Eslicarbazepine acetate

Eslicarbazepine acetate [(S)-(--)-10-acetoxy-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide] is a prodrug of eslicarbazepine (S-9-(-)-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide) and shares with carbamazepine and oxcarbazepine the dibenzazepine nucleus bearing the 5-carboxamide substitute, but is structurally different at the 10,11-position. Eslicarbazepine acetate is the latest AED to be licensed in Europe (April 2009) with the brand names Exalief and Zebinix (it will trade in USA as Stedesa).

Authorized indications

SmPC. Adjunctive therapy in adults (≥ 18 years of age) within the treatment of focal seizures with or without secondary generalisation.

FDA. Not yet licensed.

Clinical applications

Eslicarbazepine acetate is the newest AED licensed for adjunctive treatment of focal seizures. Considering its similarities with carbamazepine, eslicarbazepine acetate may be contra-indicated in generalised seizures, though this has not been assessed.

Dosage and titration

Adults. The recommended starting dose is 400 mg once daily which should be increased to 800 mg once daily after one or two weeks. Based on individual response, the dose may be increased to 1200 mg once daily. Dosing. Once daily. Therapeutic drug monitoring. Unknown. Reference range. Unknown.

Main ADRs

Frequent and/or important. Dizziness, somnolence, headache, ataxia, inattention, diplopia, tremor, nausea, vomiting.

Serious. Rash in 1.1% and hyponatraemia in 1% of total treated population.

The use of eslicarbazepine acetate is associated with increase in the PR interval. Adverse reactions associated with PR interval prolongation that include atrioventricular block, syncope and bradycardia may occur. No second or higher degree atrioventricular block was seen.

Considerations in women

Pregnancy. Category C. Studies in animals have shown reproductive toxicity.

Breastfeeding. Unknown but possibly excreted in breast milk (animal data).

Interactions with hormonal contraception. Significantly decreases the effectiveness of hormonal contraception by decreasing levonorgestrel and ethinyloestradiol levels, most likely by inducing CYP3A4.

Main mechanisms of action

Probably similar to carbamazepine – that is, inhibition of voltage-gated sodium channels. Both eslicarbazepine acetate and its metabolites stabilise the inactivated state of voltage-gated sodium channels, preventing their return to the activated state and thereby sustaining repetitive neuronal firing.

Pharmacokinetics

Oral bioavailability: high – the amount of metabolites recovered in urine corresponded to more than 90% of an eslicarbazepine acetate dose.

Protein binding: 30%

Metabolism: Eslicarbazepine acetate is rapidly and extensively biotransformed to its major active metabolite eslicarbazepine by hydrolytic first-pass metabolism. Eslicarbazepine acetate metabolites are eliminated from the systemic circulation primarily by renal excretion, in the unchanged and glucuronide conjugate forms. Minor active metabolites in plasma are R-licarbazepine and oxcarbazepine. Eslicarbazepine acetate does not affect its own metabolism or clearance.

Elimination half-life: 12–20 hours.

Drug interactions

Drug interactions may be significant. Eslicarbazepine acetate may have an inducing effect on the metabolism of drugs which are mainly eliminated by metabolism through CYP3A4 (carbamazepine, phenytoin, phenobarbital, topiramate) or conjugation through the UDP-glucuronyltransferases (lamotrigine).

When initiating or discontinuing treatment with eslicarbazepine acetate or changing the dose, it may take 2 to 3 weeks to reach the new level of enzyme activity. This time delay must be taken into account when eslicarbazepine acetate is being used just prior to or in combination with other drugs that require dose adjustment when co-administered with eslicarbazepine acetate.

Also, eslicarbazepine has inhibiting properties with respect to CYP2C19 and therefore interacts in comedication with drugs that are mainly metabolised by CYP2C19.

Concomitant administration of eslicarbazepine acetate with

• phenytoin significantly decreases exposure to eslicarbazepine (most likely caused by an induction of glucuronidation) and increases exposure to phenytoin (most likely caused by CYP2C19 inhibition)
• lamotrigine is expected to lead to interactions because glucuronidation is the major metabolic pathway for both of these drugs. However, their co-administration in healthy subjects showed a minor average pharmacokinetic interaction (exposure of lamotrigine decreased 15%)
• topiramate mildly decreases exposure to topiramate (most likely caused by a reduced bioavailability of topiramate)
• carbamazepine significantly increases the risk of diplopia, ataxia and dizziness. Carbamazepine increases eslicarbazepine clearance and vice versa.

Concomitant administration with valproate or levetiracetam appeared not to affect the exposure to eslicarbazepine.

Main disadvantages

Eslicarbazepine acetate has been developed with the intention that it should have less interaction potential with other drugs than its parent drug carbamazepine and no auto-induction by preventing the formation of toxic epoxide metabolites such as carbamazepine-10,11 epoxide. However, this appears to be an unfulfilled promise because eslicarbazepine acetate has many drug interactions. Whether it will match the success of carbamazepine is too early to assess.