Oxcarbazepine [ICNApedia]

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====== Oxcarbazepine ======
Oxcarbazepine (10,11-dihydro-10-oxo-5H-dibenz-[b,f]azepine-5-carboxamide) is a 0-keto derivative of carbamazepine, but these two AEDs have some significant differences. The anti-epileptic activity is mainly exerted via its major metabolite, hydroxy-10,11-dihydro-5H-dibenzazepine-5-carboxamide (MHD). It was first licensed as an AED in 1990 in Denmark.
===== Authorised indications =====

UK-SmPC: monotherapy or adjunctive therapy for focal seizures with or without secondarily GTCSs in patients ≥6 years of age.

FDA-PI: (1) monotherapy or adjunctive therapy in the treatment of focal seizures in adults and as monotherapy in the treatment of focal seizures in children aged 4 years and above with epilepsy, and (2) as adjunctive therapy in children aged 2 years and above with epilepsy.

===== Oxcarbazepine versus carbamazepine =====

Oxcarbazepince is similar to carbamazepine in its anti-epileptic efficacy and main mechanisms of action. However, it is better tolerated and has fewer interactions with other drugs because it does not undergo metabolism to 10,11 -epoxide. In contrast to carbamazepine, involvement of the hapatic CYP-dependent enzymes in the metabolism of oxcarbazepine is minimal. Oxcarbazepine has a lower incidence of idiosyncratic reactions than carbamazepine; but hyponatraemia is more common with oxcarbazepine than carbamazepine.

The profile of oxcarbazepine is more similar to that of the slow-release carbamazepine preparations.

===== Clinical applications =====
Oxcarbazepine is a first class AED for monotherapy, conversion to monotherapy or adjunctive therapy for all types of focal seizures with or without secondarily GTCSs.This has been documented in a series of clinical trials and by extensive clinical use. In 2003, it became the first AED to be approved by the FDA in 25 years for use as monotherapy in children with focal epilepsy.

===== Dosage and titration =====
Adults: start treatment with 150 mg/day and increase by 150 mg/day every second day until a target dose of 900–1200 mg/day is reached. Others start with 600 mg/ day and increase weekly in 600 mg increments until a maintenance dose of between 1200 and 2400 mg/day is reached. I would recommend the principle of ‘start low and go slow’ to avoid ADRs and particularly rash.

In patients with impaired renal function (creatinine clearance
Children: start with 10 mg/kg/day in two or three divided doses. The dosage can be increased by 10 mg/kg/day at approximately weekly intervals to a maximum of 30–46 mg/kg/day.
Dosing: twice or three-times daily.

TDM: because of striking pharmacokinetic changes, and clinical response, oxycarbazepine levels should be monitored throughout pregnancy and the puerperium.212,213
Reference range: MHD, 4–12 mg/l (50–140 μmol/l).

===== Main ADRs =====
Frequent and/or important: the most common CNS adverse events are headache, dizziness, fatigue, nausea, somnolence, ataxia and diplopia. Most of these are dose related, they usually occur at the start of therapy and subside during the course of therapy.

Serious: the reported rate of skin rash with oxcarbazepine is around 2% (adults) and 5% (children), as opposed to 5–10% with car bamazepine. Multiorgan hypersensitivity disorder and Stevens–Johnson syndrome have been reported.

Cross-reactivity with carbamazepine is approximately 25% (i.e. of the patients who have skin rash with carbamazepine, 25% will also have skin rash with oxcarbazepine). Therefore, given the availability of other AEDs, oxcarbazepine may not be a good option for patients who developed idiosyncratic reactions with carbamazepine or other AEDs e.g. lamotrigine and phenytoin.

Hyponatraemia (serum sodium level

Consumption of large volumes of any fluid should be discouraged.

Oxcarbazepine is contraindicated in patients with a history of atrioventricular block.

**FDA warning:** All patients who are currently taking or starting on oxcarbazepine for any indication should be monitored for notable changes in behaviour that could indicate the emergence or worsening of suicidal thoughts or behaviour or depression.

===== Considerations in women =====
Pregnancy: category C. Seizure control may be lost during pregnancy in women on oxcarbazepine.The concentration of oxcarbazepine and its metabolite decrease markedly during pregnancy and may increase several fold after delivery.

Breastfeeding: oxcarbazepine and its active metabolite are secreted in significant amounts in breast milk.

Interaction with hormonal contraception: yes.

===== Main mechanisms of action =====
Oxcarbazepine exerts its anti-epileptic activity primarily through its major metabolite MHD. Like carbamazepine, blockade of voltage-sensitive sodium channels is its main mechanism of action. Others include reduction of the release of excitatory amino acids, probably by inhibiting high voltage-activated calcium currents. An effect on potassium channels might be clinically important.

===== Pharmacokinetics =====
Oral bioavailability: >95% and peak concentrations are reached within 4–6 hours. Absorption is unaffected by food.

Protein binding: only 38% of the MHD is bound to serum proteins, as compared with 67% for the parent compound.

Metabolism: oxcarbazepine is rapidly metabolised in the liver to form the pharmacologically active MHD. This is then conjugated to a glucuronide compound and excreted in the urine as a monohydroxy derivative.

Elimination half-life: 8–10 hours. This is shorter in children and longer in the elderly.

As a neutral lipophilic substance, the active metabolite MHD of oxcarbazepine is able to diffuse rapidly through the various membranes and the blood–brain barrier.

===== Drug interactions =====
The oxcarbazepine–MHD complex lowers plasma concentrations of some drugs, such as hormonal contraceptives and lamotrigine, and increases the plasma concentration of others, such as phenytoin. Conversely, strong inducers of the CYP enzyme system, such as carbamazepine and phenytoin, lower plasma levels of MHD by 29–40%.

Combination therapy with monoamine oxidase inhibitors should be avoided, because oxcarbazepine has structural similarities with tricyclic antidepressants.

===== Main disadvantages =====
Oxcarbazepine is contraindicated in generalised seizures, such as absences or myoclonic jerks in syndromes of IGE.214 It may not be effective in neonates and children
One out of four patients have cross sensitivity to idiosyncratic reactions with carbamazepine or other AEDs.
Although it is among the first-choice AEDs for monotherapy in focal epilepsies, its use as polytherapy is less satisfactory because of drug– drug interactions.
Unless levels of oxcarbazepine are adjusted, seizures may increase during pregnancy and toxicity may appear postpartum.

===== Useful clinical notes =====
Conversion to oxcarbazepine from carbamazepine or phenytoin is complicated by the intial need for higher doses of oxcarbazepine than needed later as monotherapy.
A carbamazepine dose of 200 mg appears to be equivalent to 300 mg of oxcarbazepine.
It is possible to change from carbamazepine to oxcarbazepine abruptly, using a dose ratio of 200 mg carbamazepine to 300 mg oxcarbazepine, without the need for titration. A lower ratio 1:1 or 1:1.25 is usually better tolerated, especially if the conversion is from slow-release preparations of carbamazepine. level of concomitant medication may be affected by the removal of the enzyme-inducing effects of carbamazepine.