen durch wiederholte Gabe von Warfarin wurde die Prothrombinzeit vor, nach einer Einzeldosis sowie nach wiederholter Gabe von OCBZ gemessen und verglichen. Oxcarbazepin wurde hierzu in einer Einzeldosis von 600 mg, anschlieRend wahrend einer Woche in Dosen von 450 mg 2 x taglich verabreicht. Bei sieben der zehn Probanden mit auswertbaren Daten war die Prothrombinzeit weder nach der Einzeldosis (p = 0.299) noch nach wiederholter OCBZ-Gabe (p = 0.333) signifikant vom Basiswert verschieden. Diese Ergebnisse zeigen, da13 OCBZ keinen relevanten Effekt auf die hypothrombinamische Wirkung von Warfarin hat. (Translation supplied by uurhors)