Composition:
Each lm coated tablet contains;
Oxcarbazepine………… 300 mg
Additional ingredients:
Microcrystalline cellulose, crosspovidone, polyvinyl pyrollidone, colloidal anhydrous silica, magnesium stearate, opadry yellow 04F82782, Isopropyl alcohol & puried water.
Pharmaceutical form:
Tablets

INDICATIONS:
Kusapin is indicated for the treatment of partial seizures with or without secondary generalized tonic-clonic seizures.
Kusapin is indicated for use as monotherapy or adjunctive therapy in adults and children of 6 years of age and above.
DOSAGE AND ADMINISTRATION:
In mono and adjunctive therapy, treatment with Kusapin 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. In adjunctive therapy, as the total antiepileptic medicinal product load of the patient is increased, the dose of concomitant antiepileptic medicinal product(s) may need to be reduced and/or the Kusapin dose increased more slowly.
Kusapin can be taken with or without food.
The tablets are scored and can be broken in two halves in order to make it easier for the patient to swallow the tablet. However, the tablet cannot be divided into equal doses. Adults
Mono and adjunctive therapy:
Kusapin 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 mg/day and 2,400 mg/day.
Controlled monotherapy trials in patients not currently being treated with antiepileptic medicinal products showed 1,200 mg/day to be an effective dose; however, a dose of 2400 mg/day has been shown to be effective in more refractory patients converted from other antiepileptic medicinal products to Kusapin monotherapy.
In a controlled hospital setting, dose increases up to 2,400 mg/day have been achieved over 48 hours.
Elderly
Adjustment of the dose is recommended in the elderly with compromised renal function.
Children
In mono and adjunctive therapy:
Kusapin 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. Kusapin is recommended for use in children of 6 years of age and above.
Patients with hepatic impairment
No dosage adjustment is required for patients with mild to moderate hepatic impairment.
Patients with renal impairment
In patients with impaired renal function (creatinine clearance less than 30 ml/min) Kusapin 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.

ADVERSE EFFECTS:
The most commonly reported adverse reactions are somnolence, headache, dizziness, diplopia, nausea, vomiting and fatigue occurring in more than 10% of patients.
The undesirable effect prole by body system is based on AEs from clinical trials assessed as related to
Kusapin.
In addition, clinically meaningful reports on adverse experiences from named patient programs and post marketing experience were taken into account.
Frequency estimate* :– 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; unknown: cannot be estimated from the available data.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

DRUG INTERACTIONS:
Enzyme induction: 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 drugs, for example, immunosuppressants (e.g. ciclosporin, tacrolimus), oral contraceptives (see below), and some other antiepileptic medicinal products (e.g. carbamazepine) resulting in a lower plasma concentration of these medicinal products.
In vitro, oxcarbazepine and MHD are weak inducers of UDP-glucuronyl transferases (effects on specic 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 Kusapin or changing the dose, it may take 2 to 3 weeks to reach the new level of induction.
In case of discontinuation of Kusapin 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 discontinuation.
Hormonal contraceptives:
Kusapin was shown to have an inuence on the two components, ethinylestradiol (EE) and levonorgestrel (LNG), of an oral contraceptive. The mean AUC values of EE and LNG were decreased by 48-52 % and 32-52% respectively. Therefore, concurrent use of Kusapin with hormonal contraceptives may render these contraceptives ineffective. Another reliable contraceptive method should be used.
Enzyme inhibition:
Oxcarbazepine and MHD inhibit CYP2C19. Therefore, interactions could arise when co-administering high doses of Kusapin with medicinal products that are mainly metabolised by CYP2C19 (e.g. phenytoin). Phenytoin plasma levels increased by up to 40 % when Kusapin was given at doses above 1200 mg/day (see table below summarizing results with other anticonvulsants). In this case, a reduction of co-administered phenytoin may be required.
Antiepileptic medicinal products:
Potential interactions between Kusapin and other antiepileptic medicinal products were assessed in clinical studies. The effect of these interactions on mean AUCs and Cmin are summarised in the following table:
Summary of antiepileptic medicinal product interactions with Kusapin

Preliminary results indicate that oxcarbazepine may result in lower lamotrigine concentrations, possibly of importance in children, but the interaction potential of oxcarbazepine appears lower than seen with concomitant enzyme inducing drugs (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 4 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 Kusapin and lamotrigine has been associated with an increased risk of adverse events (nausea, somnolence, dizziness and headache).
Other medicinal product interactions:
Cimetidine, erythromycin, viloxazine, wayfaring 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.

SPECIAL WARNINGS AND PRECAUTIONS:
angioedema and reports of anaphylaxis have been received in the post-marketing period. Cases of anaphylaxis and angioedema involving the larynx, glottis, lips and eyelids have been reported in patients after taking the rst or subsequent doses of Kusapin. If a patient develops these reactions after treatment with Kusapin, the drug should be discontinued and an alternative treatment started.
Dermatological effects: Serious dermatological reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome) and erythema multiforme, have been reported very rarely in association with Kusapin use. Several isolated cases of recurrence of the serious skin reaction when rechallenged with Kusapin were reported. In case of treatment withdrawal, consideration should be given to replacing Kusapin with other antiepileptic drug therapy to avoid withdrawal seizures. Kusapin should not be restarted in patients who discontinued treatment due to a hypersensitivity reaction.
Hyponatraemia:
Experience from clinical trials shows that serum sodium levels returned towards normal when the Kusapin dosage was reduced, discontinued or the patient was treated conservatively (e.g. restricted uid 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 therapy.
All patients with cardiac insufciency and secondary heart failure should have regular weight measurements to determine occurrence of uid retention. In case of uid retention or worsening of the cardiac condition, serum sodium should be checked.
Hepatic function:
Very rare cases of hepatitis have been reported, which in most of the cases resolved favourably. When a hepatic event is suspected, liver function should be evaluated and discontinuation of Kusapin should be considered.
Hematological effects:
Very rare reports of agranulocytosis, aplastic anemia and pancytopenia have been seen in patients treated with Kusapin during post-marketing experience. Discontinuation of the medicinal product should be considered if any evidence of signicant bone marrow depression develops.
Suicidal behaviour:
Suicidal behaviour has been reported in patients treated with antiepileptic agents in several indications. A meta-analysis of randomized placebo controlled trials of antiepileptic drugs has also shown a small increased risk of suicidal ideation and behaviour.
Hormonal contraceptives
Female patients of childbearing age should be warned that the concurrent use of Kusapin with hormonal contraceptives may render this type of contraceptive ineffective.
Alcohol
Caution should be exercised if alcohol is taken in combination with Kusapin therapy, due to a possible additive sedative effect.
Hypersensitivity:
Class I (immediate) hypersensitivity reactions including rash, pruritus, urticaria.
PREGNANCY AND LACTATION:
Pregnancy
Risk related to epilepsy and antiepileptic medicinal products in general:
It has been shown that in the offspring of women with epilepsy, the prevalence of malformations is two to three 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 treatment and/or the illness is responsible has not been elucidated.
Moreover, effective anti-epileptic therapy must not be interrupted, since the aggravation of the illness is detrimental to both the mother and the foetus.
Risk related to oxcarbazepine:
Clinical data on exposure during pregnancy are still insufcient 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 these data into consideration:
If women receiving Kusapin 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 whenever possible should be preferred at least during the rst three months of pregnancy.
Patients should be counselled regarding the possibility of an increased risk of malformations and given the opportunity of antenatal 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 foetus.
Monitoring and prevention:
Antiepileptic medicinal products may contribute to folic acid deciency, a possible contributory cause of foetal abnormality. Folic acid supplementation is recommended before and during pregnancy. As the efcacy of this supplementation is not proved, a specic antenatal diagnosis can be offered even for women with a supplementary treatment of folic acid.
Data from 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.
It is recommended that clinical response should be monitored carefully in women receiving Kusapin treatment during pregnancy to ensure that adequate seizure control is maintained. Determination of changes in MHD plasma concentrations should be considered. If dosages have been increased during pregnancy, postpartum MHD plasma levels may also be considered for monitoring.
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 of pregnancy and to the newborn.
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 Kusapin by this route are unknown. Therefore, Kusapin should not be used during breast-feeding.
Effects on ability to drive and use machines
The use of Kusapin has been associated with adverse reactions such as dizziness or somnolence (see section 4.8). Therefore, patients should be advised that their physical and/ or mental abilities required for operating machinery or driving a car might be impaired

OVERDOSAGE:
Isolated cases of overdose have been reported. The maximum dose taken was approximately 24,000 mg. All patients recovered with symptomatic treatment. Symptoms of overdose include somnolence, dizziness, nausea, vomiting, hyperkinesia, hyponatraemia, ataxia and nystagmus. There is no specic 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.

CONTRAINDICATIONS:
Hypersensitivity to the active substance or to any of the Excipients

PHARMACOLOGIC PROPERTIES:
Pharmacodynamics:
The pharmacological activity of oxcarbazepine is primarily exerted through the metabolite (MHD) 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 ring, 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 signicant interactions with brain neurotransmitter or modulator receptor sites were found.
Oxcarbazepine and its active metabolite (MHD), are potent and efcacious 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 Kusapin, oxcarbazepine is completely absorbed and extensively metabolised to its pharmacologically active metabolite (MHD).
After single dose administration of 600 mg Kusapin 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.
Biotransformation:
Oxcarbazepine is rapidly reduced by cytosolic enzymes in the liver to MHD, which is primarily responsible for the pharmacological effect of Kusapin. 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 Kusapin 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. Kusapin 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 pediatric patients taking oxcarbazepine in the dose range 10-60 mg/kg/day. Weight-adjusted MHD clearance deceases as age and weight increases approaching that of adults. The mean weight 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, 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.
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.
STORAGE CONDITION:
Store below 30°C.
Keep all medicines out of reach of children.
SHELF-LIFE:
24 months
DOSAGE FORM AND PACKAGING AVAILABLE:
Clear PVC blister of 10 tablets, 3 or 10 blisters are in a carton.
NAME AND ADDRESS OF MANUFACTURER:
Kusum Healthcare Pvt. Ltd.
SP 289(A), RIICO Indl. Area,
Chopanki, Bhiwadi (Rajasthan), India
MM Reg. No.: 1812AA 7076