TEGRETOL CHEWTABS 200 MG TABLET (CHEWABLE)

Canada - English - Health Canada

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Active ingredient:
CARBAMAZEPINE
Available from:
NOVARTIS PHARMACEUTICALS CANADA INC
ATC code:
N03AF01
INN (International Name):
CARBAMAZEPINE
Dosage:
200MG
Pharmaceutical form:
TABLET (CHEWABLE)
Composition:
CARBAMAZEPINE 200MG
Administration route:
ORAL
Units in package:
100
Prescription type:
Prescription
Therapeutic area:
MISCELLANEOUS ANTICONVULSANTS
Product summary:
Active ingredient group (AIG) number: 0108674001; AHFS: 28:12.92
Authorization status:
APPROVED
Authorization number:
00665088
Authorization date:
1997-05-29

Documents in other languages

Page 1 of 46

PRODUCT MONOGRAPH

Pr

TEGRETOL

®

(carbamazepine)

TEGRETOL

®

Tablets, 200 mg

Novartis Standard

TEGRETOL

®

Chewtabs (Chewable Tablets), 100 mg and 200 mg

Novartis Standard

TEGRETOL

®

CR (Controlled-Release Tablets), 200 mg and 400 mg

Novartis Standard

TEGRETOL

®

Suspension, 100 mg/tsp (5 mL)

Novartis Standard

Anticonvulsant

For Symptomatic Relief of Trigeminal Neuralgia

Antimanic

Novartis Pharmaceuticals Canada Inc.

385 Bouchard Blvd.,

Dorval, Quebec

H9S 1A9

Date of Preparation:

April 26, 1976

Date of Revision:

May 4, 2018

Submission Control No: 213356

TEGRETOL

is a registered trademark.

Page 2 of 46

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION .........................................................3

SUMMARY PRODUCT INFORMATION ........................................................................3

INDICATIONS AND CLINICAL USE ..............................................................................3

CONTRAINDICATIONS ...................................................................................................5

WARNINGS AND PRECAUTIONS ..................................................................................5

ADVERSE REACTIONS ..................................................................................................16

DRUG INTERACTIONS ..................................................................................................20

DOSAGE AND ADMINISTRATION ..............................................................................25

OVERDOSAGE ................................................................................................................27

ACTION AND CLINICAL PHARMACOLOGY ............................................................28

STORAGE AND STABILITY ..........................................................................................30

DOSAGE FORMS, COMPOSITION AND PACKAGING .............................................30

PART II: SCIENTIFIC INFORMATION ...............................................................................32

PHARMACEUTICAL INFORMATION ..........................................................................32

CLINICAL TRIALS ..........................................................................................................32

DETAILED PHARMACOLOGY .....................................................................................33

TOXICOLOGY .................................................................................................................33

PART III: CONSUMER INFORMATION ..............................................................................41

Page 3 of 46

Pr

TEGRETOL

®

(carbamazepine)

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of

Administration

Dosage Form / Strength

Nonmedicinal Ingredients

Oral

Tablets; 200 mg

Cellulose

compounds,

magnesium

stearate,

silicon dioxide.

Oral

Chewable Tablets; 100 mg

and 200 mg

Cherry-mint flavour, cornstarch, erythrosine,

gelatin, glycerin, magnesium stearate, silicon

dioxide, sodium starch glycolate, stearic acid,

sugar.

Oral

Controlled-Release

Tablets; 200 mg and 400

Acrylic

esters,

cellulose

compounds,

iron

oxides, magnesium stearate, silicon dioxide,

talc, titanium dioxide, castor oil derivative.

Oral

Suspension; 100 mg/tsp (5

Citric

acid,

citrus-vanilla

flavour,

FD&C

Yellow

pluronic

polyol,

potassium

sorbate, propylene glycol, sucrose, sorbitol,

water, xanthan gum.

INDICATIONS AND CLINICAL USE

Epilepsy:

Adults (> 18 years of age)

TEGRETOL (carbamazepine) is indicated for use as an anticonvulsant drug either alone or in

combination with other anticonvulsant drugs.

Carbamazepine is not effective in controlling absence, myoclonic or atonic seizures, and

does not prevent the generalization of epileptic discharge. Moreover, exacerbation of

seizures may occasionally occur in patients with atypical absences.

Pediatrics (> 6 years of age):

TEGRETOL is indicated for use as an anticonvulsant drug either alone or in combination with

other anticonvulsant drugs (see DOSAGE and ADMINISTRATION,

Recommended Dose

and

Dosage Adjustment, Use in Epilepsy, Adults and Children Over 12 Years of Age and

Children 6-12 Years of Age

Page 4 of 46

Trigeminal Neuralgia

Adults (> 18 years of age)

TEGRETOL is indicated for the symptomatic relief of pain of trigeminal neuralgia only during

periods of exacerbation of true or primary trigeminal neuralgia (tic douloureux). It should not be

used preventively during periods of remission. In some patients, TEGRETOL has relieved

glossopharyngeal neuralgia. For patients who fail to respond to TEGRETOL, or who are

sensitive to the drug, recourse to other accepted measures must be considered.

Carbamazepine is not a simple analgesic and should not be used to relieve trivial facial

pains or headaches.

Pediatrics (< 18 years of age)

The safety and efficacy of TEGRETOL have not been established in patients under 18 years of

age and its use in this age group is not recommended.

Treatment of Acute Mania and Prophylaxis in Bipolar (Manic-Depressive) Disorders:

Adults (> 18 years of age)

TEGRETOL may be used as a monotherapy or as an adjunct to lithium in the treatment of acute

mania or prophylaxis of bipolar (manic-depressive) disorders in patients who are resistant to or

are intolerant of conventional antimanic drugs. Carbamazepine may be a useful alternative to

neuroleptics in such patients. Patients with severe mania, dysphoric mania or rapid cycling who

are non-responsive to lithium may show a positive response when treated with carbamazepine.

It is important to note that these recommendations are based on extensive clinical experience and

some clinical trials versus active comparison agents.

Pediatrics (< 18 years of age)

The safety and efficacy of TEGRETOL have not been established in patients under 18 years of

age and its use in this age group is not recommended.

Geriatrics (> 65 years of age)

For all indications, due to drug interactions and different antiepileptic drug pharmacokinetics, the

dosage of TEGRETOL should be selected with caution in elderly patients. (see

WARNINGS

AND

PRECAUTIONS,

Special

Populations,

Geriatrics

and

DOSAGE

AND

ADMINISTRATION,

Dosing Considerations, Geriatrics)

Page 5 of 46

CONTRAINDICATIONS

TEGRETOL (carbamazepine) is contraindicated in:

Patients who are hypersensitive to carbamazepine or to any of the components of the

tablets or suspension. For a complete listing, see

DOSAGE FORMS, COMPOSITION

AND PACKAGING

section of the product monograph.

Patients who are hypersensitive to any of the tricyclic compounds, such as: amitriptyline,

trimipramine, imipramine, or their analogues or metabolites, because of the similarity in

chemical structure.

Patients with hepatic disease, a history of bone-marrow depression, a history of hepatic

porphyria (acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda), or

serious blood disorder.

Conjunction with, or immediately after a monoamine oxidase (MAO) inhibitor

(see

DRUG INTERACTIONS)

Conjunction with itraconazole and voriconazole

(see

DRUG INTERACTIONS)

Patients

presenting

atrioventricular

heart

block

(see

WARNINGS

AND

PRECAUTIONS, Cardiovascular)

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

HEMATOLOGIC:

Although reported infrequently, serious adverse effects have been

observed during the use of TEGRETOL (carbamazepine). Agranulocytosis and aplastic

anemia, with a fatal outcome, have occurred very rarely. Leucopenia, thrombocytopenia,

hepatocellular and cholestatic jaundice, and hepatitis have also been reported. However, in

the majority of cases, leucopenia and thrombocytopenia were transient and did not signal

the onset of either aplastic anemia or agranulocytosis. It is important that TEGRETOL be

used carefully and close clinical and frequent laboratory supervision should be maintained

throughout treatment in order to detect as early as possible signs and symptoms of a

possible

blood

dyscrasia.

TEGRETOL

should

be

discontinued

if

any

evidence

of

significant bone marrow depression appears (see WARNINGS AND PRECAUTIONS).

DERMATOLOGIC:

Steven’s-Johnson Syndrome and Toxic Epidermal Necrolysis: Serious

and sometimes fatal dermatologic reactions, including Toxic Epidermal Necrolysis (TEN)

and Stevens-Johnson Syndrome (SJS), have been reported with TEGRETOL. In countries

with mainly Caucasian populations, these reactions are estimated to occur in 1 to 6 per

Page 6 of 46

10,000 new users, but in some Asian countries (e.g., Taiwan, Malaysia and the Philippines)

the risk is estimated to be about 10 times higher.

Human Leukocyte Antigens (HLA)-A*3101 and HLA-B*1502 may be risk factors for the

development of serious cutaneous adverse drug reactions. Retrospective genome-wide

studies in Japanese and Northern European populations reported an association between

severe skin reactions (SJS, TEN, Drug Rash with Eosinophilia and Systemic Symptoms

(DRESS), Acute Generalized Exanthematous Pustulosis (AGEP) and maculopapular rash)

associated with carbamazepine use and the presence of the HLA-A*3101 allele in these

patients. Similarly, in studies that included small samples of patients of Han Chinese

ancestry, a strong association was found between the risk of developing SJS/TEN and the

presence of the HLA-B*1502 allele. The HLA-B*1502 allele is found almost exclusively in

individuals with ancestry across broad areas of Asia

. It is therefore, recommended that

physicians consider HLA-A*3101 and HLA-B*1502 genotyping as a screening tool in

genetically at-risk populations (see WARNINGS AND PRECAUTIONS, Ancestry and

Allelic Variations in the HLA-A Gene and Ancestry; Allelic Variations in the HLA-B

Gene). Until further information is available, the use of TEGRETOL and other anti-

epileptic drugs associated with SJS/TEN should be avoided in patients who test positive for

the

HLA-A*3101

or

HLA-B*1502

alleles

(see

WARNINGS

AND

PRECAUTIONS,

Ancestry and Allelic Variations in the HLA-A Gene; Ancestry and Allelic Variation in the

HLA-B Gene; Important Limitations of HLA-A and HLA-B Genotyping).

Treatment

recommendations

for

dermatological

reactions:

TEGRETOL

should

be

discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs

or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative

therapy

should

be

considered.

The

use

of

other

anti-epileptic

drugs

associated

with

SJS/TEN should be avoided in patients who have shown severe dermatological reactions

during TEGRETOL treatment.

CARCINOGENICITY:

Long-term

toxicity

studies

in

rats

indicated

a

potential

carcinogenic risk (see TOXICOLOGY). Therefore, the possible risk of the drug must be

weighed

against

the

potential

benefits

before

prescribing

TEGRETOL

to

individual

patients.

Pharmacogenomics

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

The following provide a rough estimate of the frequency of HLA-B*1502 allele in various populations: from 2 to

12% in Han Chinese populations, about 8% in Thai populations, and above 15% in the Philippines and some

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

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

African populations, indigenous peoples of the Americas, Hispanic populations sampled and in Japanese (< 1%).

The estimated frequencies have limitations due to the wide variation in allele frequencies that exist within ethnic

groups, the difficulties in ascertaining ethnic ancestry and the likelihood of mixed ancestry.

Page 7 of 46

immune-mediated adverse reactions.

Ancestry and Allelic Variation in the HLA-A Gene

The frequency of the HLA-A*3101 allele, an inherited allelic variant of the HLA-A gene,

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.

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 WARNINGS AND PRECAUTIONS, Important

Limitations of HLA-A and

HLA-B Genotyping). 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 (see

WARNINGS

AND

PRECAUTIONS,

Important

Limitations

of

HLA-A

and

HLA-B

Genotyping).

Ancestry and Allelic Variation in the HLA-B Gene

In studies that included small samples of carbamazepine-treated patients of Han Chinese

and Thai origin, a strong association was found between the risk of developing SJS/TEN

and the presence of HLA-B*1502, an inherited allelic variant of the HLA-B gene. The

HLA-B*1502 allele is found almost exclusively in individuals with ancestry across broad

areas of Asia. Results of these studies suggest that the presence of the HLA-B*1502 allele

may be one of the risk factors for carbamazepine-associated SJS/TEN in patients with

Asian ancestry. Therefore, physicians should consider HLA-B*1502 genotyping as a

screening

tool

in

these

patients.

Until

further

information

is

available,

the

use

of

TEGRETOL

and other anti-epileptic

drugs

associated

with

SJS/TEN should

also

be

avoided in patients who test positive for the HLA-B*1502 allele.

Important Limitations of HLA-A and HLA-B Genotyping

HLA-A*3101 and HLA-B*1502 genotyping as screening tools have important limitations

and must never substitute for appropriate clinical vigilance and patient management.

Many patients positive for HLA-A*3101 and treated with TEGRETOL will not develop

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

Page 8 of 46

of any ethnicity can still develop these severe cutaneous adverse reactions. Similarly, many

HLA-B*1502-positive Asian patients treated with TEGRETOL will not develop SJS/TEN,

and these reactions can still occur infrequently in HLA-B*1502-negative patients of any

ethnicity. The role of other possible factors in the development of, and morbidity from,

these

severe

cutaneous

adverse

reactions,

such

as

antiepileptic

drug

(AED)

dose,

compliance,

concomitant

medications,

co-morbidities,

and

the

level

of

dermatologic

monitoring have not been studied.

In addition, it should be kept in mind that over 90% of TEGRETOL treated patients who

will experience SJS/TEN have this reaction within the first few months of treatment. This

information may be taken into consideration when deciding whether to screen genetically

at-risk patients currently on TEGRETOL.

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.

Should

signs

and

symptoms

suggest

a

severe

skin

reaction

such

as

SJS

or

TEN,

TEGRETOL should be withdrawn at once.

Hypersensitivity

TEGRETOL can trigger hypersensitivity reactions, including 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. One or more organs such as skin, liver, lungs, kidneys,

pancreas, myocardium, bone marrow, spleen, thymus, lymph nodes and colon may be affected

(see

ADVERSE REACTIONS

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

syndrome, including maculopapular rash.

In general, if signs and symptoms suggestive of hypersensitivity reactions occur, TEGRETOL

should be withdrawn immediately, and alternative therapy should be considered.

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 (TRILEPTAL

Cross-hypersensitivity can occur between carbamazepine and aromatic antiepileptic drugs (e.g.

phenytoin, primidone and phenobarbital).

General

Page 9 of 46

A tolerance may develop to the action of carbamazepine after a few months of treatment and

should be watched for (see

PART II: SCIENTIFIC INFORMATION-CLINICAL TRIALS

TEGRETOL should not be used in conjunction with the antiretroviral agent delavirdine due to

potential for loss of virologic response and possible resistance to delavirdine or to the class of

non-nucleoside reverse transcriptase inhibitors.

Anticholinergic effects

Like other tricyclic compounds, carbamazepine has a moderate anticholinergic action which is

responsible for some of its side effects. Because of its anticholinergic action, carbamazepine

should be given cautiously, if at all, to patients with increased intraocular pressure or urinary

retention.

Falls

TEGRETOL treatment has been associated with ataxia, dizziness, somnolence, hypotension,

confusional state, sedation (see

Adverse Reactions; Post-Market Adverse Drug Reactions

which may lead to falls and, consequently fractures or other injuries. For patients with diseases,

conditions, or medications that could exacerbate these effects, complete risk assessment of fall

should be considered recurrently for patients on long-term TEGRETOL treatment.

Special excipients

TEGRETOL oral suspension contains parahydroxybenzoates which may cause allergic reactions

(possibly delayed).

Carcinogenesis and Mutagenesis

Long-term toxicity studies in rats indicated a potential carcinogenic risk (see

TOXICOLOGY

Therefore, the possible risk of the drug must be weighed against the potential benefits before

prescribing TEGRETOL to individual patients.

Cardiovascular

TEGRETOL should be used cautiously in patients with a history of coronary artery disease,

organic heart disease, or congestive heart failure. Carbamazepine may suppress ventricular

automaticity

membrane-depressant

effect,

similar

that

quinidine

procainamide, associated with suppression of phase 4 depolarization of the heart muscle fiber

(see

PART II: SCIENTIFIC INFORMATION-CLINICAL TRIALS

If a defective conductive system is suspected, an ECG should be performed before administering

TEGRETOL, in order to exclude patients with atrioventricular block.

Bone Disorders

Page 10 of 46

Long-term use of antiepileptics such as carbamazepine, phenobarbital, phenytoin, primidone,

oxcarbazepine, lamotrigine and sodium valproate is associated with a risk of decreased bone

mineral density that may lead to weakened or brittle bones.

Endocrine and Metabolism

Patients with Fructose Intolerance

TEGRETOL oral suspension contains sorbitol and, therefore, should not be administered to

patients with rare hereditary problems of fructose intolerance.

Hyponatremia

Hyponatremia is known to occur with carbamazepine. Although hyponatremia occurs in 10 to

15% of patients taking carbamazepine, it is seldom symptomatic or severe enough to cause fluid

retention. 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 to 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 the elderly and

renally-compromised patients. If hyponatremia is observed, water restriction is an important

counter-measurement if clinically indicated.

Hypothyroidism

Carbamazepine can reduce serum concentrations of thyroid hormones through enzyme induction

requiring an increase in dose of thyroid replacement therapy in patients with hypothyroidism. In

order to adjust the dosage of thyroid replacement therapy, evaluation of thyroid hormone status

should be considered for patients treated with TEGRETOL, particularly for pediatric patients,

due to the potential risk of hypothyroidism and long-term adverse effects on development that

can occur in relation to undetected changes in thyroid hormone status.

Neurologic

Increased Seizure Frequency

Abrupt withdrawal of TEGRETOL may precipitate seizures. Therefore, if carbamazepine has to

be discontinued, it should be withdrawn gradually over a 6-month period. In epileptic patients,

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

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.

Page 11 of 46

In the event of exacerbation of seizures, TEGRETOL should be discontinued.

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 the plasma

levels.

A number of investigators have reported a deterioration of EEG abnormalities with regard to

focal alterations and a higher incidence of records with nil beta-activity, during carbamazepine-

combined treatment (see

PART II: SCIENTIFIC INFORMATION-CLINICAL TRIALS

Driving and using Hazardous Machines

Patients’ ability to react may be impaired by their medical condition resulting in seizures and

adverse reactions reported with TEGRETOL, including dizziness, drowsiness, ataxia, diplopia,

impaired accommodation and blurred vision. Patients should be advised not to drive or use

complex machines, or engage in other hazardous activities, until they have gained sufficient

experience on carbamazepine to gauge whether it affects their mental and/or motor performance

adversely.

Psychiatric

Because it is closely related to other tricyclic drugs, there is some possibility that carbamazepine

might

activate

latent

psychosis,

elderly

patients,

produce

agitation

confusion,

especially when combined with other drugs. Caution should also be exercised in patients with

alcohol dependence.

Suicidal ideation and behaviour

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

several indications.

All patients treated with antiepileptic drugs, irrespective of indication, 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.

An FDA meta-analysis of randomized placebo controlled trials, in which antiepileptic drugs

were used for various indications, has shown a small increased risk of suicidal ideation and

behaviour in patients treated with these drugs. The reason for this risk is not known.

There were 43892 patients treated in the placebo controlled clinical trials that were included in

the meta-analysis. Approximately 75% of patients in these clinical trials were treated for

indications other than epilepsy and, for the majority of non-epilepsy indications the treatment

Page 12 of 46

(antiepileptic

drug

placebo)

administered

monotherapy.

Patients

with

epilepsy

represented approximately 25% of the total number of patients treated in the placebo controlled

clinical trials and, for the majority of epilepsy patients, treatment (antiepileptic drug or placebo)

was administered as adjunct to other antiepileptic agents (i.e., patients in both treatment arms

were being treated with one or more antiepileptic drug). Therefore, the small increased risk of

suicidal

ideation

behaviour

reported

from

meta-analysis

(0.43%

patients

antiepileptic drugs compared to 0.24% for patients on placebo) is based largely on patients that

received monotherapy treatment (antiepileptic drug or placebo) for non-epilepsy indications. The

study design does not allow for an estimation of the risk of suicidal ideation and behaviour for

patients with epilepsy that are taking antiepileptic drugs, due both to this population being the

minority in the study, and the drug-placebo comparison in this population being confounded by

the presence of adjunct antiepileptic drug treatment in both arms.

Risk of Suicide in Patients with Bipolar Disorder

Patients with bipolar disorder may experience worsening of their depressive symptoms and/or

the emergence of suicidal ideation and behaviors (suicidality) whether or not they are taking

medications for bipolar disorder. Patients should be closely monitored for clinical worsening

(including development of new symptoms) and suicidality, especially at the beginning of a

course of treatment, or at the time of dose changes.

In addition, patients with a history of suicidal behavior or thoughts, those patients exhibiting a

significant degree of suicidal ideation prior to commencement of treatment, and young adults,

are at an increased risk of suicidal thoughts or suicide attempts, and should receive careful

monitoring during treatment.

Patients (and caregivers of patients) should be alerted about the need to monitor for any

worsening of their condition (including development of new symptoms) and /or the emergence

of suicidal ideation/behavior or thoughts of harming themselves and to seek medical advice

immediately if these symptoms present.

Prescriptions for all medications, including TEGRETOL, should be written for the smallest

quantity of tablets consistent with good patient management, in order to reduce the risk of

overdose.

Sexual Function/Reproduction

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

Skin

Mild skin reactions, e.g., isolated macular or maculopapular exanthema, usually disappear within

a few days or weeks, either during a continued course of treatment or following a decrease in

dosage. However, the patient should be kept under close surveillance because of the rare

possibility

Steven-Johnson

Syndrome

Toxic

Epidermal

Necrolysis

occurring

(see

Page 13 of 46

WARNINGS

AND

PRECAUTIONS,

Serious

Warnings

and

Precautions,

DERMATOLOGIC)

In addition to being associated with severe adverse cutaneous reactions

(see WARNINGS AND

PRECAUTIONS)

, the HLA-A*3101 allele has been found to be associated with less severe

adverse cutaneous reactions from carbamazepine, and may predict the risk of such reactions as

anticonvulsant

hypersensitivity

syndrome

non-serious

rash

(maculopapular

eruption).

However, the HLA-B*1502 allele has not been found to predict the risk of these aforementioned

skin reactions

(see WARNINGS AND PRECAUTIONS, Ancestry and Allelic Variation in

the HLA-A Gene)

Special Populations

Pregnant Women

Pregnancy

Women with epilepsy who are, or intend to become pregnant, should be treated with

special care.

In women of childbearing potential, TEGRETOL should, whenever possible, be prescribed

as monotherapy, because the incidence of congenital abnormalities in the offspring of

women treated with more than one antiepileptic drug is greater than in those of women

receiving

a

single

antiepileptic.

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.

If

pregnancy

occurs

in

a

woman

receiving

TEGRETOL,

or

if

the

need

to

initiate

TEGRETOL arises during pregnancy, the drug's expected benefits must be weighed

against its hazards, particularly during the first 3 months of pregnancy. TEGRETOL

should not be discontinued or withheld from patients if required to prevent major seizures

because of the risks posed, to both mother and fetus, by status epilepticus with attendant

hypoxia. 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.

The possibility that carbamazepine, like all major antiepileptic drugs, increases the risk of

malformations has been reported. 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 carbamazepine.

Conclusive evidence from controlled studies with carbamazepine monotherapy is lacking.

Patients

should

be

counseled

regarding

the

possibility

of

an

increased

risk

of

malformations and given the opportunity of antenatal screening.

Page 14 of 46

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

To prevent neonatal bleeding disorders, Vitamin K

1

administration to the mother during

the last weeks of pregnancy, as well as to the newborn, has been recommended.

Cholestatic hepatitis in neonates exposed to carbamazepine in the antenatal period has been

reported. Infants of mothers treated with TEGRETOL should be carefully observed for adverse

hepatobiliary effects.

A few cases of neonatal seizures and respiratory depression have been

associated with maternal TEGRETOL and other concomitant anticonvulsant drug use. A few

cases of neonatal vomiting, diarrhea, and/or decreased feeding have also been associated with

maternal TEGRETOL use. These reactions may represent a neonatal withdrawal syndrome.

Women of child-bearing potential and contraceptive measures

Women of childbearing potential should use effective contraception during treatment with

TEGRETOL and for 2 weeks after the last dose. Due to enzyme induction, TEGRETOL may

result in a failure of the therapeutic effect of oral contraceptive drugs containing estrogen and/or

progesterone. Therefore, women of child bearing potential should be advised to use alternative

contraceptive methods while on treatment with TEGRETOL.

It should be noted that the reliability of oral contraceptives may be adversely affected by

carbamazepine (see DRUG INTERACTIONS).

Nursing Women

Carbamazepine passes into breast milk in concentrations of about 25-60% of the plasma

level. No reports are available on the long-term effect of breast feeding but there have been

some reports of cholestatic hepatitis in neonates exposed to carbamazepine during breast

feeding. The benefits of breast feeding should be weighed against the possible risks to the

infant and a decision should be made whether to discontinue nursing or to discontinue

TEGRETOL, taking into account the importance of the drug to the mother. Therefore

breast-fed infants of mothers treated with carbamazepine should be carefully observed for

adverse reactions such as somnolence, allergic skin reactions and adverse hepatobiliary

effects.

Geriatrics (> 65 years of age):

Page 15 of 46

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

TEGRETOL should be selected with caution in elderly patients. In general, dose selection for an

elderly patient usually starts at the low end of the dosing range, reflecting the greater frequency

of decreased hepatic, renal, or cardiac function, and of concomitant disease.

Monitoring and Laboratory Tests

TEGRETOL should be prescribed only after a critical risk-benefit appraisal in patients with a

history of cardiac, hepatic or renal damage, adverse hematological reactions to other drugs, or

interrupted courses of therapy with TEGRETOL.

Careful clinical and laboratory supervision

should be maintained throughout treatment.

Should any signs or symptoms or abnormal

laboratory findings be suggestive of blood dyscrasia or liver disorder, TEGRETOL should be

immediately discontinued until the case is carefully reassessed.

Bone marrow function

Complete blood counts, including platelets and possibly reticulocytes and serum iron, should be

carried out before treatment is instituted, and periodically thereafter.

If definitely low or decreased white blood cell or platelet counts are observed during treatment,

patient

complete

blood

count

should

monitored

closely.

Non-progressive

fluctuating asymptomatic leucopenia, which is encountered, does not generally call for the

withdrawal of TEGRETOL. However, treatment with TEGRETOL should be discontinued if the

patient develops leucopenia which is progressive or accompanied by clinical manifestations, e.g.,

fever or sore throat, as this could indicate the onset of significant bone marrow depression.

Because the onset of potentially serious blood dyscrasias may be rapid, patients should be

made aware of early toxic signs and symptoms of a potential hematological 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 hemorrhage appear, the

patient should be advised to consult his/her physician immediately.

Hepatic function

Baseline and periodic evaluations of hepatic function must be performed, particularly in elderly

patients

patients

with

history

liver

disease.

TEGRETOL

should

withdrawn

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

Renal

function

Pre-treatment and periodic complete urinalysis and BUN determinations should be performed.

Ophthalmic examinations

Carbamazepine has been associated with pathological eye changes. Periodic eye examinations,

Page 16 of 46

including slit-lamp funduscopy and tonometry are recommended.

Plasma levels

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

levels and clinical efficacy or tolerability are rather tenuous, monitoring 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, especially where more than one drug is being used

(see DRUG

INTERACTIONS)

ADVERSE REACTIONS

Adverse Drug Reaction Overview

The reactions which have been most commonly reported with TEGRETOL (carbamazepine) are

CNS disturbances (e.g., drowsiness, headache, unsteadiness on the feet, diplopia, dizziness),

gastrointestinal disturbances (nausea, vomiting), and allergic skin reactions. These reactions

usually occur only during the initial phase of therapy, if the initial dose is too high, or when

treating elderly patients. They have rarely necessitated discontinuing TEGRETOL therapy, and

can be minimized by initiating treatment at a low dosage.

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 the plasma

levels.

The more serious adverse reactions observed are the hematologic, hepatic, cardiovascular and

dermatologic reactions, which require discontinuation of therapy.

The following adverse drug reactions from clinical and post-market experience

are listed by

MedDRA system organ class. 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).

Blood and lympathic system disorders

Very common

: leucopenia;

Common

: eosinophilia, thrombocytopenia;

Rare

: leucocytosis, lymphadenopathy,

Very rare

: agranulocytosis, aplastic anemia, pancytopenia, pure red cell aplasia, anemia,

macrocytic

anemia,

megaloblastic

anemia,

reticulocytosis,

thrombocytopenic

purpura

hemolytic anemia. In a few instances, deaths have occurred.

Page 17 of 46

Hepatobiliary disorders

Rare

: hepatitis of a 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

: erythematous rashes, urticaria which may be severe, allergic dermatitis and

rashes;

Uncommon

: exfoliative dermatitis;

Rare

: systemic lupus erythematosus, pruritis;

Very

rare

Steven

Johnson

syndrome

toxic

epidermal

necrolysis

(Lyell's

syndrome),

photosensitivity

reaction,

erythema

multiform,

erythema

nodosum,

pigmentation

disorder,

purpura, acne, diaphoresis, alopecia, neurodermatitis, hirsutism.

Nervous system disorders

Very common

: ataxia, dizziness, somnolence;

Common

: an increase in motor seizures

(see Indications)

, diplopia, headache;

Uncommon

abnormal

involuntary

movements

(e.g.,

tremor,

asterixis,

dystonia,

tics),

nystagmus;

Rare

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

speech), choreoathetosis, peripheral neuropathy, paraesthesia, muscle weakness;

Very rare

: neuroleptic malignant syndrome, aseptic meningitis with myoclonus and peripheral

eosinophilia, dysgeusia.

Cardiac disorders

Rare

: cardiac conduction disorders (including second and third degree atrioventricular heart

block);

Very rare

: arrhythmias, Stokes-Adams in patients with atrioventricular block, bradycardia,

congestive cardiac failure, aggravated coronary artery disease. Some of these cardiovascular

complications

have

fatal

outcomes.

Myocardial

infarction

arrhythmia

have

been

associated with other tricyclic compounds.

Vascular disorders

Rare:

hypertension or hypotension;

Very

Rare:

circulatory

collapse,

thromboembolism

(e.g.

pulmonary

embolism),

thrombophlebitis.

Psychiatric disorders

Rare

hallucinations

(visual

auditory),

depression,

talkativeness,

agitation,

anorexia,

restlessness, confusional state;

In some Asian countries also reported as rare. See Warnings.

Page 18 of 46

Very rare

: activation of psychosis. Very rare cases of suicide attempt and completed suicide have

been reported, however a causal relationship has not been established.

Renal and urinary disorders

Very

rare

tubulointerstitial

nephritis,

renal

failure,

renal

impairment

(e.g.,

albuminuria,

glycosuria, hematuria, oliguria sometimes associated with elevated blood pressure, and blood

urea nitrogen increased/azotemia), urinary retention, urinary frequency.

Reproductive system

Very rare

: sexual dysfunction/erectile dysfunction, spermatogenesis abnormal (with decreased

sperm count and/or motility).

Gastrointestinal disorders

Very common

: vomiting, nausea;

ommon

: dry mouth and throat;

Uncommon

: diarrhea, constipation;

Rare

: abdominal pain;

Very rare

: pancreatitis, glossitis, stomatitis;

Eye disorders

Common:

accommodation disorders (e.g. blurred vision);

Very rare

: lenticular opacities, conjunctivitis, retinal changes.

Ear and labyrinth disorders

Very rare

: hearing disorders (e.g. tinnitus, hyperacusis, hypoacusis), change in pitch perception.

Endocrine disorders

Common

: edema, fluid retention, weight increase, hyponatremia and blood osmolarity decreased

due to antidiuretic hormone (ADH)-like effect occurs, leading in rare cases to water intoxication

accompanied by lethargy, vomiting, headache, confusional state, neurological disorders;

Very rare

: galactorrhea, gynecomastia.

Metabolism and nutrition disorders

Rare:

folate deficiency, decreased appetite;

Very rare:

acute porphyria (acute intermittent porphyria and variegate porphyria), non-acute

porphyria (porphyria cutanea tarda).

Musculoskeletal, connective tissue and bone disorders

Very rare

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

cholecalciferol) leading to osteomalacia/osteoporosis, arthralgia, myalgia, muscle spasms.

Respiratory, thoracic and mediastinal system

Very

rare

pulmonary

hypersensitivity

characterized

fever,

dyspnea,

pneumonitis

pneumonia.

Page 19 of 46

Immune system disorders

Rare

delayed

multi-organ

hypersensitivity

disorder

with

fever,

rashes,

vasculitis,

lymphadenopathy, pseudo lymphoma, arthralgia, leucopenia, eosinophilia, hepatosplenomegaly,

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, hypogammaglobulinemia.

General disorders and administration site conditions

Very common

: fatigue.

Investigations

Very common:

increased gamma-glutamyltransferase (due to hepatic enzyme induction), usually

not clinically relevant;

Common:

increased

blood alkaline phosphatase;

Uncommon:

increased transaminases;

Very rare:

increased intraocular pressure, increased blood cholesterol, increased high density

lipoprotein, increased blood triglycerides. Abnormal thyroid function test: decreased L-Thyroxin

(free thyroxine, thyroxine, tri-iodothyronine) and increased blood thyroid stimulating hormone,

increased blood prolactin (usually without clinical manifestations).

Post-Market Adverse Drug Reactions

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.

Blood and lympathic system disorders:

bone marrow failure.

Gastrointestinal disorders:

colitis.

Immune system disorders:

Drug Rash with Eosinophilia and Systemic Symptoms (DRESS).

Infections and infestations:

reactivation of human herpesvirus 6 infection.

Injury, poisoning and procedural complications:

Fall (associated with TEGRETOL treatment

induced

ataxia,

dizziness,

somnolence,

hypotension,

confusional

state,

sedation)

(see

WARNINGS and PRECAUTIONS

Investigations:

bone density decreased.

Musculoskeletal, connective tissue and bone disorders:

fracture.

Page 20 of 46

Nervous system disorders:

sedation, memory impairment.

Skin

and

subcutaneous

tissue

disorders:

Acute

Generalized

Exanthematous

Pustulosis

(AGEP), lichenoid keratosis, onychomadesis.

DRUG INTERACTIONS

Overview

Cytochrome

P450

(CYP3A4)

main

enzyme

responsible

metabolizing

carbamazepine.

Enzyme Inhibition

Co-administration of CYP3A4 inhibitors may increase carbamazepine plasma concentrations and

induce adverse reactions. Drugs that have been shown, or would be expected, to increase plasma

carbamazepine levels include:

cimetidine,

danazol,

diltiazem,

macrolides,

erythromycin,

troleandomycin,

clarithromycin, fluoxetine, fluvoxamine, nefazodone, loratadine, terfenadine, isoniazid,

niacinamide,

nicotinamide,

propoxyphene,

azoles

(e.g.,

ketaconazole,

itraconazole,

fluconazole), acetazolamide, verapamil, grapefruit juice, protease inhibitors, valproate.

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

formation

10,11-transdiol

derivative

from

carbamazepine-10,11

epoxide.

administration of inhibitors of human microsomal epoxide hydrolase may result in increased

carbamazepine-10,11 epoxide plasma concentrations. Drugs that have been shown, or are

expected, to inhibit the Human microsomal epoxide hydrolase include: Valproate, Quetiapine,

felbamate, loxapine

Enzyme Induction

Co-administration of CYP3A4 inducers may increase the rate of TEGRETOL metabolism

leading

potential

decreases

carbamazepine

serum

levels

therapeutic

effect.

Alternatively, discontinuation of a CYP3A4 inducer may decrease the rate of metabolism of

carbamazepine, leading to an increase in carbamazepine plasma levels. Drugs that have been

shown, or that would be expected, to decrease plasma carbamazepine levels include:

cisplatin, doxorubicin HCl, felbamate

, rifampin, phenobarbital, phenytoin, primidone,

methsuximide, theophylline.

Increased levels of the active 10, 11-epoxide

Decreased levels of carbamazepine and increased levels of the 10, 11-epoxide

Page 21 of 46

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.

Carbamazepine, like other psycho-active drugs, may reduce the patient's alcohol tolerance; it is

therefore advisable to abstain from alcohol consumption during treatment.

Drug-Drug Interactions

Effects 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 when

administered with TEGRETOL:

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

(warfarin,

phenprocoumon,

dicoumarol,

acenocoumarol

rivaroxaban, dabigatran, apixaban, edoxaban).

Antidepressants: bupropion, citalopram,

mianserin, nefadozone,

sertraline, trazodone

,

tricyclic

antidepressants (e.g. imipramine, amitriptyline, nortryptyline, clomipramine).

Antiemetics: aprepitant.

Antiepileptics: oxcarbazepine, clobazam, clonazepam, ethosuximide, primidone, valproic acid,

felbamate, lamotrigine, eslicarbazepine, zonisamide tiagabine, topiramate. Phenytoin plasma

levels have been reported both to be raised and lowered by carbamazepine. Phenytoin has also

been shown to decrease carbamazepine plasma levels. To avoid phenytoin intoxication and

subtherapeutic concentrations of carbamazepine, it is recommended to monitor the plasma

concentration of both drugs during titration and adjust dosage accordingly. Mephenytoin plasma

levels have been reported in rare instances to increase.

Antifungals:

caspofungin,

itraconazole,

voriconazole.

TEGRETOL

should

used

combination with voriconazole or itraconazole

(see CONTRAINDICATIONS).

Antihelmintics: praziquantel, albendazole.

Antineoplastics: imatinib, irinotecan, gefitinib, cyclophosphamide, lapatinib, temsirolimus.

Page 22 of 46

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

zisprasidone, aripiprazole, paliperidone.

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

antiretroviral agent delavirdine.

Anxiolytics: alprazolam, midazolam.

Bronchodilators or anti-asthma drugs: theophylline.

Contraceptives: hormonal contraceptives.

Cardiovascular

drugs:

calcium

channel

blockers

(dihydropyridine

group),

e.g.

felodipine,

digoxin, disopyramide

quinidine, propranolol, simvastatin, atorvastatin, lovastatin, ivabradine.

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

Drugs used in erectile dysfunction: tadalafil.

Immunosuppressants: cyclosporin, everolimus, tacrolimus, sirolimus.

Thyroid agents: levothyroxine.

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

Agents that may raise carbamazepine and/or carbamazepine-10,11-epoxide plasma levels

Since an increase in carbamazepine and/or carbamazepine-10,11-epoxide plasma levels may

result

adverse

reactions

(e.g.,

dizziness,

drowsiness,

ataxia,

diplopia),

dosage

TEGRETOL

should

adjusted

accordingly

blood

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, telithromycin), ciprofloxacine.

Antidepressants:

possibly

desipramine,

fluoxetine,

fluvoxamine,

nefadozone,

paroxetine,

trazodone, viloxazine.

Antiepileptics: stiripentol, vigabatrin.

Antifungals: azoles (itraconazole, ketoconazole, fluconazole, voriconazole). TEGRETOL should

not be used in combination with voriconazole or itraconazole

(see CONTRAINDICATIONS).

Antihistamines: terfenadine, loratadine.

Antipsychotics: loxapine, olanzapine, quetiapine.

Page 23 of 46

Antituberculosis: isoniazid.

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

Carbonic anhydrase inhibitors: acetazolamide.

Cardiovascular drugs: verapamil, diltiazem.

Gastrointestinal drugs: cimetidine, omeprazole.

Muscle relaxants: oxybutynin, dantrolene.

Platelet aggregation inhibitors: ticlopidine.

Other interactions: nicotinamide.

Loxapine, felbamate, quetiapine, primidone, valproic acid and valpromide were reported to

increase concentration of the active metabolite carbamazepine-10,11-epoxide.

Agents that may decrease carbamazepine plasma levels

The dose of TEGRETOL may consequently have to be adjusted when used concomitantly with

the substances described below:

Antiepileptics: felbamate (might decrease the carbamazepine serum concentration associated

with an increase in carbamazepine epoxide levels, and might decrease the serum felbamate

levels),

methsuximide,

oxcarbazepine,

phenobarbital,

phensuximide,

phenytoin

avoid

phenytoin intoxication and subtherapeutic concentrations of carbamazepine, it is recommended

monitor

plasma

concentration

both

drugs

during

titration

(see

also

Effects

of

TEGRETOL

on

Plasma

Levels

of

Concomitant

Agents

fosphenytoin

,

primidone,

progabide, and possibly by clonazepam, valproic acid or valpromide.

Antineoplastics: cisplatin or doxorubicin.

Antituberculosis: rifampicin.

Bronchodilators or anti-asthma drugs: theophylline, aminophylline.

Dermatological drugs: isotretinoin.

Combinations that require specific consideration

Concomitant

carbamazepine

levetiracetam

been

reported

increase

carbamazepine-induced toxicity (e.g., nystagmus, nausea, vomiting).

Combined use of TEGRETOL with lithium, metoclopramide, or haloperidol, may increase the

risk of neurotoxic side effects (even in the presence of "therapeutic plasma levels").

Page 24 of 46

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

hepatotoxicity.

TEGRETOL,

like

other

anticonvulsants,

adversely

affect

reliability

hormonal

contraceptives; breakthrough bleeding may occur. Accordingly, patients should be advised to

use some alternative, non-hormonal method of contraception while taking TEGRETOL. Due to

enzyme

induction,

TEGRETOL

result

failure

therapeutic

effect

oral

contraceptive drugs containing estrogen and/or progesterone (e.g. failure of contraception).

Concomitant

medication

with

TEGRETOL

some

diuretics

(hydrochlorothiazide,

furosemide) may lead to symptomatic hyponatremia.

Carbamazepine

antagonize

effects

non-depolarising

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.

Isotretinoin has been reported to alter the bioavailability and/or clearance of carbamazepine and

carbamazepine 10,11-epoxide; carbamazepine plasma levels should be monitored.

The use of TEGRETOL in combination with MAO inhibitors (MAOIs) is contraindicated.

Before administering TEGRETOL, MAOIs should be discontinued for a minimum of 2 weeks,

or longer, if the clinical situation permits

(see CONTRAINDICATIONS)

Concomitant

carbamazepine

with

direct

acting

oral

anti-coagulants

(rivaroxaban,

dabigatran, apixaban, and edoxaban) may lead to reduced plasma concentrations of direct acting

oral anti-coagulants, which carries the risk of thrombosis. Therefore, if a concomitant use is

necessary, close monitoring of signs and symptoms of thrombosis is recommended.

Drug-Food Interactions

Agents that may raise carbamazepine and/or carbamazepine-10,11-epoxide plasma levels:

grapefruit juice.

Drug-Herb Interactions

Agents that may decrease carbamazepine plasma levels:

herbal preparations containing St

John’s wort (Hypericum perforatum).

Drug-Laboratory Interactions

Page 25 of 46

Interference with serological testing

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

interference.

Carbamazepine

10,11-epoxide

metabolite

result

false

positive

tricyclic

antidepressant concentration in fluorescence polarized immunoassay method.

DOSAGE AND ADMINISTRATION

Dosing Considerations

Geriatrics:

Due to drug interactions and different antiepileptic drug pharmacokinetics, the

dosage of TEGRETOL (carbamazepine) should be selected with caution in elderly patients. In

general, dose selection for an elderly patient usually starts at the low end of the dosing range,

reflecting

greater

frequency

decreased

hepatic,

renal,

cardiac

function,

concomitant disease.

Renal impairment/Hepatic impairment:

No data are available on the pharmacokinetics of

carbamazepine in patients with any degree of hepatic or renal impairment.

Recommended Dose

and Dosage Adjustment

Use in Epilepsy

TEGRETOL may be used alone or with other anticonvulsants. A low initial daily dosage of

TEGRETOL with a gradual increase in dosage is advised. To achieve adequate control of

seizures, dosage should be adjusted to the needs of the individual patient. Determination of

plasma levels may help in establishing the optimum dosage. In the treatment of epilepsy, the

dose of carbamazepine should be adjusted to maintain steady state plasma concentration of about

4 - 10 µg/mL (

see

ACTIONS AND CLINICAL PHARMACOLOGY)

. TEGRETOL should be

taken with meals whenever possible.

TEGRETOL Tablets, CHEWTABS and Suspension should be taken in 2 to 4 divided doses

daily.

TEGRETOL CHEWTABS and the Suspension are particularly suitable for patients who have

difficulty swallowing tablets or who need initial careful adjustment of dosage.

The controlled release characteristics of TEGRETOL CR reduce the daily fluctuations of plasma

carbamazepine. TEGRETOL CR tablets (either whole or, if so prescribed, only half a tablet)

should be swallowed unchewed with a little liquid during or after a meal. These controlled

Page 26 of 46

release tablets should be prescribed as a twice-daily dosage. If necessary, three divided doses

may be prescribed. Some patients have been reported to require a dosage increase when

switching from tablets to CR tablets. Dosage adjustments should be individualized based on

clinical response and, if necessary, plasma carbamazepine levels.

Adults and Children Over 12 Years of Age

Initially, 100 to 200 mg once or twice a day depending on the severity of the case and previous

therapeutic history. The initial dosage is progressively increased, in divided doses, until the best

response is obtained. The usual optimal dosage is 800 to 1200 mg daily. In rare instances some

adult patients have received 1600 mg. As soon as disappearance of seizures has been obtained

and maintained, dosage should be reduced very gradually until a minimum effective dose is

reached.

Children 6-12 Years of Age

Initially, 100 mg in divided doses on the first day. Increase gradually by adding 100 mg per day

until the best response is obtained. Dosage should generally not exceed 1000 mg daily. As soon

as disappearance of seizures has been obtained and maintained, dosage should be reduced very

gradually until a minimum effective dose is reached.

Combination Therapy

When added to existing anticonvulsant therapy, the drug should be added gradually while the

other anticonvulsants are maintained or gradually decreased, except for phenytoin, which may be

increased

(see WARNINGS AND PRECAUTIONS, Special Populations: Pregnant Women

and DRUG INTERACTIONS)

Use in Trigeminal Neuralgia

The initial daily dosage should be small; 200 mg taken in 2 doses of 100 mg each is

recommended. The total daily dosage can be increased by 200 mg/day until relief of pain is

obtained. This is usually achieved at dosage between 200 and 800 mg daily, but occasionally up

to 1200 mg/day may be necessary. Maximum recommended dose is 1200 mg/day. As soon as

relief of pain has been obtained and maintained, progressive reduction in dosage should be

attempted

until

minimal

effective

dosage

reached.

Because

trigeminal

neuralgia

characterized by periods of remission, attempts should be made to reduce or discontinue the use

of TEGRETOL at intervals of not more than 3 months, depending upon the individual clinical

course.

Prophylactic use of the drug in trigeminal neuralgia is not recommended.

Use in Mania and Bipolar (Manic-Depressive) Disorders

The initial daily dosage should be low, 200 to 400 mg/day, administered in divided doses,

Page 27 of 46

although higher starting doses of 400 to 600 mg/day may be used in acute mania. This dose may

be gradually increased until patient symptomatology is controlled or a total daily dose of 1600

mg is achieved. Increments in dosage should be adjusted to ensure optimal patient tolerability.

The usual dose range is 400 to 1200 mg/day administered in divided doses. Doses used to

achieve

optimal

acute

responses

tolerability

should

continued

during

maintenance

treatment. When given in combination with lithium and neuroleptics, the initial dosage should

be low, 100 mg to 200 mg daily, and then increased gradually. A dose higher than 800 mg/day is

rarely

required

when

given

combination

with

neuroleptics

lithium,

with

other

psychotropic drugs such as benzodiazepines. Plasma levels are probably not helpful for guiding

therapy in bipolar disorders.

Administration

TEGRETOL Suspension should be well shaken before use since improper re-suspension may

lead to administering an incorrect dose. Since a given dose of TEGRETOL Suspension produces

higher peak carbamazepine levels than the same dose in tablet form, it is advisable to start with

low doses and to increase slowly to avoid adverse reactions. When switching a patient from

TEGRETOL Tablets to TEGRETOL Suspension, the same number of mg per day should be

given in smaller, more frequent doses (i.e., BID Tablets to TID Suspension).

OVERDOSAGE

Lowest known lethal dose:

estimated 3.2 g (24 year old woman).

Highest known doses survived:

80 g (34 year old man); 34 g (13 year old girl); 1.4 g (23

month old girl).

Symptoms of Overdosage

presenting

signs

symptoms

overdosage

usually

involve

central

nervous,

cardiovascular, and respiratory systems, as well as the adverse drug reactions mentioned under

the Adverse Reaction section.

Central Nervous System: CNS depression, disorientation, depressed level of consciousness,

tremor, restlessness, somnolence, agitation, hallucination, coma, blurred vision, nystagmus,

mydriasis, slurred speech, dysarthria, ataxia, dyskinesia, abnormal reflexes (slowed/hyperactive),

convulsions, psychomotor disturbances, myoclonus, opisthotonia, hypothermia/ hyperthermia,

flushed skin/cyanosis, EEG changes.

Respiratory System: respiratory depression, pulmonary edema.

Cardiovascular System: tachycardia, hypotension/hypertension, conduction disturbance with

widening of QRS complex, syncope in association with cardiac arrest.

Page 28 of 46

Gastrointestinal System: nausea, vomiting, delayed gastric emptying, reduced bowel motility.

Musculoskeletal

system:

There

have

been

some

cases

which

reported

rhabdomyolysis

association with carbamazepine toxicity.

Renal Function: urinary retention, oliguria or anuria; fluid retention, and water intoxication.

Laboratory Findings: hyponatremia, hypokalemia, leukocytosis, reduced white cell count,

metabolic

acidosis,

hyperglycemia,

glycosuria,

acetonuria,

increased

muscle

creatine

phosphokinase.

Treatment of Overdosage

For up-to date information on the management of a suspected drug overdose, contact the

regional Poison Control Center.

There is no known specific antidote to TEGRETOL (carbamazepine).

Evacuate the stomach, with an emetic or by gastric lavage and then administer activated

charcoal. Delay in evacuating the stomach may result in delayed absorption, leading to relapse

during recovery from intoxication.

Hemodialysis is the effective treatment modality in the management of the carbamazepine

overdose.

Vital signs, including electrocardiogram to detect any cardiac arrhythmias or conduction defects,

should

watched

symptomatic

treatment

should

administered

required.

Hyperirritability or convulsions should be appropriately managed by standard medical care.

Hyponatremia should be appropriately managed by standard medical care.

Shock (circulatory collapse) should be treated with supportive measures, including intravenous

fluids, oxygen, and corticosteroids.

Charcoal hemoperfusion has been recommended.

Relapse and aggravation of the symptomatology on the 2nd or 3rd day after overdose, due to

delayed absorption, should be anticipated.

ACTION AND CLINICAL PHARMACOLOGY

Page 29 of 46

Pharmacodynamics

TEGRETOL (carbamazepine) has anticonvulsant properties which have been found useful in the

treatment of partial seizures (simple or complex) with and without secondary generalization, and

generalized tonic-clonic seizures. A mild psychotropic effect has been observed in some

patients, which seems related to the effect of carbamazepine in localization-related epilepsies and

syndromes.

Pharmacokinetics

Absorption:

The absorption of carbamazepine in man is relatively slow. When taken in a single

oral dose, TEGRETOL (carbamazepine tablets) and TEGRETOL CHEWTABS (carbamazepine

chewable tablets) yield peak plasma concentrations of unchanged carbamazepine within 4-24

hours. With respect to the quantity of carbamazepine absorbed, there is no clinically relevant

difference

between

various

dosage

forms.

However,

TEGRETOL

Suspension

(carbamazepine suspension) is absorbed somewhat faster than the tablet; peak plasma levels are

reached within 2 hours. Following BID dosage regimens, higher peak levels and lower trough

levels are obtained with the suspension than with the tablets. Steady-state plasma levels are

comparable for TEGRETOL Suspension given TID and TEGRETOL Tablets given BID, when

administered at the same total daily dose.

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

the dosage form of TEGRETOL.

When TEGRETOL CR (carbamazepine controlled release tablets) are administered repeatedly,

they yield a lower average maximal concentration of carbamazepine in the plasma, without a

reduction in the average minimal concentration. This tends to result in a lower incidence of

intermittent concentration-dependent adverse drug reactions. It also ensures that the plasma

concentrations remain largely stable throughout the day, thereby making it possible to manage

with a twice-daily dosage.

In patients with epilepsy, the therapeutic range for the steady-state plasma concentration of

carbamazepine generally lies between 4-10 µg/mL.

Distribution:

Carbamazepine becomes bound to serum proteins to the extent of 70-80%. The

concentration of unchanged substance in the saliva reflects the non-protein-bound portion

present in the serum (20-30%).

Metabolism:

Carbamazepine

catabolized

into

primary

pharmacologically

active

metabolite, carbamazepine-10,11 epoxide, which is then further metabolized primarily into

carbamazepine 10,11-transdiol. A small portion of the carbamazepine-10,11 epoxide is also

converted into 9-hydroxymethyl-10-carbamoyl-acridan. Additional biotransformation products

include

various

monohydroxylated

compounds

N-glucuronide

carbamazepine

produced by UGT2B7.

Page 30 of 46

elimination

half-life

unchanged

carbamazepine

plasma

averages

approximately

36 hours following a single oral dose. Repeated administration leads to autoinduction of hepatic

enzymes and an elimination half-life of only 16-24 hours, depending on the length of the

treatment. In patients receiving concomitant treatment with other enzyme-inducing antiepileptic

agents, half-life values averaging 9-10 hours have been found. The mean elimination half-life of

carbamazepine-10,11 epoxide in the plasma is about 6 hours following single oral doses of the

epoxide itself. One study in 39 children (aged 3-10 years) and 79 adults (aged 15-65 years),

suggests

that

carbamazepine

elimination

be slightly

enhanced

children.

This

data

suggests that children may require higher doses of carbamazepine (in mg/kg) than adults.

Excretion:

Only 2-3% of carbamazepine, whether administered as a single or in repeated doses,

is excreted in the urine in an unchanged form. Approximately 30% of carbamazepine is renally

eliminated via the carbamazepine-10,11 epoxide pathway with carbamazepine 10,11-trans-diol

as the main urinary metabolite.

Special Populations and Conditions

Geriatrics:

Due to drug interactions and different antiepileptic drug pharmacokinetics, the

dosage of TEGRETOL should be selected with caution in elderly patients.

Hepatic Impairment:

No data are available on the pharmacokinetics of carbamazepine in

patients with any degree of hepatic impairment.

Renal Impairment:

No data are available on the pharmacokinetics of carbamazepine in patients

with any degree of renal impairment.

STORAGE AND STABILITY

Tablets: Store at 15-25

C, protect from humidity.

CHEWTABS:

Store below 30

C, protect from humidity and light.

Store below 25

C, protect from humidity.

Suspension:

Store below 30

C, protect from humidity and light.

TEGRETOL (carbamazepine) must be kept out of the reach and sight of children.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Page 31 of 46

Availability of Dosage Forms

TEGRETOL Tablets 200 mg are white, round, flat-faced and bevel-edged. One side bears the

imprint “CG”, the other “G/K” and a score. Available in bottles of 100 & 500.

TEGRETOL CHEWTABS 100 mg are white with red specks, round, flat-faced, bevel-edged.

GEIGY engraved on one side and M/R with bisect on the other. Available in bottles of 100.

TEGRETOL CHEWTABS 200 mg are white with red specks, oval and biconvex. GEIGY

engraved on one side and P/U with bisect on the other. Available in bottles of 100.

TEGRETOL CR Tablets 200 mg are beige-orange, oval and slightly biconvex. C/G engraved on

one side and H/C engraved on the other. Fully bisected on both sides. Available in bottles of

100.

TEGRETOL

Tablets

brown-orange,

oval

slightly

biconvex.

CG/CG

engraved on one side and ENE/ENE engraved on the other. Fully bisected on both sides.

Available in bottles of 100.

TEGRETOL Suspension 100 mg/tsp is orange. Available in bottles of 450 mL.

Composition

TEGRETOL tablets contain the following non-medicinal ingredients: cellulose compounds,

magnesium stearate silicon dioxide.

TEGRETOL

CHEWTABS

contain

following

non-medicinal

ingredients:

cherry-mint

flavour, corn starch, erythrosine, gelatin, glycerin, magnesium stearate, silicon dioxide, sodium

starch glycolate, stearic acid, sugar.

TEGRETOL

contain

following

non-medicinal

ingredients:

acrylic

esters,

cellulose

compounds, iron oxides, magnesium stearate, silicon dioxide, talc, titanium dioxide, castor oil

derivative.

TEGRETOL Suspension contain the following non-medicinal ingredients:

citric acid, citrus-

vanilla flavour, FD&C Yellow No. 6, pluronic polyol, potassium sorbate, propylene glycol,

sucrose, sorbitol, water, xanthan gum.

Page 32 of 46

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Common name: carbamazepine

Chemical name: 5H-dibenzo(b,f)azepine-5carboxamide

Molecular formula and molecular mass: C

O and 236.27

Structural formula:

Physicochemical properties: White to off-white powder

Solubility: Practically insoluble in water and in acetone

CLINICAL TRIALS

Evidence supporting the efficacy of TEGRETOL (carbamazepine) as an anticonvulsant was

derived from active drug-controlled studies that enrolled patients with the following seizure

types:

Partial seizures with simple or complex symptomatology.

Generalized tonic-clonic seizures.

Mixed seizure patterns which include the above, or other partial or generalized seizures.

Carbamazepine relieves or diminishes the pain associated with trigeminal neuralgia often within

24 to 48 hours.

Carbamazepine given as a monotherapy or in combination with lithium or neuroleptics has been

found

useful

treatment

acute

mania

prophylactic

treatment

bipolar

(manic-depressive) disorders.

A tolerance may develop to the action of carbamazepine after a few months of treatment and

Page 33 of 46

should be watched for.

Carbamazepine may suppress ventricular automaticity due to its membrane-depressant effect,

similar

that

quinidine

procainamide,

associated

with

suppression

phase 4

depolarization of the heart muscle fiber.

A number of investigators have reported a deterioration of EEG abnormalities with regard to

focal alterations and a higher incidence of records with nil

-activity, during carbamazepine-

combined treatment.

DETAILED PHARMACOLOGY

When administered to mice by the oral route at the dose level of 100 mg/kg, carbamazepine

protected all animals against electroshock-induced convulsions (50 mA for 0.2 seconds) for up to

5 hours. In rats, at 50 mg/kg orally, the convulsive threshold was increased by 88%, and at the

dosage of 100 mg/kg, carbamazepine increased the convulsive threshold by about 130%. On the

other hand, very minimal effects were noted when carbamazepine was given to mice challenged

with picrotoxin and it did not block pentylenetetrazol-induced convulsions.

Carbamazepine has slight sedative and tranquilizing effects in mice but no hypnotic effect except

at almost toxic doses. Although intact and spinal animals are influenced in the same way as by

muscle relaxants, carbamazepine has no clinically significant muscle relaxant action. In animals,

carbamazepine has only a slight anticholinergic effect and no antiemetic activity. Carbamazepine

did not inhibit monoamine oxidase in the guinea pig liver at the drug concentration of 1 x 10

In rabbits, carbamazepine administered intravenously could not be given in a dosage sufficient to

produce a Stage IV anesthesia (Magnus and Girndt) without toxic effects. Hence, the anesthetic

potential is considered nil.

In experimental animals, carbamazepine depresses certain pain reflexes that are mediated by

cranial nerves, such as the linguomandibular and infraorbital reflexes. There is no general

analgesic effect and non-specific cutaneous pain is not modified by carbamazepine, except at

very high doses. In humans, the effect of carbamazepine upon trigeminal or glossopharyngeal

pain is probably largely due to blocking of bulbar, thalamic and higher synapses.

In experimental animals, carbamazepine is rapidly absorbed and rapidly equilibrated between the

blood and tissues. It does not accumulate in tissues other than adipose tissue. In the rabbit,

carbamazepine is rapidly metabolized and excreted so that blood and tissue levels are very low

within 24 hours. Only about 2% is excreted unchanged in the urine.

TOXICOLOGY

Page 34 of 46

Acute Toxicity

In mice, the oral LD

of carbamazepine is between 1100 and 3750 mg/kg; in rats, 3850-

4025 mg/kg; in rabbits, 1500-2680 mg/kg; in guinea pigs, about 920 mg/kg; and in dogs, more

than 5620 mg/kg.

The principal toxic effects in these species were laboured breathing, ataxia, clonic and tonic

convulsions, and coma. In dogs, toxic doses of carbamazepine induced severe vomiting and

defecation, in addition to disturbance of locomotor function.

Subacute and Chronic Toxicity

Subacute and chronic toxicity studies have been carried out on carbamazepine for up to one year

at dosage levels of 50, 100, 200 and 400 mg/kg in rats and 50, 100, 150 and 200 mg/kg in the

dog. In rats, at 100 and 200 mg/kg/day and above, there was evidence of hepatotoxicity including

a slight increase in ALT and histological changes in the liver. At a dosage of 400 mg/kg/day, 25

of 50 animals died, beginning at the 15th week. ALT and BUN levels were slightly increased.

The relative organ/body weight ratios were increased for the heart, liver and kidneys.

Carcinogenicity and Genotoxicity

Carbamazepine, when administered to Sprague-Dawley rats for 2 years in the diet at doses of 25,

75 and 250 mg/kg/day, resulted in a dose-related increase in the incidence of hepatocellular

tumors in females and in benign interstitial cell adenomas in the testes of males. Carbamazepine

must, therefore, be considered to be carcinogenic in Sprague-Dawley rats. Carbamazepine was

not found to be genotoxic in various standard bacterial and mammalian mutagenicity studies.

The carcinogenicity findings in rats are considered to be not relevant to the use of carbamazepine

in humans.

Testicular atrophy and deficient spermatogenesis were observed in a four week oral study with

carbamazepine in the rat at 100 mg/kg/day, but were not observed in animals dosed with 200,

500 and 1000 mg/kg/day. In a 24 week study in rats, evidence of testicular atrophy was observed

in 3 of 10 animals at 50 mg/kg/day and in one of 10 at 100 mg/kg/day, but no testicular damage

was observed at 200 mg/kg/day. In a one year study, inhibition of spermatogenesis and testicular

atrophy were noted in 6 of 19 surviving male rats receiving 400 mg/kg/day.

In dogs, there were some macroscopic gray or brownish discolorations of urinary bladders at 100

and 200 mg/kg/day in a 3 month study and at all dose levels (50, 100 and 150 mg/kg/day) in a

one year study. Histologically, the brownish pigment was found in the macrophages in the

submucosa. The pigment is considered to be a non-toxic metabolite rather than melanin or

argentaffin. In one dog, there was minimal hepatic damage after 12 months.

Reproductive Toxicity

Page 35 of 46

In the course of reproductive studies with carbamazepine in rats and rabbits, approximately 1%

of the offspring were listed as having some anomaly.

In the reproductive study in rats, two of the offspring showed kinked ribs bilaterally at doses of

250 mg/kg and 4 animals had cleft palates and talipes at 650 mg/kg. Two of the latter also had

anophthalmos. In mice and rats, carbamazepine, when given parenterally, produced a low but

nevertheless definite incidence of anomalies including anencephalia, anophthalmos, cleft palates

and rudimentary or absent tails. In one study using mice, carbamazepine (40-240 mg/kg body

weight daily, orally) caused defects (mainly dilatation of cerebral ventricles) in 4.7% of exposed

fetuses as compared with 1.3% in controls).

In nursing rats, toxicity was demonstrated by lack of weight gains and unthrifty appearance at the

dose level of 200 mg/kg.

Page 36 of 46

REFERENCES

Clinical References - Epilepsy

AMA DRUG EVALUATIONS: Anticonvulsants. American Medical Assoc Chicago, Illinois

1983; 295-328

BEERMAN B, et al. Advanced heart block aggravated by carbamazepine. Br Heart J 1975;

37: 688-691

BESSER R, et al. Slow-Release Carbamazepine in the Treatment of Epilepsy. 2. A

comparison of the 24-hour plasma levels in response to two different formulations. Akt

Neurol 1985; 12: 75-77 (Translation)

BERTILSSON L. Clinical pharmacokinetics of carbamazepine. Clin Pharmacokinet 1978; 3:

128-143

BLOMBERG J-H, et al. Treatment of epilepsy with TEGRETOL. Lakartidningen 1970;

67(38): 4305-4311 (Translation)

FAIGLE JW, and FELDMANN KF. Carbamazepine: Biotransformation. IN: Woodbury

DM et al (eds): Antiepileptic Drugs, (Raven Press, New York 1982): 2nd (ed): 483-495

GERARDIN A, et al. HENRIKSEN O, et al. How to Use Carbamazepine. In: Antiepileptic

Drug Therapy in Pediatrics. Ed Morselli PL, et al. (Raven Press NY) 1983; 237-243

HÖPPENER RJ, et al. Correlation between daily fluctuations of carbamazepine serum levels

and intermittent side effects. Epilepsia 1980; 21: 341-350

HOUBEN PFM, et al. Anticonvulsant drugs and folic acid in young mentally retarded

epileptic patients. Epilepsia 1971; 12 (3): 235-247

HUNTER J, et al. Altered calcium metabolism in epileptic children on anticonvulsants. Br

Med J 1971; 4: 202-204

HVIDBERG

Clinical

pharmacokinetics

anticonvulsants.

Clin

Pharmacokinet 1976; 1: 161-188

JANZ D, and SCHMIDT D. Anti-epileptic drugs and failure of oral contraceptives. Lancet

1974; 1: 1113

KRÄMER

Slow-Release

Carbamazepine

Treatment

Epilepsy.

Comparisons of the 24-hour plasma levels during treatment with conventional and slow-

release carbamazepine formulations. Akt Neurol 1985; 12: 70-74 (Translation)

Page 37 of 46

KRÄMER G, et al. Slow-Release Carbamazepine: Kinetic and Therapeutic Aspects. Psycho

1985; 11: 441-442 (Translation)

KRÜGER HJ. Carbamazepine in the Treatment of Epilepsy - Follow-up studies over a period

of 9 years. Med Welt 1972; 23 (24): 896 (Translation)

LAENGNER H, and DETERING K. Anti-epileptic drugs and failure of oral contraceptives.

Lancet 1974; 2: 600

LEVY RH, et al. Pharmacokinetics of Carbamazepine in normal man. Clin Pharmacol Ther

1975; 17: 657-668

LIVINGSTON Sl. Comprehensive Management of Epilepsy in Infancy, Childhood and

Adolescence. Charles C. Thomas, Publisher, 1972

MATTSON

Comparison

carbamazepine,

phenobarbital,

phenytoin

primidone in partial and secondarily generalized tonic-clonic seizures. N Engl J Med 1985;

313 (3): 145-151

MIKATI

BROWNE

Comparative

efficacy

antiepileptic

drugs.

Clin

Neuropharmacol (USA) 1988; 11 (2): 130-140

MIVILLE J. Le Tégrétol dans l'épilepsie. Vie Médi Can Fr 1972; 1: 1080-1083

MORSELLI PL, et al. Pharmacokinetic studies with carbamazepine in epileptic patients. IN:

Birkmayer

(ed.)

"Epileptic

seizures-behavior-pain",

Huber

Publisher

Bern/Stuttgart/Vienna 1975; 141-150

MORSELLI PL, and FRIGERIO A. Metabolism and pharmacokinetics of carbamazepine.

Drug Metab Rev 1975; 4 (1): 93-113

MORSELLI PL, et al. Bioavailability of two carbamazepine preparations during chronic

administration to epileptic patients. Epilepsia (USA) 1975; 16: 759-764

MORSELLI PL, and FRANCO-MORSELLI R. Clinical pharmacokinetics of antiepileptic

drugs in adults. Pharmacol Ther 1980; 10: 65-101

NAMOLI A. Prolonged Treatment with Carbamazepine (TEGRETOL) of the Convulsions

and Mental Abnormalities of Epilepsy. Riv Neurol 1972; XLII fasc. 1 (Translation)

RAMSAY RE, et al. A double-blind study comparing carbamazepine with phenytoin as

initial seizure therapy in adults. N Engl J Med 1983; 33: 904-910

RODIN EA, et al. The effects of carbamazepine on Patients with Psychomotor Epilepsy:

Results of a double blind study. Epilepsia 1974; 15: 547-561

Page 38 of 46

SILLANPÄÄ M. Carbamazepine. Pharmacology and Clinical Uses. Acta Neurol Scand

1981; 64: (Suppl. 88): 1-202

TOMSON T. Interdosage fluctuations in plasma carbamazepine concentration determine

intermittent side effects. Arch Neurol 1984; 41: 830-834

TROUPIN AS, et al. Carbamazepine as an anticonvulsant: A Pilot Study. Neurology 1974;

24: 863-869

WADA JA, et al. Pharmacokinetic comparison of tablet and suspension dosage forms of

carbamazepine. Epilepsia 1978; 19(3): 251-255

WULFSOHN M. Carbamazepine (TEGRETOL) in the Long-Term Treatment of Grand Mal

Epilepsy. South Afr Med J 1972; 46: 1091

Clinical References - Trigeminal Neuralgia

ARIEFF AJ, et al. TEGRETOL in trigeminal neuralgia. Pilot study. Trans Am Neurol Assoc

1966; 91: 186

CARNAILLE H, et al. Etude statistique de près de 700 cas de facialgies traitées par le

Tégrétol. Acta Neurol Belg 1966; 66: 175-196

GRAHAM JG, et al. Treatment of trigeminal neuralgia with carbamazepine, a follow-up

study. Br Med J 1966; 1: 210-211

HEATHFIELD KWG, et al. Treatment of trigeminal neuralgia with TEGRETOL. Br Med J

1966; 1: 481

KILLIAN JM. TEGRETOL in trigeminal neuralgia with special reference to hematopoietic

side effects. Headache 1969; 9: 58-63

LLOYD-SMITH DL, et al. A long-term low-dosage study of carbamazepine in trigeminal

neuralgia. Headache 1969; 9: 64-72

MAROTTA JT. A long-term study in trigeminal neuralgia. Headache 1969; 9: 83

MURPHY JP. TEGRETOL (carbamazepine): A new and effective medical treatment of

trigeminal neuralgia, with a note concerning its use in the syndrome of thalamic hyperpathia.

Med Ann DC 1966; 35: 658

NICOL CF. A four year double blind study of TEGRETOL in Facial Pain. Headache 1969;

9: 54-57

Page 39 of 46

RASKIND B. Trigeminal neuralgia. Definitive treatment of 46 patients. Int Surg 1966; 46: 5-

RASMUSSEN P, et al. TEGRETOL in the treatment of trigeminal neuralgia. A controlled

study of 48 patients. Proc. III Int. Cong. Neurol. Surg., Copenhagen, 1965, Excerpta Med.

Int. Cong, 1965; 110 (761): 93 (224)

SACHDEV KK, and LLOYD-SMITH DL. The use and limitations of carbamazepine in

trigeminal neuralgia. Can Med Assoc J 1967; 97: 235

Clinical References - Mania

BALLENGER JC, and POST RM. Carbamazepine in manic-depressive illness: A new

treatment. Am J Psychiatry 1980; 137: 782-790

BROWN

Carbamazepine

compared

haloperidol

acute

mania.

Clin

Psychopharmacol 1989; 4: 229-238

CHOU JC-Y. Recent advances in treatment of acute mania. J Clin Psychopharmacol 1991;

11: 3-21

GROSSI E, et al. Carbamazepine vs chlorpromazine in mania: A double-blind trial. IN:

Emrich HM, Okuma T. and Müller A.A. (eds). Anticonvulsants in affective disorders.

Excerpta medica Amsterdam 1984; 177-187

KLEIN E, et al. Carbamazepine and haloperidol v placebo and haloperidol in excited

psychoses. Arch Gen Pschiatry 1984; 41: 165-170

KRAMLINGER KG, and POST RM. Adding lithium carbonate to carbamazepine: antimanic

efficacy in treatment-resistant mania. Acta Psychiatr Scand 1989; 79: 378-385

LENZI A, et al. Use of Carbamazepine in acute psychosis: A controlled study. J Int Med Res

1986; 14: 78-84

LERER B, et al. Carbamazepine versus lithium in mania: A double-blind study. J Clin

Psychiatry 1987; 48 (3): 89-93

LUSZNAT RM, et al. Carbamazepine vs lithium in the treatment and prophylaxis of mania.

Br J Psychiatry 1988; 153: 198-204

MÖLLER HJ, et al. Double-blind evaluation of the antimanic properties of carbamazepine as

comedication to haloperidol. Prog Neuropsychopharmacol Biol Psychiatry 1989; 13: 127-136

OKUMA

Comparison

antimanic

efficacy

carbamazepine

chlorpromazine: A double-blind controlled study. Psychopharmacology 1979; 66: 211-217

Page 40 of 46

PLACIDI GF, et al. The comparative efficacy and safety of carbamazepine versus lithium: A

randomised, double-blind 3-year trial in 83 patients. J Clin Psychiatry 1986; 47: 490-494

POST RM, et al. Correlates of antimanic response to carbamazepine. Psychiatry Res 1987;

21: 71-83

POST RM. Non-lithium treatment for bipolar disorder. J Clin Psychiatry 1990; 51 (8) (Suppl

9-16)

STOLL KD, et al. Carbamazepine vs haloperidol in manic syndromes. IN: Shagass C (ed).

Biological Psychiatry 1985. Elsevier Science, Amsterdam, 1986; 332-334

Other References

CHUNG WH et al. Medical Genetics: a Marker for Stevens-Johnson Syndrome Nature

2004; 428 (6982): 486

HUNG SI et al. Genetic susceptibility to carbamazepine-induced cutaneous adverse drug

reactions. Pharmacogenetics and Genomics 2006; 16 (4): 297-306

LONJOU

marker

Stevens-Johnson

syndrome…:

ethnicity

matters. The

Pharmacogenomics Journal 2006; 6 (4): 265-268

MAN CB et al. Association between HLA-B*1502 allele and antiepileptic drug-induced

cutaneous reactions in Han Chinese. Epilepsia 2007; 48 (5): 1015-1018.

IMPORTANT: PLEASE READ

Page 41 of 46

PART III: CONSUMER INFORMATION

Pr

TEGRETOL

®

Carbamazepine

This leaflet is part III of a three-part "Product Monograph"

published

when

TEGRETOL

®

was

approved

for

sale

in

Canada and is designed specifically for Consumers. This leaflet

is

a

summary

and

will

not

tell

you

everything

about

TEGRETOL. Contact your doctor or pharmacist if you have

any questions about the drug.

ABOUT THIS MEDICATION

What the medication is used for:

TEGRETOL has been prescribed for you by your doctor:

to reduce your number of seizures;

to relieve the pain of trigeminal neuralgia;

to treat your acute mania or bipolar disorder.

What it does:

TEGRETOL

belongs

family

medicines

called

anticonvulsants for treating epilepsy. TEGRETOL is also used for

treating the pain of trigeminal neuralgia and for treating mania.

If you have any questions about how TEGRETOL works or why

this medicine has been prescribed to you, ask your doctor.

When it should not be used:

You should not use TEGRETOL if:

You are allergic (hypersensitive) to carbamazepine or to any

of the other ingredients of TEGRETOL (See

What the non-

medicinal ingredients are

) If you think you may be allergic,

ask your doctor for advice. Do not take TEGRETOL if you are

allergic

other

tricyclic

drugs

such

amitriptyline,

trimipramine, imipramine.

You have severe heart disease (heart block).

You have liver disease.

You have a history of bone marrow depression.

You have had serious blood illnesses in the past.

You have a disturbance in the production of porphyrin, a

pigment important for liver function and blood formation (also

called hepatic porphyria).

You are also taking medicines belonging to a special group of

antidepressants

called

monoamine-oxidase

inhibitors

(MAOIs).

You are also taking the drugs itraconazole or voriconazole

(Vfend) for treatment of an infection.

TEGRETOL should not be used to relieve trivial pain in the

face or headaches.

TEGRETOL suspension contains sorbitol which may cause

stomach upset and diarrhea. Patients with rare hereditary

problems

fructose

intolerance

should

take

this

medicine.

If any of the above applies to you,

tell your doctor before taking

TEGRETOL

What the medicinal ingredient is:

Carbamazepine.

What the important nonmedicinal ingredients are:

TEGRETOL 200 mg Tablets: cellulose compounds, magnesium

stearate, silicon dioxide.

TEGRETOL 100 mg and 200 mg CHEWTABS: cherry-mint

flavour,

cornstarch,

erythrosine,

gelatin,

glycerin,

magnesium

stearate, silicon dioxide, sodium starch glycolate, stearic acid,

sugar.

TEGRETOL CR 200 mg and 400 mg: acrylic esters, cellulose

compounds, iron oxides, magnesium stearate, silicon dioxide,

talc, titanium dioxide, castor oil derivative.

TEGRETOL 100 mg/tsp (5 mL) Suspension: citric acid, citrus-

vanilla flavour, FD&C Yellow No. 6, pluronic polyol, potassium

sorbate, propylene glycol, sucrose, sorbitol, water, xanthan gum.

What dosage forms it comes in:

TEGRETOL is available in the following forms:

Tablets

containing 200 mg carbamazepine.

CR tablets

(controlled-release tablets, which can be divided)

containing 200 mg or 400 mg carbamazepine.

Chewable

tablets

containing

carbamazepine.

Oral

suspension:

measure)

contain

carbamazepine.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

Blood:

Although

infrequently

reported

and

very

rarely fatal,

serious adverse effects affecting blood

cell counts have been observed during the use of

TEGRETOL. Other side effects include: low white

blood cell count, bone marrow depression, hepatitis

and signs of liver failure such as jaundice (yellowing

of

the

skin

or

eyes).

Contact

your

doctor

immediately if you are experiencing any of these

symptoms. Close clinical and frequent laboratory

supervision with your doctor should be maintained

throughout treatment with TEGRETOL in order to

detect as early as possible any possible signs of a

blood

disorder.

Your

doctor

should

discontinue

TEGRETOL, if there is significant evidence of a

bone marrow depression.

Skin: Serious and sometimes fatal skin reactions

known as Toxic Epidermal Necrolysis (TEN) and

Stevens-Johnson

Syndrome

(SJS),

have

been

reported

with

TEGRETOL.

Other

serious

skin

reactions such as Drug Rash with Eosinophilia and

IMPORTANT: PLEASE READ

Page 42 of 46

Systemic

Symptoms

(DRESS),

Acute

Generalized

Exanthematous

Pustulosis

(AGEP)

and

Maculopapular

Rash

have

also

been

reported.

Although very rare, serious forms of DRESS and

AGEP may also lead to death. Some cases of these

skin reactions have been genetically linked. Your

doctor may recommend a blood test to determine if

you belong to an at-risk population.

Contact

your

doctor

immediately

if

you

are

developing any combination of:

- a rash or any serious skin reactions such as red

skin, blistering of the lips, eyes or mouth, and skin

peeling accompanied by fever

- swollen lymph nodes

- joint pain

- enlargement of the liver and/or the spleen

- problems related to the lungs, kidneys, pancreas,

heart, bone marrow, thymus, and colon

Your doctor will determine if it is indeed drug-

related, and discontinue TEGRETOL in this case.

Cancer:

Long-term

toxicity

studies

in

rats

have

indicated

a

possible

cancer

risk

associated

with

carbamazepine. Before taking TEGRETOL, discuss

with your doctor the potential benefits and possible

risks of this treatment for you.

BEFORE you use TEGRETOL talk to your doctor or

pharmacist:

About your medical conditions, especially if you have or have

liver,

kidney,

heart

thyroid

disease

blood

disorders (including those caused by other drugs).

If you have a history, or family history, of bone disease or

have taken antiepileptics (such as phenobarbital, phenytoin,

primidone,

oxcarbazepine,

lamotrignine,

sodium

valproate

and/or carbamezepine) for a prolonged period of time.

If you are taking delavirdine, a medicine used to treat HIV-1

infection.

About any allergies you may have, especially if you have ever

shown any unusual sensitivity (rash or other signs of allergy)

to oxcarbazepine or other drugs used to treat your condition. It

is important to note that if you are allergic to TEGRETOL

(carbamazepine), there is an approximately 1 in 4 (25%)

chance

that

could

also

have

allergic

reaction

oxcarbazepine (TRILEPTAL

®

If you are pregnant. Your doctor may recommend that you

take folic acid before and during your pregnancy and vitamin

K during the last weeks of pregnancy. Your doctor may also

recommend

that

newborn

receive

vitamin

observed for liver and gall bladder problems.

If you are pregnant or planning on becoming pregnant to

discuss the potential risk of taking TEGRETOL during

pregnancy since it may cause harm or abnormalities in the

unborn child.

If you are a female of childbearing age you should use an

effective method of contraception throughout your treatment

weeks

after

your

last

dose.

taking

hormonal

contraceptive

(birth

control

medicine).

TEGRETOL

render

this

contraceptive

ineffective.

Therefore, you should use a different or additional non-

hormonal

method

contraception

while

taking

TEGRETOL.

This

should

help

prevent

unwanted

pregnancy.

If you get irregular vaginal bleeding or spotting.

If you are breast-feeding. TEGRETOL is known to pass into

breast milk. You must discuss with your doctor the benefits

of breastfeeding against any possible risks to the infant. If

you decide to breastfeed, the baby must be observed for liver

gall bladder

problems,

drowsiness, and

allergic skin

reactions.

About

other

medicines

(prescription

non-

prescription) you are taking.

About your usual alcohol consumption.

If you have increased pressure in the eye (glaucoma).

If you have difficulty passing urine (urinary retention).

If you were told by your physician that you suffer from

mental problems, a mental disorder called psychosis that may

be accompanied by confusion or agitation, or have thoughts

about suicide.

If any of the following apply to you,

tell your doctor

If an allergic reaction happens such as fever with lymph

nodes

swelling,

rash

skin

blistering,

tell

your

doctor

immediately or go to the emergency department at your

nearest hospital. (see

Side effects and what to do about

them

If you experience an increase in the number of seizures, tell

your doctor immediately.

experience

side

effects

such

drowsiness,

headache, unsteadiness on the feet, double vision, dizziness,

nausea or vomiting, consult your doctor.

If, at any time, you have thoughts of harming or killing

yourself. A small number of people being treated with

antiepileptic drugs have reported having such thoughts or

behavior. Should this happen to you, or to those in your care

caregiver

guardian,

talk

your

doctor

immediately. Close observation by a doctor is necessary in

this situation.

Do not discontinue your medication on your

own

If you have kidney problems associated with low sodium

blood level or if you have kidney problems and you are also

taking

certain

medicines

that

lower

sodium

blood

level

(diuretics such as hydrochlorothiazide, furosemide).

If you experience dizziness, drowsiness, decrease in blood

pressure, confusion, due to TEGRETOL treatment, which

may lead to falls.

TEGRETOL may affect male fertility or cause abnormal sperm.

Periodic

examinations

recommended

while

taking

TEGRETOL.

Do not drive a car or operate dangerous machinery until you are

sure

that

TEGRETOL

does

cause

dizziness,

drowsiness,

sleepiness,

blurred

double

vision,

affect

your

muscular

coordination or affect your alertness.

IMPORTANT: PLEASE READ

Page 43 of 46

INTERACTIONS WITH THIS MEDICATION

Tell your doctor or pharmacist if you are taking or have recently

taken

prescription,

non-prescription

medicines

natural

health products. It is particularly important for TEGRETOL, since

many other medicines interact with it.

You may need a change in your dose or, sometimes, to stop one of

these other medicines.

Irregularity of the menstrual period may occur in women taking

hormonal

contraceptives

(birth

control

medicines)

TEGRETOL.

hormonal

contraceptive

become

less

effective and you should use another different or additional non-

hormonal contraceptive method.

Avoid alcohol consumption when taking TEGRETOL.

Do not drink grapefruit juice or eat grapefruit since this can

increase the effect of TEGRETOL. Other juices, like orange

juice or apple juice, do not have this effect.

PROPER USE OF THIS MEDICATION

Usual dose:

Dosage should be individualised. It is very important that you take

TEGRETOL exactly as your doctor instructed.

Never

increase

decrease

recommended

dose

TEGRETOL you are taking unless your doctor tells you to.

If you are taking TEGRETOL,

do not suddenly stop taking

it

without first checking with your doctor. Your doctor will

tell you if and when you can stop taking this medicine

TEGRETOL Tablets, CHEWTABS and Suspension should be

taken

divided

doses

daily,

with

meals

whenever

possible.

TEGRETOL CR tablets should be swallowed unchewed with

a little liquid during or after a meal.

Shake TEGRETOL Suspension well before you take it or else

you may not receive the correct dose.

Adults and Children Over 12 Years of Age

Initial dose 100 to 200 mg once or twice a day. Your doctor will

decide the best dosage for you. Always follow your doctor’s

instructions.

For the treatment of trigeminal neuralgia, the maximum dose is

1200 mg a day.

Children 6-12 Years of Age

Initial dose 100 mg in divided doses on the first day. Your doctor

will decide the best dosage for you. Always follow your doctor’s

instructions.

Overdose:

In case of drug overdose, contact a health care practitioner,

hospital emergency department or regional Poison Control

Centre immediately, even if there are no symptoms.

Missed Dose:

If you miss a dose, take your TEGRETOL as soon as possible.

However, if the time is close to the next dose, do not take the

missed dose and return to your regular dosing schedule. Do not

double the dose to make up for the forgotten dose.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Side effects may include:

purple or reddish-purple bumps that may be itchy

trembling, uncontrolled body movements, muscle spasm,

loss of muscle coordination, weakness

agitation

hostility

(especially

elderly),

depression with restlessness, nervousness or other mood

mental

changes,

changes

behaviour,

confusion,

headache, memory loss

blurred vision, double vision, itching with redness and

swelling of the eye (conjunctivitis), uncontrolled eye

movements

difficulty speaking or slurred speech, taste disturbances,

dry mouth, red and sore tongue, mouth sores

ringing

other

unexplained

sounds

ears,

decreased hearing

numbness, tingling in hands and feet

unusual secretion of breast milk, breast enlargement in

men,

sexual

disturbances

(erectile

dysfunction),

male

infertility

increased sensitivity of the skin to sun, alterations in skin

pigmentation, acne, increased sweating

reactivation of herpes virus infection (can be serious

when the immune system is depressed)

complete loss of the nails, loss of hair, excessive body

and facial hair

vomiting, nausea, loss of appetite, constipation, diarrhea,

abdominal pain

dizziness, sleepiness, unsteadiness, drowsiness, fatigue

weight gain

aching joints or muscles

IMPORTANT: PLEASE READ

Page 44 of 46

experience a fall due to dizziness, drowsiness, decrease in

blood pressure, confusion

Long-term

antiepileptics

such

carbamazepine,

phenobarbital, phenytoin, primidone, oxcarbazepine, lamotrigine

and sodium valproate is associated with a risk of decreased bone

mineral density that may lead to weakened or brittle bones, or

fracture.

If any of these affects you severely, contact your doctor

TEGRETOL can cause abnormal blood test results. Your doctor

will decide when to perform blood tests and will interpret the

results.

SERIOUS SIDE EFFECTS, HOW OFTEN THEY

HAPPEN AND WHAT TO DO ABOUT THEM

Symptom / effect

Talk with your

doctor or

pharmacist

Stop taking

drug and

seek

immediate

emergency

medical

treatment

Only if

severe

In all

cases

Very

common

Decreased White

Blood Cells:

fever, sore throat,

rash, ulcers in the

mouth, swollen

glands, or more

easily getting

infections.

Suicidal

Thoughts or

Actions:

thoughts,

plans and actions

taken for the

purpose of killing

or harming

yourself.

Common

Edema:

swelling

of the ankles, feet

or lower legs.

Rare

Systemic Lupus

Erythematosus:

red blotchy rash

mainly on the face

which may be

accompanied by

fatigue, fever,

nausea, loss of

appetite.

Hallucination:

or hear things that

are not there.

High Blood

Pressure Low

Blood Pressure:

dizziness, fainting,

light-headedness.

Very rare

Glaucoma:

SERIOUS SIDE EFFECTS, HOW OFTEN THEY

HAPPEN AND WHAT TO DO ABOUT THEM

Symptom / effect

Talk with your

doctor or

pharmacist

Stop taking

drug and

seek

immediate

emergency

medical

treatment

Only if

severe

In all

cases

pressure/pain in

the eye.

Thrombophlebitis

:

swelling and

redness along a

vein which is

extremely tender

or painful when

touched.

Angioedema and

Severe Allergic

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,

unconsciousness.

Serious Skin

Reactions:

combination of

itchy skin rash,

redness, blistering

of the lips, eyes or

mouth, skin

peeling,

accompanied by

fever, chills,

headache, cough,

body aches or

swollen lymph

nodes, joint pain,

enlargement of the

liver and/or the

spleen. Any

problems related to

the lungs, kidneys,

pancreas, heart,

bone marrow,

thymus, and colon.

Hepatitis:

yellowing of the

skin or eyes, dark

urine, abdominal

pain, nausea,

vomiting, loss of

appetite.

Meningitis:

fever,

IMPORTANT: PLEASE READ

Page 45 of 46

SERIOUS SIDE EFFECTS, HOW OFTEN THEY

HAPPEN AND WHAT TO DO ABOUT THEM

Symptom / effect

Talk with your

doctor or

pharmacist

Stop taking

drug and

seek

immediate

emergency

medical

treatment

Only if

severe

In all

cases

nausea, vomiting,

headache, stiff

neck and extreme

sensitivity to

bright light.

Pancreatitis:

severe upper

abdominal pain,

vomiting, loss of

appetite.

Severe decreased

urine output due to

kidney disorders,

blood in the urine.

Frequent urination.

Porphyria:

darkening of urine,

severe abdominal

pain, excessive

sweating,

vomiting, and

anxiety.

Lack of All Blood

Cells:

tiredness,

headache, being

short of breath

when exercising,

dizziness; looking

pale, frequent

infections leading

to fever, chills,

sore throat or

mouth ulcers;

bleeding or

bruising more

easily than normal,

nose bleeds.

Neuroleptic

Malignant

Syndrome:

muscular stiffness,

high fever, altered

consciousness,

high blood

pressure, excessive

salivation.

Irregular heartbeat,

chest pain, fast or

unusually slow

heartbeat, trouble

breathing.

Thromboembolis

m (blood clot):

swelling, pain and

SERIOUS SIDE EFFECTS, HOW OFTEN THEY

HAPPEN AND WHAT TO DO ABOUT THEM

Symptom / effect

Talk with your

doctor or

pharmacist

Stop taking

drug and

seek

immediate

emergency

medical

treatment

Only if

severe

In all

cases

redness in an arm

or a leg that can be

warm to touch.

You may develop

sudden chest pain,

difficulty

breathing and heart

palpitations.

Circulatory

Collapse:

the body

is unable to

circulate blood to

the organs. This is

very serious and

can lead to death.

Disturbed

consciousness,

fainting.

Hyponatremia

(low sodium in

the blood):

lethargy,

confusion,

muscular twitching

or significant

worsening of

convulsions.

Unknown

Inflammation of

the colon:

diarrhea,

abdominal pain

and fever.

This is not a complete list of side effects. For any unexpected

effects

while

taking

TEGRETOL,

contact

your

doctor

or

pharmacist.

IMPORTANT: PLEASE READ

Page 46 of 46

HOW TO STORE IT

Store at room temperature (TEGRETOL tablets store at 15-25

and TEGRETOL CR store below 25°C, TEGRETOL

CHEWTABS and TEGRETOL Suspension store below 30°C).

Protect

from

humidity,

such

bathrooms

where

shower often.

Protect

TEGRETOL

CHEWTABS

TEGRETOL

Suspension from light.

Keep out of reach and sight of children.

REPORTING SUSPECTED SIDE EFFECTS

You can report any suspected adverse reactions associated with

the use of health products to the Canada Vigilance Program by

one of the following 3 ways:

--------------------------------------------------------------------------

Report online at www.healthcanada.gc.ca/medeffect

Call toll-free at 1-866-234-2345

Complete a Canada Vigilance Reporting Form and:

- Fax toll-free to 1-866-678-6789, or

- Mail to:

Canada Vigilance Program

Health Canada

Postal Locator 1908C

Ottawa, Ontario

K1A 0K9

Postage paid labels, Canada Vigilance Reporting Form

and the adverse reaction reporting guidelines are

available on the MedEffect

Canada Web site at

www.healthcanada.gc.ca/medeffect.

NOTE: Should you require information related to the management

of side effects, contact your health professional. The Canada

Vigilance Program does not provide medical advice.

MORE INFORMATION

Please consult your doctor or pharmacist with any questions or

concerns you may have regarding your individual condition.

This document plus the full product monograph, prepared for

health professionals can be found at:

http://www.novartis.ca

or by contacting the sponsor, Novartis Pharmaceuticals Canada

Inc., at:

1-800-363-8883

This leaflet was prepared by

Novartis Pharmaceuticals Canada Inc.

385 Bouchard Blvd.,

Dorval, Quebec

H9S 1A9

Last revised: May 4, 2018

TEGRETOL is a registered trademark.

TRILEPTAL is a registered trademark.

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