Practical guidance and considerations for ...

Epilepsy & Behavior 50 (2015) 46–49

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Brief Communication

Practical guidance and considerations for transitioning patients from oxcarbazepine or carbamazepine to eslicarbazepine acetate — Expert opinion Jukka Peltola a,⁎, Martin Holtkamp b, Rodrigo Rocamora c, Philippe Ryvlin d, Kasia Sieradzan e, Vicente Villanueva f a

Department of Neurology, Tampere University Hospital, Tampere, Finland Epilepsy-Centre Berlin-Brandenburg and Department of Neurology, Charité – Universitätsmedizin Berlin, Berlin, Germany c Epilepsy Monitoring Unit, Department of Neurology, Hospital del Mar, Universitat Autònoma de Barcelona, Barcelona, Spain d Department of Clinical Neurosciences, CHUV, Lausanne, Switzerland e Institute of Clinical Neurosciences, North Bristol NHS Trust and University of Bristol, Bristol, UK f Multidisciplinary Epilepsy Unit, Neurology Service, Hospital Universitario y Politécnico La Fe, Valencia, Spain b

a r t i c l e

i n f o

Article history: Received 8 April 2015 Revised 19 May 2015 Accepted 22 May 2015 Available online xxxx Keywords: Carbamazepine Eslicarbazepine acetate Mechanism of action Oxcarbazepine Tolerability Treatment transition

a b s t r a c t There is currently a lack of guidance on methodology and special considerations for transitioning patients from oxcarbazepine (OXC) or carbamazepine (CBZ) to eslicarbazepine acetate (ESL), if deemed clinically necessary. An advisory panel of epilepsy experts was convened to share their experience on the use of adjunctive ESL in clinical practice and to provide practical recommendations to help address this gap. When changing over from OXC to ESL, an OXC:ESL dose ratio of 1:1 should be employed to calculate the ESL target dose, and the changeover can take place overnight. No changes to comedication are required. Since CBZ has a different mechanism of action to ESL and is a stronger inducer of cytochrome P450 (CYP) enzymes, the transitioning of patients from CBZ to ESL requires careful consideration on a patient-by-patient basis. In general, a CBZ:ESL dose ratio of 1:1.3 should be employed to calculate the ESL target dose, and patients should be transitioned over a minimum period of 1–2 weeks. Special considerations include adjustment of titration schedule and target dose in elderly patients and those with hepatic or renal impairment and potential adjustment of comedications metabolized by CYP enzymes. In summary, due to structural distinctions between ESL, OXC, and CBZ, which affect mechanism of action and tolerability, there are clinical situations in which it may be appropriate to consider transitioning patients from OXC or CBZ to ESL. Changing patients over from OXC to ESL is generally more straightforward than transitioning patients from CBZ to ESL, which requires careful consideration. © 2015 Elsevier Inc. All rights reserved.

1. Introduction Eslicarbazepine acetate (ESL) is a once-daily antiepileptic drug (AED) that is approved in Europe and the USA as an adjunctive therapy for adults with focal seizures, with or without secondary generalization [1,2]. An extensive phase III program demonstrated that, at doses of 800 and 1200 mg once daily, ESL is effective in reducing focal seizures in adult patients treated with one to three concomitant AEDs and that it has a favorable safety and tolerability profile in this setting [3–6]. Eslicarbazepine acetate is a member of the dibenzazepine family of AEDs, which includes oxcarbazepine (OXC) and carbamazepine (CBZ) [7]. However, while ESL shares the dibenzazepine nucleus bearing the

⁎ Corresponding author at: Department of Neurology, Tampere University Hospital, PO Box 2000, 33521, Tampere, Finland. Tel.: +358 40 1965006; fax: +358 33 1164351. E-mail address: Jukka.Peltola@pshp.fi (J. Peltola).

http://dx.doi.org/10.1016/j.yebeh.2015.05.036 1525-5050/© 2015 Elsevier Inc. All rights reserved.

5-carboxamide substitute with OXC and CBZ, it is structurally different from these agents at the 10,11-position [8,9]. This structural distinction results in differences in pharmacokinetics, pharmacodynamics, and metabolism [10]. An advisory board of epilepsy experts was convened in order to share knowledge and experience relating to the use of adjunctive ESL in clinical practice. The consensus was that there is currently a lack of controlled, comparative, clinical evidence for OXC versus ESL or CBZ versus ESL and a need for direct head-to-head data. However, it was agreed that, based on the available evidence and the group's clinical experience, there are certain clinical situations in which it may be appropriate to transition patients from OXC or CBZ to ESL. It was also recognized that, if clinicians want to transition a patient from OXC or CBZ to ESL, there is currently a lack of information to help guide them in everyday practice. Therefore, a consensus was reached on the methodology and special considerations for transitioning patients from OXC or CBZ to ESL, if required. This article outlines these recommendations.

J. Peltola et al. / Epilepsy & Behavior 50 (2015) 46–49

2. Methodology and considerations for transitioning patients from OXC to ESL in the adjunctive setting Oxcarbazepine and eslicarbazepine acetate have a similar mode of action, and they share the same main active metabolite, eslicarbazepine (S-licarbazepine) [8,11]. However, ESL is rapidly and extensively hydrolyzed to eslicarbazepine, representing approximately 94% of its circulating moieties, with R-licarbazepine and OXC representing approximately 5% and b 1%, respectively, whereas OXC is metabolized to both the Sand R-enantiomers of licarbazepine, representing approximately 78% and 18.5% of its circulating moieties, respectively, with approximately 3.5% of the parent compound being detectible in plasma [12]. Moreover, whereas the pharmacokinetic profile of ESL allows once-daily dosing [9], OXC must be administered twice daily [13]. Studies conducted in healthy volunteers have demonstrated that the ratio of eslicarbazepine plasma exposure to daily dose for once-daily ESL versus twice-daily OXC translates into approximately 40% greater ability of once-daily ESL to deliver eslicarbazepine into the plasma, compared with twice-daily OXC [10]. In addition, plasma exposures to R-licarbazepine and OXC are N70% and N60% lower, respectively, with once-daily ESL than with twice-daily OXC [10]. Importantly, when circulating OXC crosses the blood–brain barrier, it is associated with neurological adverse events (AEs), such as dizziness and headache [12]. Based on the clinical experience of the advisors, the types of patients for whom it may be most appropriate to consider changing over from OXC to ESL are those who experience OXC-related AEs (particularly if the AEs are most evident following morning dosing) and those who are poorly compliant with twice-daily OXC dosing. This is supported by a meta-analysis of randomized, double-blind, clinical studies, which demonstrated that OXC may be associated with more frequent neurological AEs than ESL [14]. In addition, “real-world” data from the 1-year, multicenter, retrospective, noninterventional ESLIBASE study demonstrated that, of 26 patients who were changed over from OXC to ESL due to OXC-related AEs, 15 (58%) no longer had AEs after changing over to ESL [15]. The higher incidence of neurological AEs observed with OXC may be explained by the findings of a study demonstrating that there is an early peak in OXC concentration in plasma and cerebrospinal fluid following OXC administration, which is not observed following ESL administration (Fig. 1) [12]. Since OXC is an inducer of the cytochrome P450 (CYP) 3A4 and 3A5 enzymes [16], whereas ESL is an inducer of CYP3A4 only [1,2], there may also be clinical situations in which it may be appropriate to consider transitioning from OXC to ESL on the basis of safety concerns relating to OXC-related drug interaction(s). No specific special considerations are necessary for patients changing over from OXC to ESL, and the methodology is outlined in Table 1.

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Table 1 Summary of methodology and special considerations for transitioning patients from OXC or CBZ to ESL. Parameter

Transition methodology/special considerations OXC to ESL

CBZ to ESL

Target dose

• Dependent on dose of OXC • Maximum: 1200 mg/daya

• Dependent on dose of CBZ • Maximum: 1200 mg/daya • Special considerations: ○ Elderly patients ○ Hepatic impairment ○ Renal impairment

Dose ratio

OXC:ESL 1:1

CBZ:ESL 1:1.3

Timelines for change

Overnight

• Minimum 1–2 weeks; more rapidly only in inpatient setting • Special considerations: ○ Elderly patients

Setting for change

Inpatient or outpatient

Inpatient or outpatient

Changes to comedication

None required

• Special considerations: ○ Potential reduction in dose for comedications metabolized by CYP enzymes ○ Potential for pharmacodynamic interaction with concomitant sodium channel blocker(s)

Follow-up/ monitoring

Contact after 3–4 weeks

• Contact after 3–4 weeks • Special considerations: ○ Hyponatremia (all patients) ○ Hepatic function (patients with hepatic impairment) ○ Renal function (patients with reduced glomerular filtration rate)

CBZ, carbamazepine; CYP, cytochrome P450; ESL, eslicarbazepine acetate; OXC, oxcarbazepine. a ESL is currently licensed in Europe up to 1200 mg/day in the adjunctive setting [1], but has been investigated up to 1600 mg/day in the monotherapy setting [17].

The target dose of ESL following changeover is dependent on the pretransition OXC dose, and an OXC:ESL dose ratio of 1:1 should be employed to calculate the ESL dose, as previously reported by other experts [18]. Although ESL has been investigated in North American conversion to monotherapy trials at doses up to 1600 mg/day [17], only up to 1200 mg/day in the adjunctive setting is currently approved in Europe [1]. If the 1:1 dose ratio does not correspond to an exact ESL dose (according to the available ESL dose formulations), then the closest lower ESL dose should be used. Patients can be transitioned simply from

Fig. 1. Plasma (A) and CSF (B) concentration–time profiles of OXC following the last dose of a repeated-dose regimen of once-daily ESL 1200 mg and twice-daily OXC 600 mg to healthy volunteers (n = 7 in each group for plasma profile; n = 6 in each group for CSF profile). CSF, cerebrospinal fluid; ESL, eslicarbazepine acetate; OXC, oxcarbazepine. Adapted from Nunes et al., 2013 with permission [12].

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OXC to ESL overnight in an inpatient or outpatient setting. No changes to comedication are required. The patient should be followed up after 3–4 weeks. 3. Methodology and considerations for transitioning patients from CBZ to ESL in the adjunctive setting There are differences between CBZ and ESL in terms of their modes of action. Eslicarbazepine reduces voltage-gated sodium channel (VGSC) availability through enhancement of slow inactivation, whereas CBZ acts by altering fast inactivation of VGSC [19]. There are also other differences between eslicarbazepine and CBZ with regard to submaximal gamma-aminobutyric acid currents, Kv7.2 outward currents, and high- and low-affinity Cav3.2 inward currents [20]. Therefore, the transitioning of patients from CBZ to ESL is not straightforward and requires careful consideration, taking into account the specific characteristics of each individual patient on a case-by-case basis. Structural differences between the two agents mean that whereas CBZ metabolism is associated with the generation of toxic metabolites (carbamazepine-10,11-epoxide), ESL metabolism is not [21,22]. Moreover, CBZ is a potent enzyme inducer, reducing the duration and action of many drugs, including analgesics, anti-inflammatory agents, anticoagulants, antivirals, corticosteroids, statins, antihypertensive agents, oral contraceptives, and antidepressants, as well as other AEDs [16,23]. Carbamazepine also induces enzymes involved in endogenous metabolic pathways, thereby potentially contributing to the development of comorbidities such as osteoporosis, sexual dysfunction, and vascular disease [16,24,25]. By comparison, ESL is a relatively weak enzyme inducer [1,9]. For example, although ESL is associated with a small, but significant, reduction in warfarin exposure following coadministration [26], this is unlikely to be of clinical significance, and similarly, ESL shows no significant interactions with digoxin or metformin [9]. Based on this evidence and the advisors' clinical experience, the types of patients for whom it may be most appropriate to consider transitioning from CBZ to ESL are those who experience CBZ-related AEs (e.g., cognitive AEs) and those experiencing, or at risk of, metabolic AEs (e.g., hypercholesterolemia). Patients taking concomitant drugs with potential for interaction with CBZ (e.g., metformin, digoxin, valproate) and those who are poorly compliant with twice- or thrice-daily CBZ dosing could also be considered for transitioning from CBZ to ESL. Cognitive AEs are mainly associated with the standard formulation of CBZ and less so with the prolonged-release formulation; however, the prolonged-release formulation is not available in some countries. It was agreed that special considerations are required when transitioning patients from CBZ to ESL (Table 1). With the exception of elderly patients, the target ESL dose should be dependent on the patient's existing CBZ dose, and the dose ratio of CBZ to ESL should be approximately 1:1.3, since, in the experience of the authors and other experts [27], this ratio offers a similar level of efficacy for the two agents. As previously stated in Section 2, ESL is currently approved in Europe up to 1200 mg/day in the adjunctive setting [1], although it has been investigated at doses up to 1600 mg/day in the monotherapy setting [17]. Transitioning from CBZ to ESL should generally be undertaken gradually over a minimum period of 1–2 weeks to avoid the risk of seizure deterioration. Gradual transition will also help minimize the potential influence of CBZ enzyme induction on eslicarbazepine levels. More rapid transitioning is possible but should only be considered in the inpatient setting. For elderly patients, the ESL target dose should be 800 mg/day initially and then individualized. In addition, elderly patients should be transitioned more gradually over a period of at least 2 weeks and never overnight. All patients, including the elderly, should be monitored for hyponatremia by measuring sodium levels at least 2 weeks after completion of the transition and then again after 4 weeks. Other special considerations (Table 1) include the type(s) of concomitant medication the patient is taking, since its/their dosing may need to be adjusted. For example, since CBZ is a potent inducer of the

CYP family of enzymes, the doses of concomitant medications that are metabolized by these enzymes (e.g., anticoagulants) may need to be reduced as the patient transitions from CBZ to ESL. Indeed, transitioning from CBZ to ESL in patients on warfarin carries a specific risk and is not advised, since withdrawal of CBZ can result in an unwanted increase in warfarin concentration that may lead to hemorrhage [28]; if undertaken, coagulation should be closely monitored and the warfarin dosage adjusted as necessary. In addition, the potential for pharmacodynamic interactions should be carefully considered for patients taking another sodium channel blocker as a concomitant AED, particularly if it works in a similar way to ESL. For example, since eslicarbazepine and lacosamide both reduce VGSC availability through enhancement of slow inactivation [19], it is theoretically possible that the risk of AEs could increase in patients taking lacosamide when transitioned from CBZ to ESL; however, there is currently no published evidence to support this. In patients with hepatic or renal impairment, a slower dose titration and lower target dose should be applied when transitioning to ESL; in patients with an estimated glomerular filtration rate b 50–60 mL/min, the ESL target dose should be reduced by 50%. Eslicarbazepine acetate is associated with fewer hepatic AEs than CBZ [1,23]. However, in patients with hepatic impairment, the checking of liver function 2 weeks after initiating ESL should be considered. Similarly, in patients with a reduced glomerular filtration rate, the checking of kidney function 2 weeks after initiating ESL should be considered. 4. Conclusions Structural distinctions between ESL, OXC, and CBZ result in differences in pharmacokinetics, pharmacodynamics, and metabolism, which affect mode of action and tolerability. Consequently, there are clinical situations in which it might be appropriate to consider transitioning patients from OXC or CBZ to ESL. The changing over of patients from OXC to ESL is generally more straightforward than the transitioning of patients from CBZ to ESL, primarily because the modes of action of OXC and ESL are similar, whereas those of CBZ and ESL are not. In addition, CBZ is a more potent enzyme inducer than ESL, with a greater likelihood of interaction with concomitant medications and endogenous metabolic pathways. Transitioning from CBZ to ESL, therefore, requires careful consideration on a case-by-case basis. There is a need for additional evidence in the monotherapy setting in order to further refine these recommendations. Acknowledgments The advisory panel meeting resulting in the development of this article was organized and funded by Eisai Ltd. Editorial support was provided by mXm Medical Communications and funded by Eisai Ltd. The article is based on the discussions from the advisory panel meeting, with all authors contributing to the development of the paper. The opinions expressed in the article are the independent consensus views of the authors and have not been influenced by third-party sponsorship. Conflict of interest Jukka Peltola has participated in clinical trials for Eisai, UCB, and Bial; received research grants from Eisai, Medtronic, UCB, and Cyberonics; received speaker honoraria from Cyberonics, Eisai, Medtronic, Orion Pharma, and UCB; received support for travel to congresses from Cyberonics, Eisai, Medtronic, and UCB; and participated in advisory boards for Cyberonics, Eisai, Medtronic, UCB, and Pfizer. Martin Holtkamp has participated in clinical trials for Eisai, GlaxoSmithKline, Janssen Cilag, and UCB; and he has received speaker honoraria and consultancy fees from Cyberonics, Desitin, Eisai, GlaxoSmithKline, Janssen Cilag, UCB, and ViroPharma. Rodrigo Rocamora is a consultant for Eisai, Bial, UCB, GlaxoSmithKline, and Shire and receives grant and research support from Bial, Eisai, and UCB. Philippe Ryvlin has no


conflict of interest to declare. Kasia Sieradzan has received speaker fees from Eisai and UCB and an educational grant from Eisai; and has participated in advisory boards for Eisai. Vicente Villanueva has participated in advisory boards and pharmaceutical industry-sponsored symposia for Eisai Europe Ltd, Bial, UCB, Merck Sharp & Dohme, Pfizer, GlaxoSmithKline, Medtronic, and Cyberonics.

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