Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Generics [UK] Ltd t/a Mylan, Station Close, Potters Bar, Herts. EN6 1TL, United Kingdom
Pharmacotherapeutic group: Antiepileptics, Carboxamide derivatives
ATC code: N03AF02
The pharmacological activity of oxcarbazepine is primarily exerted through the metabolite (MHD) (see section 5.2). The mechanism of action of oxcarbazepine and MHD is thought to be mainly based on the 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 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 aluminium 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.
A prospective, open-label, multicentre, non-comparative, 24 week observational post marketing study has been conducted in India. Out of a study population of 816 patients, 256 paediatric patients (1 month to 19 years) with generalised tonic-clonic seizures (either secondary or primary) were treated with oxcarbazepine monotherapy. The initial oxcarbazepine dose for all patients > 6 years was 8 to 10 mg/kg/day given in 2 divided doses. For the 27 subjects aged 1 month to 6 years, the dose range for the initial dose was 4.62 to 27.27 mg/kg/day and 4.29 to 30.00 mg/kg/day maintenance dose. The primary endpoint was reduction in seizure frequency from baseline at week 24. In the age group 1 month to 6 years (n=27) the number of seizures changed from 1 [range] [1-12] to 0 [0-2], in the age group 7 years to 12 years (n=77) the frequency changed from 1 [1-22] to 0 [0-1] and in the age group 13 to 19 years (n=152), the frequency changed from 1 [1-32] to 0 [0-3]. No specific safety concerns in the paediatric patients were identified. Data supporting benefit/risk from the study regarding children under the age of 6 are inconclusive (see section 4.2).
Based on the data from the randomised controlled trials, the use of oxcarbazepine is not recommended in children below the age of 6 since safety and efficacy have not been adequately demonstrated (see section 4.2).
Following oral administration of oxcarbazepine, oxcarbazepine is completely absorbed and extensively metabolised to its pharmacologically active metabolite (MHD).
After a single dose administration of 600mg 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, oxcarbazepine can be taken with or without food.
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 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.
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).
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.
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 2400 mg/day.
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.
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).
The pharmacokinetics of oxcarbazepine were 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.
Data from a limited number of women indicate that MHD plasma levels may gradually decrease throughout pregnancy (see section 4.6).
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 younger 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.
No gender related pharmacokinetic differences have been observed in children, adults, or the elderly.
Preclinical data indicated no special hazard for humans based on safety pharmacology and genotoxicity studies with oxcarbazepine and the pharmacologically active metabolite, monohydroxy derivative (MHD).
Evidence of nephrotoxicity was noted in repeated dose toxicity rat studies but not in dog or mice studies.
Immunostimulatory tests in mice showed that MHD (and to a lesser extent oxcarbazepine) can induce delayed hypersensitivity.
Oxcarbazepine increased mutation frequencies in one Ames test in vitro in the absence of metabolic activation in one of five bacterial strains. Oxcarbazepine and MHD produced increases in chromosomal aberrations and/or polyploidy in the Chinese hamster ovary assay in vitro in the absence of metabolic activation. MHD was negative in the Ames test, and no mutagenic or clastogenic activity was found with either oxcarbazepine or MHD in V79 Chinese hamster cells in vitro. Oxcarbazepine and MHD were both negative for clastogenic or aneugenic effects (micronucleus formation) in an in vivo rat bone marrow assay.
In rats, fertility in both sexes was unaffected by oxcarbazepine at oral doses up to 150 mg/kg/day, at which there is no safety margin. Disruption of estrous cyclicity and reduced numbers of corpora lutea, implantations and live embryos were observed in female animals for MHD at doses comparable to those in humans (see section 4.6).
Standard reproductive toxicitystudies in rodents and rabbits revealed effects such as increases in the incidence of embryo-foetal mortality and/or some delay in antenatal and/or postnatal growth of the offspring at maternally toxic dose levels. There was an increase in rat foetal malformations in one of the eight embryo-foetal toxicity studies, which were conducted with either oxcarbazepine MHD, at doses which also caused maternal toxicity (see section 4.6).
In the carcinogenicity studies, liver (rats and mice), testicular and female genital tract granular cell (rats) tumours were induced in treated animals. The occurrence of liver tumours was most likely a consequence of the induction of hepatic microsomal enzymes; an inductive effect which, although it cannot be excluded, is weak or absent in patients treated with oxcarbazepine. Testicular tumours may have been induced by elevated luteinising hormone concentrations. Due to the absence of such an increase in humans, these tumours are considered to be of no clinical relevance. A dose-related increase in the incidence of granular cell tumours of the female genital tract (cervix and vagina) was noted in the rat carcinogenicity study with MHD. These effects occurred at exposure levels comparable with the anticipated clinical exposure. The mechanism for the development of these tumours has not been fully elucidated but could be related to increased estradiol levels specific to the rat. The clinical relevance of these tumours is unclear.
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