for medical use
active substance: oxcarbazepine;
1 tablet contains oxcarbazepine 300 mg;
excipients: microcrystalline cellulose, crospovidone, povidone, colloidal anhydrous silica, magnesium stearate, Opadry 04F82783 yellow coating: hypromellose, polyethylene glycol, titanium dioxide (E 171), iron oxide yellow (E 172).
Pharmaceutical form. Film coated tablets.
Basic physico-chemical properties: yellow, capsule-shaped, film coated tablets with a break-line on both sides.
Antiepileptic agents. Code АТС N03A F02.
Oxcarbazepine pharmacological activity is primarily caused by the action of its metabolite – monohydroxy derivative (MHD). Mechanism of action of oxcarbazepine and its MHD is mainly related to blockade of voltage-dependent sodium channels that leads to stabilization of over-excited nerve membranes, inhibition of repetitive neuronal discharges and reduction of synaptic conduction of impulses. Moreover, increased potassium ions conductivity and modulation of high-voltage activated calcium channels may contribute to the anticonvulsant effects. No significant interactions with brain neurotransmitters or receptor modulator sites have been demonstrated.
Animal studies have shown that oxcarbazepine and its active metabolite (MHD) are potent and effective anticonvulsants. They protected animals against generalized tonic-clonic seizures and, to a lesser extent, clonic seizures and abolished or reduced the frequency of chronically recurring focal seizures in animals with aluminum implants. No development of tolerance (i.e., attenuation of anticonvulsive activity) to tonic-clonic seizures was observed when animals were treated daily for 5 days or 4 weeks, respectively, with oxcarbazepine or MHD.
After oral use oxcarbazepine is completely absorbed and is largely metabolized forming a pharmacologically active metabolite (MHD).
After a single use of oxcarbazepine in a dose of 600 mgs to healthy male volunteers under fasted condition, mean value of Cmax of MHD is 34 µmole/l with corresponding median Тmax - 4.5 hours.
In a mass balance study that included men, only 2% of total radioactivity in plasma was due to unchanged oxcarbazepine, with approximately 70% due to MHD, and the remainder attributable to minor secondary metabolites which were rapidly excreted.
Food has no effect on the rate and extent of absorption of oxcarbazepine. Therefore, Oxapin can be taken regardless of food intake.
The apparent volume of distribution of MHD is 49L.
Approximately 40% of MHD is bound to serum proteins, predominantly to albumin. In the therapeutically relevant range the degree of binding is independent of medicine concentration in blood serum. Oxcarbazepine and MHD do not bind to alpha-1-acid glycoprotein.
Oxcarbazepine and MHD cross the placenta. In one case neonatal and maternal plasma MHD concentrations were similar.
Oxcarbazepine is rapidly reduced by cytosolic enzymes in the liver to MHD, which is primarily responsible for pharmacological effect of Oxapin. MHD is metabolized further by conjugation with glucuronic acid. Minor amounts (4% of the dose) are oxidized 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. Fecal 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, whereas 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 pharmacokinetic of MHD is linear and show dose-proportionality across the dose range of 300 to 2400 mg/day.
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).
The pharmacokinetics of oxcarbazepine was evaluated in pediatric patients taking it in the dose range 10-60 mg/kg/day. Weight-adjusted MHD clearance decreases as age and weight increase approaching that of adults. The mean weight clearance in children 6 to 12 years of age is approximately 40% higher that of adults. Therefore MHD exposure in these children is expected to be about 2/3 that of adults when treated with a similar weight-adjusted dose. As weight increases, for patients aged from 13 years of age, weight-adjusted MHD clearance is expected to reach that of adults.
Data from a limited number of women show a gradual decrease in plasma levels of MHD during pregnancy.
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 values in young and elderly volunteers show that the difference was due to age-related reductions in creatinine clearance. No special dose recommendations are necessary because therapeutic doses are individually adjusted by the doctor.
No gender-related pharmacokinetic differences have been observed in children, adults, or the elderly.
For the treatment of partial seizures with or without secondarily generalized tonic-clonic seizures as monotherapy or adjunctive therapy in adults and in children of 6 years of age and above.
Hypersensitivity to the active substance or to any of the excipients.
Interaction with other medicinal products and other forms of interaction.
Oxcarbazepine and its pharmacologically active metabolite (the monohydroxy derivative, MHD) are weak inducers in vitro and in vivo of the cytochrome P450 enzymes CYP3A4 and CYP3A5 responsible for the metabolism of a very large number of preparations, in particular, immunosuppressants (e.g. cyclosporine, tacrolimus), oral contraceptives (see below), and some other antiepileptic medicinal products (e.g. carbamazepine) resulting in a lower plasma concentrations of these medicinal products (in table 1 see summarizing results with other antiepileptic medicinal products).
Oxcarbazepine and MHD in vitro are weak inducers of UDP-glucuronyl transferases (effects on specific enzymes in this family are not known). Therefore, in vivo oxcarbazepine and MHD may have a small inducing effect on the metabolism of medicinal products which are mainly eliminated by conjugation through the UDP-glucuronyl transferases. When initiating treatment with Oxapin or changing the dose, it may take 2 to 3 weeks to reach the new level of induction.
In case of discontinuation of Oxapin therapy, a dose reduction of the concomitant medications may be necessary and should be decided upon by clinical and/or plasma level monitoring. The induction is likely to gradually decrease over 2 to 3 weeks after therapy discontinuation.
Hormonal contraceptives. Oxcarbazepine was shown to have an influence on two components of an oral contraceptives: ethinyloestradiol and levonorgestrel. The mean AUC values of ethinyloestradiol and levonorgestrel were decreased by 48-52% and 32-52%, respectively. Therefore, concurrent use of Oxapin with hormonal contraceptives may render these contraceptives ineffective. Another reliable contraceptive method should be used.
Oxcarbazepine and MHD inhibit CYP2C19. Therefore, interactions could arise when co-administering high doses of Oxapin with medicinal products that are mainly metabolized by CYP2C19 (e.g. phenytoin). Phenytoin plasma levels increased by up to 40% when oxcarbazepine was given at doses above 1.200 mg/day (in table 1 see summarizing results with other anticonvulsants). In this case, a reduction of co-administered phenytoin may be required.
Antiepileptic medicinal products
Potential interactions between oxcarbazepine and other antiepileptic medicinal products were assessed in clinical studies. The effect of these interactions on mean AUCs and Cmin are summarized in the table 1.
Information on antiepileptic medicinal product interactions with oxcarbazepine
Antiepileptic medicinal product
Influence of oxcarbazepine on antiepileptic medicinal product
Influence of antiepileptic medicinal product on MHD
(30% increase of carbamazepine-epoxide level)
* Preliminary results show that oxcarbazepine may result in lower lamotrigine concentrations, possibly of importance when administering to children, but the interaction potential of oxcarbazepine appears lower than seen with concomitant enzyme-inducing preparations (carbamazepine, phenobarbitone, and phenytoin).
Strong inducers of cytochrome P450 enzymes (i.e. carbamazepine, phenytoin and phenobarbitone) have been shown to decrease the plasma levels of MHD (29-40%) in adults. In children 6 to 12 years of age, MHD clearance increased by approximately 35% when given one of the three enzyme-inducing antiepileptic medicinal products compared to monotherapy. Concomitant therapy of oxcarbazepine and lamotrigine has been associated with an increased risk of adverse events (nausea, somnolence, dizziness and headache). When one or several antiepileptic medicinal products are concurrently administered with oxcarbazepine, a careful dose adjustment and/or plasma level monitoring may be considered on a case by case basis. This applies especially to pediatric patients treated concomitantly with lamotrigine.
No self-induction of enzymes has been observed with oxcarbazepine.
Interactions with other medicinal products
Cimetidine, erythromycin, viloxazine, warfarin and dextropropoxyphene had no effect on the pharmacokinetics of MHD.
The interaction between oxcarbazepine and MAOIs is theoretically possible based on a structural relationship of oxcarbazepine to tricyclic antidepressants.
Patients on tricyclic antidepressant therapy were included in clinical trials and no clinically relevant interactions have been observed.
The combination of lithium and oxcarbazepine might cause enhanced neurotoxicity.
Class I (immediate) hypersensitivity reactions including rash, pruritus, urticaria, angioedema and reports of anaphylaxis have been received during the post-marketing period. Cases of anaphylaxis and angioedema involving the larynx, glottis, lips and eyelids have been reported in patients after taking the first or subsequent doses of oxcarbazepine. If a patient develops these reactions after treatment with Oxapin, the medicinal product should be discontinued and an alternative treatment started.
Patients who have exhibited hypersensitivity reactions to carbamazepine should be informed that approximately 25-30% of these patients may experience hypersensitivity reactions (e.g. severe skin reactions) with Oxapin.
Hypersensitivity reactions, including multi-organ hypersensitivity reactions, may also occur in patients without history of hypersensitivity to carbamazepine. Such reactions can affect the skin, liver, blood and lymphatic system and other organs, either individually or together in the context of a systemic reaction. If signs and symptoms suggestive of hypersensitivity reactions occur, Oxapin should be withdrawn immediately.
Serious dermatological reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome) and erythema multiform, have been reported very rarely in association with oxcarbazepine use. Patients with serious dermatological reactions may require hospitalization, as these conditions may be life-threatening and very rarely be fatal. Oxcarbazepine-associated cases occurred in both children and adults. The median time to onset was 19 days. Several isolated cases of recurrence of the serious skin reaction when rechallenge with oxcarbazepine were reported. Patients who develop skin reaction with oxcarbazepine should be promptly evaluated and Oxapin withdrawn immediately unless the rash is clearly not related to drug administration. In case of treatment withdrawal, consideration should be given to replacing Oxapin with other antiepileptic drug therapy to avoid seizures, resulting from drug withdrawal. Oxapin should not be restarted in patients who discontinued oxcarbazepine treatment due to hypersensitivity reactions.
Serum sodium levels below 125 mmol/l, usually asymptomatic and not requiring adjustment of therapy, have been observed in 2.7% of oxcarbazepine-treated patients. Experience from clinical trials shows that serum sodium levels returned towards normal when the oxcarbazepine dosage was reduced, discontinued or the patient was treated conservatively (e.g. restricted fluid intake). In patients with pre-existing renal conditions associated with low sodium or in patients treated concomitantly with sodium-lowering medicinal products (e.g. diuretics, desmopressin) as well as NSAIDs (e.g. indometacin), serum sodium levels should be measured prior to initiating Oxapin therapy. Thereafter, serum sodium levels should be measured after approximately two weeks and then once monthly for the first three months during therapy, or according to clinical need. These risk factors may apply especially to elderly patients. For patients, receiving Oxapin therapy when starting on sodium-lowering medicinal products, the same approach for sodium evaluation should be followed. If clinical symptoms suggestive of hyponatremia occur on Oxapin therapy, serum sodium measurement may be considered. Other patients may have serum sodium assessed as part of their routine laboratory studies.
All patients with cardiac insufficiency and secondary heart failure should have regular weight measurements to determine occurrence of fluid retention. In case of fluid retention or worsening of the cardiac condition, serum sodium should be checked. If hyponatremia is observed, water restriction is an important measurement detector. As oxcarbazepine may, very rarely, lead to impairment of cardiac conduction, patients with pre-existing conduction disturbances (e.g. atrioventricular-block, arrhythmia) should be carefully monitored.
Very rare cases of hepatitis have been reported, which in most of the cases resolved with favorable prognosis. When a hepatic event is suspected, liver function should be evaluated and discontinuation of Oxapin should be considered.
Very rare reports of agranulocytosis, aplastic anaemia and pancytopenia have been seen in patients treated with oxcarbazepine during post-marketing experience. Discontinuation of the medicinal product should be considered if any evidence of significant bone marrow depression develops.
Suicidal ideation and behavior have been reported in patients treated with antiepileptic agents in several indications. A small increased risk of suicidal ideation and behavior is possible.
The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for oxcarbazepine intake.
Therefore patients should be monitored for signs of suicidal ideation and behavior and appropriate treatment should be considered. Patients (and caregivers) should be advised to seek medical advice in case of signs of suicidal ideation or behavior.
Female patients of reproductive age should be warned that the concurrent use of Oxapin with hormonal contraceptives may render this type of contraceptive ineffective. Other forms of contraception are recommended when using Oxapin.
Alcohol intake in combination with Oxapin therapy may lead to a possible cumulative sedative effect.
As with all antiepileptic drugs, Oxapin should be withdrawn gradually to minimize the potential of increased seizure frequency.
Use in pregnancy and lactation
The overall risk associated with epilepsy and antiepileptic drugs
It has been shown that in children of women with epilepsy, the prevalence of malformations is 2 to 3 times greater than the rate of approximately 3% in the general population. In the treated population, an increase in malformations has been noted with polytherapy; however, the extent to which the drug therapy and/or the illness is responsible has not been elucidated.
Moreover, effective antiepileptic therapy must not be interrupted, since the aggravation of the illness is very harmful for both the mother and the fetus.
Clinical data on drug administration during pregnancy are still insufficient to assess the teratogenic potential of oxcarbazepine. In animal studies, increased embryo mortality, delayed growth and malformations were observed at maternally toxic dose levels.
Taking the above mentioned into consideration:
• if women receiving Oxapin become pregnant or plan to become pregnant, the use of this product should be carefully re-evaluated. Minimum effective doses should be given, and monotherapy if possible should be preferred at least during the first three months of pregnancy;
• patients should be counseled regarding the possibility of an increased risk of malformations and given the opportunity of prenatal screening;
• during pregnancy, an effective antiepileptic oxcarbazepine 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 fetal abnormality. Folic acid supplementation is recommended before and during pregnancy. As the efficacy of this supplementation is not proved, a specific antenatal diagnosis can be offered even for women with a supplementary treatment of folic acid.
The data obtained in a limited number of women indicate that plasma levels of the active metabolite of oxcarbazepine, the 10-monohydroxy derivative (MHD), may gradually decrease throughout pregnancy. The close monitoring of clinical response in women receiving Oxapin is recommended during pregnancy to ensure adequate control of seizures that persist. The necessity to identify changes of MHD plasma concentrations should be considered. If drug doses rose during pregnancy, the possibility of MHD plasma levels in postpartum period should be considered. Postpartum MHD plasma levels may also be considered for monitoring especially in the event that drug doses were increased during pregnancy
Coagulation failure in the newborns caused by antiepileptic agents has been reported. Vitamin K1 should be administered as a preventive measure in the last few weeks of pregnancy and to the newborn.
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 compounds. The effects of oxcarbazepine on the infant through breast milk are unknown. Therefore, if treatment is required, breast-feeding should be stopped.
Influence on velocity reactions in driving motor transport and operating other mechanisms.
The use of oxcarbazepine has been associated with adverse reactions such as dizziness or drowsiness. Therefore, patients should report a possible violation of their physical and/or mental ability to work with machinery or drive vehicles.
Posology and method of administration.
In mono- and adjunctive therapy, treatment with Oxapin is initiated with a clinically effective dose divided in two doses. The dose may be increased depending on the clinical response of the patient. When other antiepileptic medicinal products are replaced by Oxapin, the dose of the concomitant antiepileptic medicinal product(s) should be reduced gradually on initiation of Oxapin therapy. As the total antiepileptic medicinal product load of the patient is increased, the dose of concomitant antiepileptic medicinal products may need to be reduced and/or the Oxapin dose increased more slowly.
Oxapin® can be taken regardless of meals.
The following dosing recommendations apply to all patients, in the absence of impaired renal function. Drug plasma level monitoring is not required for optimization of Oxapin therapy.
The tablets have a score line and can be broken in two halves in order to make it easier for the patient to swallow the tablet. Although, tablet can`t be divided into two equal doses.
Oxapin should be initiated with a dose of 600 mg/day (8-10 mg/kg/day) given in 2 divided doses. 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. Therapeutic effects are seen at doses between 600 – 2.400 mg/day.
Findings in patients, not currently being treated with antiepileptic medicinal products, showed 1.200 mg/day to be an effective dose of oxcarbazepine as monotherapy. However, a dose of 2.400 mg/day has been shown to be effective in more refractory patients converted from other antiepileptic medicinal products to oxcarbazepine monotherapy.
In a controlled hospital settings, dose increases up to 2.400 mg/day have been achieved over 48 hours.
Oxapin should be initiated with a dose of 600 mg/day (8-10 mg/kg/day) given in 2 divided doses. 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. Therapeutic responses are seen at doses between 600 – 2.400 mg/day.
In findings, daily doses from 600 to 2.400 mg/day have been shown to be effective in patients, receiving oxcarbazepine as an adjunctive therapy, although most patients were not able to tolerate the 2.400 mg/day dose without reduction of concomitant antiepileptic medicinal products, mainly because of CNS-related adverse events.
Daily doses above 2.400 mg/day of oxcarbazepine have not been studied.
Adjustment of the dose is recommended in the elderly with impaired renal function.
Oxapin is recommended for children over 6 years of age.
In mono- and adjunctive therapy, Oxapin should be initiated with a dose of 8-10 mg/kg/day, given in 2 divided doses. In adjunctive therapy, therapeutic effects were seen at a median maintenance dose of approximately 30 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 dose of 46 mg/kg/day, to achieve the desired clinical response.
In all populations (adults, elderly and children) lower drug doses may be considered, if required.
Patients with hepatic impairment
No dosage adjustment is required for patients with mild to moderate hepatic impairment. Oxcarbazepine has not been studied in patients with severe hepatic impairment. Thus, caution should be exercised when treating patients with severe hepatic impairment.
Patients with renal impairment
In patients with impaired renal function (creatinine clearance less than 30 ml/min) Oxapin therapy should be initiated at half the usual starting dose (300 mg/day) and increased, in at least weekly intervals, to achieve the desired clinical response.
Dose escalation in renally impaired patients may require more careful observation.
Oxcarbazepine is not recommended for children under 6 years of age, since safety and efficacy have not been adequately proven.
Isolated cases of overdose have been reported. The maximum acceptable dose was approximately 24.000 mg. All patients recovered with symptomatic treatment. Symptoms of overdose include somnolence, dizziness, nausea, vomiting, hyperkinesia, hyponatremia, ataxia and nystagmus. There is no specific antidote. Symptomatic and supportive treatment should be administered as appropriate. Removal of the medicinal product by gastric lavage and/or inactivation by administering activated charcoal should be considered.
Blood and lymphatic system disorders:leucopenia, thrombocytopenia, bone marrow depression, aplastic anaemia, agranulocytosis, pancytopenia, neutropenia.
Immune system disorders: hypersensitivity reactions (including multi-organ hypersensitivity) characterized by features such as rash, fever. In case of hypersensitivity reactions, other organs or systems may be affected such as the blood and lymphatic systems (e.g. eosinophilia, thrombocytopenia, leucopenia, lymphadenopathy, splenomegaly), liver (e.g. abnormal results of liver function tests, hepatitis), muscles and joints (e.g. joint swelling, myalgia, arthralgia), nervous system (e.g. hepatic encephalopathy), kidney (e.g. proteinuria, interstitial nephritis, renal failure), lungs (e.g. dyspnea, pulmonary edema, asthma, bronchospasm, interstitial lung disease), angioedema, anaphylactic reactions.
Metabolism and nutrition disorders: hyponatremia, clinically significant hyponatremia, (sodium concentration - < 125 mmol/L) associated with signs and symptoms such as seizures, encephalopathy, depressed level of consciousness, confusion (additional adverse events are mentioned also in paragraph “Nervous system disorders”), vision disorders (e.g. blurriness), hypothyroidism, vomiting, nausea, folic acid deficiency.
Psychiatric disorders: confusional state, depression, apathy, agitation (e.g. nervousness), affect lability.
Nervous system disorders: somnolence, headache, dizziness, ataxia, tremor, nystagmus, disturbance in attention, amnesia.
Eye disorders: diplopia, blurriness, vision blurred, visual disturbance.
Ear and labyrinth disorders: vertigo.
Cardiac disorders: arrhythmia, atrioventricular block, hypertension.
Gastrointestinal disorders: nausea, vomiting, diarrhea, constipation, abdominal pain, pancreatitis.
Hepato-biliary disorders: hepatitis.
Skin and subcutaneous tissue disorders: rash, alopecia, acne, urticaria, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), erythema multiforme.
Musculoskeletal, connective tissue and bone disorders: systemic lupus erythematosus.
General disorders and administration site conditions: feeling of increased fatigability, asthenia.
Abnormalities found in laboratory investigations: increase liver enzymes, increased alkaline phosphatase blood levels, decreased T4 (clinical significance is unclear), and increased lipase and/or amylase levels.
Shelf-life. 2 years.
Store at temperature NMT 25 С.
Keep it out of reach of children.
There are 10 tablets in a blister; there are 3 blisters in a carton pack.
Conditions of supply.
KUSUM HEALTHCARE PVT LTD.
SP-289 (A), RIICO Industrial area, Chopanki, Bhiwadi, Dist. Alwar (Rajasthan), India.
For the treatment of partial seizures with or without secondarily generalized tonic-clonic seizures as monotherapy or adjunctive therapy in adults and in children of 6 years of age and above.
1 tablet contains oxcarbazepine 300 mg; Antiepileptic agents.
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