Formulation:

Each film coated tablet contains

Oxcarbazepine ………..300 mg;

Description:

Capsule shape, yellow colored, film coated tablet, having break line on both sides of each tablet.

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.

Administration and Dosage:

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.

Daily doses from 600 to 2,400 mg/day have been shown to be effective in a controlled adjunctive therapy trial, although most patients were not able to tolerate the 2400 mg/day dose without reduction of concomitant antiepileptic medicinal products, mainly because of CNS-related adverse events. Daily doses above 2400 mg/day have not been studied systematically in clinical trials.

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.

ADVERSE REACTIONS:

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 profile 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 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 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 influence 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.

PRECAUTIONS

Hypersensitivity:

Class I (immediate) hypersensitivity reactions including rash, pruritus, urticaria, 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 first 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 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 therapy.

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.

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 significant 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.

Precautions in usage

Suicidal ideation and behaviour have 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. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for oxcarbazepine.

Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

Female patients of childbearing age should be warned that the concurrent use of Kusapin with hormonal contraceptives may render this type of contraceptive ineffective. Additional non-hormonal forms of contraception are recommended when using Kusapin.

Caution should be exercised if alcohol is taken in combination with Kusapin therapy, due to a possible additive sedative effect. As with all antiepileptic medicinal products, Kusapin should be withdrawn gradually to minimise the potential of increased seizure frequency.

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 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.

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.

Contraindications

Hypersensitivity to the active substance or to any of the Excipients

Pharmacokinetics:

Following oral administration of Kusapin, oxcarbazepine is completely absorbed and extensively metabolised to its pharmacologically active metabolite (MHD).

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.

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.

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).

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.

Storage conditions

Store below 30°C in dry place

Dosage forms and packaging available

Kusapin tablets are supplied in transparent blister PVC film .

Each blister contains 10 tablets and 3 such blisters are packed in a carton along with pack insert.

Caution

Food, Drugs, Devices and Cosmetics Act prohibits dispensing without prescription.

Name and address of manufacturer/marketing authorization holder

Kusum Healthcare Private Limited

SP 289 (A), RIICO Industrial Area Chopanki, Bhiwadi, India

Imported and distributed by

S.M.H.P Marketing & Consultancy

G/F Manor Bldg. 2629 Taft Avenue.

Malate, Manila, Philippines

Date of revision of package insert

Not Applicable