COMPOSITION:

Active substance:

oxcarbazepine;

1 tablet contains oxcarbazepine 300 mg;

Additional ingredients: microcrystalline cellulose

crosspovidone

povidone

colloidal anhydrous silica

magnesium stearate

Opadry 04F82782 Yellow coating.

INDICATIONS:

Treatment of partial seizures with or without generalized tonic-clonic convulsive attack as monotherapy or additional therapy in adults and children over 6 years old with epilepsy.

DOSAGE:

It is used orally

regardless of meal. Oxapin® can be used as monotherapy and in combination with other antiepileptic medicines. In both cases

treatment begins with a clinically effective dose divided into two doses. The dose may be increased according to the treatment efficacy. In case of replacement of other antiepileptic medicine by Oxapin® at the beginning of Oxapin® use the dose of replaced medicine should be gradually lowered. In case of Oxapin® usage in combination therapy it may be necessary to decrease the dose of concomitant antiepileptic agents and/or a slower increase of Oxapin® dose.

Below recommendations are for patients with normal hepatic function. This group of patients does not need in monitoring of concentrations of active substance in plasma during the therapy with Oxapin®.

There are break-lines on tablets; therefore

they can be broken into two parts for easier swallowing.

Adults:

Monotherapy:

Initial dose of this medicine is 600 mg/day (8 – 10 mg/kg of body weight per day) divided into 2 doses. If necessary it may be necessary a gradual dose increase. The dose is increased not more than by 600 mg/day at 1 week interval up to reaching of the desired therapeutical effect. Therapeutical effect is observed within the dosage range of 600 – 2400 mg/day. In steady-state conditions while ensuring of adequate control of patient’s state there is an experience of rapid dose increase up to 2400 mg/day within 48 hours.

Combination therapy:

If it is administered in combination therapy the initial dose is 600 mg/day (8 – 10 mg/kg of body weight per day) divided into 2 doses. If necessary it is possible a gradual dose increasing. The dose is increased not more than by 600 mg/day

at 1 week intervals

to achieve the desired therapeutic effect. Therapeutical effect is observed within the dosage range of 600 – 2400 mg/day.

Most patients poorly tolerated 2400 mg/day dose without the dose lowering of other antiepileptic agents

which were concomitantly used

that was associated with the occurrence of CNS adverse reactions.

Oxapin® use in daily dose more than 2400 mg has not been studied.

Children:

It is used in children over 6 years old. Recommended initial dose for children is 8 – 10 mg/kg of body weight divided into 2 intakes both in monotherapy and in Oxapin® use in combination therapy. If necessary

to achieve the desired therapeutic effect

it is possible a gradual dose increasing: at an interval of about 1 week – the dose is increased by 10 mg/kg of body weight per day to maximum daily dose at a rate of 46 mg/kg of body weight per day. In Oxapin® use in combination therapy in pediatrics in children above 6 years old an average dose of this medicine was 30 mg/kg of body weight per day.

There is no data concerning this medicine administration in children with kidney dysfunction.

Patients with liver dysfunction of mild to moderate degree do not need dosage adjustment. There is no data concerning this medicine administration in patients with severe liver dysfunction

therefore it is not recommended to use Oxapin® in this group of patients.

Recommended dose for patients with kidney dysfunction (creatinine clearance <30 ml/min) is 300 mg/day with its slow increasing (at an interval of not less than 1 week) up to reaching of the desired therapeutical effect.

ADVERSE REACTIONS:

The most frequent reports were about the following adverse reactions:

drowsiness

headache

dizziness

diplopia

nausea

vomiting

and fatigability (more than in 10% of patients).

Above adverse reactions are ranked under heading of frequency occurrence: very common (> 10%) common (1 – 10%); uncommon (0.1 – 1%); rare (0.01 – 0.1%); very rare (< 0.01%)

including isolated reports.

Blood formation system:

Uncommon – leucopenia; very rarely – inhibition of bone-marrow hematosis

agranulocytosis

aplastic anemia

granulocytopenia

pancytopenia

thrombocytopenia.

Immune system: very rarely – hypersensitivity reactions accompanied with fever and skin rash (including multi-organ disorders). In hypersensitivity reactions development there can be affected blood and lymphatic system (eosinophilia

thrombocytopenia

lymphadenopathy

splenomegaly)

muscles and joints (myalgia

joint swelling

arthralgia)

nervous system (encephalopathy)

kidney (proteinuria

interstitial nephritis

renal impairment)

lungs (dyspnea

pulmonary edema

bronchospasm

interstitial inflammation)

abnormal liver functions indexes

angioneurotic edema; single reports – anaphylactic reactions.

Metabolism:

Common – hyponatremia; very rarely – clinically significant hyponatremia (sodium concentration <125 μmole/l)

> which leads to the development of such sighs and symptoms as convulsive attack

mental confusion

diminution of consciousness

encephalopathy

visual impairment (including blurred vision)

nausea

vomiting (this hyponatremia usually occurs within the first 3 months of this medicine therapy; in some patients – in more than 1 year after Oxapin® treatment start)

folic acid deficiency is also possible; single reports – hypothyroidism.

Central nervous system:

Very common – somnolence

headache

dizziness; common – mental confusion

depression

apathy

agitation

emotional lability

ataxia

tremor

nystagmus

disorder of attention

amnesia.

Sense organs: very common – diplopia; common – visual impairment

blurred vision

vertigo.

Cardio-vascular system: very rarely – arrhythmia

AV-blockade; single reports – arterial hypertension.

Gastro-intestinal tract:

Very common – nausea and vomiting; common – diarrhea

constipation

abdominal pain; rarely – increasing of hepatic enzymes activity and alkaline phosphatase; very rarely – pancreatitis and/or increasing of lipase and/or amylase level

hepatitis.

Skin:

Common – rash

alopecia

acne; rarely – urticaria; very rarely – angioneurotic edema

Stevens-Johnson syndrome

toxic epidermal necrolysis (Lyell’s syndrome)

erythema multiforme.

Other: very common – fatigability feeling; common – asthenia; rarely – systemic lupus erythematosus.

Laboratory indexes:

Increasing of hepatic enzymes level

alkaline phosphatase; single reports – decreasing of T4 level (clinical significance is unknown).

Drug interactions:

Inhibitors of microsomal enzymes: Oxcarbazepine and its active pharmacokinetic metabolite MND are inhibitors of cytochrome CYP2S19. Thus

co-administration of high doses of Oxapin® and agents

which metabolize CYP2S19 (phenobarbital

phenytoin)

may lead to interaction. For some patients it may be necessary the dose lowering of agents-substrates of CYP2S19.

It was shown that oxcarbazepine and MND weakly or nearly interact with the following microsomal isoenzymes:

CYP1A2

CYP2A6

CYP2D9

CYP2E1

CYP4A4 and CYP4C11.

Inducers of microsomal enzymes: Being inducers of CYP3A4 and CYP3A5

which are metabolized by these enzymes:

immunosuppressive agents (cyclosporine

tacrolimus)

dihydropyridine calcium antagonists

oral contraceptives and antiepileptic drugs (eg

carbamazepine). A new level of induction is achieved during 2 – 3 weeks after the therapy start or change of this medicine dose.

Valproic acid and lamotrigine: In vitro MND is a weak inducer of UDP-glucuronyltransferase. Taking into account even weak induction capacity of oxcarbazepine and MND it may be necessary to increase doses of concomitant agents

which are metabolized by CYP3A4 system or UDP- glucuronyltransferase. In case of Oxapin® medicine withdrawal it may be necessary these drugs dosage lowering and adjustment of the final dose during 2 – 3 weeks (induction reducing is possible).

Antiepileptic agents (AEAs):

Possible interaction of Oxapin® and other AEAs

Results of previous studies have shown that oxcarbazepine may decrease lamotrigine concentration that is important for use in children; however

the potential of oxcarbazepine interaction is lower than interaction with enzyme inducers (carbamazepine

phenobarbital

phenytoin).

Phenytoin concentration in plasma is increased up to 40% in simultaneous administration of Oxapin® in dose of 1200 mg/day and more. Therefore

during usage of Oxapin® doses of more than1200 mg/day it may be necessary to decrease the dose of phenytoin. Increasing of phenobarbital concentration in serum is approximately 15% in concurrent use with Oxapin®.

Co-administration of strong inducers of cytochrome P450 isoenzymes (ie

carbamazepine

phenytoin and phenobarbital) leads to decreasing of MND concentration in plasma (by 29-40%).

In children aged 6 to 12 years old in concurrent administration of one of antiepileptic enzyme-inducing drugs clearance of MND was increased by 35% compared with monotherapy.

Co-administration of Oxapin® and lamotrigine was associated with increased risk of adverse reactions (nausea

drowsiness

dizziness and head ache) appearance. In concurrent administration of some antiepileptic medicinal products it is necessary dosage adjustment and monitoring of plasma concentrations

especially in pediatrics in patients simultaneously receiving this medicine with lamotrigine.

Oxapin® auto-induction has not been studied yet.

Hormonal contraceptives: It was found Oxapin® interaction with ethinylestradiol and levonorgestrel. Their mean values of area under the curve “concentration-time” (AUC) were decreased by 48 – 52% and 35 – 52% correspondingly. There is no data concerning other oral or implanted contraceptives. Simultaneous use of Oxapin® medicine and hormonal contraceptives may reduce the effectiveness of the last ones.

Calcium channel blockers:

Concurrent use with verapamil may decrease serum concentrations of MND by 20% (decrease of serum concentrations of MND is clinically insignificant).

Cimetidine

erythromycin

dextropropoxyphene do not influence on pharmacokinetic parameters of MND.

Viloxazine insignificantly influences on MND concentration in plasma (concentration of MND is increased by 10% after re-simultaneous use).

It was not observed any interaction with warfarin in administration of both occasional and repeated doses of Oxapin®.

Oxapin® may enhance sedative effect of ethanol.

In vitro studies confirmed a weak inductor ability of oxcarbazepine and MND in regard to isozymes of subsystems of CYP2B and CYP3A4 enzymes. Inductor influence of oxcarbazepine and MND on other CYP isozymes is unknown.

MAO inhibitors:

Oxcarbazepine interaction with inhibitors is theoretically possible due to structural interaction of oxcarbazepine and tricyclic antidepressants.

It was not observed clinically significant interactions with oxcarbazepine in patients who received antidepressant agents.

Lithium:

Concomitant use of lithium and oxcarbazepine may cause neurotoxicity.

Pregnancy and lactation:

Clinical data concerning oxcarbazepine influence during pregnancy period is insufficient to evaluate its teratogenic potential. Oxcarbazepine and monohydroxy derivative (MND) pass through placental barrier. During Oxapin® use in toxic doses it was observed an increase of embryo mortality

development and growth retardation and disorder.

If women becomes pregnant or plans to become pregnant during this medicine administration or if the problem of initiating treatment with Oxapin® arises during pregnancy

the therapy’s expected benefits must be carefully weighed against possible risk for foetus. Minimum effective doses of this medicine should be used during pregnancy. Patient should be warned about possible embryo development disorders.

During pregnancy an effective antiepileptic treatment should not be interrupted

since the aggravation of the illness is detrimental to both the mother and the fetus.

Folic acid deficiency is known to occur in pregnancy. Antiepileptic agents can aggravate this deficiency

which is one of possible reason of increased incidences of embryo development disorders; therefore

folic acid supplementation is recommended.

Antiepileptic agents use during pregnancy can lead to increased bleeding risk in the offspring. To prevent this risk it is also recommended to administer vitamin K1 to the mother during the last weeks of pregnancy as well as to the neonate.

Oxcarbazepine and monohydroxy derivative (MND) pass through placental barrier. Therefore

if necessary to use Oxapin® during lactation period a breast-feeding should be stopped.

Children:

Safety and efficacy of this medicine use in children under 6 years old has not been enough studied

therefore

it should not be administered in children of this age group.

PRECAUTIONS:

Hypersensitivity reactions may occur in patients without hypersensitivity to carbamazepine in anamnesis.

In case of hypersensitivity reactions development there may be affected circulatory and lymphatic systems (eosinophilia

thrombocytopenia

lymphadenopathy

splenomegaly)

muscles and joints (myalgia

joint edema

arthralgia)

nervous system (encephalopathy)

kidney (proteinuria

interstitial nephritis

renal failure)

lung (dyspnea

pulmonary edema

bronchospasm

interstitial inflammation)

abnormal liver function tests

angioedema

anaphylactic reactions. In case of development of hypersensitivity reactions it is necessary to discontinue Oxapin® use and appropriate therapy should be used.

During Oxapin® use it was observed hyponatremia (in 2.7% of patients)

which usually was not associated with clinical manifestations and did not require the therapy adjustment. Sodium concentration returned to norm when Oxapin® withdrawal (reducing dose) or conservative treatment (restriction of fluid intake) is used. Prior to Oxapin® therapy it is necessary to determine sodium concentration in serum in patients

who have already renal dysfunction and low sodium concentration in serum

or in patients receiving accompanying treatment with agents

which promote sodium excretion from the body (diuretics

medicines which influence on antidiuretic hormone secretion). It is necessary to monitor sodium concentration in serum every 2 weeks after the treatment start and further every month during 3 months or if necessary. Elderly patients with such risk factors need a careful attention. If there is a need for administration of diuretics and other agents

which reduce sodium concentration in serum

patients receiving Oxapin® therapy should follow the same recommendations. In case of occurrence of clinical symptoms

which allow suspecting hyponatremia

it is necessary to measure sodium concentration in serum. For other patients sodium concentration in serum may be measured during periodic blood tests.

All patients with cardiac insufficiency need a control of body weight for timely determination of liquid retention. In case of liquid retention in cardiac insufficiency symptoms progress it should be

determined sodium concentration in serum. In case of hyponatremia it is necessary to reduce a liquid use. As far as in oxcarbazepine use it is rarely possible a cardiac conduction disturbance a careful observation of patients with previous cardiac conduction disturbance (AV-blockade

arrhythmia) treated with Oxapin® is necessary.

Agranulocytosis

apalastic anemia and pancytopenia were very rarely observed in patients during Oxapin® treatment. In case of appearance of symptoms of severe inhibition of bone-marrow hematopoiesis a decision about this medicine withdrawal should be considered.

There are reports about rare cases of hepatitis development

which in most cases were successfully treated. On suspicion of hepatitis a decision about this medicine withdrawal should be considered.

Women of childbearing age

who use oral contraceptives

should be warned about the fact that concomitant administration of Oxapin® may reduce the effectiveness of hormonal contraceptives. This group of patients receiving Oxapin® is recommended to use non-hormonal contraceptives.

Use of antiepileptic agents causes an increase of suicidal ideation and behaviour occurrence. Therefore

patients should be monitored for signs of suicidal ideation and behaviour and appropriate treatment should be considered.

Concomitant use of Oxapin® and alcohol enhances a sedative effect of this medicine.

Oxapin® like other antiepileptic agents (AEAs) should be withdrawn gradually due to the risk of convulsive seizures occurrence.

Overdose:

There are single reports of this medicine overdose; maximum dose

specified in these reports

was 24 g.

Symptoms:

Somnolence

dizziness

nausea

vomiting

hyperkinesia

hyponatremia

ataxia

nystagmus.

Treatment:

There is no specific antidote. Symptomatic and supporting treatment is used. In case of recent use (within the last 2 hours) it is recommended a gastric lavage and activated charcoal use for absorption reducing.

Patients

who drive motor transport

operate other machines and mechanisms

should take into account possible unsuspected effects of central nervous system (dizziness

somnolence

mental confusion

visual and hearing impairment

movement disturbance during walking

also while walking).

Ability to influence reaction velocity while driving or operating any other mechanisms. It is recommended to avoid driving motor transport or operating other mechanisms during Oxapin® use due to dizziness

somnolence or other CNS disturbances appearance.

CONTRAINDICATIONS:

Hypersensitivity to oxcarbazepine

carbamazepin or any other preparation component.

PHARMACOLOGICAL PROPERTIES:

Pharmacodynamics:

Oxapin® pharmacological activity is primarily caused by the action of its metabolite – monohydroxy derivative (MND). Mechanism of action of oxcarbazepine and its MND is mainly related to blockade of voltage-dependent sodium channels that leads to stabilization of hyperexcited nerve membranes

inhibition of repetitive neuronal discharges and reduction of synaptic conduction of impulses.

Realization of anticonvulsant action of this medicine promotes increasing of potassium ions conductivity and modulation of voltage-dependent calcium channels. There were not observed significant interactions with brain neuromediators or binding to receptors. Oxcarbazepine and MND have a marked anticonvulsant action. Effectiveness of Oxapin® medicine in partial (focal) epileptic seizures (simple

complex

partial seizures with secondary generalization or not) and in generalized tonic-clonic seizures has been shown both in monotherapy and in Oxapin® use in combination therapy.

Pharmacokinetics:

Absorption:

After per oral use oxcarbazepine is completely absorbed and is largely metabolized forming a pharmacologically active metabolite 10-monohydroxy derivative (MND).

After a single use of Oxapin® medicine in form of film-coated tablets in a dose of 600 mgs to healthy volunteers on an empty stomach maximum MND concentration in plasma is 34 μmole/l

Тmax is approximately 4.5 hours. In pharmacokinetic studies it was shown that 25% of oxcarbazepine and 70% of MND are found in blood; the rest part is minor metabolites

which are easily excreted from plasma.

Distribution:

Imaginary volume of distribution (Vd) of MND is 49 l.

Approximately 40% of MND are bound to plasma proteins

primarily albumin. In the therapeutic range the degree of binding is independent of medicine concentration in blood serum. Oxcarbazepine and MND do not bind to α1-acid glycoprotein.CSS of MND in plasma is obtained on 2 – 3 day during Oxapin® use 2 times per day. In equilibrium pharmacokinetic parameters of MND are linear and dose-dependent within the range of daily doses of 300 – 2400 mg.

Metabolism:

Oxcarbazepine is quickly metabolised by hepatic cytosol enzymes to pharmacological active metabolite MND

which is further glucuronized. Minimum amount (about 4% of dose) is hydroxylated with formation of inactive metabolite – 10

11-hydroxy derivative (HD).

Excretion:

Oxcarbazepine is excreted as metabolites mainly via kidney (95%)

less than 1% is excreted as unchanged one. Approximately 80% of excreted metabolites are MND

49% of them are glucuronids and 27% – unchanged MND. HD is excreted as unchanged (about 3%) one

oxcarbazepine conjugates are 13%. Approximately 4% of dose are excreted with faeces.

Oxcarbazepine is quickly excreted from plasma; imaginary Т1/2 is 1.3 – 2.3 hours. Mean imaginary half-life period of MND is 9.3±1.8 hours. Steady-stable concentrations of MND in patients receiving this medicine twice a day were obtained within 2 – 3 days. Pharmacokinetics of MND is linearly proportional to the dose of medicine within the range of 300 – 2400 mg/day.

Pharmacokinetics in special clinical cases: Patients with hepatic dysfunction:

Pharmacokinetic parameters of oxcarbazepine after a single per oral use of 900 mg of this medicine were evaluated in volunteers with liver dysfunction. Liver dysfunction of mild to moderate degree did not affect pharmacokinetic parameters of oxcarbazepine and MND. Pharmacokinetics in severe liver dysfunction has not been studied.

Patients with kidney dysfunction:

There is a linear dependence of renal clearance of MND on creatinine clearance. In creatinine clearance <30 ml/min after a single dose of 300 mg of oxcarbazepine T1/2 of MND is increased up to 19 hours

and AUC is increased by 2 times.>

Children:

MND clearance

adjusted as per body weight

in children is decreased along with increasing of age and body weight

approaching clearance in adults. Clearance

adjusted as per body weight on average is higher by 40% in children aged 6 to 12 years old than in adults. Foreseen AUC of MND in children of this age group is 2/3 of AUC in adults when using the same doses (in case of body weight adjustment). It is supposed that MND clearance due to increase of body weight

adjusted as per body weight

in children more than 13 years old is equal to MND clearance in adults.

Elderly patients:

After a single dose (300 mg) and repeated dose (600 mg/day) in volunteers aged 60-82 years old Cmax in plasma and AUC values for MND were 30 – 60% higher versus those ones in young volunteers (18 – 32 years old) that was related to age decreasing of creatinine clearance.

It was not observed any difference in pharmacokinetic parameters subject to sex in childhood

adulthood or old age.

PHARMACEUTICAL CHARACTERISTICS:

General physic-chemical properties: Yellow

capsule-shaped

coated tablets with a break-line on both sides.

Shelf-life:

2 years

Storage:

Store at temperature not more 25°C

in a dry

protected from sun light place. Keep it out of reach of children.

Package:

There are 10 tablets in a blister; there are 3 blisters in a pack.

Conditions of supply:

By prescription.