TRILEPTIN 300 MG

PATIENT PACKAGE INSERT IN ACCORDANCE WITH THE

PHARMACISTS’ REGULATIONS (PREPARATIONS) – 1986

The medicine is dispensed

with a doctor’s prescription only

TRILEPTIN

®

TRILEPTIN

®

300 mg

600 mg

Film-coated tablets

Film-coated tablets

The active ingredient:

Each tablet contains:

Each tablet contains:

Oxcarbazepine 300 mg

Oxcarbazepine 600 mg

Inactive ingredients:

See section 6 ‘Further Information’.

Read this leaflet carefully in its entirety before using the

medicine. This leaflet contains concise information about the

medicine. If you have further questions, refer to the doctor or

pharmacist.

This medicine has been prescribed for you. Do not pass it on to

others. It may harm them, even if it seems to you that their medical

condition is similar.

This medicine is not intended for infants and children under two

years of age.

1. WHAT IS THE MEDICINE INTENDED FOR?

For treating epilepsy.

Therapeutic group:

Anti-epileptic.

Epilepsy is a condition in which repeated seizures and convulsions

occur. Seizures happen because of a temporary fault in the brain’s

electrical activity. Normally brain cells coordinate body movements

by sending out signals through the nerves to the muscles in an

organised, orderly way. In epilepsy, brain cells send out too many

signals in a disorderly fashion. The result can be uncoordinated

muscular activity that is called an epileptic seizure. Trileptin works

by keeping the brain’s “overexcitable” nerve cells under control,

thereby reducing the frequency of such seizures.

There are two main classes of epileptic seizures: generalized and

partial.

Generalized seizures involve a wide area of the brain, cause loss of

consciousness and can affect the whole body. There are two main

types of generalized seizures: tonic-clonic seizures (grand mal) and

absence seizures (petit mal).

Partial seizures involve a limited area of the brain (i.e. focal origin),

but may spread to the whole brain and may cause a secondarily

generalized tonic-clonic type seizure. There are two types of

partial seizures: simple and complex. In simple partial seizures,

the patient remains conscious, whereas in complex partial seizures,

the patient’s consciousness is altered.

Trileptin is used to treat partial seizures (simple, complex and

secondarily generalized seizures) and generalized tonic-clonic

seizures.

Usually, the doctor will attempt to find the one medicine that works

best but, with more severe epilepsy, a combination of two or more

medicines may be needed to control seizures. Trileptin can be used

alone or in combination with other antiepileptic medicines.

2. BEFORE USING THE MEDICINE

X

Do not use the medicine if:

You are sensitive (allergic) to oxcarbazepine (the active substance

of Trileptin) or to any of the other ingredients of the medicine

listed in section 6 ‘Further Information’.

If this applies to you, inform the doctor before taking Trileptin.

If you think that you may be allergic, consult the doctor.

Special warnings regarding use of the medicine:

Before taking Trileptin, tell the doctor if:

You have suffered in the past from unusual sensitivity (rash or

other signs of allergy) to carbamazepine or to other medicines. If

you are allergic to carbamazepine, the chances are approximately

1 in 4 (25%) that you could also develop an allergic reaction to

oxcarbazepine (Trileptin).

You have a kidney disease.

You have a liver disease.

You are taking diuretics (medicines used to help the kidneys get

rid of salt and water by increasing the amount of urine).

You have a heart disease, shortness of breath and/or swelling of

the feet or legs due to fluid build-up.

You know that your blood levels of sodium are low.

You are taking other medicines (see the detailed list regarding

taking other medicines).

You are a woman taking a hormonal contraceptive (such as

the birth-control pill), Trileptin may render this contraceptive

ineffective. Therefore, you should use a different or additional

non-hormonal contraceptive measure while you are taking Trileptin.

This should help to prevent an unwanted pregnancy. Tell your

doctor immediately if you experience irregular vaginal bleeding

or spotting. If you have any questions about this, ask your doctor

or health professional.

!

If you develop any of the following symptoms after starting

treatment with Trileptin, refer to your doctor immediately

or go to the emergency room at your nearest hospital:

If an allergic reaction happens such as swelling of lips, eyelids,

face, throat, mouth, or sudden breathing problems, fever with

swollen glands (lymph node swelling), rash or skin blistering (see

‘Some effects could be serious’).

If you develop serious skin reactions such as rash, red skin,

blistering of the lips, eyes or mouth, skin peeling accompanied by

fever (see ‘Side effects’). These reactions may be more frequent

in patients in some Asian countries (e.g. Taiwan, Malaysia and The

Philippines) and in patients with Chinese ancestry.

If you experience an increase in the frequency of seizures.

This is particularly important regarding children but may

occur in adults as well.

If you notice symptoms suggestive of hepatitis, such as jaundice

(yellowing of skin and eyes).

If you notice symptoms suggestive of blood disorders such

as tiredness, shortness of breath when exercising, looking pale,

headache, chills, dizziness, frequent infections leading to fever, sore

throat, ulcers in the mouth, bleeding or bruising more easily than

normal, nose bleeds, reddish or purplish patches or unexplained

blotches on the skin.

If at any time you have thoughts of harming or killing yourself.

A small number of people being treated with antiepileptics have

had such thoughts or behavior.

If your heartbeat is fast or unusually slow.

Do not stop treatment with Trileptin without consulting the doctor.

In order to prevent sudden worsening of the seizures, do not stop

taking the medicine abruptly.

!

If you are taking, or have recently taken other medicines

including non-prescription medicines and nutritional

supplements, tell the doctor or pharmacist. In particular, if

you are taking:

Hormonal contraceptives (such as birth-control pills) (see section

‘Special warnings regarding use of the medicine’).

Other antiepileptic medicines (such as: carbamazepine,

phenobarbital, phenytoin or lamotrigine).

Calcium blockers such as: felodipine (medicine used to treat high

blood pressure and heart problems).

Medicines which reduce the level of sodium in your blood, e.g.,

diuretics (medicines used to help the kidneys get rid of salt and

water by increasing the amount of urine); desmopressin and anti-

inflammatory non-steroidal medicines.

Medicines which control the immune system (such as ciclosporin

and tacrolimus).

Lithium and monoamine oxidase inhibitors (medicines used for

treating mood swings and certain types of depression).

!

Using Trileptin and food

The medicine can be taken with or without food.

!

Using Trileptin and consumption of alcohol

Alcohol may increase the sedative effects of Trileptin. Avoid alcohol

as much as possible and ask your doctor for advice.

!

Elderly people

Trileptin can be used in adults older than 65, while following the

doctor's instructions.

!

Children and adolescents

This medicine is not intended for infants and children under the

age of two.

In children, it is possible that the doctor will recommend monitoring

thyroid function before and during treatment.

!

Pregnancy

Tell your doctor if you are pregnant or planning to become

pregnant.

It is important to control epileptic seizures during pregnancy.

However, there may be a risk to your baby if you take antiepileptic

medicines during pregnancy. Your doctor will tell you the benefits

and potential risks involved and help you to decide whether you

should take Trileptin.

Do not stop your treatment with Trileptin during pregnancy without

consulting your doctor.

Ask your doctor or pharmacist for advice before taking any medicine

during pregnancy.

!

Breast-feeding

The active substance in Trileptin passes into the breast milk and

could cause side effects in breast-fed babies. Therefore, you should

not use Trileptin during breast-feeding.

Ask your doctor or pharmacist for advice before taking any medicine

while you are breast-feeding.

!

Women of childbearing age

If you are taking a hormonal contraceptive (such as a birth-

control pill), Trileptin may render this contraceptive ineffective.

Therefore, you must use a different or an additional non-hormonal

contraceptive during treatment with Trileptin.

!

Driving and using machines

It is important to consult your doctor regarding your ability to drive

a vehicle or operate machines, as Trileptin may cause sleepiness or

dizziness or may cause blurred vision, double vision, lack of muscle

coordination or depressed level of consciousness, especially at

the beginning of treatment or when increasing the dose. Children

should be cautioned against riding a bicycle or playing near the

road and the like.

3. HOW SHOULD YOU USE THE MEDICINE?

Always use according to the doctor’s instructions. Check with the

doctor or pharmacist if you are uncertain.

The dosage and manner of treatment will be determined by the

doctor only. The usual dosage is generally:

Trileptin should be taken twice a day, every day, at about the

same time of day, unless the doctor tells you otherwise. Taking

the tablets at the same time each day will have the best effect

on controlling epilepsy. It will also help you to remember when to

take the tablet(s).

Do not exceed the recommended dose.

How to take the medicine

Do not chew! Swallow the tablets with a little water. If necessary,

the tablets can be broken in half to help swallow them.

Duration of treatment

Your doctor will tell you how long your or your child’s treatment

with Trileptin will last. The duration of treatment is based on the

seizure type. On-going treatment for many years may be necessary

to control the seizures.

Do not change the dosage and do not stop treatment without

talking to your doctor.

Tests and follow-up

Before and during treatment with Trileptin, your doctor may perform

blood tests to determine the dose for you. The doctor will tell you

when to undergo these tests.

The blood sodium concentration may decrease during treatment

with Trileptin; therefore, it is advisable to monitor blood sodium

levels before starting treatment and during treatment, especially if

your blood sodium levels are usually low. If you are taking diuretics,

your blood sodium levels should be closely monitored.

The risk of serious skin reactions in patients of Chinese or

Thai origin, associated with oxcarbazepine, carbamazepine or

chemically-related compounds, may be predicted by testing a blood

sample of these patients. Your doctor should be able to advise if a

blood test is necessary before taking Trileptin.

If you take more Trileptin than you should

If you have taken an overdose, or if a child has accidentally swallowed

the medicine, refer immediately to a doctor or proceed to a hospital

emergency room and bring the package of the medicine with you.

Symptoms of an overdose may include: sleepiness, dizziness,

nausea, vomiting, increase in uncontrolled movements, lethargy,

confusion, muscle twitches or significant worsening of seizures,

coordination problems and/or uncontrolled eye movements.

If you forget to take Trileptin

If you have only forgotten one dose, take it as soon as you

remember. However, if it is time for your next dose, do not take

the missed dose. Just go back to your regular dosing timetable.

Never take two doses together!

If you are unsure or have forgotten to take several doses, contact

your attending doctor.

Adhere to the treatment as recommended by the doctor.

Stopping treatment

Stopping treatment with Trileptin may cause your seizures to

worsen.

Even if there is an improvement in your health, do not stop treatment

with the medicine without consulting the doctor or pharmacist.

In the event that the doctor has determined that you should stop

treatment with Trileptin, stop treatment in a gradual manner, in

order to reduce the possibility of increased frequency of epileptic

seizures to a minimum.

Do not take medicines in the dark! Check the label and the dose

each time you take a medicine. Wear glasses if you need them.

If you have further questions regarding use of the medicine, consult

the doctor or pharmacist.

4. SIDE EFFECTS

As with any medicine, use of Trileptin may cause side effects in

some users. Do not be alarmed by the list of side effects. You may

not suffer from any of them.

Some effects could be serious and may require urgent

medical treatment:

Swelling of the lips, eyelids, face, throat or mouth, accompanied by

difficulty in breathing, speaking or swallowing (signs of anaphylactic

reactions and angioedema), or other signs of hypersensitivity such

as: skin rash, fever, and pain in the muscles and joints.

Severe blistering of the skin and/or mucous membranes of the

lips, eyes, mouth, nasal passages or genitals (signs of a serious

allergic reaction).

Tiredness, feeling of shortness of breath when exercising, paleness,

headache, chills, dizziness, recurring infections leading to fever,

sore throat, mouth ulcers, bleeding or bruising more easily than

normal, nose bleeds, reddish or purplish skin patches or unexplained

blotches on the skin (signs of a decrease in the number of blood

platelets or decrease in the number of blood cells).

Rash, manifested by red blotches, mainly on the face, which may

be accompanied by fatigue, fever, nausea and loss of appetite

(signs of systemic lupus erythematosus).

Lethargy, confusion, muscular twitching or significant worsening

of convulsions (signs that may be linked to low sodium levels in

the blood) (see section ‘Special warnings regarding use of the

medicine’).

Flu-like symptoms with jaundice (signs of hepatitis).

Severe upper abdominal pain, vomiting, loss of appetite (signs

of pancreatitis).

Weight gain, tiredness, hair loss, muscle weakness, feeling cold

(signs of an under active thyroid gland).

In children under 4 years of age: somnolence, lethargy, decreased

appetite and irritability, swollen and painful joints, loss of muscle

control following disturbances to the nervous system (ataxia),

vomiting, involuntary eye movements, tremor.

Refer immediately to the attending doctor or to an emergency

room of the nearest hospital if you have any of the side

effects detailed above.

The doctor will decide whether there is a need to

immediately stop Trileptin treatment and how treatment

should be continued.

Other side effects:

Very common side effects (affecting more than 1 in every 10

patients):

tiredness; headache; dizziness; drowsiness; nausea; vomiting;

double vision.

If any of these side effects affects you severely, contact the

doctor.

Common side effects (affecting between 1-10 in every 100

patients):

trembling; problems with coordination; involuntary movement of the

eyes; feeling of anxiety and nervousness; feeling of depression; mood

swings; weakness; memory disturbances; impaired concentration;

apathy; agitation; confusion; blurred vision; constipation; diarrhea;

abdominal pain; acne; hair loss; disturbance of balance.

If any of these side effects affects you severely, contact the doctor.

Very rare side effects (affecting less than 1 in every 10,000

patients):

irregular heartbeat or very fast or very slow heart rate, high blood

pressure, vitamin B9 (folic acid) deficiency. Some of the signs of

vitamin B9 deficiency are: diarrhea, feeling of depression and signs

of decrease in the number of blood cells (see section ‘Some effects

could be serious’).

Side effects of unknown frequency

Speech impairments, bone disorders including osteopenia and

osteoporosis (thinning of the bone) and fractures in patients on

long term-treatment with Trileptin.

If any of the side effects affects you severely, contact the

doctor.

If a side effects appears, if any of the side effects worsens or if

you suffer from a side effect not mentioned in the leaflet, consult

with the doctor.

5. HOW SHOULD THE MEDICINE BE STORED?

Avoid poisoning! This medicine, and any other medicine, should be

kept in a safe place out of the reach and sight of children and/or

infants in order to avoid poisoning. Do not induce vomiting unless

explicitly instructed to do so by the doctor.

Do not use the medicine after the expiry date (exp. date) appearing

on the package. The expiry date refers to the last day of that month.

Store in the original package. Do not store above 30°C.

Do not use the medicine if the pack is damaged or shows signs

of tampering.

Return any unused tablets to the pharmacy for safe disposal.

6. FURTHER INFORMATION

In addition to the active ingredient, the medicine also contains:

Trileptin 300 mg

Tablet:

Cellulose, microcrystalline; crospovidone; hypromellose; magnesium

stearate; silica, colloidal anhydrous.

Tablet coating:

Hypromellose; talc; titanium dioxide (C.I. no. 77891, E171);

macrogol 8000; iron oxide, yellow (C.I. no. 77492, E 172).

Trileptin 600 mg

Tablet:

Cellulose; microcrystalline; crospovidone; hypromellose; magnesium

stearate; silica, colloidal anhydrous.

Tablet coating:

Hypromellose; titanium dioxide; macrogol 4000; talc; iron oxide,

red; iron oxide, black.

What does the medicine look like and what are the contents

of the package

Trileptin 300 mg:

Ovaloid, yellow, slightly biconvex film-coated tablet, with a score

and the imprint TE/TE on one side, with a score and the imprint

CG/CG on the other side.

Trileptin 600 mg:

Ovaloid, light pink colored, slightly biconvex film-coated tablet,

with a score and the imprint TF/TF on one side, with a score and

the imprint CG/CG on the other side.

Both dosages are marketed in packages of 50 tablets.

Registration Holder and address: Novartis Israel Ltd., 36

Shacham St., Petach-Tikva.

Name of manufacturer and address: Novartis Farma S.p.A., Torre

Annunziata, Italy for: Novartis Pharma AG, Basel, Switzerland.

This leaflet was checked and approved by the Ministry of Health

in August 2014.

Registration number of the medicine in the National Drug Registry

of the Ministry of Health:

300 mg Tablets - 106 80 28707

600 mg Tablets - 106 81 28708

SH TRI APL AUG14 CL V7 COR CPO CL

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CDS 130214, 2013-PSB/GLC-0639-s

ודי לע רשואו קדבנ ונכותו תואירבה דרשמ י"ע עבקנ הז ןולע טמרופ

טסוגוא

2014

TRILEPTIN

(oxcarbazepine)

300 mg, 600 mg Film-coated Tablets

Prescribing Information

1

Trade name

TRILEPTIN

300 mg, 600 mg, film-coated tablets

2

Description and composition

Pharmaceutical form

Film-coated tablets

300 mg: yellow, ovaloid, slightly biconvex tablets, scored on both sides. Embossed with TE/TE on

one side and CG/CG on the other side.

600 mg: light pink, ovaloid, slightly biconvex tablets scored on both sides. Embossed with TF/TF

on one side and CG/CG on the other side.

Active substance

Each Trileptin film-coated tablet contains 300mg or 600mg oxcarbazepine.

Active moiety

Oxcarbazepine

Excipients

Trileptin 300mg:

Tablet

core:

Silica,

colloidal

anhydrous;

crospovidone;

hypromellose;

magnesium

stearate;

cellulose, microcrystalline

Tablet coating: Hypromellose; iron oxide, yellow (C.I. no. 77492, E 172); macrogol 8000; talc;

titanium dioxide (C.I. no. 77891, E171)

Trileptin 600mg:

Tablet

core:

Silica,

colloidal

anhydrous;

crospovidone;

hypromellose;

magnesium

stearate;

cellulose, microcrystalline

Tablet coating: Iron oxide, black; iron oxide, red; titanium dioxide; macrogol 4000; talc; hypromellose

3

Indications

Treatment of primary generalised tonic-clonic seizures and partial seizures, with or without

secondary generalisation.

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4

Dosage and administration

Trileptin is not approved for use in children less than 2 years of age.

Dosage

Trileptin is suitable for use either as monotherapy or in combination with other antiepileptic drugs.

In mono- and adjunctive therapy, treatment with Trileptin is initiated with a clinically effective

dose given in two divided doses (see section 12 Clinical studies). The dose may be increased

depending on the clinical response of the patient.

When other antiepileptic drugs are replaced by Trileptin, the dose of the concomitant antiepileptic

drugs(s) should be reduced gradually on initiation of Trileptin therapy. In adjunctive therapy, as

the total antiepileptic drug load of the patient is increased, the dose of concomitant antiepileptic

drug(s) may need to be reduced and/or the Trileptin dose increased more slowly (see section 8

Interactions).

Therapeutic drug monitoring

The therapeutic effect of oxcarbazepine is primarily exerted through the active metabolite 10-

monohydroxy derivative (MHD) of oxcarbazepine (section 11 Clinical pharmacology).

Plasma level monitoring of oxcarbazepine or MHD is not routinely warranted. However, plasma

level monitoring of MHD may be considered during Trileptin therapy in order to rule out

noncompliance,

situations

where

alteration

clearance

expected,

including:

changes in renal function (see section Dosage in renal impairment)

pregnancy (see Section 9 WOCBP, pregnancy, breast feeding and fertility and section 11

Clinical Pharmacology)

concomitant use of liver enzyme-inducing drugs (see section 8 Interactions)

If any of these situations apply, the dose of Trileptin may be adjusted (based on plasma levels

measured 2-4 hours post dose) to maintain peak MHD plasma levels < 35 mg/L.

General target population

Adults

Monotherapy and adjunctive therapy

Recommended initial dose

Trileptin should be initiated with a dose of 600 mg/day (8-10 mg/kg/day) given in 2 divided doses.

Maintenance dose

Good therapeutic effects are seen at doses 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.

Maximum recommended dose

In a controlled hospital setting, dose increases up to 2,400 mg/day have been achieved over 48

hours.

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.

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Special populations

Pediatric patients

Trileptin is not approved for use in children less than 2 years of age.

Recommended initial dose

In mono- and adjunctive therapy, Trileptin should be initiated with a dose of 8-10 mg/kg/day

given in 2 divided doses.

Maintenance dose

The target maintenance dose of Trileptin for adjunctive therapy is 30-46 mg/kg/day and should be

achieved over two weeks.

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 of 60 mg/kg/day, 56% of

patients reached a final dose of at least 55 mg/kg/day.

Maximum recommended dose

If clinically indicated, the dose may be increased by a maximum of 10mg/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 (see section 11 Clinical pharmacology).

Effect of weight adjusted MHD clearance on pediatric dosage

Under adjunctive therapy and monotherapy, when normalized by body weight, apparent clearance

(L/hr/kg) of MHD (the active metabolite of oxcarbazepine) 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 11 Clinical pharmacology).

Effect of concomitant enzyme-inducing antiepileptic drugs on pediatric dosage

For children 1 month to less than 4 years of age, the influence of enzyme-inducing antiepileptic

drugs on weight-normalized apparent clearance appeared higher compared to older children. For

children 1 month to less than 4 years of age, an approximately 60% higher oxcarbazepine dose per

body weight may be required for adjunctive therapy on enzyme-inducing antiepileptic drugs

compared to monotherapy or adjunctive therapy with non-enzyme-inducing antiepileptic drugs.

For older children on enzyme-inducing antiepileptic drugs, only a slightly higher dose per body

weight may be required than their counterparts on monotherapy.

Trileptin has not been studied in controlled clinical trials in children below 1 month of age.

Geriatric patients (65 years old and above)

No special dose recommendations are necessary in

elderly patients because therapeutic doses are

individually adjusted. Dosage adjustments are recommended in elderly patients with renal impairment

(creatinine clearance <30 ml/min) (see information below on dosage in renal impairment).

Close monitoring of sodium levels is required in patients at risk of hyponatremia (see section Warnings

and precautions).

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Hepatic impairment

No dosage adjustment is required for patients with mild to moderate hepatic impairment. Trileptin

has not been studied in patients with severe hepatic impairment, therefore, caution should be

exercised when dosing such patients (see section 11 Clinical pharmacology and section 6 Warning

and precautions ).

Renal impairment

In patients with impaired renal function (creatinine clearance less than 30 mL/min) Trileptin

therapy should be initiated at half the usual starting dose (300 mg/day) and increased slowly to

achieve the desired clinical response (see section 11 Clinical pharmacology and section 6 Warning

and precautions ).

Method of administration

The tablets are scored and can be broken in two halves in order to make it easier for the patient to

swallow the tablet.

Trileptin can be taken with or without food (see section 11 Clinical pharmacology).

5

Contraindications

Known hypersensitivity to oxcarbazepine or to any of the excipients.

6

Warnings and 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 Trileptin. If a patient develops these reactions after

treatment with Trileptin, the drug 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 with Trileptin

(see section 7 Adverse drug reactions).

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 or other organs, either individually or together in the context of

a systemic reaction (see section 7 Adverse drug reactions). In general, if signs and symptoms

suggestive of hypersensitivity reactions occur, Trileptin should be withdrawn immediately.

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

Trileptin

use.

Patients

with

serious

dermatological

reactions

require

hospitalization, as these conditions may be life-threatening and very rarely be fatal. Trileptin

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 re-challenged with Trileptin

were reported. Should a patient develop a skin reaction with Trileptin, consideration should be

given to discontinuing Trileptin and prescribing another anti-epileptic drug.

Pharmacogenomics

There is growing evidence that different Human Leukocyte Antigen (HLA) alleles play a role in

association with adverse cutaneous reactions in predisposed patients.

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Association with HLA-B*1502

Retrospective studies in patients of Han Chinese and Thai origin found a strong correlation

between SJS/TEN skin reactions associated with carbamazepine and the presence in these patients

Human

Leukocyte

Antigen

(HLA)-B*1502

allele.

chemical

structure

oxcarbazepine is similar to that of carbamazepine, there is a possibility that patients carrying the

HLA-B*1502 allele also have an increased risk of SJS/TEN skin reactions with oxcarbazepine.

The frequency of HLA-B*1502 allele ranges from 2 to 12% in Han Chinese populations, from 0

to 18% in Taiwanese populations, and is about 8% in Thai populations, 10 % in the Hong Kong

(Chinese) population, and above 15% in the Philippines and some Malaysian populations.

Allele frequencies up to about 2% and 6% have been reported in Korea and India, respectively.

The frequency of the HLA-B*1502 allele is negligible in persons from European descent, several

African populations, indigenous peoples of the Americas, Hispanic populations sampled and in

Japanese (< 1%).

The allele frequencies listed here represent the percentage of chromosomes in the specified

population that carry the allele of interest, meaning that the percentage of patients who carry a

copy of the allele on at least one of their two chromosomes (i.e., the “carrier frequency”) is nearly

twice as high as the allele frequency. Therefore, the percentage of patients who may be at risk is

nearly twice the allele frequency.

Testing for the presence of the HLA-B*1502 allele should be considered in patients with ancestry

genetically

at-risk

populations

prior

initiating

treatment

with

Trileptin

(see

below

Information for healthcare professionals). The use of Trileptin should be avoided in tested patients

who are found to be positive for HLA-B*1502 unless the benefits clearly outweigh the risks.

HLA-B*1502 may be a risk factor for the development of SJS/TEN in Chinese patients taking

other anti-epileptic drugs (AED) associated with SJS/TEN. Consideration should therefore be

given to avoid use of other drugs associated with SJS/TEN in HLA-B*1502 positive patients,

when

alternative

therapies

otherwise

equally

acceptable.

Screening

generally

recommended in patients from populations in which the prevalence of HLA-B*1502 is low or in

current Trileptin users, as the risk of SJS/TEN is largely confined to the first few months of

therapy, regardless of HLA-B*1502 status.

Association with HLA-A*3101

Human Leukocyte Antigen (HLA)-A*3101 may be a risk factor for the development of cutaneous

adverse drug reactions such as SJS, TEN, DRESS, AGEP and maculopapular rash.

The frequency of the HLA-A*3101 allele varies widely between ethnic populations and its

frequency is about 2 to 5% in European populations and about 10% in the Japanese population.

The frequency of this allele is estimated to be less than 5% in the majority of Australian, Asian,

African and North American populations with some exceptions within 5 to 12%. Frequency above

15% has been estimated in some ethnic groups in South America (Argentina and Brazil), North

America (US Navajo and Sioux, and Mexico Sonora Seri) and Southern India (Tamil Nadu) and

between 10% to 15% in other native ethnicities in these same regions.

The allele frequencies listed here represent the percentage of chromosomes in the specified

population that carry the allele of interest, meaning that the percentage of patients who carry a

copy of the allele on at least one of their two chromosomes (i.e., the “carrier frequency”) is nearly

twice as high as the allele frequency. Therefore, the percentage of patients who may be at risk is

nearly twice the allele frequency.

There

some

data

that

suggest

HLA-A*3101

associated

with

increased

risk

carbamazepine-induced cutaneous adverse drug reactions including SJS, TEN, drug rash with

eosinophilia (DRESS), or less severe acute generalized exanthematous pustulosis (AGEP) and

maculopapular rash.

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There

insufficient

data

support

recommendation

testing

presence

HLA-A*3101 allele in patients, prior to initiating treatment with oxcarbazepine. Genetic screening

is generally not recommended for any current Trileptin users, as the risk of SJS/TEN, AGEP,

DRESS and maculopapular rash is largely confined to the first few months of therapy, regardless

of HLA-A*3101 status.

Limitation of genetic screening

Genetic

screening

results

must

never

substitute

appropriate

clinical

vigilance

patient

management. Many Asian patients positive for HLA-B*1502 and treated with Trileptin will not

develop SJS/TEN, and patients negative for HLA-B*1502 of any ethnicity can still develop

SJS/TEN. Similarly, many patients positive for HLA-A*3101 and treated with Trileptin will not

develop SJS, TEN, DRESS, AGEP or maculopapular rash, and patients negative for HLA-A*3101

of any ethnicity can still develop these severe cutaneous adverse reactions. The role of other

possible factors in the development of, and morbidity from, these severe cutaneous adverse

reactions, such as AED dose, compliance, concomitant medications, co-morbidities, and the level

of dermatologic monitoring have not been studied.

Information for healthcare professionals

If testing for the presence of the HLA-B*1502 allele is performed, high-resolution “HLA-B*1502

genotyping” is recommended. The test is positive if either one or two HLA-B*1502 alleles are

detected, and negative if no HLA-B*1502 alleles are detected. Similarly, if testing for the

presence of the HLA-A*3101 allele is performed, high resolution “HLA-A*3101 genotyping” is

recommended. The test is positive if either one or two HLA-A*3101 alleles are detected, and

negative if no HLA-A*3101 alleles are detected.

Risk of seizure aggravation

Risk of seizure aggravation has been reported with Trileptin. The risk of seizure aggravation is

seen especially in children but may also occur in adults. In case of seizure aggravation, Trileptin

should be discontinued.

Hyponatraemia

Serum sodium levels below 125 mmol/L, usually asymptomatic and not requiring adjustment of

therapy, have been observed in up to 2.7% of Trileptin treated patients. Experience from clinical

trials shows that serum sodium levels returned towards normal when the Trileptin 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 (e.g. inappropriate ADH

secretion like syndrome) or in patients treated concomitantly with sodium-lowering drugs (e.g.

diuretics, drugs associated with inappropriate ADH secretion), serum sodium levels should be

measured prior to initiating therapy. Thereafter, serum sodium levels should be measured after

approximately two weeks and then at monthly intervals for the first three months during therapy,

or according to clinical need. These risk factors may apply especially to elderly patients.

For patients on Trileptin therapy when starting on sodium-lowering drugs, the same approach for

sodium checks should be followed. In general, if clinical symptoms suggestive of hyponatraemia

occur on Trileptin therapy (see section 7 Adverse drug reactions), 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 hyponatraemia is observed, water

restriction

important

counter-measure.

oxcarbazepine

may,

very

rarely,

lead

impairment of cardiac conduction, patients with pre-existing conduction disturbances (e.g. AV-

block, arrhythmia) should be monitored carefully.

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Hypothyroidism

Hypothyroidism is a very rare adverse drug reaction of oxcarbazepine. Considering the importance

of thyroid hormones in children’s development after birth, it is advisable to perform a thyroid

function test before the start of Trileptin therapy in the pediatric age group, especially in children

aged two years or below. Thyroid function monitoring is recommended in the pediatric age group

while on Trileptin therapy.

Hepatic function

Very rare cases of hepatitis have been reported, which in most cases resolved favorably. In case of

suspected hepatitis, discontinuation of Trileptin should be considered. Caution should be exercised

when treating patients with severe hepatic impairment (see sections 4 Dosage and administration

and 11 Clinical pharmacology).

Renal function

In patients with impaired renal function (creatinine clearance less than 30 mL/min), caution should

be exercised during Trileptin treatment especially with regard to the starting dose and up titration

of the dose (see sections 4 Dosage and administration and 11 Clinical pharmacology).

Hematological effects

Very rare reports of agranulocytosis, aplastic anemia and pancytopenia have been seen in patients

treated with Trileptin during post-marketing experience (see section 7 Adverse drug reactions ).

However, due to the very low incidence of these conditions and confounding factors (e.g.

underlying disease, concomitant medication), causality cannot be established.

Discontinuation of the drug should be considered if any evidence of significant bone marrow

depression develops.

Suicidal ideation and behavior

Suicidal ideation and behavior have been reported in patients treated with antiepileptic agents in

several indications. A meta-analysis of randomized placebo controlled trials of antiepileptic drugs

has shown a small increased risk of suicidal ideation and behavior. The mechanism of this risk is

not known.

Therefore

patients

should

monitored

signs

suicidal

ideation

behavior,

appropriate treatment should be considered. Patients (and caregivers of patients) should be advised

to seek medical advice should signs of suicidal ideation or behavior emerge.

Interactions

Hormonal contraceptives: Female patients of childbearing age should be warned that the

concurrent use of Trileptin with hormonal contraceptives may render this type of contraception

ineffective (see sections 8 Interactions and 9 WOCBP). Additional non-hormonal forms of

contraception are recommended when using Trileptin.

Alcohol

Caution should be exercised if alcohol is taken in combination with Trileptin therapy, due to a

possible additive sedative effect.

Withdrawal effects

As with all antiepileptic drugs, Trileptin should be withdrawn gradually to minimize the potential

of increased seizure frequency.

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Driving and using machines

Adverse

reactions

such

dizziness,

somnolence,

ataxia,

diplopia,

blurred

vision,

visual

disturbances, hyponatremia and depressed level of consciousness were reported with Trileptin (for

the complete list of ADRs see section 7 Adverse drug reactions), especially at the start of

treatment or in connection with dose adjustments (more frequently during the up titration phase).

Patients should therefore exercise due caution when driving a vehicle or operating machinery.

7

Adverse drug reactions

Summary of the safety profile

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 Trileptin. In addition, clinically meaningful reports on adverse experiences

from named patient programs and post-marketing experience were taken into account.

Tabulated summary of adverse drug reactions from clinical trials

Adverse drug reactions from clinical trials (Table 7-1) are listed by MedDRA system organ class.

Within each system organ class, the adverse drug reactions are ranked by frequency, with the most

frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in

order of decreasing seriousness. In addition, the corresponding frequency category for each

adverse drug reaction is based on the following convention (CIOMS III): very common (≥1/10);

common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very

rare (<1/10,000).

Table

0-1

Adverse drug reactions

Blood and lymphatic system

disorders

Uncommon

Leucopenia.

Very rare

Bone marrow depression, aplastic anemia, agranulocytosis,

pancytopenia, thrombocytopenia, neutropenia.

Immune system disorders

Very rare

Anaphylactic reactions, hypersensitivity (including multi-

organ hypersensitivity) characterized by features such as

rash, fever. Other organs or systems may be affected such

as blood and lymphatic system (e.g. eosinophilia,

thrombocytopenia, leucopenia, lymphadenopathy,

splenomegaly), liver (e.g. hepatitis, abnormal liver

function tests), muscles and joints (e.g. joint swelling,

myalgia, arthralgia), nervous system (e.g. hepatic

encephalopathy), kidneys (e.g. renal failure, nephritis

interstitial, proteinuria), lungs (e.g. pulmonary oedema,

asthma, bronchospasms, interstitial lung disease, dyspnea),

angioedema.

Endocrine disorders

Very rare

Hypothyroidism

Metabolism and nutrition

disorders

Common

Hyponatraemia.

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Very rare

Hyponatraemia* associated with signs and symptoms such

as seizures, encephalopathy, depressed level of

consciousness, confusion (see also Nervous system

disorders for further adverse effects), vision disorders (e.g.

blurred vision), hypothyroidism, vomiting, nausea, folic

acid deficiency

Psychiatric disorders

Common

Agitation (e.g. nervousness), affect lability, confusional

state, depression, apathy.

Nervous system disorders

Very common

Somnolence, headache, dizziness.

Common

Ataxia, tremor, nystagmus, disturbance in attention,

amnesia.

Eye disorders

Very common

Diplopia.

Common

Vision blurred, visual disturbance.

Ear and labyrinth disorders

Common

Vertigo.

Cardiac disorders

Very rare

Atrioventricular block, arrhythmia.

Vascular disorders

Very rare

Hypertension.

Gastrointestinal disorders

Very common

Vomiting, nausea.

Common

Diarrhoea, abdominal pain, constipation.

Very rare

Pancreatitis and/or lipase and/or amylase increase.

Hepatobiliary disorders

Very rare

Hepatitis.

Skin and subcutaneous

tissue disorders

Common

Rash, alopecia, acne.

Uncommon

Urticaria.

Very rare

Stevens-Johnson syndrome, toxic epidermal necrolysis

(Lyell’s syndrome), angioedema, erythema multiforme.

Musculoskeletal, connective

tissue and bone disorders

Very rare

Systemic lupus erythematosus.

General disorders and

administration site

conditions

Very common

Fatigue.

Common

Asthenia.

Investigations

Uncommon

Hepatic enzymes increased, blood alkaline phosphatase

increased.

Very rare

Amylase increase, lipase increase

*Very rarely clinically significant hyponatraemia (sodium < 125 mmol/L) can develop during Trileptin use. It

generally occurred during the first 3 months of treatment with Trileptin, although there were patients who first

developed serum sodium < 125 mmol/L more than 1 year after initiation of therapy (see section 6 Warnings and

precautions).

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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 increased.

Adverse drug reactions from spontaneous reports and literature cases (frequency not known)

The following adverse drug reactions have been derived from post-marketing experience with Trileptin

via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a

population of uncertain size, it is not possible to reliably estimate their frequency, which is therefore

categorized as not known. Adverse drug reactions are listed according to system organ classes in

MedDRA. Within each system organ class, ADRs are presented in order of decreasing seriousness.

Metabolism and nutrition disorders

Inappropriate

secretion

like

syndrome

with

signs

symptoms

lethargy,

nausea,

dizziness, decrease in serum (blood) osmolality, vomiting, headache, confusional state or other

neurological signs and symptoms.

Skin and subcutaneous tissue disorders

Drug

rash

with

eosinophilia

systemic

symptoms

(DRESS),

acute

generalized

exanthematous

pustulosis (AGEP).

Injury, poisoning and procedural complications

Fall.

Nervous system disorders

Speech disorders (including dysarthria); more frequent during up titration of Trileptin dose.

Musculoskeletal, connective tissue and bone disorders

There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures in

patients on long-term therapy with Trileptin. The mechanism by which oxcarbazepine affects bone

metabolism has not been identified.

8

Interactions

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 drugs. The results

demonstrate that oxcarbazepine and its pharmacologically active metabolite (the monohydroxy

derivative, MHD) inhibit CYP2C19. Therefore, interactions could arise when co-administering

high

doses

Trileptin

with

drugs

that

metabolized

CYP2C19

(e.g.

phenobarbital,

phenytoin,

below).

some

patients

treated

with

Trileptin

drugs

metabolized

CYP2C19 dose reduction of the co-administered drugs might be necessary. In human liver

microsomes, oxcarbazepine and MHD have little or no capacity to function as inhibitors for the

following enzymes: CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1, CYP4A9 and CYP4A11.

Enzyme induction

Oxcarbazepine and MHD induce, in vitro and in vivo, cytochromes CYP3A4 and CYP3A5

responsible for the metabolism of dihydropyridine calcium antagonists, oral contraceptives, and

antiepileptic drugs (e.g. carbamazepine), resulting in a lower plasma concentration of these drugs

(see below). A decrease in plasma concentrations may also be observed for other drugs mainly

metabolized by CYP3A4 and CYP3A5, for example immunosuppressants (e.g. ciclosporin).

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In vitro, oxcarbazepine and MHD are weak inducers of UDP-glucuronyl transferase. Therefore, in

vivo they are unlikely to have an effect on drugs which are mainly eliminated by conjugation

through the UDP-glucuronyl transferases (e.g. valproic acid, lamotrigine). Even in view of the

weak induction potential of oxcarbazepine and MHD, a higher dose of concomitantly used drugs

which are metabolized via CYP3A4 or via conjugation (UDPGT) may be necessary. In the case of

discontinuation of Trileptin therapy, a dose reduction of the concomitant medication may be

necessary.

Induction studies conducted with human hepatocytes confirmed oxcarbazepine and MHD as weak

inducers

isoenzymes

sub-family.

induction

potential

oxcarbazepine/MHD on other CYP isoenzymes is not known.

Antiepileptic drugs

Potential interactions between Trileptin and other antiepileptic drugs were assessed in clinical

studies. The effect of these interactions on mean AUCs and C

are summarized in the following

table.

Table

0-2

Summary of antiepileptic drug interactions with Trileptin

Antiepileptic drug

Influence of

Trileptin on

antiepileptic drug

Influence of

antiepileptic drug on

MHD

Co-administered

Concentration

Concentration

Carbamazepine

0 - 22% decrease

40% decrease

Clobazam

Not studied

No influence

Felbamate

Not studied

No influence

Phenobarbital

14 - 15% increase

30 - 31% decrease

Phenytoin

0 - 40% increase

29 - 35% decrease

Valproic acid

No influence

0 - 18% decrease

Lamotrigine

No influence

No influence

In vivo, plasma levels of phenytoin increased by up to 40% when Trileptin was given at doses

above 1,200 mg/day. Therefore, when using doses of Trileptin greater than 1,200 mg/day during

adjunctive therapy, a decrease in the dose of phenytoin may be required (see section 4 Dosage and

administration). The increase in the phenobarbital level, however, is small (15%) when given with

Trileptin.

Strong inducers of cytochrome P450 enzymes (i.e. carbamazepine, phenytoin and phenobarbital)

have been shown to decrease the plasma levels of MHD (29-40%).

No autoinduction has been observed with Trileptin.

Hormonal contraceptives

Trileptin 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. Studies with other oral or implant contraceptives

have not been conducted. Therefore, concurrent use of Trileptin with hormonal contraceptives

may render these contraceptives ineffective (see sections 6Warnings and precautions and 9

WOCBP).

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Calcium antagonists

After repeated co-administration of Trileptin, 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% in the plasma levels of MHD. This

decrease in MHD plasma levels is not considered to be of clinical relevance.

Other drug 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

either single or repeated doses of Trileptin.

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.

9

Women of child-bearing potential (WOCBP), pregnancy, breast-

feeding and fertility

Pregnancy

Offspring of epileptic mothers are known to be more prone to developmental disorders, including

malformations. Data on a limited number of pregnancies indicate that oxcarbazepine may cause

serious birth defects when administered during pregnancy (see section 13 Non-clinical safety

data).

most

frequent

congenital

malformations

seen

with

oxcarbazepine

therapy

were

ventricular

septal

defect,

atrioventricular

septal

defect,

cleft

palate

with

cleft

lip,

Down’s

syndrome,

dysplastic

(both

unilateral

bilateral),

tuberous

sclerosis

congenital

malformation of the ear. Based on data in a North American pregnancy registry, the rate of major

congenital malformations, defined as a structural abnormality with surgical, medical, or cosmetic

importance, diagnosed within 12 weeks of birth was 2.0% (95% CI 0.6 to 5.1%) among mothers

exposed to oxcarbazepine monotherapy in the first trimester. When compared with pregnant

women not exposed to any antiepileptic drugs the relative risk (RR) of congenital abnormality in

pregnant women on oxcarbazepine is (RR) 1.6, 95% CI 0.46 to 5.7.

Taking these data into consideration:

If women receiving Trileptin become pregnant, or plan to become pregnant, or if the need to

initiate treatment with Trileptin arises during pregnancy, the drug’s potential benefits must be

carefully

weighed

against

potential

risk

fetal

malformations.

This

particularly

important during the first three months of pregnancy.

Minimum effective doses should be given.

In women of childbearing age, Trileptin should be administered as monotherapy, whenever

possible.

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 treatment should not be interrupted, since the

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

Monitoring and prevention

Antiepileptic drugs may contribute to folic acid deficiency, a possible contributory cause of fetal

abnormality. Folic acid supplementation is recommended before and during pregnancy.

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Due to physiological changes during pregnancy, plasma levels of the active metabolite of oxcarbazepine,

10-monohydroxy

derivative

(MHD),

gradually

decrease

throughout

pregnancy.

recommended

that

clinical

response

should

monitored

carefully

women

receiving

Trileptin

treatment during pregnancy and determination of changes in MHD plasma concentrations should be

considered to ensure that adequate seizure control is maintained throughout pregnancy(see section 4

Dosage and administration and section 11 Clinical pharmacology). 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 K

should be administered as a preventive measure in the last few weeks of

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.

Women of child-bearing potential and contraceptive measures

Women of child bearing potential should be advised to use highly effective contraception (preferably

non-hormonal; e.g. intrauterine implants) while on treatment with Trileptin. Trileptin may result in a

failure

therapeutic

effect

oral

contraceptive

drugs

containing

ethinylestradiol

(EE)

levonorgestrel (LNG) (see sections 6 Warning and precautions and 8 Interactions).

Breast-feeding

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

Trileptin by this route are unknown. Therefore, Trileptin should not be used during breast-feeding.

Fertility

There are no human data on fertility.

In rats, fertility in both sexes was unaffected by oxcarbazepine or MHD at oral doses up to 150 and 450

mg/kg/day, respectively. However, disruption of estrous cyclicity and reduced numbers of corpora lutea,

implantations and live embryos were observed in female animals at the highest dose of MHD.

10

Overdosage

Isolated cases of overdose have been reported. The maximum dose taken was approximately

48,000 mg.

Signs and symptoms

Electrolyte and fluid balance conditions: hyponatremia

Eye disorders: diplopia, miosis, blurred vision

Gastrointestinal disorders: nausea, vomiting, hyperkinesia

General disorders and administration site conditions: fatigue

Investigations: respiratory rate depression, QTc prolongation

Nervous

system

disorders:

drowsiness

somnolence,

dizziness,

ataxia,

nystagmus,

tremor,

disturbances in coordination (coordination abnormal), convulsion, headache, coma, loss of consciousness,

dyskinesia

Psychiatric disorders: aggression, agitation, confusional state

Vascular disorders: hypotension

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Respiratory, thoracic and mediastinal disorders: dyspnoea

Management

There is no specific antidote. Symptomatic and supportive treatment should be administered as

appropriate. Removal of the drug by gastric lavage and/or inactivation by administering activated

charcoal should be considered.

11

Clinical pharmacology

Pharmacotherapeutic group, ATC

Pharmacotherapeutic group: Antiepileptics, ATC code: N03A F02

Mechanism of action (MOA)

pharmacological

activity

Trileptin

(oxcarbazepine)

primarily

exerted

through

metabolite

(MHD)

oxcarbazepine

(see

Pharmacokinetics

(PK)

Biotransformation/Metabolism). The mechanism of action of oxcarbazepine and MHD is thought

mainly

based

blockade

voltage-sensitive

sodium

channels,

thus

resulting

stabilization of hyperexcited neural membranes, inhibition of repetitive neuronal firing, and

diminishment of propagation of synaptic impulses. In addition, increased potassium conductance

modulation

high-voltage

activated

calcium

channels

also

contribute

anticonvulsant

effects.

significant

interactions

with

brain

neurotransmitter

modulator

receptor sites were found.

Pharmacodynamics (PD)

Oxcarbazepine and its active metabolite (MHD), are potent and efficacious anticonvulsants in

animals. They protected rodents against generalized 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.

tolerance

(i.e.

attenuation

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 (PK)

Absorption

Following oral administration of Trileptin tablets, oxcarbazepine is completely absorbed and

extensively metabolized to its pharmacologically active metabolite (10-monohydroxy derivative,

MHD).

After single dose administration of 600mg Trileptin tablets to healthy male volunteers under

fasted conditions, the mean C

value of MHD was 34 micromol/L, with a corresponding median

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, Trileptin can

be taken with or without food (see section 4 Dosage and administration).

Distribution

The apparent volume of distribution of MHD is 49 liters.

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Approximately 40% of MHD is bound to serum proteins, predominately 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.

Biotransformation/Metabolism

Oxcarbazepine is rapidly reduced by cytosolic enzymes in the liver to MHD, which is primarily

responsible

pharmacological

effect

Trileptin.

metabolized

further

conjugation

with

glucuronic

acid.

Minor

amounts

dose)

oxidized

pharmacologically inactive metabolite (10, 11-dihydroxy derivative, DHD).

Elimination

Oxcarbazepine

cleared

from

body

mostly

form

metabolites,

which

predominantly excreted by the kidneys. More than 95% of the dose appears in the urine, with less

than

unchanged

oxcarbazepine.

Fecal

excretion

accounts

less

than

administered dose. Approximately 80% of the dose is excreted in the urine either as glucuronides

(49%)

unchanged

(27%),

whereas

inactive

accounts

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±1.8h.

Linearity/non-linearity

Steady-state plasma concentrations of MHD are reached within 2 to 3 days in patients when

Trileptin 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

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. Trileptin has

not been studied in patients with severe hepatic impairment.

Renal impairment

There is a linear correlation between creatinine clearance and the renal clearance of MHD. When

Trileptin 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 up to 19 hours, with a two fold

increase in AUC.

Pediatrics

Weight-adjusted MHD clearance decreases as age and weight increases approaching that of adults.

The mean weight-adjusted clearance in children 1 month to less than 4 years of age is 93% higher

than that of adults. Therefore, MHD exposure in these children is expected to be about one-half

that of adults when treated with a similar weight-adjusted dose. The mean weight-adjusted

clearance in children 4 to 12 years of age is 43% 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, the

weight-adjusted MHD clearance is expected to reach that of adults.

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Pregnancy

Due to physiological changes during pregnancy, MHD plasma levels may gradually decrease

throughout

pregnancy

(see

section

Dosage

administration

section

WOCBP,

pregnancy, breast-feeding and fertility).

Geriatrics

Following administration of single (300 mg) and multiple doses (600 mg/day) of Trileptin in

elderly volunteers (60 to 82 years of age), the maximum plasma concentrations and AUC values

of MHD were 30 to 60% higher than in younger volunteers (18 to 32 years of age). Comparisons

of creatinine clearance in young and elderly volunteers indicate that the difference was due to age-

related

reductions

creatinine

clearance.

special

dose

recommendations

necessary

because therapeutic doses are individually adjusted.

Gender

No gender related pharmacokinetic differences have been observed in children, adults, or the

elderly.

12

Clinical studies

A total of 10 double blind, well controlled trials, 2 in adjunctive therapy and 8 in monotherapy

were conducted in patients with partial seizures which included the seizure subtypes of simple,

complex and partial seizures evolving to secondarily generalized seizures. All comparative trials

also included patients with generalized tonic-clonic seizures.

dose-control

monotherapy

substitution

trials

which

patients

received

variety

concomitant

antiepileptic

drugs

which

included

carbamazepine,

gabapentin,

lamotrigine,

phenytoin, and valproate confirm efficacy when these antiepileptic drugs were substituted by

Trileptin. Two trials were conducted in children (aged 3 to 17 years), one in adjunctive therapy

versus placebo, the other a monotherapy comparison with phenytoin.

Efficacy was demonstrated with doses ranging from 600 mg/day to 2,400 mg/day in all the

primary efficacy parameters which included mean or percentage change in seizure frequency from

baseline in the adjunctive trials and time to meeting pre-defined exit criteria or the percentage of

patients meeting exit criteria in the monotherapy trials.

An adjunctive therapy, rater-blind, trial in children (aged 1 month to less than 4 years) with

inadequately-controlled

partial

seizures

concomitant

antiepileptic

drugs

conducted, comparing two doses of oxcarbazepine. The primary measure of effectiveness was a

between group comparison of the absolute change in study specific seizure frequency per 24 hours

compared to the seizure frequency at baseline. This comparison was statistically significant in

favor of Trileptin 60 mg/kg/day.

A monotherapy, rater-blind, trial in children (aged 1 month to 16 years) with inadequately

controlled or new-onset partial seizures was conducted comparing two doses of oxcarbazepine.

The primary measure of effectiveness was a between group comparison of the time to meet exit

criteria which was not statistically significant. The majority of patients in both treatment groups

did not experience any video EEG-confirmed seizures during the study and completed this 5-day

study without exiting.

It has been shown that Trileptin has similar efficacy to other first line antiepileptic drugs (i.e.

valproic acid, phenytoin and carbamazepine) with a statistically significantly better tolerability

profile than phenytoin as judged by withdrawals due to adverse events and, a statistically

significant longer retention rate (i.e. proportion of patients who stayed on treatment). Similar

proportions of patients with partial and generalized tonic-clonic seizures, who were treated with

Trileptin, were seizure free over the 12 month treatment period of these trials.

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13

Non-clinical safety data

Preclinical data indicated no special hazard for humans based on repeated dose toxicity, safety

pharmacology and genotoxicity studies with oxcarbazepine and the pharmacologically active

metabolite, monohydroxy derivative (MHD).

Immunotoxicity

Immunostimulatory tests in mice showed that MHD (and to a lesser extent oxcarbazepine) can

induce delayed hypersensitivity.

Mutagenicity

Oxcarbazepine increased mutation frequencies in one Ames test in vitro in the absence of

metabolic activation in one of five bacterial strains. Oxcarbazepine and MHD produced increases

in chromosomal aberrations and/or polyploidy in the Chinese hamster ovary assay in vitro in the

absence of metabolic activation. MHD was negative in the Ames test, and no mutagenic or

clastogenic activity was found with either oxcarbazepine or MHD in V79 Chinese hamster cells in

vitro.

Oxcarbazepine

were

both

negative

clastogenic

aneugenic

effects

(micronucleus formation) in an in vivo rat bone marrow assay.

Carcinogenicity

In the carcinogenicity studies, liver (rats and mice), testicular and female genital tract granular cell

(rats) tumors were induced in treated animals. The occurrence of liver tumors was most likely a

consequence of the induction of hepatic microsomal enzymes; an inductive effect which, although

it cannot be excluded, is weak or absent in patients treated with Trileptin. Testicular tumors may

have been induced by elevated luteinizing hormone concentrations. Due to the absence of such an

increase in humans, these tumors are considered to be of no clinical relevance. A dose-related

increase in the incidence of granular cell tumors of the female genital tract (cervix and vagina)

was noted in the rat carcinogenicity study with MHD. These effects occurred at exposure levels

comparable with the anticipated clinical exposure. The mechanism for the development of these

tumors has not been fully elucidated but could be related to increased estradiol levels specific to

the rat. The clinical relevance of these tumors is unclear.

Reproductive toxicity

Standard reproductive toxicity studies in rodents and rabbits revealed effects such as increases in

the incidence of embryo-fetal mortality and/or some delay in antenatal and/or postnatal growth of

the offspring at maternally toxic dose levels. There was an increase in rat fetal malformations in

one of the eight embryo-fetal toxicity studies, which were conducted with either oxcarbazepine or

MHD, at doses which also caused maternal toxicity (see section 9 WOCBP, pregnancy, breast-

feeding and fertility). The overall evidence from all animal studies indicates that oxcarbazepine

has minor teratogenic potential at doses relevant to humans. However, the animal studies were

insufficient to rule out a teratogenic effect of oxcarbazepine.

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14

Pharmaceutical information

Incompatibilities

None known.

Special precautions for storage

Do not store above 30

C. Store in the original package.

Trileptin must be kept out of the reach and sight of children.

Manufacturer

Novartis Farma S.p.A, Torre Annunziata, Italy

For: Novartis Pharma AG, Basel, Switzerland.

Registration Holder

Novartis Israel Ltd., 36 Shacham St., Petach-Tikva.