Pharmacotherapeutic group: Antiepileptics. ATC code: N03AF02.
Pharmacology: Pharmacodynamics: Pharmacodynamic effects: The pharmacological activity of oxcarbazepine is primarily exerted through the metabolite (MHD) (see Pharmacokinetics as follows). The mechanism of action of oxcarbazepine and MHD is thought to be mainly based on blockade of voltage-sensitive sodium channels, thus resulting in stabilisation of hyperexcited neural membranes, inhibition of repetitive neuronal firing, and diminishment of propagation of synaptic impulses. In addition, increased potassium conductance and modulation of high-voltage activated calcium channels may also contribute to the anticonvulsant effects. No significant interactions with brain neurotransmitter or modulator receptor sites were found.
Oxcarbazepine and its active metabolite (MHD) are potent and efficacious anticonvulsants in animals. They protected rodents against generalised tonic-clonic and, to a lesser degree, clonic seizures, and abolished or reduced the frequency of chronically recurring partial seizures in Rhesus monkeys with aluminum implants. No tolerance (i.e. attenuation of anticonvulsive activity) against tonic-clonic seizures was observed when mice and rats were treated daily for 5 days or 4 weeks, respectively, with oxcarbazepine or MHD.
Pharmacokinetics: Absorption: Following oral administration of oxcarbazepine, it is completely absorbed and extensively metabolised to its pharmacologically active metabolite (MHD).
After single dose administration of 600 mg oxcarbazepine to healthy male volunteers under fasted conditions, the mean Cmax value of MHD was 34 μmol/l, with a corresponding median tmax of 4.5 hours.
In a mass balance study in man, only 2 % of total radioactivity in plasma was due to unchanged oxcarbazepine, approximately 70 % was due to MHD, and the remainder attributable to minor secondary metabolites which were rapidly eliminated.
Food has no effect on the rate and extent of absorption of oxcarbazepine, therefore, Kusapin can be taken with or without food.
Distribution: The apparent volume of distribution of MHD is 49 litres.
Approximately 40 % of MHD is bound to serum proteins, predominantly to albumin. Binding was independent of the serum concentration within the therapeutically relevant range. Oxcarbazepine and MHD do not bind to alpha-1-acid glycoprotein.
Oxcarbazepine and MHD cross the placenta. Neonatal and maternal plasma MHD concentrations were similar in one case.
Metabolism: Oxcarbazepine is rapidly reduced by cytosolic enzymes in the liver to MHD, which is primarily responsible for the pharmacological effect of oxcarbazepine. MHD is metabolised further by conjugation with glucuronic acid. Minor amounts (4 % of the dose) are oxidised to the pharmacologically inactive metabolite (10, 11-dihydroxy derivative, DHD).
Elimination: Oxcarbazepine is cleared from the body mostly in the form of metabolites which are predominantly excreted by the kidneys. More than 95 % of the dose appears in the urine, with less than 1 % as unchanged oxcarbazepine. Faecal excretion accounts for less than 4 % of the administered dose. Approximately 80 % of the dose is excreted in the urine either as glucuronides of MHD (49 %) or as unchanged MHD (27 %), whereas the inactive DHD accounts for approximately 3 % and conjugates of oxcarbazepine account for 13% of the dose.
Oxcarbazepine is rapidly eliminated from the plasma with apparent half-life values between 1.3 and 2.3 hours. In contrast, the apparent plasma half-life of MHD averaged 9.3 ± 1.8 h.
Dose proportionality: Steady-state plasma concentrations of MHD are reached within 2 - 3 days in patients when oxcarbazepine is given twice a day. At steady-state, the pharmacokinetics of MHD are linear and show dose proportionality across the dose range of 300 to 2,400 mg/day.
Special populations: Patients with hepatic impairment: The pharmacokinetics and metabolism of oxcarbazepine and MHD were evaluated in healthy volunteers and hepatically impaired subjects after a single 900 mg oral dose. Mild to moderate hepatic impairment did not affect the pharmacokinetics of oxcarbazepine and MHD. Oxcarbazepine has not been studied in patients with severe hepatic impairment.
Patients with renal impairment: There is a linear correlation between creatinine clearance and the renal clearance of MHD. When oxcarbazepine is administered as a single 300 mg dose, in renally impaired patients (creatinine clearance < 30 mL/min) the elimination half-life of MHD is prolonged by 60-90 % (16 to 19 hours) with a two fold increase in AUC compared to adults with normal renal function (10 hours).
Children: The pharmacokinetics of oxcarbazepine was evaluated in clinical trials in paediatric patients taking oxcarbazepine in the dose range 10-60 mg/kg/day. Weight-adjusted MHD clearance decreases as age and weight increases approaching that of adults. The mean weight-adjusted clearance in children 4 to 12 years of age is approximately 40% higher than that of adults. Therefore, MHD exposure in these children is expected to be about two-thirds that of adults when treated with a similar weight-adjusted dose. As weight increases, for patients 13 years of age and above, the weight-adjusted MHD clearance is expected to reach that of adults.
Pregnancy: Data from a limited number of women indicate that MHD plasma levels may gradually decrease throughout pregnancy (see Use in Pregnancy & Lactation).
Elderly: Following administration of single (300 mg) and multiple doses (600 mg/day) of oxcarbazepine in elderly volunteers (60 - 82 years of age), the maximum plasma concentrations and AUC values of MHD were 30% - 60% higher than in younger volunteers (18 - 32 years of age). Comparisons of creatinine clearances in young and elderly volunteers indicate that the difference was due to age-related reductions in creatinine clearance. No special dose recommendations are necessary because therapeutic doses are individually adjusted.
Gender: No gender related pharmacokinetic differences have been observed in children, adults, or the elderly.