Indications:
OXATRILEPAZINE (Oxcarbazepine) is indicated for use as mono-therapy or adjunctive therapy in the treatment of partial seizures in adults and as mono therapy in the treatment of partial seizures in children aged 4 years and above with epilepsy, and as adjunctive therapy in children aged 2 years and above with epilepsy.
Dosage:
Posology:
OXATRILEPAZINE is suitable for use either as mono-therapy or in combination with other antiepileptic medicinal products. In mono and adjunctive therapy, treatment with OXATRILEPAZINE is initiated with a clinically effective dose given in two divided doses. The dose may be increased depending on the clinical response of the patient. When other antiepileptic medicinal products are replaced by OXATRILEPAZINE, the dose of the concomitant antiepileptic medicinal products should be reduced gradually on initiation of OXATRILEPAZINE therapy. In adjunctive therapy, as the total antiepileptic medicinal product load of the patient is increased, the dose of the concomitant antiepileptic medicinal products may need to be reduced and/or the OXATRILEPAZINE dose increased slowly. OXATRILEPAZINE can be taken with or without food.
Method of administration:
The following dosing recommendations apply to all patients, in the absence of impaired renal function. Drug plasma level monitoring is not necessary to optimise OXATRILEPAZINE therapy.
The tablets are scored and can be broken in two halves in order to make it easier for the patient to swallow the tablet. For younger children, who cannot swallow tablets or where the required dose cannot be administered using tablets, OXATRILEPAZINE oral suspension is available.
. Adults and elderly patients:
Mono-therapy:
OXATRILEPAZINE should be initiated with a dose of 600 mg/day (8-10 mg/kg/day) given in 2 divided doses. Good therapeutic effects are seen between 600 mg/day and 2,400 mg /day. If clinically indicated the dose may be increased by a maximum of 600 mg/day increments at approximately weekly intervals from the starting dose to achieve the desired clinical response. In a controlled hospital setting, dose increases up to 2,400 mg/day have been achieved over 48 hours.
Adjunctive therapy:
OXATRILEPAZINE should be initiated with a dose of 600 mg/day (8-10 mg/kg/day) given in 2 divided doses. Good therapeutic effects are seen between 600 mg/day and 2,400 mg /day. If clinically indicated the dose may be increased by a maximum of 600 mg/day increments at approximately weekly intervals form the starting dose to achieve the desired clinical response.
Daily doses above 2,400 mg/day have not been studied systematically in clinical trials.
There is only limited experience with doses up to 4,200 mg/day.
Children:
In mono- and adjunctive therapy, OXATRILEPAZINE should be initiated with a dose of 8-10 mg/kg/day given in 2 divided doses.
In an adjunctive therapy trial in pediatric patients (aged 3 to 17 years), in which the intention was to reach a target daily dose of 46 mg/kg/day, the median daily dose was 31 mg/kg/day with a range of 6 to 51 mg /kg/day.
In an adjunctive therapy trial in pediatric patients (aged 1 month to less than 4 years), in which the intention was to reach a target daily dose 60 mg/kg/day and 56% of patients reached a final dose of at least 55 mg/kg/day.
If clinically indicated, the dose may be increased by a maximum of 10 mg/kg/day increments at approximately weekly intervals from the starting dose, to a maximum daily dose of 60 mg/kg/day, to achieve the desired clinical response. Under adjunctive therapy and mono-therapy, when normalized body weight , apparent clearance (L/hr/kg) decreased with age such that children 1 month to less than 4 years of age may require twice the Oxcarbazepine dose per body weight compared to adults ; and children 4 to 12 years of age may require a 50% higher Oxcarbazepine dose per body weight compared to adults (see section Pharmacokinetics). for children 1 month to less than 4 years of age, the influence of enzyme – including antiepileptic medicinal products on their weight – normalized apparent clearance appeared higher compared to older children. For children 1 month to less than 4 years of age, 60% higher oxcarbazepine dose per body weight may be required for adjunctive therapy on enzyme – including antiepileptic medicinal products relative to mono-therapy or adjunctive therapy with non- enzyme- including antiepileptic medicinal products. For older children on enzyme –including antiepileptic medicinal products, only a slightly higher dose per body weight may be required than their counterparts on mono-therapy. OXATRILEPAZINE has not been studied in controlled clinical trials in children below 1 month of age.
Patients with hepatic impairment:
No dosage adjustment is required for patients with mild to moderate hepatic impairment. OXATRILEPAZINE has not been studied in patients with severe hepatic impairment. Therefore, caution should be exercised when dosing severely impaired patients.
Patients with renal impairment:
In patients with impaired renal function (Creatinine clearance less than 30 ml/min) OXATRILEPAZINE therapy should be initiated at half the usual starting dose (300 mg/day) and increased slowly to achieve the desired clinical response.

Side effect:
Pregnancy:
Data on a limited number of pregnancies indicate that oxcarbazepine may cause serious birth defects (e.g. cleft palate) when administrated during pregnancy. In animal studies, increased embryo mortality, delayed growth and malformations were observed at maternally toxic dose levels.

Take these data into consideration:
- If woman receiving OXATRILEPAZINE become pregnant, or plan to become pregnant, or if the need to initiate treatment with OXATRILEPAZINE arises during pregnancy, the medicinal product’s potential benefits must be carefully weighed against the potential risk of foetal malformations. This is particularly important during the first three months of pregnancy.
- Minimum effective doses should be given.
- In woman of childbearing age, OXATRILEPAZINE should be administrated as monotherapy, whenever possible.
- Patients should be counseled regarding the possibility of increased risk malformations and given the opportunity of antenatal screening.
- During pregnancy, an effective antiepileptic treatment must not be interrupted, since the aggravation of the illness is detrimental to both the mother and the fetus.
Monitoring and prevention:
Antiepileptic medicinal products may contribute to folic acid deficiency, a possible contributory cause of foetal abnormality. Folic acid supplementation is recommended before and during pregnancy. Due to physiological changes during pregnancy, plasma levels of the active metabolite of oxcarbazepine, the 10 monohydroxy derivative (MHD), may gradually decrease throughout pregnancy.
It is recommended that clinical response should be monitored carefully in woman receiving OXATRILEPAZINE treatment during pregnancy and determination of changes in MHD plasma concentration should be considered to ensure that adequate seizure control is maintained throughout pregnancy. Postpartum MHD plasma levels may also be considered for monitoring especially in the event that medication was increased during pregnancy.
In the newborn child:
Bleeding disorders in the newborn caused by antiepileptic agents have been reported. As a precaution, vitamin K1, should be administered as a preventive measure in the last few weeks pregnancy and to the newborn.
Oxcarbazepine and its active metabolite (MHD) cross the placenta.
Neonatal and maternal plasma MHD concentrations were similar in one case.
Lactation:
Oxcarbazepine and its active metabolite (MHD) are excreted in human breast milk. A milk-to-plasma concentration ratio of 0.5 was found for both. The effects on the infant exposed to OXATRILEPAZINE by this route are unknown. Therefore, OXATRILEPAZINE should not used during breast feeding.
EFFECT ON ABILITY TO DRIVE AND USE MACHINES:
The use of OXATRILEPAZINE has been associated with adverse reactions such as dizziness or somnolence. Therefore, patients should be advised that their physical and /or mental abilities required for operating machinery or driving a car might be impaired.
UNDESIRABLE EFFECTS:
The most commonly reported adverse reactions are somnolence, headache, dizziness, diplopia, nausea, vomiting, and fatigue occurring in more than 10% of patients.
In clinical trials, adverse events (AEs) were generally mild to moderate in severity, of transient nature and occurred predominantly at the start of treatment.
The analysis of the undesirable effect profile by body system is based on AEs from clinical trials assessed as related to OXATRILEPAZINE.
In addition, clinically meaningful reports on adverse experiences from named patient programs and post-marketing experience were taken into account.
Adverse reactions (table 2) are ranked under heading of frequency, the most frequent first, using the following convention: very common: (≥1/10); common: (≥1/100, <1/10); uncommon: (≥1/1,000, <1/100); rare: (≥1/10,000, <1/1,000); very rare: (<1/10,000), including isolated reports.

Very rarely clinically significant hyponatraemia (sodium < 125mmol/L) can develop during OXATRILEPAZINE use. It generally occurred during the first 3 months of treatment with OXATRILEPAZINE, although there were patients who first developed a serum sodium < 125 mmol/L than 1 year after initiation of therapy.
In clinical trials in children aged 1 month to less than 4 years, the most commonly reported adverse reaction was somnolence occurring in approximately 11% of patients. Adverse reactions occurring at an incidence of ≥1% - <10% (common) were: ataxia, irritability, vomiting, lethargy, fatigue, nystagmus, tremor, decreased appetite, and blood uric acid increase.

Drug interaction:
Enzyme inhibition :
Oxcarbazepine was evaluated in human liver microsomes to determine its capacity to inhibit the major cytochrome P450 enzymes responsible for the metabolism of other medicinal products. The results demonstrate that Oxcarbazepine and its pharmacologically active metabolite (the monohydroxy derivative, MHD) inhibit the CYP2C19. Therefore, interactions could arise when CO-administering high doses of OXATRILEPAZINE with medicinal products that are metabolized by CYP2C19 (e.g. Phenobarbital, Phenytoin, see below). In some patient treated with OXATRILEPAZINE and medicinal products metabolized via CYP2C19 a reduction of the co-administered medicinal products might be necessary.
In human liver microsomes, Oxcarbazepine and MHD have little or no capacity to function as inhibitor for the following enzymes: CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1, CYP4A9 and CYP4A11.
Enzyme induction:
Oxcarbazepine and MHD induce in vitro and in vivo , the cytochrome CYP3A4and CYP3A5 responsible for the metabolism of dihydropyridine calcium antagonist , oral contraceptives and antiepileptic medicinal products (e.g. carbamazepine)resulting in lower plasma concentration of these medicinal products(see below).
Such level of decrease in plasma concentrations may also be observed in other drug mainly metabolized by CYP3A4 and CYP3A5, for example immune-suppressants (e.g. Ciclosporin). in vitro, Oxcarbazepine and MHD are weak inducer of UDP-glucuronyl transferase and, therefore in vivo they are unlikely to have an effect on medicinal product which are mainly eliminated by conjugation through the UDP-glucuronyl transferase ( e.g. valproic acid , lamotrigine). Even in view of the weak induction potential of Oxcarbazepine and MHD, a higher dose of concomitantly used medicinal products which are metabolized via CYP3A4 or via conjugation (UDPGT) may be necessary. In the case of discontinuation of OXATRILEPAZINE therapy, a dose reduction of the concomitant medication may be necessary. Induction studies conducted with human hepatocytes confirmed Oxcarbazepine and MHD as weak inducers of isoenzymes of the 2b and 3A4CYP sub family .the induction potential of Oxcarbazepine and MHD on other CYP iso-enzymes is not known.

n vivo, the plasma levels of phenytoin increase by 40%, when OXATRILEPAZINE was at doses above 1,200 mg/day. Therefore, when using doses of OXATRILEPAZINE greater than 1,200 mg/day during adjunctive therapy, a decrease in the dose of Phenytoin may be required. The increase of Phenobarbital level, however, is small (15%) when given with OXATRILEPAZINE.
Hormonal contraceptives:
OXATRILEPAZINE was shown to have an influence on the two components, Ethinylestradiol (EE) and Levonogesrel (LNG), of oral contraceptive.
The mean AUC values of EE and LNG were decreased by 48-52% and 32-52%, respectively. Studies with other oral or implant contraceptives have not been conducted. Therefore, concurrent use of OXATRILEPAZINE with hormonal contraceptives may render these contraceptives ineffective.
Calcium antagonists:
After repeated co-administration of OXATRILEPAZINE, the AUC values of felodipine were lowered by 28%. However, the plasma levels remained in the recommended therapeutic range.
On the other hand, verapamil produced a decrease of 20% of the plasma levels of MHD. This decrease in plasma levels of MHD is not considered to be of clinical relevance.
Other medicinal product interactions:
Cimetidine, erythromycin and dextropropoxyphene had no effect on the pharmacokinetics of MHD, whereas viloxazine produced minor changes in the MHD plasma levels (about 10% higher after repeated co- administration). Results with warfarin show no evidence of interaction with single or repeated doses of OXATRILEPAZINE.

Packages:
10 Scored Film Coated Tablets 300 gm

10 Scored Film Coated Tablets 600 gm