TEGRETOL CR 200 MG

Israel - English - Ministry of Health

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Active ingredient:
CARBAMAZEPINE
Available from:
NOVARTIS ISRAEL LTD
ATC code:
N03AF01
Pharmaceutical form:
TABLETS SLOW RELEASE
Composition:
CARBAMAZEPINE 200 MG
Administration route:
PER OS
Prescription type:
Required
Manufactured by:
NOVARTIS FARMA S.P.A., ITALY
Therapeutic group:
CARBAMAZEPINE
Therapeutic area:
CARBAMAZEPINE
Therapeutic indications:
Epilepsy, trigeminal neuralgia, diabetes insipidus, mania, prophylactic in manic-depressive illness
Authorization number:
041 24 25416 00
Authorization date:
2014-05-31

Documents in other languages

Patient Information leaflet Patient Information leaflet - Arabic

25-01-2021

Patient Information leaflet Patient Information leaflet - Hebrew

14-09-2016

Uncommon (these side effects may affect

up to 1 in every 100 patients):

Trembling, uncontrolled body movements,

muscle spasms.

Rare (these side effects may affect up to

1 in every 1,000 patients):

Itching, swollen glands, agitation or

hostility (especially in the elderly),

fainting, difficulty in speaking or slurred

speech, depression with restlessness,

nervousness or other mood or mental

changes, hallucinations, blurred vision,

double vision, itching with redness and

swelling of the eye (conjunctivitis),

feeling pressure/pain in the eye (signs

of increased pressure in the eye),

uncontrolled eye movements, ringing or

other unexplained sounds in the ears,

decreased hearing, troubled breathing,

chest pain, fast or unusually slow heart

rate, numbness, tingling in hands and

feet, weakness, frequent urination,

sudden decrease in amount of urine, taste

disturbances, unusual secretion of breast

milk, breast enlargement in men, swelling

and redness along a vein with heightened

sensitivity to touch, often experienced

as painful (thrombophlebitis), increased

sensitivity of the skin to sun, softening or

thinning or weakening of bones causing

an increased risk of bone fractures (lack

of vitamin D, osteoporosis).

Very rare (these side effects may affect

less than 1 in every 10,000 patients):

Increased

cholesterol,

pulmonary

embolism (blood clot in the lungs), blood

clots, cataract.

Some

side

effects

unknown

frequency:

Reactivation of herpes virus infection

(can be serious when the immune system

is depressed), complete loss of the nails,

fracture, decrease in the measure of the

bone density.

Usually the following side effects

do not need medical attention.

However, if they last for more than

a few days or are bothersome, check

with your doctor.

Very common (these side effects may

affect more than 1 in 10 patients):

Vomiting, nausea, dizziness, sleepiness,

unsteadiness, weight gain.

Common (these side effects may affect

up to 1 in every 10 patients):

Headache, dry mouth.

Rare (these side effects may affect up to

1 in every 1,000 patients):

Constipation, diarrhea, abdominal pain,

aching joints or muscles, increased

sweating, loss of appetite, loss of hair,

excessive body and facial hair, sexual

disturbances, male infertility, red and

sore tongue, mouth sores, alterations in

skin pigmentation, acne.

Side effects of unknown frequency:

Drowsiness, memory loss, purple or

reddish-purple bumps that may be

itchy.

If one or more of these side effects affects

you severely, tell your doctor.

If a side effects occurs, if one of the side

effects worsens or if you suffer from a

side effect not mentioned in the leaflet,

you must 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 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.

Keep out of the reach and sight of

children.

Tablets: Store below 25°C and in the

original package in order to protect from

moisture.

CR Tablets: Store below 25°C and protect

from moisture.

Syrup: Store below 30°C, protect from

light.

After first opening the bottle, store below

25°C and use within 3 months.

Return any unused medicine to the

pharmacy.

6. FURTHER INFORMATION

In addition to the active ingredient, the

medicine also contains:

Tegretol CR 200 mg, Tegretol CR 400

The tablet:

Cellulose, microcrystalline; Sodium

carboxymethylcellulose; Polyacrylate

dispersion 30 per cent; Ethylcellulose

aqueous dispersion; Talc; Silica colloidal

anhydrous; Magnesium stearate

Each CR 200 mg tablet contains

approximately 2.3 mg sodium.

Each CR 400 mg tablet contains

approximately 4.6 mg sodium.

The tablet coating:

Hypromellose; Talc; Titanium dioxide;

Castor oil, polyoxyl hydrogenated; Iron

oxide yellow; Iron oxide red.

Tegretol 200 mg:

Cellulose microcrystalline; Carmellose

sodium; Magnesium stearate; Silica,

colloidal anhydrous.

Each tablet contains approximately

0.46 mg sodium.

Tegretol Syrup 2%:

Polyethylene glycol 400 stearate;

Saccharin sodium; Hydroxyethyl cellulose;

dispersible cellulose (Microcrystalline

cellulose+Sodium CMC); Sorbitol liquid;

Propylene

glycol;

Methylparaben;

Propylparaben; Sorbic acid; Caramel

aroma 52929A; Purified water.

5 ml syrup contains 2 mg saccharin

sodium,

liquid

sorbitol,

approximately 0.6 mg sodium and

preservatives:

Methylparaben 6 mg, Propylparaben 1.5

mg, Sorbic acid 5 mg.

How does the medicine look like

and what are the contents of the

package

Tegretol CR 200 mg:

Beige-orange, oval, slightly biconvex

tablet. H/C imprinted on one side and

C/G on the other side. Score line on both

sides.

Marketed in a pack of 50 tablets.

Tegretol CR 400 mg:

Brownish-orange, oval, slightly biconvex

tablet. ENE/ENE imprinted on one side

and CG/CG on the other side. Score line

on both sides.

Marketed in a pack of 30 tablets.

Tegretol 200 mg:

White, round, flat tablet with beveled

edges. The imprint CG on one side, the

imprint G/K and a score line on the other

side.

Marketed in a pack of 50 tablets.

Tegretol Syrup 2% :

White, viscous suspension.

Marketed in a bottle that contains 250

Registration holder and address:

Novartis Israel Ltd., 36 Shacham St.,

Petach-Tikva.

Manufacturer and address: Tegretol

200 mg, Tegretol CR 200 mg, Tegretol

CR 400 mg: Novartis Farma SpA, Torre

Annunziata, Italy, for Novartis Pharma

AG, Basel, Switzerland.

Tegretol Syrup 2%: Delpharm Huningue

SAS, Huningue, France, for Novartis

Pharma AG, Basel, Switzerland.

This leaflet was checked and approved by

the Ministry of Health in July 2014.

Registration numbers of the medicine in

the National Drug Registry of the Ministry

of Health:

Tegretol CR 200 mg Tablets:

041-24-25416

Tegretol CR 400 mg Tablets:

041-23-25417

Tegretol 200 mg Tablets:

015-41-24602

Tegretol Syrup 2%:

022-90-24971

SH TEG APL JUL14 CL V6 COR CPO CL

SH TEG APL JUL14 CL V6 COR CPO CL

:ﺹﺮﻘﻟﺍ ﺀﻼﻃ :ﻎﻠﻣ ٢٠٠ ﻝﻮﺘﻳﺮﭽﺗ .ﻡﻮﻳﺩﻮﺻ ﻎﻠﻣ ٠٫٤٦ ﻲﻟﺍﻮﺣ ﻰﻠﻋ ﺹﺮﻗ ﻞﻛ ﻱﻮﺘﺤﻳ :٪٢ ﺏﺍﺮﺷ ﻝﻮﺘﻳﺮﭽﺗ ،ﻡﻮﻳﺩﻮﺼﻟﺍ ﻦﻳﺭﺎﻜﺳ ﻎﻠﻣ ٢ ﻰﻠﻋ ﻱﻮﺘﺤﺗ ﺏﺍﺮﺷ ﻞﻠﻣ ٥ ﻡﻮﻳﺩﻮﺻ ﻎﻠﻣ ٠٫٦ ﻲﻟﺍﻮﺣ ،ﻞﺋﺎﺳ ﻝﻮﺘﻴﺑﺭﻮﺳ ﻎﻠﻣ ٨٧٥ :ﺔﻈﻓﺎﺣ ﺩﺍﻮﻣﻭ ﺔﺒﻠﻌﻟﺍ ﻯﻮﺘﺤﻣ ﻮﻫ ﺎﻣﻭ ﺀﺍﻭﺪﻟﺍ ﻭﺪﺒﻳ ﻒﻴﻛ :ﻎﻠﻣ ٢٠٠

ﻝﻮﺘﻳﺮﭽﺗ ﻦﻣ

ﻼﻴﻠﻗ ﺏﺪﺤﻣ ،ﻱﻮﻀﻴﺑ ،ﺞﻴﺑ ـ ﻲﻟﺎﻘﺗﺮﺑ ﻪﻧﻮﻟ ﺹﺮﻗ

،ﺪﺣﺍﻭ ﺐﻧﺎﺟ ﻦﻣ

ﻪﻴﻠﻋ ﻉﻮﺒﻄﻣ .ﻦﻴﺒﻧﺎﺠﻟﺍ .ﻦﻴﺒﻧﺎﺠﻟﺍ ﻦﻣ ﺮﻄﺸﻠﻟ ﻂﺧ ،ﻲﻧﺎﺜﻟﺍ ﺐﻧﺎﺠﻟﺍ ﻦﻣ

ﺎﺻﺮﻗ ٥٠ ﺕﺍﺫ ﺔﺒﻠﻌﺑ ﻕ

ﻮﺴﻣ :ﻎﻠﻣ ٤٠٠

ﻝﻮﺘﻳﺮﭽﺗ

ﻼﻴﻠﻗ ﺏﺪﺤﻣ ،ﻱﻮﻀﻴﺑ ،ﻲﻨﺑ ـ ﻲﻟﺎﻘﺗﺮﺑ ﻪﻧﻮﻟ ﺹﺮﻗ ﺐﻧﺎﺟ ﻦﻣ

ENE/ENE

ﻪﻴﻠﻋ ﻉﻮﺒﻄﻣ .ﻦﻴﺒﻧﺎﺠﻟﺍ ﻦﻣ ﺮﻄﺸﻠﻟ ﻂﺧ ،ﻲﻧﺎﺜﻟﺍ ﺐﻧﺎﺠﻟﺍ ﻦﻣ

CG/CG

،ﺪﺣﺍﻭ .ﻦﻴﺒﻧﺎﺠﻟﺍ ﻦﻣ

ﺎﺻﺮﻗ ٣٠ ﺕﺍﺫ ﺔﺒﻠﻌﺑ ﻕ

ﻮﺴﻣ :ﻎﻠﻣ ٢٠٠ ﻝﻮﺘﻳﺮﭽﺗ .ﺔﻠﺋﺎﻣ ﻑﺍﺮﻃﺃ ﻭﺫ ،ﺢﻄﺴ

ﻣ ،ﺮﻳﺪﺘﺴﻣ ،ﺾﻴﺑﺃ ﺹﺮﻗ ﺐﻧﺎﺠﻟﺍ ﻦﻣ

،ﺪﺣﺍﻭ ﺐﻧﺎﺟ ﻦﻣ

ﻪﻴﻠﻋ ﻉﻮﺒﻄﻣ .ﺮﻄﺸﻠﻟ ﻂﺧﻭ ﻲﻧﺎﺜﻟﺍ

ﺎﺻﺮﻗ ٥٠ ﺕﺍﺫ ﺔﺒﻠﻌﺑ ﻕ

ﻮﺴﻣ :٪٢ ﺏﺍﺮﺷ ﻝﻮﺘﻳﺮﭽﺗ .ﺾﻴﺑﺃ ،ﺝﺰﻟ ﻖﻠﻌﻣ .ﻞﻠﻣ ٢٥٠ ﻱﻮﺤﺗ ﺔﻨﻴﻨﻗ ﻦﻤﺿ ﻕ

ﻮﺴﻣ :ﻪﻧﺍﻮﻨﻋﻭ ﺯﺎﻴﺘﻣﻹﺍ ﺐﺣﺎﺻ ﻡﺎﺣﺎﺷ ﻉﺭﺎﺷ ،.ﺽ.ﻡ ﻞﻴﺋﺍﺮﺳﺇ ﺲﻴﺗﺭﺎﭬﻮﻧ .ﺎﭭﻜﺗ ـ ﺢﺘﻴﭘ ،٣٦ :ﻪﻧﺍﻮﻨﻋﻭ ﺞﺘﻨﻤﻟﺍ ﻢﺳﺇ ﻝﻮﺘﻳﺮﭽﺗ ،ﻎﻠﻣ ٢٠٠

ﻝﻮﺘﻳﺮﭽﺗ ،ﻎﻠﻣ ٢٠٠ ﻝﻮﺘﻳﺮﭽﺗ ،.ﻱﺇ .ﻲﭘ .ﺱﺇ ﺎﻣﺭﺎﻓ ﺲﻴﺗﺭﺎﭬﻮﻧ :ﻎﻠﻣ ٤٠٠

ﺎﻣﺭﺎﻓ ﺲﻴﺗﺭﺎﭬﻮﻧ ﻞﺟﺃ ﻦﻣ ﺎﻴﻟﺎﻄﻳﺇ ،ﺎﺗﺎﻳﺰﻧﻮﻧﺃ ﻱﺭﻮﺗ .ﺍﺮﺴﻳﻮﺳ ،ﻝﺯﺎﺑ ،ﻲﺟ ﻲﻳﺍ ،.ﺱﺇ.ﻱﺇ .ﺱﺇ ﭻﻨﻴﻧﻮﻫ ﻡﺭﺎﻔﻠﻳﺩ :٪٢ ﺏﺍﺮﺷ ﻝﻮﺘﻳﺮﭽﺗ ،ﻲﺟ ﻲﻳﺍ ﺎﻣﺭﺎﻓ ﺲﻴﺗﺭﺎﭬﻮﻧ ﻞﺟﺃ ﻦﻣ ﺎﺴﻧﺮﻓ ،ﭻﻨﻴﻧﻮﻫ .ﺍﺮﺴﻳﻮﺳ ،ﻝﺯﺎﺑ ﺎﻫﺍﻮﺘﺤﻣﻭ ﺓﺮﺸﻨﻟﺍ ﻩﺬﻫ ﺔﻐﻴﺻ ﺔﺤﺼﻟﺍ ﺓﺭﺍﺯﻭ ﺕﺮﻗﺃ ٢٠١٤ ﺯﻮﻤﺗ :ﺦﻳﺭﺎﺗ ﻲﻓ ﺺﺧ

ﺭﻭ ﺺﺤ

ﻲﻣﻮﻜﺤﻟﺍ ﺔﻳﻭﺩﻷﺍ ﻞﺠﺳ ﻲﻓ ﺀﺍﻭﺪﻟﺍ ﻞﺠﺳ ﻢﻗﺭ :ﺔﺤﺼﻟﺍ ﺓﺭﺍﺯﻭ ﻲﻓ :ﺹﺍﺮﻗﺃ ﻎﻠﻣ ٢٠٠

CR

ﻝﻮﺘﻳﺮﭽﺗ ٠٤١-٢٤-٢٥٤١٦ :ﺹﺍﺮﻗﺃ ﻎﻠﻣ ٤٠٠

CR

ﻝﻮﺘﻳﺮﭽﺗ ٠٤١-٢٣-٢٥٤١٧ :ﺹﺍﺮﻗﺃ ﻎﻠﻣ ٢٠٠ ﻝﻮﺘﻳﺮﭽﺗ ٠١٥-٤١-٢٤٦٠٢ : ٪٢ ﺏﺍﺮﺷ ﻝﻮﺘﻳﺮﭽﺗ ٠٢٢-٩٠-٢٤٩٧١ ﻩﺬﻫ ﺔﻏﺎﻴﺻ ﺖﻤﺗ ،ﺓﺀﺍﺮﻘﻟﺍ ﻦﻳﻮﻬﺗﻭ ﺔﻟﻮﻬﺳ ﻞﺟﺃ ﻦﻣ ﻥﺈﻓ ،ﻚﻟﺫ ﻦﻣ ﻢﻏﺮﻟﺍ ﻰﻠﻋ .ﺮﻛﺬﻤﻟﺍ ﺔﻐﻴﺼﺑ ﺓﺮﺸﻨﻟﺍ .ﻦﻴﺴﻨﺠﻟﺍ ﻼﻜﻟ ﺺﺼﺨﻣ ﺀﺍﻭﺪﻟﺍ

Hypromellose; Talc; Titanium dioxide;

Castor oil, polyoxyl hydrogenated; Iron

oxide yellow; Iron oxide red.

Cellulose microcrystalline; Carmellose

sodium; Magnesium stearate; Silica,

colloidal anhydrous.

Polyethylene glycol 400 stearate;

Saccharin sodium; Hydroxyethyl cellulose;

dispersible cellulose (Microcrystalline

cellulose+Sodium CMC); Sorbitol liquid;

Propylene glycol; Methylparaben;

Propylparaben; Sorbic acid; Caramel

aroma 52929A; Purified water.

Methylparaben 6 mg, Propylparaben

1.5 mg, Sorbic acid 5 mg

Hormonal contraception (birth control

pills) may be less effective and therefore,

other forms of contraception should be

considered. This is detailed in the section

‘Special warnings regarding use of the

medicine’.

!

Use of Tegretol and food

Do not drink grapefruit juice or eat

grapefruit since this can increase the

effect of Tegretol. Other juices, such as

orange juice or apple juice, do not have

this effect.

!

Use of Tegretol and alcohol

consumption

Do not drink alcohol while under

treatment with Tegretol.

!

Children and older people

Tegretol may be safely used in children

and in elderly patients, when keeping to

the doctor’s instructions. As necessary,

special information will be given, such

as the need for carefully adjusting the

dosage and close supervision (see

also section 3 ‘How should you use the

medicine’ and section 4 ‘Side Effects’).

!

Pregnancy

Tell your doctor if you are pregnant or

plan to become pregnant.

It is important to control epileptic

seizures during pregnancy. However,

there is a possible risk to your baby if

you take antiepileptic medication during

pregnancy. Your doctor will explain to

you the potential risk of taking Tegretol

during pregnancy.

Do not stop treatment with Tegretol

during pregnancy without consulting

with your doctor.

If you were exposed to this medicine

during pregnancy, especially during

the first trimester, you must consult a

doctor in order to evaluate the risk of

fetal damage.

!

Breast-feeding

Tell your doctor if you are breast-

feeding.

The active ingredient in Tegretol passes

into the breast milk. As long as your doctor

agrees and your baby is closely watched

for side effects, you may breast-feed.

However, if side effects appear, e.g. if

your baby gets very sleepy, stop breast-

feeding and tell your doctor.

!

Women of child-bearing potential

Irregularity of the menstrual period

may occur in women taking hormonal

contraceptives (birth control pills) and

Tegretol. For further information, see the

section ‘Special warnings regarding use

of the medicine’.

!

Driving and using machines

Tegretol may cause sleepiness, dizziness,

blurred vision, double vision or lack of

muscular coordination especially when

starting treatment or increasing the dose.

Therefore, caution must be exercised

when driving a car, operating machinery

or during any activity which requires

alertness. Children should be cautioned

about riding a bicycle or playing near the

street, and the like.

!

Important information about some

of the medicine’s ingredients

Tegretol Syrup:

One ml of Tegretol syrup contains 175

mg of sorbitol. When taken according

to the dosage recommendations, the

maximum daily dose contains 17.5 g of

sorbitol. Sorbitol may cause abdominal

discomfort and diarrhoea. Do not use this

preparation if you have rare hereditary

problems of fructose intolerance.

Te g r e t o l

s y r u p

c o n t a i n s

parahydroxybenzoates which may cause

allergic reactions (possibly delayed).

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.

Be sure to take this medicine regularly and

exactly as your doctor instructed. This will

help you to get the best results and reduce

the chance of serious side effects.

Do not increase the dose, the frequency

of taking the medicine or the duration

of treatment from what was instructed

by the doctor.

Dosage

The dosage and manner of treatment will

be determined by the doctor only.

Do not exceed the recommended

dose.

Manner of Administration

Tegretol is always given (except possibly

on the first day) in divided daily doses.

Take the medicine during or after a

meal.

Tablets: Do not chew! Swallow the

medicine with some water. If necessary,

the tablets can be halved along the score

line.

Syrup: Shake well before use.

Directions for using the preparation

– general instructions

With liquid medicines, you must use a

measuring spoon, syringe or dropper

meant for measuring the correct dose

of medicine.

If a spoon or other measuring device was

not attached to the package, consult the

pharmacist.

Do not use a household spoon to measure

the amount of the medicine. Household

spoons differ in size and you may not get

the correct amount of medicine.

Child-resistant caps have significantly

reduced the number of cases of

medicine-induced poisoning each year.

However, if you find it difficult to open

the bottle, you can ask the pharmacist

to remove the safety mechanism in the

cap and make it into a regular easy-open

cap.

Tests and follow-up

It is very important that your doctor

checks your progress at regular visits.

The doctor may take periodic blood

tests, especially when you start taking

the medicine. This is quite usual and

nothing to worry about.

Before and during treatment with this

medicine, the following tests should be

conducted: urine, liver and kidney function,

and also, general blood count including

platelets and iron levels in the blood.

During treatment, testing of carbamazepine

and calcium levels in the blood should

be performed. The risk of serious skin

reactions in patients of Chinese or Thai

origin associated with carbamazepine

or similar chemical compounds can be

detected by testing a blood sample of

these patients. The doctor will advise

whether the blood test is necessary before

starting treatment with Tegretol.

If you forget to take Tegretol

If you forget to take a dose, take it as

soon as you remember. However, if it is

almost time for your next dose, do not

take the missed one; just go back to

your regular dosing timetable. Do not

take a double dose to make up for the

forgotten dose.

Be sure to adhere to the treatment as

recommended by the doctor.

Taking more Tegretol than required

If you have accidentally taken too much

of the medicine, refer to your doctor

straight away. You may require medical

attention.

If you experience difficulty in breathing,

a fast and irregular heart rate, loss of

consciousness, fainting, shakiness,

nausea and/or vomiting, your dose may

be too high. Stop taking the medicine and

refer to your doctor immediately.

If you took 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.

Stopping treatment

Do not suddenly stop treatment with the

medicine without consulting the doctor,

in order to prevent sudden worsening

of seizures.

The doctor will tell you whether and how

to stop treatment with the medicine (see

‘Special warnings regarding use of the

medicine’).

Additional instructions

If you are about to undergo any kind of

surgery, including dental or emergency

treatment, or any procedure that requires

anesthesia, tell the attending doctor that

you are taking Tegretol.

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 a doctor or

pharmacist.

4. SIDE EFFECTS

As with any medicine, use of Tegretol

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.

Most of the side effects are mild to

moderate and usually disappear after a

few days of treatment.

Some effects could be serious

(These side effects may affect up to 1 in

every 1,000 patients)

If you experience one or more of

the following side effects, check

with your doctor immediately or

make sure that someone else will

do this for you. These effects may

be early signs of serious damage to

your blood system, liver, kidneys or

other organs and may need urgent

medical treatment.

Fever, sore throat, rash, ulcers in the

mouth, swollen glands or catching

infections more easily than usual (signs

of lack of white blood cells).

Fatigue, headache, shortness of breath

during physical activity, dizziness;

paleness, frequent infections leading to

fever, chills, sore throat or mouth ulcers;

bleeding or bruising more easily than

normal, nose bleeds (signs of lack of all

types of blood cells).

Red blotchy rash mainly on the face

which may be accompanied by fatigue,

fever, nausea, loss of appetite (signs of

systemic lupus erythematosus).

Yellowing of the white of the eyes or of

the skin (signs of hepatitis).

Dark urine (sign of porphyria or

hepatitis)

Severely decreased urine output due to

kidney disorders, blood in the urine.

Severe

upper

abdominal

pain,

vomiting, loss of appetite (signs of

pancreatitis).

Skin rash, redness of the skin, blistering

of the lips, eyes or mouth, skin peeling,

accompanied by fever, chills, headache,

cough, body pain (signs of serious skin

reactions).

Swelling of the face, eyes, or tongue,

difficulty swallowing, wheezing, hives

and generalized itching, rash, fever,

abdominal cramps, chest discomfort

or tightness, difficulty breathing, loss

of consciousness (signs of angioedema

and severe allergic reactions).

Lethargy, confusion, muscle twitching

or significant worsening of convulsions

(symptoms that may be linked to low

sodium levels in the blood).

Fever, nausea, vomiting, headache,

stiff neck and extreme sensitivity to

bright light (signs of meningitis).

Muscle stiffness, high fever, altered

consciousness, high blood pressure,

excessive

salivation

(signs

neuroleptic malignant syndrome)

Irregular heart rate, chest pain.

Disturbed consciousness, fainting.

Diarrhea, abdominal pain and fever

(signs of an inflammation of the colon).

The frequency of this side effect is

unknown.

If you experience any of these, refer to

the doctor straight away.

Other side effects

If you experience one or more of

the following side effects contact

the doctor as soon as possible,

since medical supervision may be

necessary:

Very common (these side effects may

affect more than 1 in 10 patients):

Loss of muscle coordination, inflammation

of the skin with itchy rash and redness,

itchy rash.

Common (these side effects may affect

up to 1 in every 10 patients):

Swelling of the ankles, feet or lower legs

(edema), changes in behavior, confusion,

weakness, increase in seizures (fits, due

to insufficient amount of sodium in your

body).

PATIENT PACKAGE INSERT

IN ACCORDANCE WITH THE

PHARMACISTS’ REGULATIONS

(PREPARATIONS) – 1986

The medicine is dispensed

with a doctor’s prescription only

TEGRETOL CR

200 mg

Slow Release Tablets

Active ingredient:

Each tablet contains:

Carbamazepine 200 mg

TEGRETOL CR

400 mg

Slow Release Tablets

Active ingredient:

Each tablet contains:

Carbamazepine 400 mg

TEGRETOL

200 mg

Tablets

Active ingredient:

Each tablet contains:

Carbamazepine 200 mg

TEGRETOL

Syrup 2%

Syrup

Active ingredient:

Each 5 ml contains:

Carbamazepine 100 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.

1. WHAT IS THE MEDICINE INTENDED

FOR?

Tegretol is used to treat certain types of

seizures (epilepsy), to treat trigeminal

neuralgia (a sharp recurring pain in the

face), to treat diabetes insipidus, to treat

mania disorder and to prevent manic

depression (bipolar mood disorders).

Therapeutic group:

Antiepileptic, neurotropic, psychotropic.

Do not use this medicine for common

pain.

Epilepsy is a disorder characterized by

two or more seizures. Seizures occur

when messages from the brain to the

muscles are not properly passed on by

the nerve pathways. Tegretol helps to

control the passing-on of these messages.

Tegretol also regulates nerve function for

the other diseases mentioned above.

2. BEFORE USING THE MEDICINE

You may only take Tegretol after a full

medical examination.

X

Do not use the medicine if:

you are allergic (hypersensitive)

carbamazepine

other

structurally similar medicines (such

as oxcarbazepine and tricyclic anti-

depressants) or to any of the other

ingredients of the medicine listed in

section 6 ‘Further Information’.

you have atrioventricular block.

you suffer or have suffered from bone

marrow suppression or a serious blood

disease.

you have a disturbance in the production

of porphyrin, a pigment important for

liver function and blood formation (also

called ‘hepatic porphyria’).

you are taking medicines belonging

to a certain group of antidepressants

called monoamine-oxidase inhibitors

(MAOIs).

If this applies to you, tell your doctor

before taking Tegretol.

If you think you may be allergic, ask

your doctor for advice.

Special warnings regarding use of

the medicine:

!

Before treatment with Tegretol, tell

the doctor if:

you have blood illnesses (including

those caused by other drugs).

you have ever shown unusual sensitivity

(rash or any other sign of allergy) to

oxcarbazepine or to any other medicine.

It is important to know that if you are

allergic to carbamazepine, the chances

are approximately 1 in 4 (25%) that you

could also have an allergic reaction to

oxcarbazepine (Trileptin).

you have or have had heart, liver or

kidney disease in the past.

you have increased pressure in the eye

(glaucoma) or if you cannot retain your

urine.

you were told by your attending

doctor that you suffer from a mental

disorder called psychosis that may

be accompanied by confusion or

agitation.

you are taking hormonal contraceptives

(birth control pills). Tegretol may render

these contraceptives ineffective.

Therefore, you should use a different

or additional non-hormonal method

of contraception while you are taking

Tegretol. This should help to prevent an

unwanted pregnancy.

Inform your doctor immediately if you

experience unusual vaginal bleeding

or spotting. If you have any questions

about this, ask your doctor or health

care professional.

Inform the doctor immediately about

any of the following effects:

If an allergic reaction happens such as

fever with swelling of the lymph nodes,

skin rash or blistering, tell your doctor

immediately or go to the emergency

room at your nearest hospital (see ‘Side

effects’).

Serious skin reactions (such as Stevens-

Johnson Syndrome and toxic epidermal

necrolysis) have been reported (rarely)

during use of Tegretol. The rash is

usually accompanied by mouth,

throat, nose and genital ulcers and

conjunctivitis (red and swollen eyes).

These serious skin reactions usually

appear after flu-like symptoms, fever,

headache and body pain. The rash

may progress to blistering and peeling

of skin. During the first months of

treatment, the risk of serious skin

reactions is increased.

Serious skin reactions are more frequent

in patients of Asian origin. The risk can

be checked by blood tests in patients

of this origin (e.g. Taiwan, Malaysia and

The Philippines).

If a rash or one of these skin reactions

develops, stop using Tegretol and tell

your doctor immediately or go to the

emergency room at the hospital.

If you experience an increase in the

number of seizures, refer to your doctor

immediately.

If you notice symptoms of hepatitis,

such as jaundice (yellowing of skin

and eyes), refer to your doctor

immediately.

If at any time you have thoughts of

harming or killing yourself. A small

number

people

treated

with

antiepileptics have had such thoughts

and behaviour.

If you have kidney problems associated

with low blood sodium levels or if you

have kidney problems and you are also

taking certain medicines that lower

blood sodium levels (diuretics such as

hydrochlorothiazide, furosemide).

Do not stop your treatment with Tegretol

without first checking with the doctor.

To prevent sudden worsening of the

seizures, do not discontinue your

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,

inform the doctor if you are taking:

a n a l g e s i c s

t h a t

c o n t a i n

dextropropoxyphene, tramadol or

methadone;

analgesics and anti-inflammatory drugs,

e.g. ibuprofen, paracetamol;

androgens, e.g. danazol;

tetracycline

antibiotics,

e.g.

doxycycline or macrolide antibiotics,

e.g. erythromycin, troleandomycin,

josamycin, clarithromycin;

antidepressants, e.g. desipramine,

fluoxetine, fluvoxamine, nefazodone,

paroxetine, trazodone, viloxazine;

antiepileptic drugs, especially phenytoin,

oxcarbazepine or phenobarbital but

also: stiripentol, vigabatrin, clobazam,

clonazepam, ethosuximide, primidone,

and valproic acid;

azole antifungals, e.g. itraconazole,

ketoconazole, fluconazole, voriconazole;

antihistamines: loratadine, terfenadine;

antipsychotic medicines: loxapine,

olanzapine, quetiapine, clozapine or

risperidone;

antituberculosis medicines: isoniazid,

rifampicin;

antivirals: protease inhibitors for HIV

treatment (e.g. ritonavir);

carbonic

anhydrase

inhibitors:

acetazolamide;

heart medicines, e.g. calcium channel

blockers

(diltiazem,

verapamil),

digoxin;

medicines for the digestive system, e.g.

cimetidine, omeprazole;

muscle relaxants, e.g. oxybutynin,

dantrolene;

Platelet aggregation inhibitors, e.g.

ticlopidine;

antiasthmatic

preparations,

e.g.

theophylline and aminophylline;

herbal preparations containing St. John’s

wort;

anticoagulants,

e.g.

warfarin,

p h e n p ro c o u m o n ,

d i c o u m a ro l ,

acenocoumarol;

antineoplastics: imatinib;

hormonal contraceptives; medicines

containing oestrogens/progesterones;

lithium, metoclopramide;

neuroleptic medicines, e.g. haloperidol,

thioridazine;

corticosteroids, e.g. prednisolone,

dexamethasone;

thyroid medicines: levothyroxine;

immunosuppressants, e.g. cyclosporine,

everolimus;

diuretics:

hydrochlorothiazide,

furosemide;

isotretinoin;

nicotinamide;

antimalarials, e.g., mefloquine;

a n t i - w o r m

m e d i c i n e s ,

e . g . ,

praziquantel.

It is possible that there will be a need

to change the dosage or occasionally to

stop taking one of the medicines.

Page 1

TEG API JUL14 CL V5

COR CPO MoH

CDS 210313

הנוממה תחקורה תרהצה

:

םידיחיה םייונישה םניה הז ןולעב םינמוסמה םייונישה יכ תאזב הריהצמ ינא

ההז ןולעה םדבלמו רשואש ןולעל ילויב

2014

לע

תואירבה דרשמ ידי

ןולעב םיעיפומה רישכתה יטרפ לכ תוכיאה תודועתבו םושירה תודועתב םושרה תא םימאות תוינכדעה

.

םדוקה ומשב םושירה לעב עיפומ תוכיאה תודועתב

ג ייא ססיורס המראפ סיטרבונ

המיתח

________________________ :

םושירה לעב

עב לארשי סיטרבונ

"

הנוממ תחקור

טמרופ ע עבקנ הז ןולע

"

רשואו קדבנ ונכותו תואירבה דרשמ י

לע

ודי

ילוי

2014

TEGRETOL

®

(carbamazepine)

200 mg tablets

200 mg and 400 mg CR tablets

100 mg / 5 mL

syrup

Prescribing Information

1

Trade name

TEGRETOL

200 mg tablets

TEGRETOL

CR 200 mg (slow release film-coated tablets)

TEGRETOL

CR 400 mg (slow release film-coated tablets)

TEGRETOL

syrup 2%

2

Description and composition

Pharmaceutical forms

Tablets: 200 mg carbamazepine.

CR tablets: (slow release film-coated tablets, divisible): 200 mg and 400 mg carbamazepine.

Syrup: 5 mL (= 1 measure) contain 100 mg carbamazepine.

Active substance:

Carbamazepine.

Excipients

Tablets:

Davidovich

Roni

Digitally signed by Davidovich Roni

DN: SERIALNUMBER=872416 +

CN=Davidovich Roni, OU=PH,

OU=people, DC=novartis, DC=com

Reason: I am approving this document.

Date: 2016.01.10 15:24:32 +02:00

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TEG API JUL14 CL V5

COR CPO MoH

CDS 210313

Cellulose microcrystalline; carmellose sodium, low substituted; magnesium stearate; silica, colloidal

anhydrous.

Each tablet contains approximately 0.46 mg sodium.

CR tablets:

Cellulose microcrystalline; carboxymethylcellulose sodium; polyacrylate dispersion 30%; ethylcellulose

aqueous dispersion; talc; silica colloidal anhydrous; magnesium stearate. Film coating: hypromellose; talc;

titanium dioxide (C.I. No. 77891, E171); castor oil, polyoxyl hydrogenated; iron oxide yellow (C.I. No.

77492, E172); iron oxide red (C.I. No. 77491, E172).

Each CR 200 mg tablet contains approximately 2.3 mg sodium.

Each CR 400 mg tablet contains approximately 4.6 mg sodium.

Syrup:

Polyethylene glycol 400 stearate (macrogol stearate); saccharin sodium; hydroxyethylcellulose 300 mPa s

(HEC 250); dispersible cellulose (microcrystalline cellulose and carboxymethylcellulose sodium); sorbitol

liquid (sorbitol 70% non crystallising); propylene glycol; methylparaben (methylparahydroxybenzoate);

propylparaben (propylparahydroxybenzoate); sorbic acid; caramel aroma 52929A; water purified.

5 ml syrup contains 2 mg saccharin sodium, 875 mg liquid sorbitol, approximately 0.6 mg sodium and

preservatives: Methylparaben 6 mg, Propylparaben 1.5 mg, Sorbic acid 5 mg.

3

Indications

Epilepsy, Trigeminal neuralgia, Diabetes insipidus, Mania, prophylactic in manic-depressive illness.

4

Dosage and administration

Epilepsy

When possible, Tegretol should be prescribed as monotherapy.

Treatment should be initiated with a low daily dosage, to be slowly increased until an optimal effect is

obtained.

The dose of carbamazepine should be adjusted to the needs of the individual patient to achieve adequate

control of seizures. Determination of plasma levels may help in establishing the optimum dosage. In the

treatment of epilepsy, the dose of carbamazepine usually requires total plasma-carbamazepine concentrations

of about 4 to 12 micrograms/mL (17 to 50 micromoles/liter) (see section 6 Warnings and precautions).

When Tegretol is added to existing antiepileptic therapy, this should be done gradually while maintaining, or

if necessary, adapting the dosage of the other antiepileptic(s) (see sections 8 Interactions and 11 Clinical

pharmacology - Pharmacokinetics).

General target population / Adults

Dosage in Epilepsy

Oral forms:

Initially, 100 to 200 mg once or twice daily; the dosage should be slowly raised until – generally at 400 mg 2

to 3 times daily – an optimum response is obtained. In some patients 1600 mg or even 2000 mg daily may be

appropriate.

Page 3

TEG API JUL14 CL V5

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CDS 210313

Dosage in Acute mania and maintenance treatment of bipolar affective disorders

Dosage range: about 400 to 1600 mg daily, the usual dosage being 400 to 600 mg daily given in 2 to 3 divided

doses. In acute mania, the dosage should be increased rather quickly, whereas small dosage increments are

recommended for maintenance therapy of bipolar disorders in order to ensure optimal tolerability.

Dosage in Trigeminal neuralgia

The initial dosage of 200 to 400 mg should be slowly raised daily until freedom from pain is achieved

(normally at 200 mg 3 to 4 times daily). The dosage should then be gradually reduced to the lowest possible

maintenance level. Maximum recommended dose is 1200 mg/day. When pain relief has been obtained,

attempts should be made to gradually discontinue therapy, until another attack occurs.

Dosage in Diabetes insipidus centralis

Average dosage for adults: 200 mg 2 to 3 times daily. In children the dosage should be reduced proportionally

to the child's age and body weight.

Special populations

Renal impairment / Hepatic impairment

No data are available on the pharmacokinetics of carbamazepine in patients with impaired hepatic or renal

function.

Pediatrics / Children and adolescents

Dosage in Epilepsy

Oral forms:

For children aged 4 years or less, a starting dose of 20 to 60 mg/day, increasing by 20 to 60 mg every second

day, is recommended. For children over the age of 4 years, therapy may begin with 100 mg/day, increasing at

weekly intervals by 100 mg.

Maintenance dosage: 10 to 20 mg/kg body weight daily in divided doses, e.g.

Up to 1 year of age:

100 to 200 mg daily (= 5 to 10mL = 1-2 measures of syrup)

1 to 5 years of age:

200 to 400 mg daily (= 10 to 20 mL = 2

1-2 measures of syrup)

6 to 10 years of age:

400 to 600 mg daily (= 20 to 30 mL = 2-3

2 measures of syrup)

11 to 15 years of age:

600 to 1000 mg daily (= 30 to 50 mL = 3

2-3 measures of syrup (plus an extra

measure of 5 mL in case of administration of 1000 mg))

>15 years of age:

800 to 1200 mg daily (same as adult dose)

Maximum recommended dose

Up to 6 years of age: 35 mg/kg/day

6-15 years of age: 1000 mg/day

>15 years of age: 1200 mg/day.

Dosage in Diabetes insipidus centralis

In children the dosage should be reduced proportionally to the child's age and body weight. Average dosage

for adults: 200 mg 2 to 3 times daily.

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CDS 210313

Geriatrics

Dosage in Trigeminal neuralgia

Due to drug interactions and different antiepileptic drug pharmacokinetics, the dosage of Tegretol should be

selected with caution in elderly patients.

In elderly patients, an initial dose of 100 mg twice daily is recommended. The initial dosage of 100 mg twice

daily should be slowly raised daily until freedom from pain is achieved (normally at 200 mg 3 to 4 times

daily). The dosage should then be gradually reduced to the lowest possible maintenance level. Maximum

recommended dose is 1200 mg/day. When pain relief has been obtained, attempts should be made to gradually

discontinue therapy, until another attack occurs.

Method of administration

The tablets and the syrup (to be shaken before use) may be taken during, after, or between meals. Tablets

should be taken with a little liquid.

The CR tablets (either whole or, if so prescribed, only half a tablet) should be swallowed unchewed with a

little liquid. The syrup (one measure = 5 mL = 100 mg; half a measure = 2.5 mL = 50 mg) is particularly

suitable for patients who have difficulty in swallowing tablets or need initial careful adjustment of the dosage.

As a result of slow, controlled release of the active substance from the CR tablets, these are designed to be

taken in a twice-daily dosage regimen.

Since a given dose of Tegretol syrup will produce higher peak levels than the same dose in tablet form, it is

advisable to start with low doses and increase them slowly so as to avoid adverse reactions.

Switching patients from Tegretol tablets to syrup: this should be done by giving the same number of mg per

day in smaller, more frequent doses (e.g. syrup three times a day (t.i.d.) instead of tablets twice a day (b.i.d)).

Switching patients from conventional tablets to CR tablets: clinical experience shows that in some patients the

dosage in the form of CR tablets may need to be increased.

5

Contraindications

Known hypersensitivity to carbamazepine or structurally related drugs (e.g. tricyclic antidepressants) or

any other component of the formulation

Patients with atrioventricular block

Patients with a history of bone-marrow depression

Patients with a history of hepatic porphyrias (e.g. acute intermittent porphyria, variegate porphyria,

porphyria cutanea tarda)

The use of Tegretol is contraindicated in combination with monoamine-oxidase inhibitors (MAOIs) (8

Interactions)

6

Warnings and precautions

Tegretol should be given only under medical supervision. Tegretol should be prescribed only after a critical

benefit-risk appraisal and under close monitoring in patients with a history of cardiac, hepatic, or renal

damage, adverse haematological reactions to other drugs, or interrupted courses of therapy with Tegretol.

Haematological effects

Agranulocytosis and aplastic anaemia have been associated with Tegretol; however, due to the very low

incidence of these conditions, meaningful risk estimates for Tegretol are difficult to obtain. The overall risk in

Page 5

TEG API JUL14 CL V5

COR CPO MoH

CDS 210313

the general untreated population has been estimated at 4.7 persons per million per year for agranulocytosis and

2.0 persons per million per year for aplastic anaemia.

Transient or persistent decreased platelet or white blood cell counts occur occasionally to frequently in

association with the use of Tegretol. However, in the majority of cases these effects prove transient and are

unlikely to signal the onset of either aplastic anaemia or agranulocytosis. Nonetheless, complete pretreatment

blood counts, including platelets (and possibly reticulocytes and serum iron), should be obtained at baseline,

and periodically thereafter.

If the white blood cell or platelet count is definitely low or decreased during treatment, the patient and the

complete blood count should be closely monitored. Tegretol should be discontinued if any evidence of

significant bone-marrow depression appears.

Patients should be made aware of early toxic signs and symptoms of a potential haematological problem, as

well as symptoms of dermatological or hepatic reactions. If reactions such as fever, sore throat, rash, ulcers in

the mouth, easy bruising, petechial or purpuric haemorrhage appear, the patient should be advised to consult

his physician immediately.

Serious dermatologic reactions

Serious dermatologic reactions, including toxic epidermal necrolysis (TEN; also known as Lyell's syndrome)

and Stevens-Johnson syndrome (SJS), have been reported with Tegretol. Patients with serious dermatological

reactions may require hospitalization, as these conditions may be life-threatening and may be fatal. Most of

the SJS/TEN cases appear in the first few months of treatment with Tegretol. These reactions are estimated to

occur in 1 to 6 per 10,000 new users in countries with mainly Caucasian populations but the risk in some

Asian countries is estimated to be about 10 times higher. If signs and symptoms suggestive of severe skin

reactions (e.g. SJS, Lyell’s syndrome/TEN) appear, Tegretol should be withdrawn at once and alternative

therapy should be considered.

Pharmacogenomics

There is growing evidence of the role of different HLA alleles in predisposing patients to immune-mediated

adverse reactions.

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 of the Human Leukocyte

Antigene (HLA)-B*1502 allele. The frequency of HLA-B*1502 allele ranges from 2 to 12% in Han Chinese

populations and is about 8% in Thai populations. Higher reporting rates of SJS (rare rather than very rare) are

reported in some countries in Asia (e.g. Taiwan, Malaysia and the Philippines) in which there is a higher

frequency of the HLA-B*1502 allele in the population (e.g. 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 of 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 HLA-B*1502 allele should be considered in patients with ancestry in genetically

at-risk populations, prior to initiating treatment with Tegretol (see below Information for the healthcare

professionals). The use of Tegretol 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

SJS/TEN

Chinese

patients

taking

other

anti-epileptic

drugs

(AED)

associated

with

SJS/TEN.

Page 6

TEG API JUL14 CL V5

COR CPO MoH

CDS 210313

Consideration should therefore be given to avoiding use of other drugs associated with SJS/TEN in HLA-

B*1502 positive patients, when alternative therapies are otherwise equally acceptable. Screening is not

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

Screening is generally not recommended for any current Tegretol users, as the risk of SJS/TEN is largely

confined to the first few months of therapy, regardless of HLA-B*1502 status.

The identification of subjects carrying the HLA-B*1502 allele and the avoidance of carbamazepine therapy in

these subjects has been shown to decrease the incidence of carbamazepine-induced SJS/TEN.

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. Retrospective genome-wide

studies in Japanese and Northern European populations reported association between severe skin reactions

(SJS, TEN, DRESS, AGEP and maculopapular rash) associated with carbamazepine use and the presence of

the HLA-A*3101 allele in these patients.

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 5-12%. Prevalence 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%-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.

Testing for the presence of HLA-A*3101 allele should be considered in patients with ancestry in genetically

at-risk populations (for example, patients of the Japanese and Caucasian populations, patients who belong to

the indigenous populations of the Americas, Hispanic populations, people of southern India, and people of

Arabic descent), prior to initiating treatment with Tegretol

(see below

Information for the

healthcare

professionals). The use of Tegretol should be avoided in patients who are found to be positive for HLA-

A*3101, unless the benefits clearly outweigh the risks. Screening is generally not recommended for any

current Tegretol 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 for appropriate clinical vigilance and patient management.

Many Asian patients positive for HLA-B*1502 and treated with Tegretol will not develop SJS/TEN and

patients negative for HLA-B*1502 of any ethnicity can still develop SJS/TEN. Similarly many patients

positive

HLA-A*3101

treated

with

Tegretol

will

develop

SJS,

TEN,

DRESS,

AGEP

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 the health-care professionals

testing

presence

HLA-B*1502

allele

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.

Page 7

TEG API JUL14 CL V5

COR CPO MoH

CDS 210313

Similarly if testing for the presence of the HLA-A*3101 allele is performed, high-resolution “HLA-A*3101

genotyping” respectively 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.

Other dermatologic reactions

Mild skin reactions, e.g. isolated macular or maculopapular exanthema, can also occur and are mostly

transient and not hazardous. They usually disappear within a few days or weeks, either during the continued

course of treatment or following a decrease in dosage. However, since it may be difficult to differentiate the

early signs of more serious skin reactions from mild transient reactions, the patient should be kept under close

surveillance with consideration given to immediately withdrawing the drug should the reaction worsen with

continued use.

The HLA-A*3101 allele has also been found to be associated with less severe adverse cutaneous reactions

from carbamazepine and may predict the risk of these reactions from carbamazepine, such as anticonvulsant

hypersensitivity syndrome or non-serious rash (maculopapular eruption). However, the HLA-B*1502 allele

has not been found to predict the risk of these aforementioned skin reactions.

Hypersensitivity

Tegretol may trigger hypersensitivity reactions, including Drug Rash with Eosinophilia and Systemic

Symptoms (DRESS), a delayed multi-organ hypersensitivity disorder with fever, rash, vasculitis,

lymphadenopathy, pseudo lymphoma, arthralgia, leukopenia, eosinophilia, hepato-splenomegaly, abnormal

liver function tests and vanishing bile duct syndrome (destruction and disappearance of the intrahepatic bile

ducts), that may occur in various combinations. Other organs may also be affected (e.g. lungs, kidneys,

pancreas, myocardium, colon). See section 7 Adverse drug reactions.

The HLA-A*3101 allele has been found to be associated with the occurrence of hypersensitivity syndrome,

including maculopapular rash.

Patients who have exhibited hypersensitivity reactions to carbamazepine should be informed that

approximately 25 to 30 % of these patients may experience hypersensitivity reactions with oxcarbazepine

(Trileptin

Cross-hypersensitivity can occur between carbamazepine and phenytoin.

In general, if signs and symptoms suggestive of hypersensitivity reactions occur, Tegretol should be

withdrawn immediately.

Seizures

Tegretol should be used with caution in patients with mixed seizures which includes absences, either typical

or atypical. In all these conditions, Tegretol may exacerbate seizures. In the event of exacerbation of seizures,

Tegretol should be discontinued.

Hepatic function

Baseline and periodic evaluations of hepatic function must be performed during treatment with Tegretol,

particularly in patients with a history of liver disease and in elderly patients. The drug should be withdrawn

immediately in cases of aggravated liver dysfunction or active liver disease.

Renal function

Baseline and periodic complete urinalysis and BUN determinations are recommended.

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Hyponatremia

Hyponatremia is known to occur with carbamazepine. In patients with pre-existing renal conditions associated

with low sodium or in patients treated concomitantly with sodium-lowering medicinal products (e.g. diuretics,

medicinal products associated with inappropriate ADH secretion), serum sodium levels should be measured

prior

initiating

carbamazepine

therapy.

Thereafter,

serum

sodium

levels

should

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. If hyponatraemia is observed,

water restriction is an important counter-measurement if clinically indicated.

Hypothyroidism

Carbamazepine may reduce serum concentrations of thyroid hormones through enzyme induction requiring an

increase in dose of thyroid replacement therapy in patients with hypothyroidism. Hence thyroid function

monitoring is suggested to adjust the dosage of thyroid replacement therapy.

Anticholinergic effects

Tegretol has shown mild anticholinergic activity. Patients with increased intraocular pressure and urinary

retention should therefore be closely observed during therapy (see section 7 Adverse drug reactions).

Psychiatric effects

The possibility of activation of a latent psychosis and, in elderly patients, of confusion or agitation should be

borne in mind.

Suicidal ideation and behaviour

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

indications. A meta-analysis of randomized placebo controlled trials of antiepileptic drugs has shown a small

increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known.

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

should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should

signs of suicidal ideation or behaviour emerge.

Endocrinological effects

Breakthrough bleeding has been reported in women taking Tegretol while using hormonal contraceptives. The

reliability of hormonal contraceptives may be adversely affected by Tegretol and women of childbearing

potential should be advised to consider using alternative forms of birth control while taking Tegretol.

Monitoring of plasma levels

Although correlations between dosage and plasma levels of carbamazepine, and between plasma levels and

clinical efficacy or tolerability are rather tenuous, monitoring of the plasma levels may be useful in the

following situations: dramatic increase in seizure frequency/verification of patient compliance, during

pregnancy, when treating children or adolescents; in suspected absorption disorders; in suspected toxicity

when more than one drug is being used (see section 8 Interactions).

Dose reduction and withdrawal effects

Abrupt withdrawal of Tegretol may precipitate seizures therefore carbamazepine should be withdrawn

gradually over a 6-month period. If treatment with Tegretol has to be withdrawn abruptly in a patient with

epilepsy, the switch to the new antiepileptic compound should be made under cover of a suitable drug.

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Interactions

Co-administration of inhibitors of CYP3A4 or inhibitors of epoxide hydrolase with carbamazepine can induce

adverse

reactions

(increase

carbamazepine

carbamazepine-10,

epoxide

plasma

concentrations

respectively). The dosage of Tegretol should be adjusted accordingly and/or the plasma levels monitored.

Co-administration

CYP3A4

inducers

with

carbamazepine

decrease

carbamazepine

plasma

concentrations

therapeutic

effect,

while

discontinuation

CYP3A4

inducer

increase

carbamazepine plasma concentrations. The dosage of Tegretol may have to be adjusted.

Carbamazepine is a potent inducer of CYP3A4 and other phase I and phase II enzyme systems in the liver,

and may therefore reduce plasma concentrations of co-medications mainly metabolized by CYP3A4 by

induction of their metabolism. See section 8 Interactions.

Female patients of childbearing potential should be warned that the concurrent use of Tegretol with hormonal

contraceptives may render this type of contraceptive ineffective (see sections 8 Interactions and 9 Women of

child-bearing potential, pregnancy, breast-feeding and fertility). Alternative non-hormonal forms of

contraception are recommended when using Tegretol.

Driving and using machines

The patient's ability to react may be impaired by the medical condition resulting in seizures and adverse

reactions including dizziness, drowsiness, ataxia, diplopia, impaired accommodation and blurred vision

reported with Tegretol, especially at the start of treatment or in connection with dose adjustments. Patients

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

Special excipients

Tegretol syrup contains parahydroxybenzoates which may cause allergic reactions (possibly delayed). It also

contains sorbitol and, therefore, should not be administered to patients with rare hereditary problems of

fructose intolerance.

7

Adverse drug reactions

Summary of the safety profile

Particularly at the start of treatment with Tegretol, or if the initial dosage is too high, or when treating elderly

patients, certain types of adverse reaction occur very commonly or commonly, e.g. CNS adverse reactions

(dizziness, headache, ataxia, drowsiness, fatigue, diplopia); gastrointestinal disturbances (nausea, vomiting),

and allergic skin reactions.

The dose-related adverse reactions usually abate within a few days, either spontaneously or after a transient

dosage reduction. The occurrence of CNS adverse reactions may be a manifestation of relative overdosage or

significant fluctuation in plasma levels. In such cases it is advisable to monitor plasma levels.

Tabulated summary of adverse drug reactions compiled from clinical trials and from

spontaneous reports

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).

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Table

0-1

Adverse drug reactions

Blood and lymphatic system disorders

Very common:

leukopenia.

Common:

thrombocytopenia, eosinophilia.

Rare:

leukocytosis, lymphadenopathy.

Very rare:

agranulocytosis, aplastic anaemia, pancytopenia, aplasia pure red cell,

anaemia, anaemia megaloblastic, reticulocytosis, haemolytic anaemia.

Immune system disorders

Rare:

a delayed multiorgan hypersensitivity disorder with fever, rashes,

vasculitis, lymphadenopathy, pseudo lymphoma, arthralgia,

leukopenia, eosinophilia, hepato-splenomegaly, abnormal liver function

tests and vanishing bile duct syndrome (destruction and disappearance

of the intrahepatic bile ducts), occurring in various combinations. Other

organs may also be affected (e.g. lungs, kidneys, pancreas,

myocardium, colon).

Very rare:

anaphylactic reaction, angioedema, hypogammaglobulinaemia.

Endocrine disorders

Common:

oedema, fluid retention, weight increase, hyponatraemia and blood

osmolarity decreased due to an antidiuretic hormone (ADH)-like effect

leading in rare cases to water intoxication accompanied by lethargy,

vomiting, headache, confusional state, neurological disorders.

Very rare:

galactorrhoea, gynecomastia.

Metabolism and nutrition disorders

Rare:

folate deficiency, decreased appetite.

Very rare:

porphyria acute (acute intermittent porphyria and variegate porphyria),

porphyria non-acute (porphyria cutanea tarda).

Psychiatric disorders

Rare:

hallucinations (visual or auditory), depression, aggression, agitation,

restlessness, confusional state.

Very rare:

activation of psychosis.

Nervous system disorders

Very common:

Ataxia, dizziness, somnolence.

Common:

Diplopia, headache.

Uncommon:

abnormal involuntary movements (e.g. tremor, asterixis, dystonia, tics),

nystagmus.

Rare:

dyskinesia, eye movement disorder, speech disorders (e.g. dysarthria,

slurred speech), choreoathetosis, neuropathy peripheral, paraesthesia,

paresis.

Very rare:

neuroleptic malignant syndrome, aseptic meningitis with myoclonus

and peripheral eosinophilia, dysgeusia.

Eye disorders

Common

accommodation disorders (e.g. blurred vision)

Very rare:

lenticular opacities, conjunctivitis.

Ear and labyrinth disorders

Very rare:

hearing disorders, e.g. tinnitus, hyperacusis , hypoacusis, change in

pitch perception.

Cardiac disorders

Rare:

cardiac conduction disorders.

Very rare:

arrhythmia, atrioventricular block with syncope, bradycardia, cardiac

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failure congestive, coronary artery disease aggravated.

Vascular disorders

Rare:

hypertension or hypotension

Very Rare:

circulatory

collapse,

embolism

(e.g.

pulmonary

embolism),

thrombophlebitis.

Respiratory, thoracic and mediastinal disorders

Very rare:

pulmonary

hypersensitivity

characterized

e.g.

fever,

dyspnoea,

pneumonitis or pneumonia.

Gastrointestinal disorders

Very common:

Vomiting, nausea.

Common:

Dry mouth.

Uncommon:

diarrhoea, constipation.

Rare:

abdominal pain.

Very rare:

pancreatitis, glossitis, stomatitis.

Hepatobiliary disorders

Rare:

hepatitis of cholestatic, parenchymal (hepatocellular) or mixed type,

vanishing bile duct syndrome, jaundice.

Very rare:

hepatic failure, granulomatous liver disease.

Skin and subcutaneous tissue disorders

Very common:

urticaria which may be severe, dermatitis allergic.

Uncommon:

dermatitis exfoliative.

Rare:

systemic lupus erythematosus, pruritus.

Very rare:

Stevens-Johnson syndrome*, toxic epidermal necrolysis,

photosensitivity reaction, erythema multiforme, erythema nodosum,

pigmentation disorder, purpura, acne, hyperhydrosis, alopecia,

hirsutism .

Musculoskeletal, connective tissue and bone disorders

Rare

muscular weakness

Very rare:

bone metabolism disorders (decrease in plasma calcium and blood 25-

hydroxy-cholecalciferol) leading to osteomalacia/osteoporosis,

arthralgia, myalgia, muscle spasms.

Renal and urinary disorders

Very rare:

tubulointerstitial nephritis, renal failure, renal impairment (e.g.

albuminuria, haematuria, oliguria, and blood urea increased/azotemia),

urinary retention, urinary frequency.

Reproductive system

Very rare:

sexual dysfunction/erectile dysfunction, spermatogenesis abnormal

(with decreased sperm count and/or motility).

General disorders and administration site conditions

Very common

fatigue.

Investigations

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Very common:

gamma-glutamyltransferase

increased

(due

hepatic

enzyme

induction), usually not clinically relevant.

Common:

blood alkaline phosphatase increased.

Uncommon:

transaminases increased.

Very rare:

intraocular

pressure

increased,

blood

cholesterol

increased,

high

density lipoprotein increased, blood triglycerides increased. Thyroid

function

test

abnormal:

decreased

L-Thyroxin

(free

thyroxine,

thyroxine, tri-iodothyronine) and increased blood thyroid stimulating

hormone,

usually

without

clinical

manifestations,

blood

prolactin

increased.

* In some Asian countries also reported as rare. See also section 6 Warnings and precautions.

Additional adverse drug reactions from spontaneous reports (frequency not known)

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

Infections and infestations

Reactivation of Human herpesvirus 6 infection.

Blood and lymphatic system disorders

Bone marrow failure.

Nervous system disorders

Sedation, memory impairment.

Gastrointestinal disorders

Colitis.

Immune system disorders

Drug Rash with Eosinophilia and Systemic Symptoms (DRESS).

Skin and subcutaneous tissue disorders

Acute Generalized Exanthematous Pustulosis (AGEP), lichenoid keratosis, onychomadesis.

Musculoskeletal and connective tissue disorders

Fracture.

Investigations

Bone density decreased.

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

on long-term therapy with carbamazepine. The mechanism by which carbamazepine affects bone metabolism

has not been identified.

There is increasing evidence regarding the association of genetic markers and the occurrence of cutaneous

ADRs such as SJS, TEN, DRESS, AGEP and maculopapular rash. In Japanese and European patients, these

reactions have been reported to be associated with the use of carbamazepine and the presence of the HLA-

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A*3101 allele. Another marker, HLA-B*1502 has been shown to be strongly associated with SJS and TEN

among individuals of Han Chinese, Thai and some other Asian ancestry .

8

Interactions

Cytochrome P450 3A4 (CYP3A4) is the main enzyme catalyzing formation of the active metabolite

carbamazepine-10,11-epoxide. Coadministration of inhibitors of CYP3A4 may result in increased

carbamazepine plasma concentrations which could induce adverse reactions. Coadministration of CYP3A4

inducers might increase the rate of carbamazepine metabolism, thus leading to potential decreases in the

carbamazepine serum level and therapeutic effect. Similarly, discontinuation of a CYP3A4 inducer may

decrease the rate of metabolism of carbamazepine, leading to an increase in carbamazepine plasma levels.

Carbamazepine is a potent inducer of CYP3A4 and other phase I and phase II enzyme systems in the liver,

and may therefore reduce plasma concentrations of comedications mainly metabolized by CYP3A4 by

induction of their metabolism.

Human microsomal epoxide hydrolase has been identified as the enzyme responsible for the formation of the

10,11-transdiol derivative from carbamazepine-10,11 epoxide. Co-administration of inhibitors of human

microsomal epoxide hydrolase may result in increased carbamazepine-10,11 epoxide plasma concentrations.

Interactions resulting in a contraindication

The use of Tegretol is contraindicated in combination with monoamine-oxidase inhibitors (MAOIs); before

administering Tegretol MAOIs should be discontinued for a minimum of 2 weeks, or longer if the clinical

situation permits (see section 5 Contraindications).

Agents that may raise carbamazepine plasma levels

Since raised plasma carbamazepine levels may result in adverse reactions (e.g. dizziness, drowsiness,

ataxia, diplopia), the dosage of Tegretol should be adjusted accordingly and/or the plasma levels

monitored when used concomitantly with the substances described below:

Analgesics, anti-inflammatory drugs: dextropropoxyphene, ibuprofen.

Androgens: danazol.

Antibiotics: macrolide antibiotics (e.g. erythromycin, troleandomycin, josamycin, clarithromycin,

ciprofloxacine).

Antidepressants: possibly desipramine, fluoxetine, fluvoxamine, nefazodone, paroxetine, trazodone,

viloxazine.

Antiepileptics: stiripentol, vigabatrin.

Antifungals: azoles (e.g. itraconazole, ketoconazole, fluconazole, voriconazole). Alternative anti-convulsants

may be recommended in patients treated with voriconazole or itraconazole.

Antihistamines: loratadine, terfenadine.

Antipsychotics: olanzapine.

Antituberculosis: isoniazid.

Antivirals: protease inhibitors for HIV treatment (e.g. ritonavir).

Carbonic anhydrase inhibitors: acetazolamide.

Cardiovascular drugs: diltiazem, verapamil.

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Gastrointestinal drugs: possibly cimetidine, omeprazole.

Muscle relaxants: oxybutynin, dantrolene.

Platelet aggregation inhibitors: ticlopidine.

Other interactions: grapefruit juice, nicotinamide (only in high dosage).

Agents that may raise the active metabolite carbamazepine-10,11-epoxide plasma levels

Since raised plasma carbamazepine-10,11-epoxide levels may result in adverse reactions (e.g. dizziness,

drowsiness, ataxia, diplopia), the dosage of Tegretol should be adjusted accordingly and/or the plasma

levels monitored when used concomitantly with the substances described below:

Loxapine, quetiapine, primidone, progabide, valproic acid, valnoctamide and valpromide.

Agents that may decrease carbamazepine plasma levels

The dose of Tegretol may have to be adjusted when used concomitantly with the substances described

below:

Antiepileptics: felbamate, methsuximide, oxcarbazepine, phenobarbital, phensuximide, phenytoin (to avoid

phenytoin intoxication and subtherapeutic concentrations of carbamazepine it is recommended to adjust the

plasma concentration of phenytoin to 13 micrograms /mL before adding carbamazepine to the treatment) and

fosphenytoin, primidone, and, although the data are partly contradictory, possibly also clonazepam.

Antineoplastics: cisplatin or doxorubicin.

Antituberculosis: rifampicin.

Bronchodilatators or anti-asthma drugs: theophylline, aminophylline.

Antimalarials: mefloquine may antagonise the anticonvulsant effect of carbamazepine.

Dermatological drugs: isotretinoin.

Other interactions: herbal preparations containing St John's wort (Hypericum perforatum).

Effect of Tegretol on plasma levels of concomitant agents

Carbamazepine may lower the plasma level, or diminish - or even abolish - the activity of certain drugs.

The dosage of the following drugs may have to be adjusted to clinical requirements:

Analgesics, anti-inflammatory agents: buprenorphine, methadone, paracetamol (long term administration of

carbamazepine and paracetamol (acetaminophen) may be associated with hepatotoxicity), phenazone

(antipyrine), tramadol.

Antibiotics: doxycycline, rifabutin.

Anticoagulants: oral anticoagulants (e.g. warfarin, phenprocoumon, dicoumarol and acenocoumarol).

Antidepressants: bupropion, citalopram, mianserin, nefazodone, sertraline, trazodone, tricyclic antidepressants

(e.g. imipramine, amitriptyline, nortriptyline, clomipramine).

Antiemetics: aprepitant

Antiepileptics: clobazam, clonazepam, ethosuximide, felbamate, lamotrigine, oxcarbazepine, primidone,

tiagabine, topiramate, valproic acid, zonisamide. To avoid phenytoin intoxication and subtherapeutic

concentrations of carbamazepine it is recommended to adjust the plasma concentration of phenytoin to 13

micrograms /mL before adding carbamazepine to the treatment. There have been rare reports of an increase in

plasma mephenytoin levels.

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Antifungals: itraconazole, voriconazole. Alternative anti-convulsants may be recommended in patients treated

with voriconazole or itraconazole.

Antihelmintics: praziquantel, albendazole.

Antineoplastics: imatinib, cyclophosphamide, lapatinib, temsirolimus.

Antipsychotics: clozapine, haloperidol and bromperidol, olanzapine, quetiapine, risperidone, ziprasidone,

aripiprazole, paliperidone.

Antivirals: protease inhibitors for HIV treatment (e.g. indinavir, ritonavir, saquinavir).

Anxiolytics: alprazolam, midazolam.

Bronchodilatators or anti-asthma drugs: theophylline.

Contraceptives: hormonal contraceptives (alternative contraceptive methods should be considered).

Cardiovascular drugs: calcium channel blockers (dihydropyridine group) e.g. felodipine, digoxin, simvastatin,

atorvastatin, lovastatin, cerivastatin, ivabradine.

Corticosteroids: corticosteroids (e.g. prednisolone, dexamethasone).

Drugs used in erectile dysfunction: tadalafil.

Immunosuppressants: ciclosporin, everolimus, tacrolimus, sirolimus.

Thyroid agents: levothyroxine.

Other drug interactions: products containing oestrogens and/or progesterones.

Combinations that require specific consideration

Concomitant use of carbamazepine and levetiracetam has been reported to increase carbamazepine-induced

toxicity.

Concomitant use of carbamazepine and isoniazid has been reported to increase isoniazid-induced

hepatotoxicity.

Combined use of carbamazepine and lithium or metoclopramide on the one hand, and carbamazepine and

neuroleptics (haloperidol, thioridazine) on the other, may lead to increased neurological adverse reactions

(with the latter combination even in the presence of ‘therapeutic plasma levels’).

Concomitant medication with Tegretol and some diuretics (hydrochlorothiazide, furosemide) may lead to

symptomatic hyponatraemia.

Carbamazepine may antagonize the effects of non-depolarizing muscle relaxants (e.g. pancuronium). Their

dosage may need to be raised, and patients should be monitored closely for more rapid recovery from

neuromuscular blockade than expected.

Carbamazepine, like other psychoactive drugs, may reduce alcohol tolerance. It is therefore advisable for the

patient to abstain from alcohol.

Interference with serological testing

Carbamazepine may result in false positive perphenazine concentrations in HPLC analysis due to interference.

Carbamazepine and the 10,11-epoxide metabolite may result in false positive tricyclic antidepressant

concentration in fluorescence polarized immunoassay method.

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9

Women of child-bearing potential, pregnancy, breast-feeding and fertility

Pregnancy

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

malformations.Although conclusive evidence from controlled studies with carbamazepine monotherapy is

lacking, developmental disorders and malformations, including spina bifida and also other congenital

anomalies, e.g. craniofacial defects, cardiovascular malformations, hypospadias and anomalies involving

various body systems, have been reported in association with the use of Tegretol. 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 3.0% (95% CI 2.1 to

4.2%) among mothers exposed to carbamazepine monotherapy in the first trimester and 1.1% (95% CI 0.35 to

2.5%) among pregnant women not taking any antiepileptic drug (relative risk 2.7, 95% CI 1.1 to 7.0).

Taking these data into consideration:

Pregnant women with epilepsy should be treated with special care.

If women receiving Tegretol become pregnant or plan to become pregnant, or if the problem of

initiating treatment with Tegretol arises during pregnancy, the drug's expected benefits must be

carefully weighed against its possible hazards, particularly in the first 3 months of pregnancy.

In women of childbearing potential Tegretol should, wherever possible, be prescribed as

monotherapy, because the incidence of congenital abnormalities in the offspring of women treated

with a combination of antiepileptic drugs is greater than in those of mothers receiving the individual

drugs as monotherapy. The risk of malformations following exposure to carbamazepine as

polytherapy may vary depending on the specific drugs used and may be higher in polytherapy

combinations that include valproate.

Minimum effective doses should be given and monitoring of plasma levels is recommended. The

plasma concentration could be maintained in the lower side of the therapeutic range 4 to 12

micrograms/mL provided seizure control is maintained. There is evidence to suggest that the risk of

malformation with carbamazepine may be dose-dependent i.e. at a dose < 400mg per day, the rates of

malformation were lower than with higher doses of carbamazepine.

Patients should be counseled 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:

Folic acid deficiency is known to occur in pregnancy. Antiepileptic drugs have been reported to aggravate

folic acid deficiency. This deficiency may contribute to the increased incidence of birth defects in the

offspring of treated epileptic women. Folic acid supplementation has therefore been recommended before and

during pregnancy.

In the neonate:

In order to prevent bleeding disorders in the offspring, it has also been recommended that vitamin K1 be given

to the mother during the last weeks of pregnancy as well as to the neonate.

There have been a few cases of neonatal seizures and/or respiratory depression associated with maternal

Tegretol and other concomitant anticonvulsant drug use. A few cases of neonatal vomiting, diarrhoea and/or

decreased feeding have also been reported in association with maternal Tegretol use. These reactions may

represent a neonatal withdrawal syndrome.

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Women of child-bearing potential and contraceptive measures

Due to enzyme induction, Tegretol may result in a failure of the therapeutic effect of oral contraceptive drugs

containing oestrogen and/or progesterone. Women of child bearing potential should be advised to use

alternative contraceptive methods while on treatment with Tegretol.

Breast-feeding

Carbamazepine passes into the breast milk (about 25 to 60% of plasma concentrations). The benefits of breast-

feeding should be weighed against the remote possibility of adverse effects occurring in the infant. Mothers

taking Tegretol may breast-feed their infants, provided the infant is observed for possible adverse reactions

(e.g. excessive somnolence, allergic skin reaction). There have been some reports of cholestatic hepatitis in

neonates exposed to carbamazepine during antenatal and or during breast feeding. Therefore breast-fed infants

of mothers treated with carbamazepine should be carefully observed for adverse hepatobiliary effects.

Fertility

There have been very rare reports of impaired male fertility and/or abnormal spermatogenesis.

10

Overdosage

Signs and symptoms

The presenting signs and symptoms of overdosage usually involve the central nervous, cardiovascular,

respiratory systems and the adverse drug reactions mentioned under section 7 Adverse drug reaction.

Central nervous system

CNS depression; disorientation, depressed level of consciousness, somnolence, agitation, hallucination, coma;

blurred

vision,

slurred

speech,

dysarthria,

nystagmus,

ataxia,

dyskinesia,

initially

hyper-reflexia,

later

hyporeflexia; convulsions, psychomotor disturbances, myoclonus, hypothermia, mydriasis.

Respiratory system

Respiratory depression, pulmonary oedema.

Cardiovascular system

Tachycardia, hypotension, at times hypertension, conduction disturbance with widening of QRS complex;

syncope in association with cardiac arrest.

Gastrointestinal system

Vomiting, delayed gastric emptying, reduced bowel motility.

Musculoskeletal system

There have been some cases which reported rhabdomyolysis in association with carbamazepine toxicity.

Renal function

Retention of urine, oliguria or anuria; fluid retention, water intoxication due to an ADH-like effect of

carbamazepine.

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Laboratory findings

Hyponatraemia,

possibly

metabolic

acidosis,

possibly

hyperglycaemia,

increased

muscle

creatine

phosphokinase.

Management

There is no specific antidote.

Management should initially be guided by the patient's clinical condition; admission to hospital. Measurement

of the plasma level to confirm carbamazepine poisoning and to ascertain the size of the overdose.

Evacuation of the stomach, gastric lavage, and administration of activated charcoal. Delay in evacuating the

stomach may result in delayed absorption, leading to relapse during recovery from intoxication. Supportive

medical care in an intensive care unit with cardiac monitoring and careful correction of electrolyte imbalance.

Special recommendations

Charcoal hemoperfusion has been recommended Hemodialysis is the effective treatment modality in the

management of the carbamazepine overdose.

Relapse and aggravation of symptomatology on the 2

and 3

day after overdose, due to delayed absorption,

should be anticipated.

11

Clinical pharmacology

Pharmacotherapeutic group, ATC

Therapeutic class: antiepileptic, neurotropic, and psychotropic agent; (ATC Code: N03 AF01).

Dibenzazepine derivative.

Mechanism of action (MOA)

The mechanism of action of carbamazepine, the active substance of Tegretol, has only been partially

elucidated. Carbamazepine stabilizes hyperexcited nerve membranes, inhibits repetitive neuronal discharges,

and reduces synaptic propagation of excitatory impulses. It is conceivable that prevention of repetitive firing

of sodium-dependent action potentials in depolarized neurons via use- and voltage-dependent blockade of

sodium channels may be its main mechanism of action.

Whereas reduction of glutamate release and stabilization of neuronal membranes may account mainly for the

antiepileptic effects, the depressant effect on dopamine and noradrenaline turnover could be responsible for

the antimanic properties of carbamazepine.

Pharmacodynamics (PD)

As an antiepileptic agent its spectrum of activity embraces: partial seizures (simple and complex) with and

without secondary generalization; generalized tonic-clonic seizures, as well as combinations of these types of

seizures.

In clinical studies Tegretol given as monotherapy to patients with epilepsy - in particular children and

adolescents - has been reported to exert a psychotropic action, including a positive effect on symptoms of

anxiety and depression as well as a decrease in irritability and aggressiveness. As regards cognitive and

psychomotor performance, in some studies equivocal or negative effects, depending also upon dosages

administered, were reported. In other studies, a beneficial effect on attentiveness, cognitive

performance/memory was observed.

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As a neurotropic agent Tegretol is clinically effective in a number of neurological disorders, e.g. it prevents

paroxysmal attacks of pain in idiopathic and secondary trigeminal neuralgia; in addition, it is used for the

relief of neurogenic pain in a variety of conditions, including tabes dorsalis, post-traumatic paresthesia, and

post-herpetic neuralgia; in alcohol-withdrawal syndrome it raises the lowered convulsion threshold and

improves withdrawal symptoms (e.g. hyperexcitability, tremor, impaired gait); in diabetes insipidus centralis,

Tegretol reduces the urinary volume and relieves the feeling of thirst.

As a psychotropic agent Tegretol proved to have clinical efficacy in affective disorders, i.e. as treatment for

acute mania as well as for maintenance treatment of (manic-depressive) bipolar affective disorders, when

given either as monotherapy or in combination with neuroleptics, antidepressants, or lithium, in excited

schizo-affective disorder and excited mania in combination with other neuroleptics, and in rapid cycling

episodes.

Pharmacokinetics (PK)

Absorption

Carbamazepine is absorbed almost completely but relatively slowly from the tablets. The conventional tablets

yield mean peak plasma concentrations of the unchanged substance within 12 hours, following single oral

doses. With the oral suspension, mean peak plasma concentrations are attained within 2 hours. With respect to

the amount of active substance absorbed, there is no clinically relevant difference between the oral dosage

forms. After a single oral dose of 400 mg carbamazepine (tablets) the mean peak concentration of unchanged

carbamazepine in the plasma is approx. 4.5 micrograms/mL.

When CR tablets are administered singly and repeatedly, they yield about 25% lower peak concentrations of

active substance in plasma than the conventional tablets; the peaks are attained within 24 hours. The CR

tablets provide a statistically significant decreased fluctuation index, but not a significant decreased Cmin at

steady state. The fluctuation of the plasma concentrations with a twice-daily dosage regimen is low. The

bioavailability of Tegretol CR tablets is about 15% lower than that of the other oral dosage forms.

Steady-state plasma concentrations of carbamazepine are attained within about 1 to 2 weeks, depending

individually upon auto-induction by carbamazepine and hetero-induction by other enzyme-inducing drugs, as

well as on pretreatment status, dosage, and duration of treatment.

The steady-state plasma concentrations of carbamazepine considered as ‘therapeutic range’ vary considerably

interindividually: for the majority of patients a range between 4 to 12 micrograms/mL corresponding to 17 to

50 micromol/L has been reported. Concentrations of carbamazepine-10,11-epoxide (pharmacologically active

metabolite): about 30% of carbamazepine levels.

Ingestion of food has no significant influence on the rate and extent of absorption, regardless of the dosage

form of Tegretol.

Distribution

Assuming complete absorption of carbamazepine, the apparent volume of distribution ranges from 0.8 to 1.9

L/kg.

Carbamazepine crosses the placental barrier.

Carbamazepine is bound to serum proteins to the extent of 70 to 80%. The concentration of unchanged

substance in cerebrospinal fluid and saliva reflects the non-protein bound portion in the plasma (20 to 30%).

Concentrations in breast milk were found to be equivalent to 25 to 60% of the corresponding plasma levels.

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Biotransformation/metabolism

Carbamazepine is metabolized in the liver, where the epoxide pathway of biotransformation is the most

important one, yielding the 10,11-transdiol derivative and its glucuronide as the main metabolites.

Cytochrome P450 3A4 has been identified as the major isoform responsible for the formation of the

pharmacologically active carbamazepine-10,11 epoxide from carbamazepine. Human microsomal epoxide

hydrolase has been identified as the enzyme responsible for the formation of the 10,11-transdiol derivative

from carbamazepine-10,11 epoxide. 9-Hydroxy-methyl-10-carbamoyl acridan is a minor metabolite related to

this pathway. After a single oral dose of carbamazepine about 30% appears in the urine as end-products of the

epoxide pathway. Other important biotransformation pathways for carbamazepine lead to various

monohydroxylated compounds, as well as to the N-glucuronide of carbamazepine produced by UGT2B7.

Elimination

The elimination half-life of unchanged carbamazepine averages approx. 36 hours following a single oral dose,

whereas after repeated administration it averages only 16 to 24 hours (auto-induction of the hepatic mono-

oxygenase system), depending on the duration of the medication. In patients receiving concomitant treatment

with other liver-enzyme inducing drugs (e.g. phenytoin, phenobarbitone), half-life values averaging 9 to 10

hours have been found.

The mean elimination half-life of the 10,11-epoxide metabolite in the plasma is about 6 hours following single

oral doses of the epoxide itself.

After administration of a single oral dose of 400 mg carbamazepine, 72% is excreted in the urine and 28% in

the faeces. In the urine, about 2% of the dose is recovered as unchanged drug and about 1% as the

pharmacologically active 10,11-epoxide metabolite.

Special populations

Children

Owing to enhanced carbamazepine elimination, children may require higher doses of carbamazepine (in

mg/kg) than adults.

Elderly

There is no indication of altered pharmacokinetics of carbamazepine in elderly patients as compared with

young adults.

Patients with hepatic or renal impairment

No data are available on the pharmacokinetics of carbamazepine in patients with impaired hepatic or renal

function.

12

Clinical studies

No recent clinical trials have been conducted with Tegretol.

13

Non-clinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of single and repeated

dose toxicity, genotoxicity and carcinogenic potential. However, the animal studies were insufficient to rule

out a teratogenic effect of carbamazepine.

Carcinogenicity

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In rats treated with carbamazepine for 2 years, there was an increased incidence of hepatocellular tumors in

females and benign testicular tumors in males. However, there is no evidence that these observations are of

any relevance to the therapeutic use of carbamazepine in humans.

Genotoxicity

Carbamazepine was not found to be genotoxic in various standard bacterial and mammalian mutagenicity

studies.

Reproductive toxicity

The cumulative evidence from various animal studies in mice, rats and rabbits indicates that carbamazepine

has no or only minor teratogenic potential at doses relevant to man. However, the animal studies were

insufficient to rule out a teratogenic effect of carbamazepine. In a reproduction study in rats, nursing offspring

demonstrated a reduced weight gain at a maternal dosage level of 192 mg/kg/day.

14

Pharmaceutical information

Incompatibilities

None known.

Special precautions for storage

Tablets: store below 25°C and protect from moisture.

CR tablets: store below 25°C and protect from moisture.

Syrup: store below 30°C and protect from light. After first opening of the bottle, store below 25°C and use

within 3 months.

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

Instructions for use and handling

There is no specific instruction for use/handling.

Manufacturer:

TEGRETOL 200 mg tablets, TEGRETOL 200 mg and 400 mg CR tablets:

Novartis Farma SPASpA, Torre Annunziata, Italy

For: Novartis Pharma AG, Basel, Switzerland.

TEGRETOL 100 mg / 5 mL syrup:

Delpharm Huningue SAS, Huningue, France

For: Novartis Pharma AG, Basel, Switzerland.

Registration Holder:

Novartis Pharma Services AGIsrael Ltd., 36 Shacham St., Petach-Tikva.

Registration numbers:

TEGRETOL 200 mg tablets:

015-41-24602

Page 22

TEG API JUL14 CL V5

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CDS 210313

TEGRETOL 200 mg CR tablets:

041-24-25416

TEGRETOL 400 mg CR tablets:

041-23-25417

TEGRETOL syrup 2%:

022-90-24971

אפורל ןולעב )תוחיטב עדימ ( הרמחה לע העדוה ןכדועמ(

05.2013

)

:ךיראת :תילגנאב רישכת םש

Tegretol 200mg / Tegretol CR 200mg / Tegretol CR 400mg / Tegretol syrup 2%

:םושירה רפסמ

[

24602

[ ]

25416-7

[ ]

24971

]

:םושירה לעב םש י'ג ייא ססיורס המראפ סיטרבונ !דבלב תורמחהה טוריפל דעוימ הז ספוט רשואמ טסקט – רוחש טסקט יתחת וק םע טסקט

ןולעל טסקט תפסוה – רשואמה הצוח וק םע טסקט

ןולעהמ טסקט תקיחמ – רשואמה בוהצב ןמוסמה טסקט הרמחה – תושקובמה תורמחהה ןולעב קרפ יחכונ טסקט שדח טסקט

Dosage and

administration

Special populations

Renal impairment / Hepatic

impairment

No data are available on the

pharmacokinetics of carbamazepine in

patients with impaired hepatic or renal

function

Contraindications

The use of Tegretol is not recommended

in combination with monoamine-oxidase

inhibitors (MAOIs)

The use of Tegretol is not recommended

contraindicated in combination with

monoamine-oxidase inhibitors (MAOIs)

Warnings and

precautions

Association with HLA-B*1502

Retrospective studies in patients of Han

Chinese ancestry found a strong

correlation between SJS/TEN skin

reactions associated with carbamazepine

and the presence in these patients of the

Human Leukocyte Antigene (HLA)-

B*1502 allele.

Association with HLA-B*1502

Retrospective studies in patients of Han

Chinese and Thai origin ancestry found a

strong correlation between SJS/TEN skin

reactions associated with carbamazepine

and the presence in these patients of the

Human Leukocyte Antigene (HLA)-

B*1502 allele.

Hypersensitivity

Tegretol may trigger hypersensitivity

reactions, including

Drug Rash with

Eosinophilia and Systemic Symptoms

(DRESS),

a delayed multi-organ

hypersensitivity disorder with fever, rash,

vasculitis, lymphadenopathy, pseudo

lymphoma, arthralgia, leukopenia,

eosinophilia, hepato-splenomegaly,

abnormal liver function tests and

Anticholinergic effects

Tegretol has shown mild anticholinergic

activity. Patients with increased

intraocular pressure should therefore be

closely observed during therapy.

vanishing bile duct syndrome (destruction

and disappearance of the intrahepatic bile

ducts),

that may

occur in various

combinations. Other organs may also be

affected (e.g. lungs, kidneys, pancreas,

myocardium, colon)

Hyponatremia

Hyponatremia is known to occur with

carbamazepine. In patients with pre-

existing renal conditions associated with

sodium

patients

treated

concomitantly

with

sodium-lowering

medicinal

products

(e.g.

diuretics,

medicinal

products

associated

with

inappropriate ADH secretion),

serum

sodium levels should be measured prior

initiating

carbamazepine

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. If hyponatraemia is observed,

water restriction is an important counter-

measurement if clinically indicated.

Hypothyroidism

Carbamazepine may reduce serum

concentrations of thyroid hormones

through enzyme induction requiring an

increase in dose of thyroid replacement

therapy in patients with hypothyroidism.

Hence thyroid function monitoring is

suggested to adjust the dosage of thyroid

replacement therapy

Anticholinergic effects

Tegretol has shown mild anticholinergic

activity. Patients with increased

intraocular pressure and urinary retention

should therefore be closely observed

during therapy.

Interactions

Co-administration

inhibitors

CYP3A4

inhibitors

epoxide

hydrolase with carbamazepine can induce

adverse

reactions

(increase

carbamazepine or carbamazepine-10, 11

epoxide

plasma

concentrations

4.7

Effects on ability to drive and

use machines

The patient's ability to react may be

impaired by dizziness and drowsiness

caused by Tegretol, especially at the start

of treatment or in connection with dose

adjustments; patients should therefore

exercise due caution when driving a

vehicle or operating machinery.

respectively). The dosage of Tegretol

should be adjusted accordingly and/or the

plasma levels monitored.

Co-administration of CYP3A4 inducers

with

carbamazepine

decrease

carbamazepine

plasma

concentrations

therapeutic

effect,

while

discontinuation of a CYP3A4 inducer

increase

carbamazepine

plasma

concentrations. The dosage of Tegretol

may have to be adjusted.

Carbamazepine is a potent inducer of

CYP3A4 and other phase I and phase II

enzyme systems in the liver, and may

therefore reduce plasma concentrations of

co-medications mainly metabolized by

CYP3A4

induction

their

metabolism. See section 8 Interactions.

Female patients of childbearing potential

should be warned that the concurrent use

of Tegretol with hormonal contraceptives

may render this type of contraceptive

ineffective (see sections 8

Interactions

and 9 Women of child-bearing potential,

pregnancy, breast-feeding and fertility).

Alternative non-hormonal forms of

contraception are recommended when

using Tegretol

Driving and using machines

The patient's ability to react may be

impaired by the medical condition

resulting in seizures and adverse reactions

including dizziness, and drowsiness,

ataxia, diplopia, impaired accommodation

and blurred vision reported with caused

by Tegretol, especially at the start of

treatment or in connection with dose

adjustments.; p Patients should therefore

exercise due caution when driving a

vehicle or operating machinery.

Adverse drug

reactions

Immune system disorders

Very rare: hypogammaglobulinaemia

Metabolism and nutrition disorders

Rare:

decreased appetite

Nervous system disorders

Very rare:

aseptic meningitis with

myoclonus and peripheral eosinophilia,

dysgeusia

Additional adverse drug reactions

from spontaneous reports (frequency

not known)

Infections and infestations

Reactivation of Human herpesvirus 6

infection.

Blood and lymphatic system disorders

Bone marrow failure.

Nervous system disorders

Sedation, memory impairment.

Gastrointestinal disorders

Colitis.

Skin and subcutaneous tissue disorders

... lichenoid keratosis, onychomadesis

Musculoskeletal and connective tissue

disorders

Fracture.

Investigations

Bone density decreased.

Interactions

The use of Tegretol is not recommended

in combination with monoamine-oxidase

inhibitors (MAOIs)

Effect of Tegretol on plasma levels of

concomitant agents

Antibiotics: doxycycline

Antifungals: itraconazole

Cardiovascular drugs:

calcium channel

blockers

(dihydropyridine group) e.g.

felodipine, digoxin

Interactions resulting in a

contraindication

The use of Tegretol is not recommended

contraindicated in combination with

monoamine-oxidase inhibitors (MAOIs)

Effect of Tegretol on plasma levels of

concomitant agents

Antibiotics: doxycycline, rifabutin

...

Antifungals: itraconazole, voriconazole

Cardiovascular drugs: calcium channel

blockers (dihydropyridine group) e.g.

felodipine, digoxin,

simvastatin,

atorvastatin, lovastatin, cerivastatin,

ivabradine

Interference with serological testing

Carbamazepine may result in false

positive perphenazine concentrations in

HPLC analysis due to interference.

Carbamazepine and the 10,11-epoxide

metabolite may result in false positive

tricyclic antidepressant concentration in

fluorescence polarized immunoassay

method.

Women of child-

bearing

potential,

pregnancy,

breast-feeding

and fertility

Pregnancy

Minimum effective doses should be given

and monitoring of plasma levels is

recommended.

Pregnancy

The risk of malformations following

exposure to carbamazepine as

polytherapy may vary depending on the

specific drugs used and may be higher in

polytherapy combinations that include

valproate

Minimum effective doses should be given

and monitoring of plasma levels is

recommended. The plasma concentration

could be maintained in the lower side of

the therapeutic range 4 to 12 micrograms/

mL provided seizure control is

maintained. There is evidence to suggest

that the risk of malformation with

carbamazepine may be dose-dependent

i.e. at a dose < 400mg per day, the rates

of malformation were lower than with

higher doses of carbamazepine.

Women of child-bearing potential and

contraceptive measures

Due to enzyme induction, Tegretol may

result in a failure of the therapeutic effect

of oral contraceptive drugs containing

oestrogen and/or progesterone. Women

of child bearing potential should be

advised to use alternative contraceptive

methods while on treatment with

Tegretol

Breast-feeding

There have been some reports of

cholestatic hepatitis in neonates exposed

to carbamazepine during antenatal and or

during breast feeding. Therefore breast-

fed infants of mothers treated with

carbamazepine should be carefully

observed for adverse hepatobiliary

effects.

Overdosage

Central nervous system

... depressed level of consciousness

Musculoskeletal system

There have been some cases which

reported rhabdomyolysis in association

with carbamazepine toxicity

ןכרצל ןולעב )תוחיטב עדימ ( הרמחה לע העדוה ןכדועמ(

05.2013

:ךיראת :תילגנאב רישכת םש

Tegretol 200mg / Tegretol CR 200mg / Tegretol CR 400mg / Tegretol syrup 2%

:םושירה רפסמ

[

24602

[ ]

25416-7

[ ]

24971

]

:םושירה לעב םש י'ג ייא ססיורס המראפ סיטרבונ !דבלב תורמחהה טוריפל דעוימ הז ספוט רשואמ טסקט – רוחש טסקט יתחת וק םע טסקט

ןולעל טסקט תפסוה – רשואמה הצוח וק םע טסקט

ןולעהמ טסקט תקיחמ – רשואמה בוהצב ןמוסמה טסקט הרמחה – קורי טסקט טמרופל רבעמהמ םיעבונה םייוניש - שדחה תושקובמה תורמחהה ןולעב קרפ יחכונ טסקט שדח טסקט תודחוימ תורהזא שומישל תועגונה הפורתב ולא ללוכ( םד תלחמ ךל שי םא .)תורחא תופורת ידי-לע תומרגנה

רבגומ יניע ךות ץחל ךל שי םא )המוקואלג( ךל שי םא תלחמ

תולחמ

ללוכ( םד תופורת ידי-לע תומרגנה ולא .)תורחא

רבגומ יניע ךות ץחל ךל שי םא )המוקואלג( רוצאל לוכי ךניא םא וא ךלש ןתשה תא

תורושקה הילכב תויעב ךל שי םא םדב הכומנ ןרתנ תמרל

ךל שי םא וא

תופורת םג לטונ התאו הילכב תויעב ןרתנה תמר תא תודירומה תומיוסמ ןוגכ םינתשמ( םדב )דימסורופ ,דיזאיתורולכורדיה תופורת תליטנ תורחא ,וא ןונימב יונישב ךרוצ היהיש ןכתי תחא תא קיספהל ,םיתיעל תופורתה

תולולג( ילנומרוהה העינמה יעצמא )ןוירה תעינמל

ףיעסב טרופמ -

שומישל תועגונה תודחוימ תורהזא" "הפורתב ליגב םישנ תוירופה תוירופה ליגב םישנ הלולע תסווה רוזחמ לש תורידס יא יעצמא תולטונה םישנב שחרתהל תעינמל תולולג( םיילנומרוה העינמ .לוטרגטו )ןוירה

שי ףסונ טוריפל

תודחוימ תורהזא" ףיעסל תונפל

."הפורתב שומישל תועגונה שומישו הגיהנ תונוכמב םויה ייח לע הפורתה עיפשת ךיא ?ךלש םוי םורגל לולע וז הפורתב שומישה שוטשטל וא תרוחרחסל וא תוינונשיל וא לופיטה תליחתב רקיעב ,היארה בייחמ ןכ לעו ,ןונימ םילעמ רשאכ תלעפהב ,בכרב הגיהנב תוריהז תוליעפ לכבו תונכוסמ תונוכמ רשאב .תיברימ בל תמושת תבייחמה לע הביכרמ םריהזהל שי םידליל תברקב םיקחשממ וא םיינפוא המודכו שיבכה תונוכמב שומישו הגיהנ וז הפורתב שומישה לוטרגט לולע וא תרוחרחסל וא תוינונשיל םורגל ,היארה שוטשטל וא הלופכ הייארל םירירשב היצנידרואוק רסוחל

רקיעב םילעמ רשאכ וא לופיטה תליחתב ןונימ

תוריהז בייחמ ןכ לעו ,

שי ןכל רהזהל תלעפהב ,בכרב הגיהנב תונוכמ תונכוסמ תוליעפ לכבו בל תמושת תבייחמה

תיברימ רשאב . לע הביכרמ םריהזהל שי םידליל תברקב םיקחשממ וא םיינפוא המודכו שיבכה בקעמו תוקידב תויניצר תוירוע תובוגתל ןוכיסה ידנליאת וא יניס אצוממ םילפוטמב תובוכרתל וא ןיפזמברקל תורושקה תקידבב יוזיחל ןתינ ,תימיכ תומודה .הלא םילפוטמ לש םד תמגוד הצוחנ םד תקידב םאה ץעיי אפורה .לוטרגט תליטנ ינפל לוטרגט תליטנ שרדנהמ רתוי יישק :םניה רתי תנמ לש םינמיס ,רידס אלו ריהמ בל בצק ,המישנ /ו הליחב ,דער ,ןופליע ,הרכה ןדבוא .האקה וא שרדנהמ רתוי לוטרגט תליטנ ,תוילבט ידמ רתוי תועטב תלטנ םא דימ אפורל הנפ

קקדזתש ןכתי .

תיאופר החגשהל

:םניה רתי תנמ לש םינמיס ךנה םא שיגרמ

ריהמ בל בצק ,המישנ יישק ,ןופליע ,הרכה ןדבוא ,רידס אלו האקה וא/ו הליחב ,דער ןכתי , ידמ ההובג ךלש הנמהש

תא קספה דימ אפורל הנפו הפורתה תליטנ

ללוכ( חותינ רובעל דמוע ךנה םא הלועפ לכ וא )ילטנד-םייניש חותינ אפורל חוודל שי המדרהב הכורכה וז הפורת תליטנ לע םידרמה תופסונ תוארוה חותינ רובעל דמוע ךנה םא ,והשלכ ילטנד לופיט ללוכ

םוריח לופיט וא

)ילטנד-םייניש חותינ ללוכ(

לכ וא המדרהב הכורכה הלועפ

חוודל שי אפורל לוטרגט לטונ ךנהש לפטמה וז הפורת תליטנ לע םידרמה יאוול תועפות תובייחמה יאוול תועפות תדחוימ תוסחייתה תורידנ בצמב םירחא םייוניש וא תונבצע ... חורה תויהל תויושע תומיוסמ תועפות תויניצר

םינמיס( םוחו ןטב באכ ,לושלש תעפות לש תוחיכשה .)יעמה תקלדל העודי הניא וזה יאוולה

תופסונ יאוול תועפות

תורידנ םייוניש וא תונבצע ... םירחא בצמב

חורה םירחא םיישפנ םייוניש וא

השלוח תוחיכשב תומיוסמ יאוול תועפות :העודי הניאש ףיגנ םוהיז לש שדחמ לועפש רשאכ יניצר תויהל יושע( ספרהה הרישנ ,)תאכודמ תינוסיחה תכרעמה הדירי ,רבש ,םיינרופיצה לש האלמ םצעה תופיפצ תדימב

יאוולה תועפות ,ללכ ךרדב תושרוד ןניא תואבה לופיט החגשה יאופר

ת

ןה םא ,םלוא . וא םימי רפסמל רבעמ תוכשמנ .אפורל תונפל שי ,דרטמ תווהמ

תוחיכשב תומיוסמ יאוול תועפות :העודי הניאש תויוחיפנ ,ןורכיזה דוביא ,םונמנ תומדמדא-תולוגס וא תולוגס תודרגמ תויהל תויושעש

הלא תועפותמ רתוי וא תחא םא ,רומח ןפואב ךילע העיפשמ

הנפ

אפורל

,הרימחמ יאוולה תועפותמ תחא םא יאוול תעפותמ לבוס התא רשאכ וא ץעייתהל ךילע ,ןולעב הרכזוה אלש אפורה םע חקורה וא

הנסחא םידלי לש םדי גשיהמ קיחרהל שי םדי גשיהמ קיחרהל שי םוחתו םתייאר

םידלי לש

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