1. Introduction
Carbamazepine (CBZ) is one of the older antiepileptic drugs (AEDs), both in the US and worldwide. Neurologists and non-neurologists have become very familiar with its spectrum of efficacy, advantages and limitations, and as a result it is one of the most used AEDs.
Since the mid-1990s, newer or second-generations AEDs have become available, including recently two different but structurally related compounds: oxcarbazepine (OXC) and eslicarbazepine acetate (ESL). Together with different formulations of CBZ (Carbatrol, Tegretol-XR), and generic formulations, this means that clinicians have many choices within this class of AEDs. This review will compare and discuss the various advantages and disadvantages of this family of AEDs.
We reviewed available information on CBZ (Tegretol, Tegretol XR, and Carbatrol), oxcarbazepine (Trileptal and Oxtellar XR) as well as the newer eslicarbazepine acetate (Aptiom).
The review will focus on the newer branded products, but in addition to brand name medications, many are available in generic forms, making for even more choices. In general, generics have the advantages that they are less expensive. However, since they are from multiple manufacturers, generic medications can be less consistent, since the FDA definition of bioequivalence has a (reasonable) margin of error. The general consensus, including from American Academy of Neurology (AAN), is that generic medications are generally an acceptable option. However, because small differences in pharmacokinetics can result in significant side effects or breakthrough seizures, automatic substitutions without notification of the neurologist should not be done routinely.[Citation1,Citation2]
2. Mechanism of action
Like several other AEDs (e.g. phenytoin, lamotrigine), the mechanism of action of this dibenzazepine class of AEDs is thought to be inhibition of the voltage-gated sodium channel. CBZ, OXC, and ESL exert their pharmacologic effect by binding to and stabilizing the inactivated state of the voltage-gated sodium channel (VGSC). This prevents the channel from reverting back to the resting form, which would be then susceptible to a depolarization and subsequent repetitive neuronal firing. Compared to CBZ and OXC, ESL has a higher selectivity for the inactivated state vs. the resting state of the VGSC, giving ESL a greater inhibitory effect on rapidly firing neurons over those with normal activity, though it is not clear if this is clinically relevant.[Citation3–Citation6] Eslicarbazepine, the main active metabolite of both OXC and ESL, has been found to act preferentially on slow inactivation of the sodium channels compared to CBZ and OXC. Furthermore, unlike CBZ and OXC, ESL is much more selective for the Cav3.2 channels.
3. Compounds, chemistry, and formulation
CBZ is the oldest in this class of dibenzazepine AEDs. It has a dibenzazepine nucleus with a 5-carboxamide substituent. CBZ is metabolized via CYP3A4 into Carbamazepine-10,11-epoxide, an active metabolite. This epoxide metabolite is thought to contribute to central nervous system toxicity and other untoward adverse effects. In addition, with chronic use, CBZ can induce its own metabolism (autoinduction), and it is a potent inducer of several of the cytochrome (CYP) P450 enzymes and uridine-glucuronyl transferases (UGT).[Citation7,Citation8] There are several available dosage forms for CBZ. It is available as an immediate release formulation, both oral suspension and tablet (Tegretol) that is dosed two to four times per day. CBZ was later formulated into extended release, 12-hour formulations (Tegretol-XR and Carbatrol) to allow for twice daily dosing and more stable blood levels. Tegretol-XR® is available as a tablet that must be swallowed whole and should not be crushed or chewed. Carbatrol has an original delivery system and is formulated as a capsule with three different types of beads: immediate release, extended release, and enteric release. In the near future, an intravenous formulation of CBZ will likely be available.
Oxcarbazepine is a structural derivative of CBZ with a ketone substitution on the dibenzazepine ring at the 10 position. It can inhibit CYP2C19 and induce CYP3A4/5. This structural difference offers OXC a reduced risk of serious side effects compared to CBZ and lacks significant auto-inducing properties. Following oral administration, OXC is reduced to its active metabolite, 10,11-dihydro-10-hydroxy-carbazepine (monohydroxy derivative, MHD). MHD is then further broken down to the inactive metabolite 10,11-trans-dihydroxy metabolite (DHD). Formulations of OXC include immediate release preparations (generic oxcarbazepine and trileptal) that are typically dosed twice daily. The once daily formulation Oxtellar XR must be taken on an empty stomach, at least 1 hour before or 2 hours after a meal, and must be administered whole without crushing or chewing the tablet.
ESL is the newest member of the dibenzazepine family of AEDs, and is structurally different than CBZ and OXC. Like them, ESL has a dibenzazepine nucleus with a 5-carboxyamide substitute, but it is structurally different at the 10, 11-position, giving it unique pharmacokinetic and pharmacodynamics properties. ESL can inhibit CYP2C19 and induce CYP3A4. Following oral administration, eslicarbazepine acetate is rapidly and highly absorbed from the gastrointestinal tract. It then undergoes rapid and extensive hepatic first pass metabolism via hydrolysis to the major active metabolite eslicarbazepine (S-licarbazepine), Eslicarbazepine accounts for greater total systemic drug exposure. ESL is then converted to a lesser extent to the minor active metabolites R-eslicarbazepine and OXC.[Citation5,Citation9] Compared to OXC, ESL has a higher eslicarbazepine-to-(R)-licarbazepine area under the curve (AUC).[Citation10]
Another important pharmacokinetic feature of ESL is that, like OXC, it is not metabolized to CBZ-10,11- epoxide [Citation3,Citation5] ESL does not produce induction or auto-induction. In addition, ESL has been shown to have a ‘cleaner’ metabolism compared to OXC and it is suggested to have a more favorable safety profile and fewer drug interactions.[Citation5,Citation9]
Eslicarbazepine acetate is rapidly converted to the active metabolite eslicarbazepine providing a longer duration of action in the CSF. This rapid conversion supports once-daily dosing for ESL compared to twice daily for OXC and CBZ. In the United States, ESL is formulated as 200 mg, 400 mg, 600 mg, and 800 mg tablets for oral administration.[Citation3]
4. Efficacy
It is a general consensus that there is no significant difference in efficacy among AEDs, old versus new, within the second-generation agents, much less among the various compounds of the CBZ class. All have comparable efficacy in decreasing partial seizures with or without generalization. Thus, realistically, efficacy is not a differentiating factor among various AEDs.[Citation11]
5. Adverse events, tolerability, safety
CBZ side effects are well known and documented. The most common ones are nausea, vomiting, dizziness, drowsiness, swollen tongue, dry mouth, and loss of balance or coordination. The active molecule of CBZ-10, 11 -epoxide (formed by oxidation of the double bond between C-10 and C-11), appears to provide great antiepileptic efficacy but contributes significantly to clinical toxicity. OXC was developed to provide a compound chemically similar enough to CBZ to mimic its efficacy, but improving its tolerability. Nonetheless, the common side effects of OXC are overall similar to CBZ. Rash is significantly reduced with OXC. The most common side effects of eslicarbazepine are also similar to CBZ and OXC: dizziness, somnolence, nausea, headache, diplopia, vomiting, fatigue, vertigo, ataxia, blurred vision, and tremor. A common concern is hyponatremia, which has been reported with all 3 agents to various degrees. A cross-sectional study indicated oxcarbazepine is associated with a greater incidence of hyponatremia when compared with CBZ.[Citation3–Citation5,Citation12] With regard to thyroid abnormalities, there is no evidence to suggest that thyroid disorders are more or less common in CBZ, OXC, ESL. All three have thyroid disorders listed in their prescribing information. Thyroid function test has been reported to show decreased values with CBZ. OXC use was associated with decrease in T4, without changes in T3 or TSH. ESL may affect thyroid function assays but not thyroid function (see ).
Table 1. Summary Table (based on prescribing information).
6. Serious idiosyncratic adverse effects
CBZ is associated with serious idiosyncratic adverse effects, and has a black-box warning with serious dermatological reactions, including toxic epidermal necrolysis (TEN) and Stevens–Johnson syndrome (SJS). Occurrence is estimated to be 1 in 6 per 10,000 new users mainly in Caucasian populations, and the risk is to be 10 higher in some Asian countries due to HLA-B *1502. Aplastic anemia and agranulocytosis have a black-box warning since they also have been associated with the use of CBZ. OXC and ESL do not have these black-box warning. It is thought that the avoidance of the epoxide metabolite circumvents some of these hypersensitivity reactions.
7. FDA indication
Like most new AEDs on the US market, all new members of the CBZ family are initially approved as adjunct treatment for partial (focal) epilepsy in adults. Eventually, some have obtained a formal indication in pediatrics and for monotherapy; however, those official indications are largely at times symbolic, since all AEDs are routinely used off label in children and in monotherapy. Aptiom is now approved for both adjunctive and monotherapy treatment of partial-onset seizures. Oxtellar XR is approved for adjunctive treatment of partial-onset seizures in adults and children 6–17 years. Oxcarbazepine (Trileptal and its generics) is approved for use in monotherapy and adjunctive therapy in adults and children (older than 2 as adjunctive and older than 4 as monotherapy).
Regarding indications outside of epilepsy, Tegretol, Tegretol-XR, Carbatrol have FDA approval for trigeminal neuralgia. At this time Trileptal (OXC), Oxtellar XR (OXC), and Aptiom (ESL) are only approved for epilepsy. Whether or not they have similar efficacy to CBZ outside of epilepsy is quite possible but unknown (see ).
8. Administration, titration, dosing
In regard to administration and titration, there are significant differences among the compounds, which may play an important role in choosing the best medication for a particular patient.
Generic CBZ, Tegretol and Tegretol XR should all be taken with food. Tegretol-XR is available as a tablet that must be swallowed whole and should not be crushed or chewed. Carbatrol is formulated as a capsule with three different types of beads: immediate release, extended release, and enteric release. It may be opened and sprinkled on food to ease administration. Oxcarbazepine is available in tablet and oral suspension and can be administered without regard to meals. The once-daily formulation Oxtellar XR must be taken on an empty stomach (1 hour before or 2 hours after a meal) and must be administered whole without crushing or chewing the tablet. Lastly, Aptiom can be administered with or without food, and tablets can be administered whole or crushed.[Citation2–Citation4]
Another key aspect is the frequency of dosing, since most patients prefer medications that are taken less frequently. Tegretol-XR and Trileptal are twice-daily formulations, and the rest of the medications are once daily. This is important for compliance, as it has been documented that patients who are prescribed medications that are dosed two to four times daily are more likely to miss doses than a once-daily formulation.[Citation4,Citation5,Citation9,Citation13,Citation14] Aptiom and Oxtellar XR have the advantages of being indicated once daily. Oxtellar XR utilizes a novel proprietary extended-release technology which slows absorption and provides consistent plasma levels over a 24-hour period. In addition to compliance, extended release formulations and medications with a long half-life may also improve tolerability with fewer peak–trough fluctuations, thus allowing patients to achieve appropriate target doses.
The recommended titration for Tegretol, Tegretol XR, and Carbatrol is similar, with a starting dose of 400 mg daily, then an increase by 200 mg weekly. A slightly faster titration is available for Trileptal and Oxtellar XR (600 mg daily, increase by 600 mg weekly), and Aptiom (400 mg daily, increase by 400 mg to 600 weekly). Maintenance dosing for CBZ should be between 1000 and 1200 mg daily; OXC should be 1200 mg daily. For ESL, a maintenance dose of 800–1200 mg daily should be targeted (see ).[Citation4,Citation5,Citation9,Citation13,Citation14]
9. Pricing and cost
Older medications like Tegretol, Tegretol XR, and Carbatrol are inexpensive compared to the newer medications: Trileptal, Oxtellar XR, and Aptiom. The newer brand medications are generally more expensive. In some cases, cost to the patient will weigh more heavily than efficacy, since if the patient cannot afford to take the product, then the medication will not provide any efficacy (see ).
Table 2. Pricing table.[Citation15]
10. Conclusion/expert opinion
Overall, there are few and relatively minor differentiating features among the various CBZ-related preparations. For selected patients, one may offer advantages over another.
Cost may be the most significant difference among these agents. AWP (average wholesale price) is the price to pharmacy and may not reflect the cost to patient. Actual cost to the patient depends on multiple factors, including dose, formulation, geography, insurance, and copay.
Declaration of interest
S Benbadis has served as a consultant for Acorda, Cyberonics, Eisai, Lundbeck, Sunovion, UCB Pharma, Upsher-Smith; is on the speakers bureau for Cyberonics (Livanova), Eisai, GlaxoSmithKline, Lundbeck, Sunovion, UCB Pharma; and has received grant support from Acorda, Cyberonics, GW Pharmaceuticals, Lundbeck, Sepracor, Sunovion, UCB Pharma and, Upsher-Smith. S Benbadis has received royalties as an author or Editor for Emedicine-Medscape-WebMD and UpToDate. He is also on the Editorial Board for Emedicine-Medscape-WebMD, Epileptic Disorders, Epilepsy and Behavior, and Expert Review of Neurotherapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
References
- Privitera M. Generic substitution of antiepileptic drugs. What’s a clinician to do? Neurol Clin Pract. 2013;3(2):161–164.
- Labiner DM, Paradis PE, Manjunath R, et al. Generic antiepileptic drugs and associated medical resource utilization in the United States. Neurology. 2010;74(20):1566–1574.
- Aptiom [package insert]. Marlborough, MA: Sunovion Pharmaceuticals; 2013 Nov.
- Keating GM. Eslicarbazepine Acetate: a review of its use as adjunctive therapy in refractory partial-onset seizures. CNS Drugs. 2014;28:583–600.
- Verrotti A, Loiacono G, Rossi A, et al. Eslicarbazepine acetate: an update on efficacy and safety in epilepsy. Epilepsy Res. 2014;108:1–10.
- Bonifácio MJ, Sheridan RD, Parada A, et al. Interaction of the novel anticonvulsant, BIA 2-093, with voltage-gated sodium channels: comparison with carbamazepine. Epilepsia. 2001;42(5):600–608.
- Patsalos PN, Fröscher W, Pisani F, et al. The importance of drug interactions in epilepsy therapy. Epilepsia. 2002;43(4):365–385.
- Zaccara G, Perucca E. Interactions between antiepileptic drugs, and between antiepileptic drugs and other drugs. Epileptic Disord. 2014;16(4):409–432.
- Banach M, Borowicz KK, Czuczwar SJ. Pharmacokinetic/pharmacodynamics evaluation of eslicarbazepine for the treatment of epilepsy. Expert Opin Drug Metab Toxicol. 2015;11(4):639–648.
- Bialer M, Soares-da-Silva P. Pharmacokinetics and drug interactions of eslicarbazepine acetate. Epilepsia. 2012;53(6):935–946.
- Benbadis S, Stefan H, Morita D, et al. Pharmacologic decision-making in the treatment of focal epilepsy — a critical comparison of antiepileptic drugs. US Neurol. 2014;10:2–13.
- Dong X, Leppik IE, White J, et al. Hyponatremia from oxcarbazepine and carbamazepine. Neurology. 2005;65:1976–1978.
- Hainzl D, Parada A, Soares-da-Silva P. Metabolism of two new antiepileptic drugs and their primcipal metabolites S(+)- and R(-)-10,11-dihydro-10-hydroxy carbamazepine. Epilepsy Res. 2001;(44):197–206.
- Sperling MR, Abou-Khalil B, Harvey J, et al. Eslicarbazepine acetate as adjunctive therapy in patients with uncontrolled partial-onset seizures: results of a phase III, double-blind, randomized, placebo-controlled trial. Epilepsia. 2015;56(2):244–253.
- Lexi-Drugs. Lexicomp. Hudson, OH: Wolters Kluwer Health, Inc; [cited 2015 Dec 9]. Available from: http://online.lexi.com.