TOPAMAX 50

Israel - English - Ministry of Health

Buy It Now

Active ingredient:
TOPIRAMATE
Available from:
J-C HEALTH CARE LTD
ATC code:
N03AX11
Pharmaceutical form:
FILM COATED TABLETS
Composition:
TOPIRAMATE 50 MG
Administration route:
PER OS
Prescription type:
Required
Manufactured by:
CILAG AG, SWITZERLAND
Therapeutic group:
TOPIRAMATE
Therapeutic area:
TOPIRAMATE
Therapeutic indications:
In adjunctive therapy of adults and children (from 2 years) with partial seizures and generalized tonic-clonic seizures. In adjunctive therapy of seizures with Lennox-Gastaut syndrome in adults and children. Topamax is indicated as monotherapy in patients with newly diagnosed epilepsy in children aged 7 years and above or for conversion to monotherapy in patients with epilepsy. Topamax is indicated in adults for the prevention of migraines. The use of Topamax in the acute treatment of migraine has not been studied.
Authorization number:
107 56 29032 00
Authorization date:
2012-09-30

Documents in other languages

Patient Information leaflet Patient Information leaflet - Arabic

25-01-2021

Patient Information leaflet Patient Information leaflet - Hebrew

14-12-2016

PATIENT PACKAGE INSERT

IN ACCORDANCE WITH THE

PHARMACISTS’ REGULATIONS

(PREPARATIONS) - 1986

The medicine is dispensed

with a doctor’s prescription only

Name of the preparation and its form:

Topamax

®

25

The active ingredient and its quantity -

Each tablet contains:

Topiramate 25 mg

Name of the preparation and its form:

Topamax

®

50

The active ingredient and its quantity -

Each tablet contains:

Topiramate 50 mg

Name of the preparation and its form:

Topamax

®

100

The active ingredient and its quantity -

Each tablet contains:

Topiramate 100 mg

Name of the preparation and its form:

Topamax

®

200

The active ingredient and its quantity -

Each tablet contains:

Topiramate 200 mg

Read this leaflet carefully in its entirety

before using the medicine. This leaflet

contains concise information about the

medicine. If you have further questions,

refer to the doctor or pharmacist.

This medicine has been prescribed to treat

you. Do not pass it on to others. It may

harm them, even if it seems to you that

their medical condition is similar.

This medicine is not intended for infants

and for children under 2 years of age and

as a monotherapy in children under 7 years

of age.

1. WHAT IS THE MEDICINE INTENDED

FOR?

The medicine is intended for:

∙ Treatment of seizures. For use in

combination with other medicines in

adults and children from 2 years of age

and above, or as a monotherapy in adult

patients and in children aged 7 years

and above.

∙ Prevention of migraine in adults. The

preparation is not intended for alleviating

pain during a migraine attack.

Therapeutic group: Antiepileptics

2. BEFORE USING THE MEDICINE

Do not use the medicine if:

∙ You are sensitive to the active

ingredient or any of the additional

ingredients contained in the medicine,

listed in section 6.

∙ To prevent migraine if you are pregnant

or think you are pregnant or if you are

of child-bearing age and do not use

effective contraception.

Special warnings regarding use of the

medicine:

Do not use the medicine without

consulting

the

doctor

before

commencing treatment if you have:

Impaired function of the kidney, kidney

problems, especially kidney stones or if

you are a patient undergoing dialysis

∘ A history of problems related to blood

and body fluids (metabolic acidosis)

∘ Liver problems

∘ Eye problems (especially if you have

glaucoma)

∘ Growth problems

∘ If you are on a ketogenic diet (a low-

carbohydrate and high-fat diet)

∘ You are pregnant or may become

pregnant (see section “Pregnancy

breastfeeding”

further

information)

If any of the conditions above apply to

you, speak with the doctor before using

the medicine.

∙ It is important that you do not stop taking

the medicine without first consulting the

doctor.

∙ Do not take any other medicine

containing topiramate, given to you as

a substitute for this medicine, without

first consulting the doctor.

∙ You may lose weight while taking

Topamax. Weigh yourself regularly

during the course of treatment with

Topamax. If you lose a lot of weight or

if a child taking Topamax does not gain

enough weight, consult the doctor.

∙ In a small number of patients treated

with antiepileptics, such as Topamax,

suicidal thoughts or suicidal behavior

have been reported. In case suicidal

thoughts occur, refer to the doctor

immediately!

∙ Pay attention to any change in mood,

behavior, thoughts and emotions,

especially to sudden changes. Refer

to the doctor immediately if you are

suffering from any of the following

symptoms, especially if it is new,

worsens or worries you: suicide

attempt, depression/anxiety/irritability

that is new or has worsened, a feeling

of restlessness, panic attack, sleeping

difficulties (insomnia), aggressive

behavior, anger, violence, dangerous

impulsive behavior, a sharp rise in

activeness and thought (mania), other

abnormal changes in thoughts or

mood.

∙ Topamax may cause eye problems.

Severe eye problems include reduced

vision, with or without pain and redness

in the eye, blockage of fluids in the eye

causing intraocular pressure (glaucoma).

These problems may lead to permanent

vision loss, if left untreated. Inform

the doctor immediately of any new

symptoms in the eyes and, in particular,

of new vision problems.

∙ Topamax may cause decreased sweating

and increased body temperature (fever).

Monitor symptoms of reduced sweating

and fever, especially in children and in

hot weather. Medical attention may

be necessary. Refer to the doctor

immediately, if you have fever, fever

that does not go down or decreased

sweating.

∙ Topamax may increase the acid levels

in the blood (metabolic acidosis). If left

untreated, metabolic acidosis may lead

to brittle or soft bones, kidney stones,

slowed growth rate in children, and if

you are pregnant, may harm the fetus.

Metabolic acidosis can be with or

without symptoms. You may feel tired,

loss of appetite, changes in heart rate,

difficulty in thinking clearly. The doctor

must perform blood tests to check acid

levels in your blood, before and during

the course of treatment. If you are

pregnant, speak to the doctor if you are

suffering from metabolic acidosis.

If you are taking, or have recently

taken, other medicines, including non-

prescription medicines or nutritional

supplements,

tell

the

doctor

or

pharmacist. In particular, inform the doctor

or pharmacist if you are taking:

∙ Other medicines that affect or decrease

your level of thinking, concentration

or muscle coordination (e.g., central

nervous system depressants such as

muscle relaxants and sedatives and

hypnotics).

∙ Birth control pills. Topamax may make

your birth control pills less effective.

∙ Tell the doctor if you experience changes

in your menstrual cycle while using

contraception and Topamax.

∙ Other antiepileptics.

∙ Risperidone

(for

treatment

schizophrenia).

∙ Lithium

(for

treatment

manic

depression).

∙ Hydrochlorothiazide, propranolol,

diltiazem (for treatment of heart problems

and to lower blood pressure).

∙ Metformin, pioglitazone, glyburide (for

treatment of diabetes).

∙ Amitriptyline, venlafaxine (for treatment

of depression).

∙ Flunarizine (to prevent migraines and to

treat vertigo).

Hypericum perforatum

(St. John’s wort,

a herbal medicine to treat depression).

Use of the medicine and food

Topamax can be taken with or after food

or between meals.

Be sure to drink lots of fluids during the

course of treatment (to lower the risk of

formation of kidney stones).

Do not go on a ketogenic diet (a low-

carbohydrate and high-fat diet) during the

course of treatment with Topamax.

Use of the medicine and alcohol

consumption

Abstain from drinking alcohol during the

course of treatment with the medicine.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, think

you may be pregnant or are planning a

pregnancy, consult the doctor before

commencing treatment.

The doctor will talk to you about using

contraceptives as well as whether

Topamax is suitable for you.

As with other antiepileptics, there is a risk

of harm to the fetus if Topamax is taken

during pregnancy.

Consult the doctor regarding the risks and

benefits of using Topamax to treat epilepsy

during pregnancy.

Do not use the medicine to prevent migraine

if you are pregnant, think you are pregnant

or are of child-bearing age and you are not

using effective contraceptives.

If you are breastfeeding and being

treated with Topamax, inform the doctor

immediately of any unusual effects in your

baby.

Driving and operating machinery

Use of the medicine may cause dizziness,

tiredness and visual problems. Do not drive

or operate dangerous machines before first

talking with the doctor. Children should

be cautioned against riding a bicycle or

playing near the road, and the like.

Important information about some of

the ingredients in the medicine

Topamax tablets contain lactose.

If you suffer from an intolerance to certain

sugars, consult the doctor before using

the medicine.

3. HOW SHOULD THE MEDICINE BE

USED?

Always use according to the doctor’s

instructions.

Check with the doctor or pharmacist if you

are uncertain.

The dosage and treatment regimen will be

determined by the doctor only.

The doctor will usually start with a low

dosage of Topamax and will gradually

increase the dosage until the dosage

suitable for you is found.

Do not exceed the recommended

dose.

Swallow Topamax tablets whole, with a lot

of water. Do not crush/halve/chew since

the tablet may leave a bitter taste.

Topamax can be taken with or after food

or between meals.

Be sure to drink a lot during the course of

treatment to prevent formation of kidney

stones.

If you accidentally took a higher

dosage

If you took an overdose, or if a child has

accidentally swallowed the medicine, refer

immediately to a hospital emergency room

and bring the package of the medicine

with you. Do not induce vomiting unless

explicitly instructed to do so by a doctor!

If you took an overdose, you may feel

sleepy, tired or less alert, experience lack

of coordination, difficulty speaking or

difficulty concentrating, double vision or

blurred vision, feel depressed or nervous,

abdominal pain, seizures or dizziness due

to low blood pressure.

Overdose can occur when you take other

medicines together with Topamax.

If you forgot to take this medicine at

the required time, take a dose as soon as

you remember, but if you remember close

to the time for taking the next dose, skip

the forgotten dose and continue as usual.

Never take two doses together!

If you forgot two or more doses, contact

the doctor.

Adhere

treatment

regimen

recommended by the doctor.

Even if there is an improvement in your

health, do not stop treatment without

consulting the doctor, as symptoms may

return. If the doctor decides to discontinue

treatment, the dosage will be gradually

lowered over several days.

Do not take medicines in the dark! Check

the label and the dose each time you

take medicine. Wear glasses if you need

them.

If you have further questions regarding

use of the medicine, consult the doctor

or pharmacist.

4. SIDE EFFECTS

As with any medicine, use of Topamax may

cause side effects in some users. Do not

be alarmed by the list of side effects. You

may not suffer from any of them.

Effects which require special attention:

Refer to the doctor immediately if you

notice any of the following effects:

Very common side effects - effects that

occur in more than one in ten users:

depression (new onset or increased

severity).

Common side effects - effects that occur

in up to 1 in 10 users:

seizures, anxiety, nervousness, mood

changes, confusion, disorientation,

concentration disturbances, slowed

thinking, loss of memory, memory

problems (new onset, sudden change or

deterioration), kidney stones, frequent or

painful urination.

Uncommon side effects - effects that

occur in up to 1 in 100 users:

increased acid level in the blood (may cause

breathing problems including shortness of

breath, loss of appetite, nausea, vomiting,

excessive tiredness and fast or uneven

heartbeats), decreased or termination of

sweating (especially in young children

exposed to high temperatures), thoughts

and attempts of serious self-harm, loss of

part of the field of vision.

Rare side effects - effects that occur in

up to 1 in 1,000 users:

glaucoma (blockage of fluid in the eye,

causing intraocular pressure, pain or

decreased vision).

Other side effects, of which the doctor

should be informed if they worsen:

Very common side effects - effects

which occur in more than one in ten

users:

∙ Nasal congestion, runny nose, sore

throat

∙ Tingling, pain and/or numbness of

various body parts

∙ Tiredness or sleepiness

∙ Dizziness

∙ Diarrhea

∙ Nausea

∙ Weight loss

Common side effects - effects that occur

in up to 1 in 10 users:

∙ Anemia (low blood count)

∙ Allergic reaction (such as skin rash,

redness, itching, facial swelling, hives)

∙ Decreased appetite or loss of appetite

∙ Aggression, anxiety, anger, abnormal

behavior

∙ Difficulty falling or staying asleep

∙ Problems with speech, slurred speech

∙ Clumsiness or lack of coordination,

feeling of unsteadiness when walking

∙ Decreased ability to complete routine

tasks

∙ Decrease/change/absence of sense of

taste

∙ Involuntary trembling

∙ Rapid, uncontrollable movements of the

eyes

∙ Visual disturbances, such as double

vision, blurred vision, decreased vision,

difficulty focusing

∙ Sensation of spinning (vertigo), ringing

in the ears, ear pain

∙ Shortness of breath

∙ Cough

∙ Nose bleed

∙ Fever

∙ Weakness

∙ General unwell feeling

∙ Vomiting

∙ Constipation

∙ Abdominal pain or discomfort in the

stomach

∙ Indigestion

∙ Stomach

intestinal

infection/

inflammation

∙ Dry mouth

∙ Hair loss

∙ Itching

∙ Joint pain or swelling

∙ Muscle cramps or muscle spasms,

muscle aches or weakness

∙ Chest pain

∙ Weight gain

Uncommon side effects - effects that

occur in up to 1 in 100 users:

∙ Abnormal blood count, including

decrease in number of white blood cells

or platelets or an increase in the number

of eosinophils

∙ Low potassium levels in the blood

∙ Increase in liver enzyme levels

∙ Swollen glands in the neck, armpit or

groin

∙ Increased appetite

∙ Elevated mood

∙ Hearing, seeing or feeling things that

are not there, severe mental disorder

(psychosis)

∙ Apathetic emotions, unusual suspicions,

panic attacks

∙ Problems with reading, speech disorders,

problems with handwriting

∙ Restlessness or hyperactivity

∙ Slowed thinking, decreased wakefulness

or alertness

∙ Slow body movements or reduced

mobility

∙ Abnormal and involuntary or repetitive

muscle movements

∙ Fainting

∙ Impaired/abnormal sense of touch

∙ Impaired or distorted or absence of

sense of smell

∙ Feeling/sensation preceding a migraine

or a certain type of seizure

∙ Eye problems including dry eyes,

sensitivity of the eyes to light, involuntary

eyelid twitching, tearing

∙ Decreased or loss of hearing, loss of

hearing in one ear

∙ Irregular or slow heartbeat, palpitations

∙ Low blood pressure or drop in blood

pressure upon standing (therefore, some

people taking Topamax may feel faint,

dizzy or may pass out when they stand

or sit up suddenly)

∙ Flushing, feeling warm

∙ Pancreatitis

∙ Flatulence, heartburn, feeling of bloating

or abdominal fullness

∙ Bleeding gums, increased production of

saliva, drooling, bad breath

∙ Increased thirst sensation and drinking

large amounts of fluids

∙ Skin discoloration

∙ Muscle stiffness, side pain

∙ Blood in urine, urinary incontinence, a

sense of urgency in urination, pain in the

kidney area

∙ Sexual dysfunction, difficulty getting or

keeping an erection

∙ Flu-like illness

∙ Cold sensation in the fingers and toes

∙ Feeling drunk

∙ Learning disabilities

Rare side effects - effects that occur in

up to 1 in 1,000 users:

∙ Abnormally elevated mood

∙ Loss of consciousness

∙ Blindness in one eye, temporary

blindness, night blindness

∙ Lazy eye

∙ Swelling in and around the eye

∙ Raynaud’s phenomenon - a disorder that

affects the blood vessels in the fingers

and toes; causes pain, tenderness,

numbness, tingling sensation or color

change (from white to blue and then

to red) in the fingers and toes when

exposed to the cold

∙ Inflammation of the liver, liver failure

∙ Stevens-Johnson syndrome - a life-

threatening skin reaction, in which the

upper layer of the skin separates from

the lower layer, manifested by warts

in many mucosal sites (such as the

mouth, nose, and eyes), a skin rash and

blisters

∙ Erythema multiforme - a condition in

which red spots appear on the skin,

which can blister

∙ Bad skin odor

∙ Discomfort in the arms or legs

∙ Kidney problems

Additional side effects, whose frequency

is unknown:

∙ Maculopathy - a disease of the macula

area of the eye. This is the small spot in

the retina where vision is keenest. If you

notice a change or decrease in vision -

refer to the doctor.

∙ Toxic epidermal necrolysis - a skin

effect related to, but more severe than,

Stevens-Johnson syndrome. It is also

life-threatening and characterized by

widespread blisters and separation of

the skin (see rare side effects).

Side effects in children

The side effects in children are generally

similar to those seen in adults. However,

the following side effects may be more

common in children than in adults:

- Concentration problems

- Increased acid level in the blood

- Thoughts of serious self-harm

- Tiredness

- Decreased or increased appetite

- Aggression, abnormal behavior

- Difficulty falling or staying asleep

- Feeling of unsteadiness when walking

- Not feeling well

- Decrease in potassium levels in the

blood

- Not displaying or not feeling emotions

- Watery eyes

- Slow or irregular heartbeat

Other side effects that may occur in

children are:

Common side effects - occur in up to

1 in 10 users

- Sensation of spinning (vertigo)

- Vomiting

- Fever

Uncommon side effects - occur in up

to 1 in 100 users

- Increased eosinophil (a type of white

blood cell) level in the blood

- Hyperactivity

- Feeling warm

- Learning disabilities

If a side effect occurs, if one of the side

effects worsens or if you suffer from side

effects not mentioned in the leaflet, consult

the doctor.

Side effects can be reported to the Ministry

of Health by clicking on the link “Report

Side Effects of Drug Treatment” found on

the Ministry of Health homepage (www.

health.gov.il), that directs you to the online

form for reporting side effects.

5. HOW SHOULD THE MEDICINE BE

STORED?

Avoid poisoning! This medicine, and any

other medicine, should be kept in a safe

place out of the reach of children and/or

infants in order to avoid poisoning. Do not

induce vomiting unless explicitly instructed

to do so by the doctor.

Do not use the medicine after the expiry

date (exp. Date) that appears on the

package. The expiry date refers to the

last day of that month.

After first opening the bottle, do not use

the medicine for more than 3 months.

Storage:

Do not store above 25°C. Store in the

original package.

6. FURTHER INFORMATION

In addition to the active ingredient, the

medicine also contains:

Lactose Monohydrate; Microcrystalline

Cellulose; Sodium Starch Glycolate;

Pregelatinised

Starch;

Magnesium

Stearate; Carnauba Wax.

The Topamax 25 tablet also contains:

Opadry White (YS-1-7706-G)

The Topamax 50 tablet also contains:

Opadry Light Yellow (YS-1-6382-G)

The Topamax 100 tablet also contains:

Opadry Yellow (YS-1-6370-G)

The Topamax 200 tablet also contains:

Opadry Pink (YS-1-1456-G)

The lactose monohydrate content in the

Topamax 25, 50, 100, 200 mg tablets is:

30.85,

61.70,

123.40,

43.50

respectively.

What does the medicine looks like and

what are the contents of the package?

Topamax 25 mg: a film-coated, round,

white-colored tablet, with “TOP” written

on one side and “25” on the other side.

Topamax 50 mg: a film-coated, round,

light yellow-colored tablet, with “TOP”

written on one side and “50” on the other

side.

Topamax 100 mg: a film-coated, round,

yellow-colored, tablet with “TOP” written

on one side and “100” on the other side.

Topamax 200 mg: a film-coated, round,

salmon-colored tablet, with “TOP” written

on one side and “200” on the other side.

The tablets are provided in a plastic bottle.

Each bottle contains 60 tablets.

Registration Holder and address: J-C

Health Care Ltd., Kibbutz Shefayim

6099000, Israel.

Manufacturer and address:

Cilag Ltd., Schaffausen, Switzerland.

This leaflet was checked and approved by

the Ministry of Health in May 2016.

Registration number of the medicine in

the National Drug Registry of the Ministry

of Health:

Topamax tablets:

25 mg - 1075529031

50 mg - 1075629032

100 mg - 1075729033

200 mg - 1075829034

Topamax SH 07/16

Topamax SH 07/16

J-C 2016

Page 1 of 21

1.

NAME OF THE MEDICINAL PRODUCT

Topamax 25 mg film-coated tablets

Topamax 50 mg film-coated tablets

Topamax 100 mg film-coated tablets

Topamax 200 mg film-coated tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

One tablet contains 25 mg of topiramate.

One tablet contains 50 mg of topiramate.

One tablet contains 100 mg of topiramate.

One tablet contains 200 mg of topiramate.

Excipients with known effect

also includes lactose monohydrate:

One 25 mg tablet contains 30.85 mg lactose monohydrate

One 50 mg tablet contains 61.70 mg lactose monohydrate

One 100 mg tablet contains 123.40 mg lactose monohydrate

One 200 mg tablet contains 43.50 mg lactose monohydrate

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Film-coated tablet.

25 mg: White round film coated tablets, “TOP” on one side, “25” on the other, with white core.

50 mg: Light yellow round film coated tablets, “TOP” on one side, “50” on the other, with white core.

100 mg: Yellow round film coated tablets, “TOP” on one side, “100” on the other, with white core.

200 mg: Salmon round film coated tablets, “TOP” on one side, “200” on the other, with white core.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

TOPAMAX

is indicated as adjunctive therapy for adults

and children aged 2 and above with partial onset

seizures or generalized tonicclonic seizures

TOPAMAX

is also indicated in adults

children as adjunctive therapy

for the treatment of seizures

associated with Lennox-Gastaut syndrome.

TOPAMAX

can be prescribed as monotherapy in patients with recently diagnosed epilepsy in adults and children

aged 7 and above or for conversion to monotherapy in patient with epilepsy.

TOPAMAX

is indicated in adults for the

prevention of migraines. The use

TOPAMAX in the

acute

treatment

of migraine has not been studied

4.2

Posology and method of administration

Posology

It is recommended that therapy be initiated at a low dose followed by titration to an effective dose.

Dose and titration rate should be guided by clinical response.

It is not necessary to monitor topiramate plasma concentrations to optimize therapy with

TOPAMAX

On rare occasions, the addition of

TOPAMAX

to phenytoin may require an adjustment of the dose of

Page 2 of 21

Topamax_spc_Jul2020_ref_EU SmPC Sep2019

phenytoin to achieve optimal clinical outcome. Addition or withdrawal of phenytoin and

carbamazepine to adjunctive therapy with

TOPAMAX

may require adjustment of the dose of

TOPAMAX

In patients with or without a history of seizures or epilepsy, antiepileptic drugs (AEDs) including

topiramate should be gradually withdrawn to minimize the potential for seizures or increased seizure

frequency. In clinical trials, daily dosages were decreased in weekly intervals by 50-100 mg in adults

with epilepsy and by 25-50 mg in adults receiving topiramate at doses up to 100 mg/day for migraine

prophylaxis. In paediatric clinical trials, topiramate was gradually withdrawn over a 2-8 week period.

Adjunctive Therapy Epilepsy

Adults

Therapy should begin at 25 - 50 mg nightly for one week.

Use of lower initial doses has been reported,

but has not been studied systematically.

Subsequently, at weekly or bi-weekly intervals, the dose should

be increased by 25 - 50 to 100 mg/day and taken in two divided doses. Dose titration should be guided by clinical

outcome. Some patients may achieve efficacy with once-a-day dosing.

In clinical trials as adjunctive therapy, 200

mg was effective and was the lowest dosage studied. This is

therefore considered the minimum effective dose.

The usual daily dose is 200 - 400 mg in two divided doses. Individual patients have received doses as high as

1600 mg/day.

These dosing recommendations apply to all adults, including the elderly, in the absence of

underlying renal disease

. (See

SPECIAL WARNINGS AND SPECIAL PRECAUTIONS FOR USE

Children Aged 2 And Above

The recommended total daily dose of TOPAMAX

(topiramate) as adjunctive therapy is approximately 5 to 9

mg/kg/day in two divided doses. Titration should begin at 25 mg (or less, based on a range of 1 to 3 mg/kg/day)

nightly for the first week. The dosage should then be increased at 1- or 2-week intervals by increments of 1 to 3

mg/kg/day (administered in two divided doses), to achieve optimal clinical response. Dose titration should be

guided by clinical outcome.

Daily doses

up to 30 mg/kg/day have been studied and were generally well tolerated.

Monotherapy

Epilepsy

General

When concomitant

antiepileptic drugs (

AEDs

) are withdrawn to achieve monotherapy with topiramate,

consideration should be given to the effects this may have on seizure control. Unless safety concerns require an

abrupt withdrawal of the concomitant AED, a gradual discontinuation at the rate of approximately one

-third of

the concomitant AED dose every 2 weeks is recommended.

When enzyme inducing

drugs

are withdrawn, topiramate levels will increase. A decrease in

TOPAMAX

dosage may be required if clinically indicated.

Adults

Dose and titration should be guided by clinical response. Titration should begin at 25 mg nightly for

1 week. The dosage should then be increased at 1- or 2-week intervals by increments of 25 or

50 mg/day, administered in two divided doses. If the patient is unable to tolerate the titration

regimen, smaller increments or longer intervals between increments can be used.

The recommended initial target dose for topiramate monotherapy in adults is 100 mg/day.and the

maximum recommended daily dose is 500 mg. Some patients with refractory forms of epilepsy have

tolerated topiramate monotherapy at doses of 1,000 mg/day. These dosing recommendations apply to

all adults including the elderly in the absence of underlying renal disease.

Page 3 of 21

Topamax_spc_Jul2020_ref_EU SmPC Sep2019

Children

Dose and titration rate in children should be guided by clinical outcome. Treatment of children

aged 7

years

and above

should begin at 0.5 to 1 mg/kg nightly for the first week. The dosage should then be

increased at 1 or 2 week intervals by increments of 0.5 to 1 mg/kg/day, administered in two divided

doses. If the child is unable to tolerate the titration regimen, smaller increments or longer intervals

between dose increments can be used.

The recommended initial target dose range for topiramate monotherapy in children aged seven years

and above is 100 to 400 mg/day. Children with recently diagnosed partial onset seizures

have received

doses of

up to

500 mg/day

Migraine

Adults

The recommended total daily dose of topiramate for prophylaxis of migraine headache is 100 mg/day

administered in two divided doses. Titration should begin at 25 mg nightly for 1 week. The dosage

should then be increased in increments of 25 mg/day administered at 1-week intervals. If the patient is

unable to tolerate the titration regimen, longer intervals between dose adjustments can be used.

Some patients may experience a benefit at a total daily dose of 50 mg/day. Patients have received a

total daily dose up to 200 mg/day. This dose may be benefit in some patients, nevertheless, caution is

advised due to an increase incidence of side effects.

Dose and titration rate should be guided by clinical outcome (See Pharmacodynamic Properties).

Pediatric population

Topamax

(topiramate) is not recommended for treatment or prevention of migraine in children due to

insufficient data on safety and efficacy.

General dosing recommendations for Topamax in special patient populations

Renal impairment

In patients with impaired renal function (CL

≤ 70 mL/min) topiramate should be administered with

caution as the plasma and renal clearance of topiramate are decreased. Subjects with known renal

impairment may require a longer time to reach steady-state at each dose. Half of the usual starting

and maintenance dose is recommended (see section 5.2).

In patients with end-stage renal failure, since topiramate is removed from plasma by haemodialysis, a

supplemental dose of

Topamax

equal to approximately one-half the daily dose should be administered

on haemodialysis days. The supplemental dose should be administered in divided doses at the

beginning and completion of the haemodialysis procedure. The supplemental dose may differ based

on the characteristics of the dialysis equipment being used (see section 5.2).

Hepatic impairment

In patients with moderate to severe hepatic impairment topiramate should be administered with

caution as the clearance of topiramate is decreased.

Elderly

No dose adjustment is required in the elderly population providing renal function is intact.

Method of administration

Topamax

is available in film-coated tablets for oral administration. It is recommended that film-coated

tablets not be broken.

Topamax

can be taken without regard to meals.

Page 4 of 21

Topamax_spc_Jul2020_ref_EU SmPC Sep2019

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Migraine prophylaxis in pregnancy and in women of childbearing potential if not using a highly

effective method of contraception.

4.4

Special warnings and precautions for use

In situations where rapid withdrawal of topiramate is medically required, appropriate monitoring is

recommended (see section 4.2).

As with other AEDs, some patients may experience an increase in seizure frequency or the onset of

new types of seizures with topiramate. These phenomena may be the consequence of an overdose, a

decrease in plasma concentrations of concomitantly used AEDs, progress of the disease, or a

paradoxical effect.

Adequate hydration while using topiramate is very important. Hydration can reduce the risk of

nephrolithiasis (see below). Proper hydration prior to and during activities such as exercise or exposure

to warm temperatures may reduce the risk of heat-related adverse reactions (see section 4.8).

Women of childbearing potential

Topiramate may cause fetal harm and fetal growth restriction (small for gestational age and low birth

weight) when administered to a pregnant woman. The North American Antiepileptic Drug pregnancy

registry data for topiramate monotherapy showed an approximate 3-fold higher prevalence of major

congenital malformations (4.3%), compared with a reference group not taking AEDs (1.4%). In

addition, data from other studies indicate that, compared with monotherapy, there is an increased risk

of teratogenic effects associated with the use of AEDs in combination therapy.

Before the initiation of treatment with topiramate in a woman of childbearing potential, pregnancy

testing should be performed and a highly effective contraceptive method advised (see section 4.5).

The patient should be fully informed of the risks related to the use of topiramate during pregnancy

(see sections 4.3 and 4.6).

Oligohydrosis

Oligohydrosis (decreased sweating) has been reported in association with the use of topiramate.

Decreased sweating and hyperthermia (rise in body temperature) may occur especially in young

children exposed to high ambient temperature.

Mood disturbances/depression

An increased incidence of mood disturbances and depression has been observed during topiramate

treatment.

Suicide/suicide ideation

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

several indications. A meta-analysis of randomised placebo-controlled trials of AEDs has shown a small

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

available data do not exclude the possibility of an increased risk for topiramate.

In double blind clinical trials, suicide related events (SREs) (suicidal ideation, suicide attempts and

suicide) occurred at a frequency of 0.5% in topiramate treated patients (46 out of 8,652 patients

treated) and at a nearly 3-fold higher incidence than those treated with placebo (0.2%; 8 out of

4,045 patients treated).

Page 5 of 21

Topamax_spc_Jul2020_ref_EU SmPC Sep2019

Patients therefore 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.

Nephrolithiasis

Some patients, especially those with a predisposition to nephrolithiasis, may be at increased risk for

renal stone formation and associated signs and symptoms such as renal colic, renal pain or flank pain.

Risk factors for nephrolithiasis include prior stone formation, a family history of nephrolithiasis and

hypercalciuria (see below – Metabolic acidosis). None of these risk factors can reliably predict stone

formation during topiramate treatment. In addition, patients taking other medicinal products

associated with nephrolithiasis may be at increased risk.

Decreased renal function

In patients with impaired renal function (CL

≤ 70 mL/min) topiramate should be administered with

caution as the plasma and renal clearance of topiramate are decreased. For specific posology

recommendations in patients with decreased renal function, see section 4.2.

Decreased hepatic function

In hepatically-impaired patients, topiramate should be administered with caution as the clearance of

topiramate may be decreased.

Acute myopia and secondary angle closure glaucoma

A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been

reported in patients receiving

TOPAMAX

Symptoms include acute onset of decreased visual acuity

and/or ocular pain. Ophthalmologic findings can include myopia, anterior chamber shallowing, ocular

hyperaemia (redness) and increased intraocular pressure. Mydriasis may or may not be present. This

syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens

and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating

TOPAMAX

therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age,

secondary angle closure glaucoma associated with topiramate has been reported in paediatric patients

as well as adults. Treatment includes discontinuation of

TOPAMAX

as rapidly as possible in the

judgment of the treating physician, and appropriate measures to reduce intraocular pressure. These

measures generally result in a decrease in intraocular pressure.

Elevated intraocular pressure of any aetiology, if left untreated, can lead to serious sequelae including

permanent vision loss.

A determination should be made whether patients with history of eye disorders should be treated

with topiramate.

Visual field defects

Visual field defects have been reported in patients receiving topiramate independent of elevated

intraocular pressure. In clinical trials, most of these events were reversible after topiramate

discontinuation. If visual field defects occur at any time during topiramate treatment, consideration

should be given to discontinuing the drug.

Metabolic acidosis

Hyperchloremic, non-anion gap, metabolic acidosis (i.e. decreased serum bicarbonate below the

normal reference range in the absence of respiratory alkalosis) is associated with topiramate

treatment. This decrease in serum bicarbonate is due to the inhibitory effect of topiramate on renal

carbonic anhydrase. Generally, the decrease in bicarbonate occurs early in treatment although it can

occur at any time during treatment. These decreases are usually mild to moderate (average decrease

Page 6 of 21

Topamax_spc_Jul2020_ref_EU SmPC Sep2019

of 4 mmol/l at doses of 100 mg/day or above in adults and at approximately 6 mg/kg/day in paediatric

patients). Rarely, patients have experienced decreases to values below 10 mmol/l. Conditions or

therapies that predispose to acidosis (such as renal disease, severe respiratory disorders, status

epilepticus, diarrhoea, surgery, ketogenic diet, or certain medicinal products) may be additive to the

bicarbonate lowering effects of topiramate.

Chronic, untreated metabolic acidosis increases the risk of nephrolithiasis and nephrocalcinosis, and

may potentially lead to osteopenia (see above – Nephrolithiasis).

Chronic metabolic acidosis in paediatric patients can reduce growth rates. The effect of topiramate on

bone-related sequelae has not been systematically investigated in paediatric or adult populations.

Depending on underlying conditions, appropriate evaluation including serum bicarbonate levels is

recommended with topiramate therapy. If signs or symptoms are present (e.g. Kussmaul’s deep

breathing, dyspnoea, anorexia, nausea, vomiting, excessive tiredness, tachycardia or arrhythmia),

indicative of metabolic acidosis, measurement of serum bicarbonate is recommended. If metabolic

acidosis develops and persists, consideration should be given to reducing the dose or discontinuing

topiramate (using dose tapering).

Topiramate should be used with caution in patients with conditions or treatments that represent a risk

factor for the appearance of metabolic acidosis.

Impairment of cognitive function

Cognitive impairment in epilepsy is multifactorial and may be due to the underlying aetiology, due to

the epilepsy or due to the antiepileptic treatment. There have been reports in the literature of

impairment of cognitive function in adults on topiramate therapy which required reduction in dosage

or discontinuation of treatment. However, studies regarding cognitive outcomes in children treated

with topiramate are insufficient and its effect in this regard still needs to be elucidated.

Hyperammonemia and encephalopathy

Hyperammonemia with or without encephalopathy has been reported with topiramate treatment (see

section 4.8). The risk for hyperammonemia with topiramate appears dose-related. Hyperammonemia

has been reported more frequently when topiramate is used concomitantly with valproic acid (see

section 4.5).

In patients who develop unexplained lethargy or changes in mental status associated with topiramate

monotherapy or adjunctive therapy, it is recommended to consider hyperammonemic encephalopathy

and measuring ammonia levels.

Nutritional supplementation

Some patients may experience weight loss whilst on treatment with topiramate. It is

recommended that patients on topiramate treatment should be monitored for weight loss.

dietary supplement or increased food intake may be considered if the patient is losing weight while on

topiramate.

Lactose intolerance

Topimax tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total

lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Sodium

Each tablet contains less than 1 mmol sodium (23 mg), and is essentially ‘sodium free’.

Page 7 of 21

Topamax_spc_Jul2020_ref_EU SmPC Sep2019

4.5

Interaction

with other medicinal products and other forms of interaction

Effects of TOPAMAX

to other antiepileptic medicinal products

The addition of Topamax to other AEDs (phenytoin, carbamazepine, valproic acid, phenobarbital,

primidone) has no effect on their steady-state plasma concentrations, except in the occasional patient,

where the addition of

TOPAMAX

to phenytoin may result in an increase of plasma concentrations of

phenytoin. This is possibly due to inhibition of a specific enzyme polymorphic isoform (CYP2C19).

Consequently, any patient on phenytoin showing clinical signs or symptoms of toxicity should have

phenytoin levels monitored.

A pharmacokinetic interaction study of patients with epilepsy indicated the addition of topiramate to

lamotrigine had no effect on steady state plasma concentration of lamotrigine at topiramate doses of

100 to 400 mg/day. In addition, there was no change in steady state plasma concentration of

topiramate during or after removal of lamotrigine treatment (mean dose of 327 mg/day).

Topiramate inhibits the enzyme CYP 2C19 and may interfere with other substances metabolized via

this enzyme (e.g., diazepam, imipramin, moclobemide, proguanil, omeprazol).

Effects of other antiepileptic medicinal products on

TOPAMAX

Phenytoin and carbamazepine decrease the plasma concentration of

topiramate.

The addition or

withdrawal of phenytoin or carbamazepine to

TOPAMAX

therapy may require an adjustment in dosage

of the latter. This should be done by titrating to clinical effect. The addition or withdrawal of valproic

acid does not produce clinically significant changes in plasma concentrations of

TOPAMAX

and,

therefore, does not warrant dosage adjustment of

TOPAMAX

The results of these interactions are

summarized below:

AED Coadministered

AED Concentration

Topimax Concentration

Phenytoin

↔**

Carbamazepine (CBZ)

Valproic acid

Lamotrigine

Phenobarbital

Primidone

= No effect on plasma concentration (≤15% change)

= Plasma concentrations increase in individual patients

= Plasma concentrations decrease

= Not studied

= antiepileptic drug

Other medicinal product interactions

Digoxin

In a single-dose study, serum digoxin area under plasma concentration curve (AUC) decreased 12%

due to concomitant administration of

TOPAMAX

The clinical relevance of this observation has not

been established. When

TOPAMAX

is added or withdrawn in patients on digoxin therapy, careful

attention should be given to the routine monitoring of serum digoxin.

Central nervous system depressants

Concomitant administration of TOPAMAX

and alcohol or other central nervous system (CNS)

depressant medicinal products has not been evaluated in clinical studies. It is recommended that

TOPAMAX

not be used concomitantly with alcohol or other CNS depressant medicinal products.

Page 8 of 21

Topamax_spc_Jul2020_ref_EU SmPC Sep2019

St John’s Wort (Hypericum perforatum)

A risk of decreased plasma concentrations resulting in a loss of efficacy could be observed with

co-administration of topiramate and St John’s Wort. There have been no clinical studies evaluating this

potential interaction.

Oral contraceptives

In a pharmacokinetic interaction study in healthy volunteers with a concomitantly

administered combination oral contraceptive product containing 1

mg norethindrone (NET)

plus 35

ethinyl estradiol (EE),

TOPAMAX

given in the absence of other medications at doses

of 50 to 200

mg/day was not associated with statistically significant changes in mean exposure

(AUC) to either component of the oral contraceptive. In another study, exposure to EE was

statistically significantly decreased at doses of 200, 400, and 800

mg/day (18%, 21%, and 30%,

respectively) when given as adjunctive therapy in

epilepsy

patients taking valproic acid. In both

studies,

TOPAMAX

-200 mg

/day in healthy volunteers and 200

-800 mg

/day in epilepsy

patients) did not significantly affect exposure to NET. Although there was a dose

dependent

decrease in EE exposure for doses between 200

mg/day (in epilepsy patients), there was

no significant dose

dependent change in EE exposure for doses of 50

mg/day (in healthy

volunteers). The clinical significance of the changes observed is not known.

The possibility of

decreased contraceptive efficacy and increased breakthrough bleeding should be considered in

patients taking combination oral contraceptive products with

TOPAMAX

Patients taking estrogen

containing contraceptives should be asked to report any change in their bleeding patterns.

Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding.

Lithium

In healthy volunteers, there was an observed reduction (18% for AUC) in systemic exposure for lithium

during concomitant administration with topiramate 200 mg/day. In patients with bipolar disorder, the

pharmacokinetics of lithium were unaffected during treatment with topiramate at doses of

200 mg/day; however, there was an observed increase in systemic exposure (26% for AUC) following

topiramate doses of up to 600 mg/day. Lithium levels should be monitored when co-administered with

topiramate.

Risperidone

Drug-drug interaction studies conducted under single dose conditions in healthy

volunteers and

multiple dose conditions in patients with bipolar disorder, yielded similar results. When administered

concomitantly with topiramate at escalating doses of 100, 250 and 400 mg/day there was a reduction

in risperidone (administered at doses ranging from 1 to 6 mg/day) systemic exposure (16% and 33%

for steady-state AUC at the 250 and 400 mg/day doses, respectively). However, differences in AUC for

the total active moiety between treatment with risperidone alone and combination treatment with

topiramate were not statistically significant.Minimal alterations in the pharmacokinetics of the total

active moiety (risperidone plus 9-hydroxyrisperidone) and no alterations for 9-hydroxyrisperidone

were observed. There were no significant changes in the systemic exposure of the risperidone total

active moiety or of topiramate. When topiramate was added to existing risperidone (1-6 mg/day)

treatment, adverse events were reported more frequently than prior to topiramate (250-400 mg/day)

introduction (90% and 54% respectively). The most frequently reported AE’s when topiramate was

added to risperidone treatment were: somnolence (27% and 12%), paraesthesia (22% and 0%) and

nausea (18% and 9% respectively).

Hydrochlorothiazide (HCTZ)

A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state

pharmacokinetics of HCTZ (25 mg every 24 h) and topiramate (96 mg every 12 h) when administered

alone and concomitantly. The results of this study indicate that topiramate C

increased by 27% and

AUC increased by 29% when HCTZ was added to topiramate. The clinical significance of this change is

Page 9 of 21

Topamax_spc_Jul2020_ref_EU SmPC Sep2019

unknown. The addition of HCTZ to topiramate therapy may require an adjustment of the topiramate

dose. The steady-state pharmacokinetics of HCTZ were not significantly influenced by the concomitant

administration of topiramate. Clinical laboratory results indicated decreases in serum potassium after

topiramate or HCTZ administration, which were greater when HCTZ and topiramate were administered

in combination.

Metformin

A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state

pharmacokinetics of metformin and topiramate in plasma when metformin was given alone and when

metformin and topiramate were given simultaneously. The results of this study indicated that

metformin mean C

and mean AUC

0-12h

increased by 18% and 25%, respectively, while mean CL/F

decreased 20% when metformin was co-administered with topiramate. Topiramate did not affect

metformin t

The clinical significance of the effect of topiramate on metformin pharmacokinetics is

unclear. Oral plasma clearance of topiramate appears to be reduced when administered with

metformin. The extent of change in the clearance is unknown. The clinical significance of the effect of

metformin on topiramate pharmacokinetics is unclear.

When

TOPAMAX

is added or withdrawn in patients on metformin therapy, careful attention should be

given to the routine monitoring for adequate control of their diabetic disease state.

Pioglitazone

A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state

pharmacokinetics of topiramate and pioglitazone when administered alone and concomitantly. A 15%

decrease in the AUC

of pioglitazone with no alteration in C

max,ss

was observed. This finding was not

statistically significant. In addition, a 13% and 16% decrease in C

max,ss

and AUC

respectively, of the

active hydroxy-metabolite was noted as well as a 60% decrease in C

max,ss

and AUC

of the active keto-

metabolite. The clinical significance of these findings is not known. When

TOPAMAX

is added to

pioglitazone therapy or pioglitazone is added to

TOPAMAX

therapy, careful attention should be given

to the routine monitoring of patients for adequate control of their diabetic disease state.

Glibenclamide

A drug-drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state

pharmacokinetics of glibenclamide (5 mg/day) alone and concomitantly with topiramate (150 mg/day).

There was a 25% reduction in glibenclamide AUC

during topiramate administration. Systemic

exposure of the active metabolites, 4-trans-hydroxy-glyburide (M1) and 3-cis-hydroxyglyburide (M2),

were also reduced by 13% and 15%, respectively. The steady-state pharmacokinetics of topiramate

were unaffected by concomitant administration of glibenclamide.

When topiramate is added to glibenclamide therapy or glibenclamide is added to topiramate therapy,

careful attention should be given to the routine monitoring of patients for adequate control of their

diabetic disease state.

Other forms of interactions

Agents predisposing to nephrolithiasis:

TOPAMAX

, when used concomitantly with other agents predisposing to nephrolithiasis, may increase

the risk of nephrolithiasis. While using

TOPAMAX

agents like these should be avoided since they may

create a physiological environment that increases the risk of renal stone formation.

Valproic acid

Concomitant administration of topiramate and valproic acid has been associated with

hyperammonemia with or without encephalopathy in patients who have tolerated either medicinal

product alone. In most cases, symptoms and signs abated with discontinuation of either medicinal

Page 10 of 21

Topamax_spc_Jul2020_ref_EU SmPC Sep2019

product (see section 4.4 and section 4.8). This adverse reaction is not due to a pharmacokinetic

interaction.

Hypothermia, defined as an unintentional drop in body core temperature to <35°C, has been reported

in association with concomitant use of topiramate and valproic acid (VPA) both in conjunction with

hyperammonemia and in the absence of hyperammonemia. This adverse event in patients using

concomitant topiramate and valproate can occur after starting topiramate treatment or after

increasing the daily dose of topiramate.

Warfarin

Decreased Prothrombin Time/International Normalized Ratio (PT/INR) has been reported in patients

treated with topiramate in combination with warfarin. Therefore, INR should be carefully monitored in

patients concomitantly treated with topiramate and warfarin.

Additional pharmacokinetic drug interaction studies

Clinical studies have been conducted to assess the potential pharmacokinetic drug interaction

between topiramate and other agents. The changes in C

or AUC as a result of the interactions are

summarized below. The second column (concomitant drug concentration) describes what happens to

the concentration of the concomitant drug listed in the first column when topiramate is added. The

third column (topiramate concentration) describes how the coadministration of a drug listed in the

first column modifies the concentration of topiramate.

Summary of Results from Additional Clinical Pharmacokinetic Drug Interaction Studies

Concomitant Drug

Concomitant Drug

Concentration

a

Topiramate Concentration

a

Amitriptyline

↔ 20% increase in C

AUC of nortriptyline

metabolite

Dihydroergotamine (Oral and

Subcutaneous)

Haloperidol

↔ 31% increase in AUC of the

reduced metabolite

Propranolol

↔ 17% increase in C

4-OH propranolol (TPM 50 mg

q12h)

9% and 16% increase in C

9% and17% increase in AUC

(40 and 80 mg propranolol

q12h respectively)

Sumatriptan (Oral and

Subcutaneous)

Pizotifen

Diltiazem

25% decrease in AUC of diltiazem

and 18% decrease in DEA, and

for DEM*

20% increase in AUC

Venlafaxine

Flunarizine

16% increase in AUC

(TPM 50 mg q12h)

% values are the changes in treatment mean C

or AUC with respect to monotherapy

No effect on C

and AUC (≤15% change) of the parent compound

Not studied

*DEA =

des acetyl diltiazem, DEM = N-demethyl diltiazem

Flunarizine AUC increased 14% in subjects taking flunarizine alone. Increase in exposure may be

attributed to accumulation during achievement of steady state.

Page 11 of 21

Topamax_spc_Jul2020_ref_EU SmPC Sep2019

4.6

Fertility, pregnancy and lactation

Pregnancy

Risk related to epilepsy and AEDs in general

Specialist advice should be given to women who are of childbearing potential. The need for

treatment with AEDs should be reviewed when a woman is planning to become pregnant. In

women being treated for epilepsy, sudden discontinuation of AED therapy should be avoided

as this may lead to breakthrough seizures that could have serious consequences for the

woman and the unborn child.

Monotherapy should be preferred whenever possible because

therapy with multiple AEDs could be associated with a higher risk of congenital malformations than

monotherapy, depending on the associated antiepileptics.

Risk related to topiramate

Topiramate was teratogenic in mice, rats and rabbits (see section 5.3). In rats, topiramate crosses the

placental barrier.

In humans, topiramate crosses the placenta and similar concentrations have been reported in the

umbilical cord and maternal blood.

Clinical data from pregnancy registries indicate that infants exposed to topiramate monotherapy have:

An increased risk of congenital malformations (particularly cleft lip/palate, hypospadias, and

anomalies involving various body systems) following exposure during the first trimester. The

North American Antiepileptic Drug pregnancy registry data for topiramate monotherapy showed

an approximate 3-fold higher prevalence of major congenital malformations (4.3%), compared

with a reference group not taking AEDs (1.4%). In addition, data from other studies indicate

that, compared with monotherapy, there is an increased risk of teratogenic effects associated

with the use of AEDs in combination therapy. The risk has been reported to be dose dependent;

effects were observed in all doses. In women treated with topiramate who have had a child

with a congenital malformation, there appears to be an increased risk of malformations in

subsequent pregnancies when exposed to topiramate.

A higher prevalence of low birth weight (<2500 grams) compared with a reference group.

An increased prevalence of being small for gestational age (SGA; defined as birth weight below

the 10

percentile corrected for their gestational age, stratified by sex). The long term

consequences of the SGA findings could not be determined.

Indication epilepsy

It is recommended to consider alternative therapeutic options in women of childbearing potential. If

topirmate is used in women of childbearing potential, it is recommended that highly effective

contraception be used (see section 4.5), and that the woman is fully informed of the known risks of

uncontrolled epilepsy to the pregnancy and the potential risks of the medicinal product to the foetus.

If a woman plans a pregnancy, a preconceptional visit is recommended in order to reassess the

treatment, and to consider other therapeutic options. In case of administration during the first

trimester, careful prenatal monitoring should be performed.

Indication migraine prophylaxis

Topiramate is contraindicated in pregnancy and in women of childbearing potential if a highly effective

method of contraception is not used (see sections 4.3 and 4.5).

Breast-feeding

Animal studies have shown excretion of topiramate in milk. The excretion of topiramate in human milk

has not been evaluated in controlled studies. Limited observations in patients suggest an extensive

excretion of topiramate into human milk. Effects that have been observed in breastfed

newborns/infants of treated mothers, include diarrhea, drowsiness, irritability and inadequate weight

Page 12 of 21

Topamax_spc_Jul2020_ref_EU SmPC Sep2019

gain. Therefore, a decision must be made whether to suspend breast-feeding or to discontinue/

abstain from topiramate therapy taking into account the benefit of breast-feeding for the child and the

benefit of topiramate therapy for the women (see section 4.4).

Fertility

Animal studies did not reveal impairment of fertility by topiramate (see section 5.3). The effect of

topiramate on human fertility has not been established.

4.7

Effects on ability to drive and use machines

Topamax

has minor or moderate influence on the ability to drive and use machines.

TOPAMAX

acts on

the central nervous system and may produce drowsiness, dizziness or other related symptoms. It may

also cause visual disturbances and/or blurred vision. These adverse reactions could potentially be

dangerous in patients driving a vehicle or operating machinery, particularly until such time as the

individual patient's experience with the medicinal products established.

4.8

Undesirable effects

The safety of topiramate was evaluated from a clinical trial database consisting of 4,111 patients

(3,182 on topiramate and 929 on placebo) who participated in 20 double-blind trials and

2,847 patients who participated in 34 open-label trials, respectively, for topiramate as adjunctive

treatment of primary generalized tonic-clonic seizures, partial onset seizures, seizures associated with

Lennox-Gastaut syndrome, monotherapy for newly or recently diagnosed epilepsy or migraine

prophylaxis. The majority of adverse reactions were mild to moderate in severity. Adverse reactions

identified in clinical trials, and during post-marketing experience (as indicated by “*”) are listed by

their incidence in clinical trials in Table 1. Assigned frequencies are as follows:

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

Not known

cannot be estimated from the available data

The most common adverse reactions (those with an incidence of >5% and greater than that observed

in placebo in at least 1 indication in double-blind controlled studies with topiramate) include: anorexia,

decreased appetite, bradyphrenia, depression, expressive language disorder, insomnia, coordination

abnormal, disturbance in attention, dizziness, dysarthria, dysgeusia, hypoesthesia, lethargy, memory

impairment, nystagmus, paresthesia, somnolence, tremor, diplopia, vision blurred, diarrhoea, nausea,

fatigue, irritability, and weight decreased.

Table 1: Topiramate Adverse Reactions

System Organ Class Very common

Common

Uncommon

Rare

Not known

Infections and

infestations

nasopharyngitis*

Blood and

lymphatic system

disorders

anaemia

leucopenia,

thrombocytopenia

lymphadenopathy,

eosinophilia

neutropenia*

Immune system

disorders

hypersensitivity

allergic

oedema*

Page 13 of 21

Topamax_spc_Jul2020_ref_EU SmPC Sep2019

Table 1: Topiramate Adverse Reactions

System Organ Class Very common

Common

Uncommon

Rare

Not known

Metabolism and

nutrition disorders

anorexia,

decreased appetite

metabolic acidosis,

hypokalaemia,

increased appetite,

polydipsia

acidosis

hyperchloraemic

hyperammonemi

hyperammonemi

encephalopathy*

Psychiatric

disorders

depression

bradyphrenia,

insomnia,

expressive

language

disorder,

anxiety,

confusional state,

disorientation,

aggression,

mood

altered, agitation,

mood swings,

depressed mood,

anger, abnormal

behaviour

suicidal ideation,

suicide attempt,

hallucination,

psychotic disorder,

hall

ucination

auditory,

hallucination visual,

apathy, lack of

spontaneous

speech, sleep

disorder,

affect

lability, libido

decreased,

restlessness, crying,

dysphemia,

euphoric

mood,

paranoia,

rseveration,

panic attack,

tearfulness,

reading

disorder,

initial i

nsomnia,

flat

affect, thinking

abnormal, loss of

libido, listless,

middle

insomnia,

distractibility, early

morning awakening,

panic reaction,

elevated mood

mania, panic

diso

rder, feeling

of despair*,

hypomania

Page 14 of 21

Topamax_spc_Jul2020_ref_EU SmPC Sep2019

Table 1: Topiramate Adverse Reactions

System Organ Class Very common

Common

Uncommon

Rare

Not known

Nervous system

disorders

paraesthesia,som

nolence dizziness

disturbance in

attention, memory

impairment,

amnesia, cognitive

disorder, mental

impairment,

psychomotor sk

ills

impaired,

convulsion,

coordination

abnormal, tremor,

lethargy,

hypoaesthesia,

nystagmus,

dysgeusia, balance

disorder,

dysarthr

ention tremor,

sedation

depressed level of

consciousness,

grand mal

convulsion, visual

field defe

complex partial

seizures,

speech

disorder,

psychomotor

hyperactivity,

syncope, sensory

disturbance,

drooling,

hypersomnia,

aphasia, repetitive

spee

hypokinesia,

dyskinesia, dizziness

postural, poor

quality sleep,

burning sensation,

sory loss,

parosmia, cerebellar

syndrome,

dysaesthesia,

hypogeusia, stupor,

clumsiness, aura,

ageusia, dysgraphia,

dysphasia,

neuropathy

peripheral,

presyncope,

dyst

onia,

formication

apraxia, circadian

rhythm sleep

disorder,

hyperaest

hesia,

hyposmia,

anosmia,

essential

tremor, akinesia,

unresponsive to

stimuli

Eye disorders

vision blurred,

diplopia, visual

disturbance

visual acuity

reduced, scotoma,

myopia*, abnorm

sensation in eye*,

eye,

photophobi

blepharospasm,

lacrimation

increased,

photopsia,

mydriasis,

presbyopia

blindness

unilateral,

blindness transient,

glaucoma,

commodation

disorder,

altered

visual depth

perception,

scintillating

scotoma, eyelid

edema*, night

blindness,

amblyopia

angle closure

glaucoma*,

maculopathy*,

eye movement

disorder*,

conjunctival

oedema*

Ear and labyrinth

disorders

vertigo, tinnitus,

ear pain

deafness

, deafness

unilateral,

deafness

neurosensory, ear

discomfort,

hearing

mpaired

Page 15 of 21

Topamax_spc_Jul2020_ref_EU SmPC Sep2019

Table 1: Topiramate Adverse Reactions

System Organ Class Very common

Common

Uncommon

Rare

Not known

Cardiac disorders

bradycardia, sinus

bradycardia,

palpitations

Vascular disorders

hypotension,

orthostatic

hypotension,flushin

g, hot flush

Raynaud's

phenomenon

Respiratory,

thoracic and

mediastinal

disorders

dyspnoea,

epistaxis, nasal

congestion,

rhinorrhoea

cough*

dyspnoea

exertional

paranasal sinus

hypersecretion,

dysphonia

Gastrointestinal

disorders

nausea, diarrhoea vomiting,

constipation,

abdominal pain

upper, dyspepsia,

abdominal pain,

dry mouth,

stomach

discomfort,

paraest

hesia oral,

gastritis,

abdominal

discomfort

pancreatitis,

flatulence,

gastrooesophageal

reflux disea

abdominal pain

lower,

hypoaesthesia oral,

gingival

bleeding,

abdominal

distension,

epigastric

discomfort,

abdominal

tenderness, salivary

persecretion,

oral pain, breath

odour,

glossodynia

Hepatobiliary

disorders

hepatitis, hepatic

failure

Skin and

subcutaneous

tissue disorders

alopecia, rash,

pruritus

anhidrosis,

hypoaesthesia

facial,

urti

caria,

erythema,

pruritus

generalised, rash

macular, sk

discolouration,

dermatitis allergic,

swelling face

Stevens

-Johnson

syndrome*

erythema

multiforme*, skin

odour abnormal,

periorbital

oedema*,

urticaria localised

toxic

dermal

necrolysis*

Musculoskeletal

and connective

tissue disorders

arthralgia, m

uscle

spasms, myalgia,

muscle twitching,

muscular

weakness,

musculoskeletal

chest pain

joint swelling*,

musculoskeletal

stiffness, flank p

ain,

muscle fatigue

limb discomfort*

Page 16 of 21

Topamax_spc_Jul2020_ref_EU SmPC Sep2019

Table 1: Topiramate Adverse Reactions

System Organ Class Very common

Common

Uncommon

Rare

Not known

Renal and urinary

disorders

nephrolithiasis,

pollakiuria, dysuria,

nephrocalcinosis*

calculus urinary,

urinary

incontinence,

haematuria,

incontinence,

micturition urgency,

rena

l colic, renal

pain

calculus ureteric,

renal tubular

acidosis*

Reproductive

system and breast

disorders

erectile dysfunction,

sexual dysfunction

General disorders

and administration

site conditions

fatigue

pyrexia, a

sthenia,

irritability, gait

disturbance,

feeling abnormal,

malaise

hyperthermia,

thirst, influe

nza like

illness*,

sluggishness,

peripheral coldness,

feeling drunk,

feeling jittery

face oede

Investigations

weight decreased

weight increased*

crystal urine

present, tandem

gait test abnormal,

white blood cel

count decreased,

Increase in liver

enzymes

blood bicarbonate

decreased

Social

circumstances

learning disability

identified as an adverse reaction from postmarketing spontaneous reports. Its frequency was calculated based on the incidence in clinical

trials, or was calculated if the event did not occur in clinical trials.

Paediatric population

Congenital malformations and fetal growth restrictions (see section 4.4 and section 4.6).

Paediatric population

Adverse reactions reported more frequently (

2-fold) in children than in adults in double-blind

controlled studies include:

Decreased appetite

Increased appetite

Hyperchloraemic acidosis

Hypokalaemia

Abnormal behaviour

Aggression

Apathy

Initial insomnia

Suicidal ideation

Disturbance in attention

Lethargy

Circadian rhythm sleep disorder

Poor quality sleep

Lacrimation increased

Sinus bradycardia

Page 17 of 21

Topamax_spc_Jul2020_ref_EU SmPC Sep2019

Feeling abnormal

Gait disturbance.

Adverse reactions that were reported in children but not in adults in double-blind controlled studies

include:

Eosinophilia

Psychomotor hyperactivity

Vertigo

Vomiting

Hyperthermia

Pyrexia

Learning disability.

Reporting of suspected adverse reactions

Reporting

suspected

adverse

reactions

after

authorisation

medicinal

product

important.

allows

continued

monitoring

benefit/risk

balance

medicinal

product.Any suspected adverse events should be reported to the Ministry of Health according

to the National Regulation by using an online form http://sideeffects.health.gov.il

4.9

Overdose

Signs and symptoms

Overdoses of topiramate have been reported. Signs and symptoms included convulsions, drowsiness,

speech disturbances, blurred vision, diplopia, impaired mentation, lethargy, abnormal coordination,

stupor, hypotension, abdominal pain, agitation, dizziness and depression. The clinical consequences

were not severe in most cases, but deaths have been reported after overdoses with multiple medicinal

products including topiramate.

Topiramate overdose can result in severe metabolic acidosis (see section 4.4).

Treatment

In the event of overdose, topiramate

overdose, if the ingestion is recent, the stomach

should be

discontinued and general supportive treatment given until clinical toxicity has been diminished or

resolved.The patient should be well hydrated. Haemodialysis has been shown to be an effective means

of removing topiramate from the body. Other measures may also be taken at the physician’s

discretion.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: antiepileptics, other antiepileptics, antimigraine preparations, ATC code:

N03AX11.

Topiramate is classified as a sulfamate-substituted monosaccharide. The precise mechanism by which

topiramate exerts its antiseizure and migraine prophylaxis effects are unknown. Electrophysiological

and biochemical studies on cultured neurons have identified three properties that may contribute to

the antiepileptic efficacy of topiramate.

Action potentials elicited repetitively by a sustained depolarization of the neurons were blocked by

topiramate in a time-dependent manner, suggestive of a state-dependent sodium channel blocking

action. Topiramate increased the frequency at which γ-aminobutyrate (GABA) activated GABA

Page 18 of 21

Topamax_spc_Jul2020_ref_EU SmPC Sep2019

receptors, and enhanced the ability of GABA to induce a flux of chloride ions into neurons, suggesting

that topiramate potentiates the activity of this inhibitory neurotransmitter.

This effect was not blocked by flumazenil, a benzodiazepine antagonist, nor did topiramate increase

the duration of the channel open time, differentiating topiramate from barbiturates that modulate

GABA

receptors.

Because the antiepileptic profile of topiramate differs markedly from that of the benzodiazepines, it

may modulate a benzodiazepine-insensitive subtype of GABA

receptor. Topiramate antagonized the

ability of kainate to activate the kainate/AMPA (α -amino-3-hydroxy-5-methylisoxazole-4-propionic

acid) subtype of excitatory amino acid (glutamate) receptor, but had no apparent effect on the activity

of N-methyl-D-aspartate (NMDA) at the NMDA receptor subtype. These effects of topiramate were

concentration-dependent over a range of 1 µM to 200 µM, with minimum activity observed at 1 µM to

10 µM.

In addition, topiramate inhibits some isoenzymes of carbonic anhydrase. This pharmacologic effect is

much weaker than that of acetazolamide, a known carbonic anhydrase inhibitor, and is not thought to

be a major component of topiramate's antiepileptic activity.

In animal studies, topiramate exhibits anticonvulsant activity in rat and mouse maximal electroshock

seizure (MES) tests and is effective in rodent models of epilepsy, which include tonic and absence-like

seizures in the spontaneous epileptic rat (SER) and tonic and clonic seizures induced in rats by kindling

of the amygdala or by global ischemia. Topiramate is only weakly effective in blocking clonic seizures

induced by the GABA

receptor antagonist, pentylenetetrazole.

Studies in mice receiving concomitant administration of topiramate and carbamazepine or

phenobarbital showed synergistic anticonvulsant activity, while combination with phenytoin showed

additive anticonvulsant activity. In well-controlled add-on trials, no correlation has been demonstrated

between trough plasma concentrations of topiramate and its clinical efficacy. No evidence of tolerance

has been demonstrated in man

Absence seizures

Two small one arm studies were carried out with children aged 4-11 years old (CAPSS-326 and

TOPAMAT-ABS-001). One included 5 children and the other included 12 children before it was

terminated early due to lack of therapeutic response. The doses used in these studies were up to

approximately 12 mg/kg in study TOPAMAT-ABS-001 and a maximum of the lesser of 9 mg/kg/day or

400 mg/day in study CAPSS-326. These studies do not provide sufficient evidence to reach conclusion

regarding efficacy or safety in the paediatric population.

5.2

Pharmacokinetic properties

The film-coated tablet and hard capsule formulations are bioequivalent.

The pharmacokinetic profile of topiramate compared to other AEDs shows a long plasma half-life,

linear pharmacokinetics, predominantly renal clearance, absence of significant protein binding, and

lack of clinically relevant active metabolites.

Topiramate is not a potent inducer of drug metabolizing enzymes, can be administered without regard

to meals, and routine monitoring of plasma topiramate concentrations is not necessary. In clinical

studies, there was no consistent relationship between plasma concentrations and efficacy or adverse

events.

Page 19 of 21

Topamax_spc_Jul2020_ref_EU SmPC Sep2019

Absorption

Topiramate is rapidly and well absorbed. Following oral administration of 100 mg topiramate to

healthy subjects, a mean peak plasma concentration (C

) of 1.5 µg/ml was achieved within 2 to

3 hours (T

Based on the recovery of radioactivity from the urine the mean extent of absorption of a 100 mg oral

dose of

C-topiramate was at least 81%. There was no clinically significant effect of food on the

bioavailability of topiramate.

Distribution

Generally, 13 to 17% of topiramate is bound to plasma protein. A low capacity binding site for

topiramate in/on erythrocytes that is saturable above plasma concentrations of 4 µg/ml has been

observed. The volume of distribution varied inversely with the dose. The mean apparent volume of

distribution was 0.80 to 0.55 l/kg for a single dose range of 100 to 1200 mg. An effect of gender on the

volume of distribution was detected, with values for females circa 50% of those for males. This was

attributed to the higher percent body fat in female patients and is of no clinical consequence.

Biotransformation

Topiramate is not extensively metabolized (~20%) in healthy volunteers. It is metabolized up to 50% in

patients receiving concomitant antiepileptic therapy with known inducers of drug metabolizing

enzymes. Six metabolites, formed through hydroxylation, hydrolysis and glucuronidation, have been

isolated, characterized and identified from plasma, urine and faeces of humans. Each metabolite

represents less than 3% of the total radioactivity excreted following administration of

C-topiramate.

Two metabolites, which retained most of the structure of topiramate, were tested and found to have

little or no anticonvulsant activity.

Elimination

In humans, the major route of elimination of unchanged topiramate and its metabolites is via the

kidney (at least 81% of the dose). Approximately 66% of a dose of

C-topiramate was excreted

unchanged in the urine within four days. Following twice a day dosing with 50 mg and 100 mg of

topiramate the mean renal clearance was approximately 18 ml/min and 17 ml/min, respectively. There

is evidence of renal tubular reabsorption of topiramate. This is supported by studies in rats where

topiramate was co-administered with probenecid, and a significant increase in renal clearance of

topiramate was observed. Overall, plasma clearance is approximately 20 to 30 ml/min in humans

following oral administration.

Linearity/non-linearity

Topiramate exhibits low intersubject variability in plasma concentrations and, therefore, has

predictable pharmacokinetics. The pharmacokinetics of topiramate are linear with plasma clearance

remaining constant and area under the plasma concentration curve increasing in a dose-proportional

manner over a 100 to 400 mg single oral dose range in healthy subjects. Patients with normal renal

function may take 4 to 8 days to reach steady-state plasma concentrations. The mean C

following

multiple, twice a day oral doses of 100 mg to healthy subjects was 6.76 µg/ml. Following

administration of multiple doses of 50 mg and 100 mg of topiramate twice a day, the mean plasma

elimination half-life was approximately 21 hours.

Use with other AEDs

Concomitant multiple-dose administration of topiramate, 100 to 400 mg twice a day, with phenytoin

or carbamazepine shows dose proportional increases in plasma concentrations of topiramate.

Renal impairment

The plasma and renal clearance of topiramate are decreased in patients with moderate and severe

impaired renal function (CL

≤ 70 ml/min). As a result, higher steady-state topiramate plasma

Page 20 of 21

Topamax_spc_Jul2020_ref_EU SmPC Sep2019

concentrations are expected for a given dose in renal-impaired patients as compared to those with

normal renal function. In addition, patients with renal impairment will require a longer time to reach

steady-state at each dose. In patients with moderate and severe renal impairment, half of the usual

starting and maintenance dose is recommended.

Topiramate is effectively removed from plasma by haemodialysis. A prolonged period of hemodialysis

may cause topiramate concentration to fall below levels that are required to maintain an anti-seizure

effect. To avoid rapid drops in topiramate plasma concentration during hemodialysis, a supplemental

dose of topiramate may be required. The actual adjustment should take into account 1) the duration

of dialysis period, 2) the clearance rate of the dialysis system being used, and 3) the effective renal

clearance of topiramate in the patient being dialyzed.

Hepatic impairment

Plasma clearance of topiramate decreased a mean of 26% in patients with moderate to severe hepatic

impairment. Therefore, topiramate should be administered with caution in patients with hepatic

impairment.

Elderly population

Plasma clearance of topiramate is unchanged in elderly subjects in the absence of underlying renal

disease.

Paediatric population (pharmacokinetics, up to 12 years of age)

The pharmacokinetics of topiramate in children, as in adults receiving add-on therapy, are linear, with

clearance independent of dose and steady-state plasma concentrations increasing in proportion to

dose. Children, however, have a higher clearance and a shorter elimination half-life. Consequently, the

plasma concentrations of topiramate for the same mg/kg dose may be lower in children compared to

adults. As in adults, hepatic enzyme inducing AEDs decrease the steady-state plasma concentrations.

5.3

Preclinical safety data

In nonclinical studies of fertility, despite maternal and paternal toxicity as low as 8 mg/kg/day, no

effects on fertility were observed, in male or female rats with doses up to 100 mg/kg/day.

In preclinical studies, topiramate has been shown to have teratogenic effects in the species studied

(mice, rats and rabbits). In mice, fetal weights and skeletal ossification were reduced at 500 mg/kg/day

in conjunction with maternal toxicity. Overall numbers of fetal malformations in mice were increased

for all drug-treated groups (20, 100 and 500 mg/kg/day).

In rats, dosage-related maternal and embryo/fetal toxicity (reduced fetal weights and/or skeletal

ossification) were observed down to 20 mg/kg/day with teratogenic effects (limb and digit defects) at

400 mg/kg/day and above. In rabbits, dosage-related maternal toxicity was noted down to

10 mg/kg/day with embryo/fetal toxicity (increased lethality) down to 35 mg/kg/day, and teratogenic

effects (rib and vertebral malformations) at 120 mg/kg/day.

The teratogenic effects seen in rats and rabbits were similar to those seen with carbonic anhydrase

inhibitors, which have not been associated with malformations in humans. Effects on growth were also

indicated by lower weights at birth and during lactation for pups from female rats treated with 20 or

100 mg/kg/day during gestation and lactation. In rats, topiramate crosses the placental barrier.

In juvenile rats, daily oral administration of topiramate at doses up to 300 mg/kg/day during the period

of development corresponding to infancy, childhood, and adolescence resulted in toxicities similar to

those in adult animals (decreased food consumption with decreased body weight gain, centrolobullar

hepatocellular hypertrophy). There were no relevant effects on long bone (tibia) growth or bone

Page 21 of 21

Topamax_spc_Jul2020_ref_EU SmPC Sep2019

(femur) mineral density, preweaning and reproductive development, neurological development

(including assessments on memory and learning), mating and fertility or hysterotomy parameters.

In a battery of in vitro and in vivo mutagenicity assays, topiramate did not show genotoxic potential.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Core tablet:

Lactose Monohydrate

Microcrystalline Cellulose

Pregelatinized Starch

Sodium Starch Glycolate (Type A)

Magnesium Stearate

Carnauba wax

Film-coating:

OPADRY

White YS-1-7706-G

OPADRY

Light Yellow YS-1-6382-G

OPADRY

Yellow YS-1-6370-G

OPADRY

Pink

YS-1-1456-G

OPADRY

contains:

Hypromellose 3mPa.s (E464)

Hypromellose 6mPa.s (E464)

Macrogol 400

Polysorbate 80

And as colourants, titanium dioxide E171 (all strengths), iron oxide yellow E172 (50 and 100 mg), and

iron oxide red E172 (200 mg)

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

The expiry date of the product is indicated on the packaging materials,

After first opening, use within 3 months but not past its expiry date.

6.4

Special precautions for storage

Do not store above Store in the original package to protect the tablets from moisture.

7. Manufacturer :

Cilag AG, Hochstrasse 201, CH-8205, Schaffhausen, Switzerland

8. License Holder:

J-C Health Care Ltd.

Kibbutz Shefayim 6099000

Israel

Revised in July 2020

ל ןולעב )תוחיטב עדימ ( הרמחה לע העדוה ל ןולעב )תוחיטב עדימ ( הרמחה לע העדוה ל ןולעב )תוחיטב עדימ ( הרמחה לע העדוה ןכרצ ןכרצ ןכרצ

ךיראת

:

17.05.2016

תילגנאב רישכת םש

:

TOPAMAX 25, 50,100,200

רפסמ

י

םושיר

:

תוילבט סקמפוט

:ג"מ

107 55 29031 00

תוילבט סקמפוט

:ג"מ

107 56 29032 00

תוילבט סקמפוט

:ג"מ

107 57 29033 00

קמפוט תוילבט ס

:ג"מ

107 58 29034 00

םושירה לעב םש

:

C Health care

-

J

תושקובמה תורמחהה

ןולעב קרפ

יחכונ טסקט

שדח טסקט

שמתשהל ןיא ילבמ הפורתב ינפל אפורב ץעוויהל לופיטה תלחתה

םא

ןוירהב ךנה םא

,ןוירהל סנכיהל היושע

תבשוח וא נהש ןוירהב ך

)ףסונ עדימל "הקנהו ןוירה" ףיעס יאר(

ךנה םא הקינמ

עדימל "הקנהו ןוירה" ףיעס יאר( )ףסונ

לש יוקל דוקפתמ רבעב תלבס וא לבוס ךנה םא הילכה

דחוימב תוילכב םינבאמ לבוס התאש הרקמב

הזילאידב לפוטמה הלוח ךנהש וא

םא ל הרושקה תויעב לש הירוטסיה ךל שי םדה ילזונ

יאר( ןוירהב ךנהש תבשוח וא ,ןוירהל סנכיהל היושע , ןוירהב ךנה םא .)ףסונ עדימל "הקנהו ןוירה" ףיעס

.)ףסונ עדימל "הקנהו ןוירה" ףיעס יאר( הקינמ ךנה םא

רבעב תלבס וא לבוס ךנה םא הילכה לש יוקל דוקפתמ

הרקמב דחוימב

לבוס התא

תוילכב תויעב

דוחייב

הלוח ךנהש וא תוילכב םינבא הזילאידב לפוטמה

ךל שי םא

תצמח( ףוגהו םדה ילזונל הרושקה תויעב לש הירוטסיה תילובטמ

metabolic acidosis

דבכה לש יוקל דוקפתמ רבעב תלבס וא לבוס ךנה םא

דבכב תויעב

מ לבוס ךניה

תילובטמ תצמח( ףוגהו

metabolic acidosis

לש יוקל דוקפתמ רבעב תלבס וא לבוס ךנה םא דבכה

לש יוקל דוקפתמ רבעב תלבס וא לבוס ךנה םא

םייניע

לבוס ךנה םא דוחייב ת/

)המוקואלג

םא הלידג תויעב ךל שי

תלד הטאיד( תינגוטק הטאיד עצבמ ךנה םא ברו תומימחפ )םינמוש ת

בצמ תויעב ,ןואכידמ רבעב תלבס וא לבוס ךנה םא ינדבוא תוגהנתה וא תובשחמ וא חור

, תוכר ,תושלח , תוכירפ תומצעמ לבוס ךנה םא םצע תופיפצב הדירי

(osteomalacia,

osteoporosis, osteopenia)

המישנ תויעב וא תואירב תויעבמ לבוס ךנה םא

לשלשמ ךנה םא

ךנה םא

חותינ רובעל דמוע

ךילע ,יהשלכ הפורתל וא והשלכ ןוזמל שיגר ךנה םא תליטנ ינפל אפורל ךכ לע עידוהל

.הפורתה

יעצמאב הנשמתשת תוירופה ליגב םישנש ץלמומ לופיטה ךשמב )אפורה םע תוצעייתהב( םיתואנ העינמ רישכתב

ומיש קיספהל ןיא .אפורה םע תוצעייתה ינפל הפורתב ש

רבעב תלבס וא לבוס ךנה םא

קפתמ דו םייניעה לש יוקל

םייניעב תויעב

)המוקואלגמ לבוס ךנה םא דוחייב(

שי םא

ךל

הלידג תויעב

)םינמוש תברו תומימחפ תלד הטאיד( תינגוטק הטאיד עצבמ ךנה םא

)ףסונ עדימל הקנהו ןוירה ףיעס יאר( ןוירהל סנכיהל היושע וא ןוירהב ךניה

הטאיד( תינגוטק הטאיד עצבמ ךנה םא )םינמוש תברו תומימחפ תלד

וא תובשחמ וא חור בצמ תויעב ,ןואכידמ רבעב תלבס וא לבוס ךנה םא .תוינדבוא תוגהנתה

םצע תופיפצב הדירי , תוכר ,תושלח , תוכירפ תומצעמ לבוס ךנה םא

(osteomalacia, osteoporosis, osteopenia)

המישנ תויעב וא תואירב תויעבמ לבוס ךנה םא

ה םא לשלשמ ךנ

חותינ רובעל דמוע ךנה םא

ךכ לע עידוהל ךילע ,יהשלכ הפורתל וא והשלכ ןוזמל שיגר ךנה םא .הפורתה תליטנ ינפל אפורל

םיתואנ העינמ יעצמאב הנשמתשת תוירופה ליגב םישנש ץלמומ רישכתב לופיטה ךשמב )אפורה םע תוצעייתהב(

אפורה םע תוצעייתה ינפל הפורתב שומיש קיספהל ןיא

שומישה םרט אפורה םע חחוש ,ךילא םיטנוולר הלעמ םיבצמהמ דחא םא .הפורתב

.אפורה םע הליחת תוצעייתה אלל הפורתה תא תחקל קיספת אל יכ בושח

וז הפורתל ףילחתכ ךל תנתינה טמריפוט הליכמה תרחא הפורת לכ תחקל ןיא יתה אלל .אפורה םע הליחת תוצעי

עובק ןפואב לקשיהל שי .ךלקשממ דבאת סקמפוטב שומישה ןמזבו ןכתי .סקמפוט םע לופיטה ןמזב

הלוע וניא סקמפוטב לפוטמה דלי וא בר לקשמ דבאמ ךנה םא קיפסמ

.אפורב ץעוויהל שי ,לקשמב

הפורתב שומיש לוהוכלא תכירצו

תוניי תותשל ןיא

אקשמ וא לופיטה תפוקתב םיפירח תו הפורתה םע

תוניי תותשל ןיא

הפורתה םע לופיטה תפוקתב םיפירח תואקשמ וא

תייתשמ ענמהל שי

.הפורתה םע לופיטה תפוקתב לוהוכלא

הקנהו ןוירה

תויהל היושע ךנהש תבשוח ,הקינמ וא ןוירהב ךנה םא ל תננכתמ וא ןוירהב אפורה םע יצעייתה ,ןוירהל סנכיה נפל לופיטה תליחת י תחקל הלוכי תא םאה טילחי אפורה . סקמפוט

תננכתמ וא ןוירהב תויהל היושע ךנהש תבשוח ,הקינמ וא ןוירהב ךנה םא .לופיטה תליחת ינפל אפורה םע יצעייתה ,ןוירהל סנכיהל

העינמ יעצמאב שומיש לע ךמע חחושי אפורה

המיאתמ סקמפוט םאה םג ומכ ךל

שומישו הגיהנ תונוכמב

הפורתב שומישה

חרחסל םורגל לוכי

תויעבו תופייע ,ת ןכו הייאר

ןכ לעו תונרעב םוגפל

הגיהנב תוריהז בייחמ נכוסמ תונוכמ תלעפהב ,בכרב תבייחמה תוליעפ לכבו תו

םיינפוא לע הביכרמ םריהזהל שי םידליל רשאב .תונר המודכו שיבכה תבריקב םיקחשממ וא

ל םורגל לוכי הפורתב שומישה הייאר תויעבו תופייע ,תרוחרחס

םוגפל ןכ לכבו תונכוסמ תונוכמ תלעפהב ,בכרב הגיהנב תוריהז בייחמ ןכ לעו תונרעב וא םיינפוא לע הביכרמ םריהזהל שי םידליל רשאב .תונרע תבייחמה תוליעפ .המודכו שיבכה תבריקב םיקחשממ

ע הליחת חחושתש ינפל תונכוסמ תונוכמב שמתשת וא גהנת לא .אפורה ם

שיבכה תברקב םיקחשממ וא םיינפוא לע הביכרמ םריהזהל שי םידליל רשאב .המודכו

שמתשת דציכ ?הפורתב

תוחפ וא ףייע,ינונשי שוחתו ןכתי רתי תנמ תלטנ םא םיישק ,תוליגר אל ףוג תועונת ,היצנידרואוק רסוח ,ינריע הייאר,זוכירב ישוק וא רובידב ישוק ,הכילהבו הדימעב ,תונבצע וא ןואכיד תשוחת ,תשטשוטמ הייאר וא הלופכ פ ,ןטב באכ

םיסוכר

,םיליגר אל

תרוחרחס

םד ץחל בקע תוליגר אל בל תומיעפ וא ךומנ

הל לוכי רתי ןונימ תופורת לטונ התא רשאכ שחרת .סקמפוט םע דחי תורחא

,ינריע תוחפ וא ףייע,ינונשי שוחתו ןכתי רתי תנמ תלטנ םא הווחת רסוח ,היצנידרואוק ,הכילהבו הדימעב םיישק ,תוליגר אל ףוג תועונת

וא רובידב ישוק

תונבצע וא ןואכיד תשוחת ,תשטשוטמ הייאר וא הלופכ הייאר,זוכירב ישו

םיסוכריפ ,ןטב באכ

םיליגר אל ךומנ םד ץחל בקע תרוחרחס , בל תומיעפ וא תוליגר אל

סקמפוט םע דחי תורחא תופורת לטונ התא רשאכ שחרתהל לוכי רתי ןונימ

יאוול תועפות

ןיחבמ ךנה םא ידיימ ןפואב אפורל הנפ

תועפותה תחאב :תואבה

דאמ תוחיכש יאוול תועפות

-

רתויב תועיפומש תועפות הרשעמ דחא שמתשממ )הרמחה וא שדח( ןואכיד :

תוחיכש יאוול תועפות

-

ב תועיפומש תועפות

-

1-11

ךותמ םישמתשמ

111

םייוניש ,תונבצע ,הדרח ,םיסוכריפ : יא ,לובליב ,חורה בצמב

הטאה ,זוכירב תוערפה ,תואצמתה וא ימואתפ יוניש ,שדח( ןורכיזב תויעב ,ןורכיז דוביא ,הבישחב .תבאוכ וא הפוכת הנתשה ,תוילכב םינבא ,)הרמחה

תוחיכש ןניאש יאוול תועפות

-

ב תועיפומש תועפות

-

1-11

ךותמ םישמתשמ

10111

לולע( םדב הצמוחה תמרב היילע : ,ןובאית דוביא ,המישנ רצוק ללוכ המישנב תויעבל םורגל חב ו תוריהמ בל תוקיפדו תמזגומ תופייע ,תואקה,הלי

וא אל העזהה ןדבוא וא הדירי ,)תווש

העיגפל תונויסינו תובשחמ , הרומח תימצע

תא עדיי תורימחמו הדימב רשא תופסונ יאוול תועפות :אפורה

דאמ תוחיכש יאוול תועפות

-

רתויב תועיפומש תועפות :הרשעמ דחא שמתשממ

תלזנ ,ףאב שדוג

וא ןורג באכ

םינוש םיקלחב השוחת רסוח וא/ו באכ ,הריקד ףוגב

תוינונשי וא םונמנ

תופייע

תרוחרחס

לושלש

הליחב

לקשמב הדירי

:תואבה תועפותה תחאב ןיחבמ ךנה םא ידיימ ןפואב אפורל הנפ

דאמ תוחיכש יאוול תועפות

-

דחא שמתשממ רתויב תועיפומש תועפות הרשעמ )הרמחה וא שדח( ןואכיד :

ל תועפות תוחיכש יאוו

-

תועיפומש תועפות

דעב

1

ךותמ

11

םישמתשמ

ב

-

1-11

ךותמ םישמתשמ

111

,חורה בצמב םייוניש ,תונבצע ,הדרח ,םיסוכר יא ,לובליב

תויעב ,ןורכיז דוביא ,הבישחב הטאה ,זוכירב תוערפה ,תואצמתה וא הפוכת הנתשה ,תוילכב םינבא ,)הרמחה וא ימואתפ יוניש ,שדח( ןורכיזב

.תבאוכ

תוחיכש ןניאש יאוול תועפות

-

תועיפומש תועפות

דעב

1

ךותמ

111

םישמתשמ

ב

-

1-11

ךותמ םישמתשמ

10111

םדב הצמוחה תמרב היילע ,תואקה,הליחב ,ןובאית דוביא ,המישנ רצוק ללוכ המישנב תויעבל םורגל לולע( תוריהמ בל תוקיפדו תמזגומ תופייע

וא

דבוא וא הדירי ,)תווש אל העזהה ן

)תוהובג תורוטרפמטל םיפושחה םיריעצ םידליב דוחייב(

תונויסינו תובשחמ , ,הרומח תימצע העיגפל .הייארה הדשמ קלח דוביא

תורימחמו הדימב רשא תופסונ יאוול תועפות

י

:אפורה תא עדי

דאמ תוחיכש יאוול תועפות

-

דחא שמתשממ רתויב תועיפומש תועפות :הרשעמ

תלזנ ,ףאב שדוג

וא ןורג באכ

ףוגב םינוש םיקלחב השוחת רסוח וא/ו באכ ,הריקד

תוינונשי וא םונמנ

תופייע

תרוחרחס

לושלש

הליחב

לקשמב הדירי

תוחיכש יאוול תועפות

-

תועיפומש תועפות

דעב

1

ךותמ

11

םישמתשמ

ב

-

1-11

ךותמ םישמתשמ

111

:

תוחיכש יאוול תועפות

-

תועיפומש תועפות

דעב

1

ךותמ

11

םישמתשמ

ב

-

1-11

ךותמ םישמתשמ

111

:

הימנא

)הכומנ םד תריפס(

וגת ,תוימומדא ,רועב החירפ ןוגכ( תיגרלא הב )תדפרס ,םינפב תוחיפנ ,דרג

ןובאית ןדבוא וא ןובאיתב הדירי

סעכ ,הדרח ,תונפקות

,םירירש סוכרפ ,םירירשב תיווע וא תוצווכתה םירירש תשלוח וא םיבאכ

תורידנ יאוול תועפות

-

תועיפומש תועפות

ב

-

1-11

ךותמ םישמתשמ

110111

:

מ חור בצמ ליגר אל ןפואב םמור

הרכה ןדבוא

הליל ןורוויע ,ינמז ןורוויע ,תחא ןיעב ןורוויע

הלצע ןיע

ןיעל ביבסמש המקרב תוחיפנ

:העודי הניא ןתוחיכשש ,תופסונ יאוול תועפות

"היטפולוקמ"

")הלוקמ( םתכ"ה רוזא לש הלחמ הייארה הבש תיתשרב הנטקה הדוקנה יהוז .ןיעב מב .רתויב הדחה הניה וא יונישב ןיחבמ ךנהו הדי הייארב הדיריב

.אפורל תונפל שי

ליער סימרדיפא תנומסת

Toxic epidermal

necrolysis

םורדניסמ רתוי הרומח תירוע העפות תויחופלשב תנייפואמה םייח תנכסמו ןוסנו'ג סנביטס יאוול תועפות י/האר( . רועה תודרפיהו תוטשופמ .)תורידנ

והובג הינומא תומר םדב תוהובג הינומא תומר .םדב ת ,תונרע טאהל ,תילטנמ תוליעפ לע העיפשהל תולולע

הימנא

)הכומנ םד תריפס(

וגת תוחיפנ ,דרג ,תוימומדא ,רועב החירפ ןוגכ( תיגרלא הב )תדפרס ,םינפב

ןובאית ןדבוא וא ןובאיתב הדירי

סעכ ,הדרח ,תונפקות

הליגר אל תוגהנתה

,םירירשב תיווע וא תוצווכתה םירירש סוכרפ תשלוח וא םיבאכ , םירירש

תורידנ יאוול תועפות

-

תועיפומש תועפות

דעב

1

ךותמ

1111

תשמ םישמ

ב

-

1-11

ךותמ םישמתשמ

110111

:

ליגר אל ןפואב םמורמ חור בצמ

הרכה ןדבוא

הליל ןורוויע ,ינמז ןורוויע ,תחא ןיעב ןורוויע

הלצע ןיע

ןיעל ביבסמש המקרב תוחיפנ

תוחיפנ ןיעב

ןיעל ביבסמו

:העודי הניא ןתוחיכשש ,תופסונ יאוול תועפות

"היטפולוקמ"

קמ( םתכ"ה רוזא לש הלחמ הדוקנה יהוז .ןיעב ")הלו ךנהו הדימב .רתויב הדחה הניה הייארה הבש תיתשרב הנטקה הייארב הדיריב וא יונישב ןיחבמ

.אפורל תונפל שי

ליער סימרדיפא תנומסת

Toxic epidermal necrolysis

העפות תנייפואמה םייח תנכסמו ןוסנו'ג סנביטס םורדניסמ רתוי הרומח תירוע ופמ תויחופלשב .)תורידנ יאוול תועפות י/האר( . רועה תודרפיהו תוטש

תולולע םדב תוהובג הינומא תומר .םדב תוהובג הינומא תומר תופייעל םורגל ,תונרע טאהל ,תילטנמ תוליעפ לע העיפשהל תארקנה הפורת םע חקלינ סקמפוט רשאכ שחרתמ רבדה .תואקהלו .תיאורפלו הצמוח

םידליב יאוול תועפות תמו םירגב

םירגובמב ולאל יללכ ןפואב תומוד םידליב יאוולה תועפות

תועפות םלוא רשאכ שחרתמ רבדה .תואקהלו תופייעל םורגל .תיאורפלו הצמוח תארקנה הפורת םע חקלינ סקמפוט

םירגבתמו םידליב יאוול תועפות

םירגובמב ולאל יללכ ןפואב תומוד םידליב יאוולה תועפות

ות ,םלוא רתוי ההובג תורידתב תוארנ תומיוסמ יאוול תועפ רשאמ םידליב רתוי תורומח תויהל תולוכי וא/ו םידליב .םירגובמ

דוביא וא הדירי תוללוכ רתוי תורומח ןניה רשא יאוול תועפות תולולעש יאוול תועפות .םדב הצמוחה תמרב הילעו העזה ש תולחמ תוללוכ םידליב רתוי ההובג תורידתב שחרתהל

.תונוילעה המישנה יכרד

העזהה תומכב הדיריל םידליב דחוימב בל םישל שי .ףוגה תרוטרפמטב הילעו

:םירגובמ רשאמ םידליב רתוי תוחיכש תויהל תולולע תואבה יאוולה

זוכירב תויעב

םדב הצמוחה תמרב היילע

הרומח תימצע העיגפ לע תובשחמ

תופייע

ןובאתב היילע וא הדירי

הליגר אל תוגהנתה ,תונפקות

ןושיל וא םדריהל ישוק

הכילהב תוביצי רסוח תשוחת

הבוט אל השגרה

םדב ןגלשא תומרב הדירי

תושגר לש השוחת רסוח וא הגצה רסוח

תועמוד םייניע

ליגר אל וא יטיא בל בצק

:םידליב שחרתהל תולולעה תורחא יאוול תועפות

יאוול תועפות תוחיכש

-

תועיפומ

דעב

1

ךותמ

11

םישמתשמ

)וגיטרו( רורחיס תשוחת

האקה

םוח

יאוול תועפות תוחיכש אל

-

תועיפומ

דעב

1

ךותמ

111

םישמתשמ

םדב )הנבל םד תירודכ לש גוס( םיליפונוזאה תמרב הילע

תויביטקארפיה

םוח תשוחת

הדימל יישק

תולוכי וא/ו םידליב רתוי ההובג תורידתב תוארנ תומיוסמ יאוול תועפות ,םלוא תויהל

.םירגובמ רשאמ םידליב רתוי תורומח

הילעו העזה דוביא וא הדירי תוללוכ רתוי תורומח ןניה רשא יאוול תועפות רתוי ההובג תורידתב שחרתהל תולולעש יאוול תועפות .םדב הצמוחה תמרב .תונוילעה המישנה יכרד לש תולחמ תוללוכ םידליב

דיריל םידליב דחוימב בל םישל שי הילעו העזהה תומכב ה .ףוגה תרוטרפמטב

)תוחיטב עדימ ( הרמחה לע העדוה )תוחיטב עדימ ( הרמחה לע העדוה )תוחיטב עדימ ( הרמחה לע העדוה ל ןולעב ל ןולעב ל ןולעב אפור אפור אפור

םי/שקובמה םי/יונישה לע םיטרפ

ןולעב קרפ

יחכונ טסקט

שדח טסקט

QUALITATIVE AND

QUANTITATIVE

COMPOSITION

Excipients with known effect

Also includes lactose monohydrate:

tablet

contains

30.85

lactose

monohydrate;

tablet

contains

61.70

lactose

monohydrate;

tablet

contains

123.40

lactose

monohydrate;

tablet

contains

43.50

lactose

monohydrate.

For the full list of excipients, see section 6.1.

Posology And

Method Of

Administration

Migraine

Adults

recommended

total

daily

dose

topiramate

prophylaxis

migraine

headache is 100 mg/day administered in

two divided doses. Titration should begin at

nightly

week.

dosage

should then be increased in increments of

25 mg/day administered at 1-week intervals.

patient

unable

tolerate

titration regimen, longer intervals between

dose adjustments can be used.

Some patients may experience a benefit at

a total daily dose of 50 mg/day. Patients

have received a total daily dose up to 200

mg/day. Dose and titration rate should be

guided

clinical

outcome

(See

Pharmacodynamic Properties).

Migraine

Adults

The recommended total daily dose of topiramate for

prophylaxis of migraine headache is 100 mg/day

administered in two divided doses. Titration should

begin at 25 mg nightly for 1 week. The dosage

should

then

increased

increments

mg/day

administered

1-week

intervals.

patient is unable to tolerate the titration regimen,

longer intervals between dose adjustments can be

used.

Some patients may experience a benefit at a total

daily dose of 50 mg/day. Patients have received a

total daily dose up to 200 mg/day. This dose may

be benefit in some patients, nevertheless, caution is

advised

increase

incidence

side

effects.

Dose and titration rate should be guided by clinical

outcome (See Pharmacodynamic Properties).

Paediatric population

Topamax

(topiramate)

recommended

treatment or prevention of migraine in children due

to insufficient data on safety and efficacy.

Special Populations

Elderly

dose

adjustment

required

elderly

population providing renal function is intact.

Contraindications

Migraine prophylaxis in pregnancy and in

women of childbearing potential if not using

effective methods of contraception.

Migraine prophylaxis in pregnancy and in women of

childbearing potential if not using a highly

effective

methods of contraception.

Special warnings and

precautions for use

Renal Impairment

The major route of elimination of unchanged

topiramate and its metabolites is via the

kidney. Renal elimination is dependent on

renal function and is independent of age.

Patients

with

moderate

severe

renal

impairment may take 10 to 15 days to reach

Renal Impairment

major

route

elimination

unchanged

topiramate and its metabolites is via the kidney.

Renal elimination is dependent on renal function

and is independent of age. Patients with moderate

or severe renal impairment may take 10 to 15 days

reach

steady-state

plasma

concentrations

steady-state

plasma

concentrations

compared to 4 to 8 days in patients with

normal renal function.

As with all patients, the titration schedule

should be guided by clinical outcome (i.e.,

seizure control, avoidance of side effects)

with the knowledge that subjects with known

renal impairment may require a longer time

to reach steady-state at each dose (See

Posology

Method

Administration;

Pharmacokinetic Properties).

Suicide/Suicidal Ideation

Antiepileptic

drugs

(AEDs),

including,

TOPAMAX

, increase the risk of suicidal

thoughts or behavior in patients taking these

drugs for any indication. A meta-analysis of

randomized placebo-controlled trials of anti-

epileptic drugs has shown an increased risk

of suicidal ideation and behavior (0.43% on

anti-epileptic

drugs

versus

0.24%

placebo). The mechanism of this risk is not

known.

In double-blind clinical trials, suicide related

events (suicidal ideation, suicide attempts,

suicide)

occurred

frequency

0.5% in topiramate treated patients (46 out

of 8,652 patients treated) compared to 0.2%

treated with placebo (8 out of 4,045 patients

treated).

completed

suicide

compared to 4 to 8 days in patients with normal

renal function.

As with all patients, the titration schedule should be

guided by clinical outcome (i.e., seizure control,

avoidance of side effects) with the knowledge that

subjects with known renal impairment may require a

longer time to reach steady-state at each dose (See

Posology

Method

Administration;

Pharmacokinetic Properties).

Suicide/Suicidal Ideation

Antiepileptic drugs (AEDs), including, TOPAMAX

increase the risk of suicidal thoughts or behavior in

patients taking these drugs for any indication. A

meta-analysis

randomized

placebo-controlled

trials of anti-epileptic drugs has shown an increased

risk of suicidal ideation and behavior (0.43% on

anti-epileptic drugs versus 0.24% on placebo). The

mechanism of this risk is not known.

Suicidal ideation and behaviour have been reported

patients

treated

with

anti-epileptic

agents

several indications. A meta-analysis of randomised

placebo-controlled trials of AEDs has shown a small

increased risk of suicidal ideation and behaviour.

The mechanism of this risk is not known and the

available data do not exclude the possibility of an

increased risk for topiramate.

reported in a bipolar disorder double-blind

trial in a patient on topiramate.

Metabolic Acidosis

Hyperchloremic, non-anion gap, metabolic

acidosis (i.e., decreased serum bicarbonate

below the normal reference range in the

absence of chronic respiratory alkalosis) is

associated with topiramate treatment. This

decrease in serum bicarbonate is due to the

inhibitory

effect

topiramate

renal

carbonic

anhydrase.

Generally,

decrease

bicarbonate

occurs

early

treatment although it can occur at any time

during

treatment.

These

decreases

usually mild to moderate (average decrease

of 4 mmol/L at doses of 100 mg/day or

above

adults

approximately

mg/kg/day

pediatric

patients);.

Rarely,

patients

experience

decreases

values

below

mmol/L.

Conditions

therapies that predispose to acidosis (such

renal

disease,

severe

respiratory

disorders,

status

epilepticus,

diarrhea,

surgery, ketogenic diet, or certain s drugs)

may be additive to the bicarbonate lowering

effects of topiramate.

In double-blind clinical trials, suicide related events

(suicidal

ideation,

suicide

attempts,

suicide)

occurred

frequency

0.5%

topiramate

treated patients (46 out of 8,652 patients treated)

compared to 0.2% treated with placebo (8 out of

4,045 patients treated). One completed suicide was

reported in a bipolar disorder double-blind trial in a

patient on topiramate.

Metabolic Acidosis

Hyperchloremic, non-anion gap, metabolic acidosis

(i.e.,

decreased

serum

bicarbonate

below

normal reference range in the absence of chronic

respiratory alkalosis) is associated with topiramate

treatment. This decrease in serum bicarbonate is

due to the inhibitory effect of topiramate on renal

carbonic

anhydrase.

Generally,

decrease

bicarbonate occurs early in treatment although it

occur

time

during

treatment.

These

decreases are usually mild to moderate (average

decrease of 4 mmol/L at doses of 100 mg/day or

above in adults and at approximately 6 mg/kg/day

pediatric

patients);.

Rarely,

patients

experience decreases to values below 10 mmol/L.

Conditions or therapies that predispose to acidosis

(such

renal

disease,

severe

respiratory

disorders,

status

epilepticus,

diarrhea,

surgery,

ketogenic diet, or certain medicinal products drugs)

Chronic

metabolic

acidosis

increases

risk

renal

stone

formation

potentially lead to osteopenia.

Chronic, untreated metabolic acidosis may

increase

risk

nephrolithiasis

nephrocalcinosis,

also

result

osteomalacia

(referred

rickets

pediatric patients) and/or osteoporosis with

an increased risk for fractures.

Chronic

metabolic

acidosis

pediatric

patients can reduce growth rates. The effect

of topiramate on growth and bone-related

sequelae

been

systematically

investigated

pediatric

adult

populations.

Hyperammonemia and Encephalopathy

(Without and With Concomitant Valproic

Acid [VPA] Use)

Hyperammonemia/Encephalopathy

Without

Concomitant

Valproic

Acid

(VPA)

Topiramate treatment has produced

hyperammonemia (in some instances dose-

related) in clinical investigational programs

of adolescents (12-16 years) who were

may be additive to the bicarbonate lowering effects

of topiramate.

Chronic metabolic acidosis increases the risk of

renal stone formation and may potentially lead to

osteopenia.

Chronic, untreated metabolic acidosis may increase

the risk for nephrolithiasis or nephrocalcinosis, and

may also result

osteomalacia (referred to as

rickets

pediatric

patients)

and/or

osteoporosis

with an increased risk for fractures.

Chronic metabolic acidosis in pediatric patients can

reduce growth rates. The effect of topiramate on

growth and bone-related sequelae has not been

systematically

investigated

pediatric

adult

populations.

Hyperammonemia and Encephalopathy (Without and

With Concomitant Valproic Acid [VPA] Use)

Hyperammonemia/Encephalopathy

Without

Concomitant Valproic Acid (VPA)

Topiramate treatment has produced

hyperammonemia (in some instances dose-related)

in clinical investigational programs of adolescents

(12-16 years) who were treated with topiramate

monotherapy for migraine prophylaxis (incidence

treated with topiramate monotherapy for

migraine prophylaxis (incidence above the

upper limit of normal, 22% for placebo, 26%

for 50 mg/day, 41% for 100 mg/day) and in

very young pediatric patients (124 months)

who were treated with adjunctive topiramate

for partial onset epilepsy (8% for placebo,

10% for 5 mg/kg/day, 0% for 15 mg/kg/day,

9% for 25 mg/kg/day). TOPAMAX® is not

approved as monotherapy for migraine

prophylaxis in adolescent patients or as

adjunctive treatment of partial onset

seizures in pediatric patients less than 2

years old. In some patients, ammonia was

markedly increased (>50% above upper

limit of normal). In adolescent patients, the

incidence of markedly increased

hyperammonemia was 6% for placebo, 6%

for 50 mg, and 12% for 100 mg topiramate

daily.

The hyperammonemia associated with

topiramate treatment occurred with and

without encephalopathy in placebo-

controlled trials and in an open-label,

extension trial. Dose-related

hyperammonemia was also observed in the

extension trial in pediatric patients up to 2

above the upper limit of normal, 22% for placebo,

26% for 50 mg/day, 41% for 100 mg/day) and in

very young pediatric patients (124 months) who

were treated with adjunctive topiramate for partial

onset epilepsy (8% for placebo, 10% for 5

mg/kg/day, 0% for 15 mg/kg/day, 9% for 25

mg/kg/day). TOPAMAX® is not approved as

monotherapy for migraine prophylaxis in adolescent

patients or as adjunctive treatment of partial onset

seizures in pediatric patients less than 2 years old.

In some patients, ammonia was markedly increased

(>50% above upper limit of normal). In adolescent

patients, the incidence of markedly increased

hyperammonemia was 6% for placebo, 6% for 50

mg, and 12% for 100 mg topiramate daily.

The hyperammonemia associated with topiramate

treatment occurred with and without

encephalopathy in placebo-controlled trials and in

an open-label, extension trial. Dose-related

hyperammonemia was also observed in the

extension trial in pediatric patients up to 2 years old.

Clinical symptoms of hyperammonemic

encephalopathy often include acute alterations in

level of consciousness and/or cognitive function

with lethargy or vomiting.

Hyperammonemia with and without encephalopathy

years old. Clinical symptoms of

hyperammonemic encephalopathy often

include acute alterations in level of

consciousness and/or cognitive function

with lethargy or vomiting.

Hyperammonemia

with

without

encephalopathy has also been observed in

post-marketing reports in patients who were

taking

topiramate

without

concomitant

valproic acid (VPA).

Hyperammonemia/Encephalopathy

With

Concomitant Valproic Acid (VPA)

Concomitant

administration

topiramate

valproic

acid

(VPA)

been

associated with hyperammonemia with or

without

encephalopathy

patients

have tolerated either drug alone based upon

post-marketing

reports.

Although

hyperammonemia

asymptomatic,

clinical

symptoms

hyperammonemic

encephalopathy

often

include

acute

alterations in level of consciousness and/or

cognitive function with lethargy or vomiting.

In most cases, symptoms and signs abated

with

discontinuation

either

drug.

This

has also been observed in post-marketing reports in

patients

were

taking

topiramate

without

concomitant valproic acid (VPA).

Hyperammonemia/Encephalopathy

With

Concomitant Valproic Acid (VPA)

Concomitant

administration

topiramate

valproic

acid

(VPA)

been

associated

with

hyperammonemia with or without encephalopathy

in patients who have tolerated either drug alone

based

upon

post-marketing

reports.

Although

hyperammonemia may

asymptomatic,

clinical

symptoms

hyperammonemic

encephalopathy

often

include

acute

alterations

level

consciousness

and/or

cognitive

function

with

lethargy or vomiting. In most cases, symptoms and

signs abated with discontinuation of either drug.

This

adverse

reaction

pharmacokinetic interaction.

Although TOPAMAX® is not indicated for use in

infants/toddlers

(1-24

months),

TOPAMAX®

with

concomitant VPA clearly produced a dose-related

increase

incidence

treatment-emergent

hyperammonemia (above the upper limit of normal,

0% for placebo, 12% for 5 mg/kg/day, 7% for 15

mg/kg/day,

mg/kg/day)

adverse

reaction

pharmacokinetic interaction.

Although TOPAMAX® is not indicated for

infants/toddlers

(1-24

months),

TOPAMAX® with concomitant VPA clearly

produced

dose-related

increase

incidence

treatment-emergent

hyperammonemia (above the upper limit of

normal,

placebo,

mg/kg/day, 7% for 15 mg/kg/day, 17% for

mg/kg/day)

investigational

program. Markedly increased, dose-related

hyperammonemia (0% for placebo and 5

mg/kg/day, 7% for 15 mg/kg/day, 8% for 25

mg/kg/day)

also

occurred

these

infants/toddlers.

Dose-related

hyperammonemia was similarly observed in

long-term

extension

trial

these

very

young, pediatric patients .

Hyperammonemia

with

without

encephalopathy has also been observed in

post-marketing

reports

patients

taking

topiramate with VPA.

hyperammonemia

associated

with

topiramate treatment appears to be more

common

when

topiramate

used

investigational program. Markedly increased, dose-

related hyperammonemia (0% for placebo and 5

mg/kg/day,

mg/kg/day,

mg/kg/day) also occurred in these infants/toddlers.

Dose-related

hyperammonemia

similarly

observed in a long-term extension trial in these very

young, pediatric patients .

Hyperammonemia with and without encephalopathy

has also been observed in post-marketing reports in

patients taking topiramate with VPA.

The hyperammonemia associated with topiramate

treatment

appears

more

common

when

topiramate is used concomitantly with VPA.

Monitoring for Hyperammonemia

Patients

with

inborn

errors

metabolism

reduced hepatic mitochondrial activity may be at an

increased risk for hyperammonemia with or without

encephalopathy. Although not studied, topiramate

treatment

interaction

concomitant

topiramate

valproic

acid

treatment

exacerbate existing defects or unmask deficiencies

in susceptible persons.

patients

develop

unexplained

lethargy,

vomiting, or changes in mental status associated

with any topiramate treatment, hyperammonemic

concomitantly with VPA.

Monitoring for Hyperammonemia

Patients with inborn errors of metabolism or

reduced hepatic mitochondrial activity may

increased

risk

hyperammonemia

with

without

encephalopathy.

Although

studied,

topiramate

treatment

interaction

concomitant

topiramate

valproic

acid

treatment may exacerbate existing defects

unmask

deficiencies

susceptible

persons.

patients

develop

unexplained

lethargy,

vomiting,

changes

mental

status

associated

with

topiramate

treatment,

hyperammonemic

encephalopathy should be considered and

an ammonia level should be measured.

Hypothermia with Concomitant Valproic Acid (VPA)

Hypothermia,

defined

unintentional

drop in body core temperature to <35°C,

been

reported

association

with

topiramate

with

concomitant

valproic

acid

(VPA)

both

conjunction

with

encephalopathy

should

considered

ammonia level should be measured.

Hypothermia with Concomitant Valproic Acid (VPA) Use

Hypothermia, defined as an unintentional drop in

body core temperature to <35°C, has been reported

in association with topiramate use with concomitant

valproic

acid

(VPA)

both

conjunction

with

hyperammonemia

absence

hyperammonemia. This adverse reaction in patients

using concomitant topiramate and valproate can

occur after starting topiramate treatment or after

increasing

daily

dose

topiramate

Consideration

should

given

stopping

topiramate or valproate in patients who develop

hypothermia, which may be manifested by a variety

clinical

abnormalities

including

lethargy,

confusion, coma, and significant alterations in other

major organ systems such as the cardiovascular

and respiratory systems. Clinical management and

assessment should include examination of blood

ammonia levels.

Paresthesia

Paresthesia (usually tingling of the extremities), an

effect associated with the use of other carbonic

anhydrase

inhibitors,

appears

common

effect

TOPAMAX®

Paresthesia

more

hyperammonemia and in the absence of

hyperammonemia. This adverse reaction in

patients using concomitant topiramate and

valproate can occur after starting topiramate

treatment or after increasing the daily dose

topiramate

Consideration

should

given to stopping topiramate or valproate in

patients who develop hypothermia, which

may be manifested by a variety of clinical

abnormalities including lethargy, confusion,

coma, and significant alterations in other

major

organ

systems

such

cardiovascular

respiratory

systems.

Clinical

management

assessment

should

include

examination

blood

ammonia levels.

Paresthesia

Paresthesia

(usually

tingling

extremities), an effect associated with the

use of other carbonic anhydrase inhibitors,

appears

common

effect

TOPAMAX®

Paresthesia

more

frequently

reported

monotherapy

epilepsy

trials

migraine

prophylaxis

trials than in the adjunctive therapy epilepsy

trials.

majority

instances,

paresthesia

lead

treatment

frequently

reported

the monotherapy

epilepsy

trials and migraine prophylaxis trials than in the

adjunctive therapy epilepsy trials. In the majority of

instances, paresthesia did not lead to treatment

discontinuation.

Hyperammonemia

Encephalopathy

(Without

With Concomitant Valproic Acid® [VPA] Use)

Hyperammonemia/Encephalopathy Without Concomitant

Valproic Acid (VPA)

Topiramate treatment has produced hyperammonemia (in

some instances dose-related) in a clinical investigational

program in adolescent patients (12 to 17 years) given

topiramate for migraine prophylaxis. The incidence of

hyperammonemia

(above

upper

limit

normal

reference) at any time in the trial was 9% for placebo,

14% for 50 mg, and 26% for 100 mg topiramate daily. In

some patients, hyperammonemia was observed at the

end of the trial at the final visit. The incidence of markedly

increased

hyperammonemia

least

higher

above upper limit of normal) at any time in the trial in

adolescent patients was also increased at 100 mg/day

(9%) compared to 50 mg topiramate (0%) or placebo

(3%).

During

this

trial,

markedly

increased

ammonia

levels returned to normal in all but one patient (in whom

ammonia

level

fell

high

instead

markedly

abnormal).

Topiramate treatment has produced hyperammonemia in

a clinical investigational program in very young pediatric

discontinuation.

patients

months)

were

treated

with

adjunctive topiramate for partial onset epilepsy (8% for

placebo, 10% for 5 mg/kg/day, 0% for 15 mg/kg/day, 9%

mg/kg/day).

some

patients,

ammonia

markedly increased (≥ 50% above upper limit of normal).

hyperammonemia

associated

with

topiramate

treatment occurred with and without encephalopathy in

placebo-controlled trials and in an open-label, extension

trial

infants

with

refractory

epilepsy.

Dose-related

hyperammonemia was observed in the extension trial in

pediatric patients up to 2 years old. Clinical symptoms of

hyperammonemic

encephalopathy

often

include

acute

alterations

level

consciousness

and/or

cognitive

function

with

lethargy

vomiting.

TOPAMAX

approved

adjunctive

treatment

partial

onset

seizures in pediatric patients less than 2 years old.

Hyperammonemia with and without encephalopathy has

also been observed in post-marketing reports in patients

who were taking topiramate without concomitant valproic

acid (VPA).

Hyperammonemia/Encephalopathy

With

Concomitant

Valproic Acid (VPA)

Concomitant administration of topiramate and valproic

acid (VPA) has been associated with hyperammonemia

with or without encephalopathy in patients who have

tolerated either drug alone based upon post-marketing

reports.

Although

hyperammonemia

asymptomatic,

clinical

symptoms

hyperammonemic

encephalopathy often include acute alterations in level of

consciousness and/or cognitive function with lethargy or

vomiting. In most cases, symptoms and signs abated with

discontinuation of either drug. This adverse reaction is

not due to a pharmacokinetic interaction.

Although

TOPAMAX

indicated

infants/toddlers

(1–24

months),

TOPAMAX

with

concomitant

clearly

produced

dose-related

increase

incidence

treatment-emergent

hyperammonemia (above the upper limit of normal, 0%

for placebo, 12% for 5 mg/kg/day, 7% for 15mg/kg/day,

17% for 25 mg/kg/day) in an investigational program.

Markedly increased, dose-related hyperammonemia (0%

for placebo and 5 mg/kg/day, 7% for 15 mg/kg/day, 8%

for 25 mg/kg/day) also occurred in these infants/toddlers.

Dose-related hyperammonemia was similarly observed in

a long-term extension trial in these very young, pediatric

patients [see Use in Specific Populations (8.4)].

Hyperammonemia with and without encephalopathy has

also been observed in post-marketing reports in patients

taking topiramate with VPA.

hyperammonemia

associated

with

topiramate

treatment appears to be more common when topiramate

is used concomitantly with VPA.

Monitoring for Hyperammonemia

Patients with inborn errors of metabolism or reduced

hepatic mitochondrial activity may be at an increased risk

hyperammonemia

with

without

encephalopathy.

Although

studied,

topiramate

treatment

interaction of concomitant topiramate and valproic acid

treatment may exacerbate existing defects or unmask

deficiencies in susceptible persons.

In patients who develop unexplained lethargy, vomiting,

changes

mental

status

associated

with

topiramate treatment, hyperammonemic encephalopathy

should be considered and an ammonia level should be

measured

Interactions With

Other Medicinal

Products And

Other Forms Of

Interaction

Oral Contraceptives: In a pharmacokinetic

interaction study in healthy volunteers with a

concomitantly

administered

combination

oral contraceptive product containing 1 mg

norethindrone (NET) plus 35 mcg ethinyl

estradiol

(EE),

TOPAMAX

given

absence of other medications at doses of 50

mg/day

associated

with

statistically

significant

changes

mean

exposure (AUC) to either component of the

oral

contraceptive.

another

study,

exposure to EE was statistically significantly

decreased at doses of 200, 400, and 800

mg/day (18%, 21%, and 30%, respectively)

when given as adjunctive therapy in patients

taking

valproic

acid.

both

studies,

TOPAMAX

(50 mg/day to 800 mg/day) did

significantly

affect

exposure

NET.

Although

there

dose

dependent

decrease in EE exposure for doses between

Oral

Contraceptives:

pharmacokinetic

interaction

study

healthy

volunteers

with

concomitantly

administered

combination

oral

contraceptive

product

containing

norethindrone (NET) plus 35 mcg ethinyl estradiol

(EE), TOPAMAX

given in the absence of other

medications at doses of 50 to 200 mg/day was not

associated with statistically significant changes in

mean exposure (AUC) to either component of the

oral contraceptive. In another study, exposure to EE

was statistically significantly decreased at doses of

200, 400, and 800 mg/day (18%, 21%, and 30%,

respectively) when given as adjunctive therapy in

patients

taking

valproic

acid.

both

studies,

TOPAMAX

mg/day

mg/day)

(50-

200mg/day

healthy

volunteers

200-

800mg/day in epilepsy patients) did not significantly

affect exposure to NET. Although there was a dose

dependent

decrease

exposure

doses

between 200-800 mg/day (in epilepsy patients) ,

200-800 mg/day, there was no significant

dose dependent change in EE exposure for

doses

50-200

mg/day

clinical

significance of the changes observed is not

known.

there was no significant dose dependent change in

exposure

doses

50-200

mg/day

healthy volunteers). The clinical significance of the

changes observed is not known.

pregnancy

USE DURING PREGNANCY

Studies in animals have shown reproductive

toxicity (see PRECLINICAL SAFETY DATA

Section ). In rats, topiramate crosses the

placental barrier.

There are no adequate and well-controlled

studies

using

TOPAMAX

pregnant

women.

TOPAMAX

cause

fetal

harm

when

administered to a pregnant woman. Data

from

pregnancy

registries

indicate

that

infants exposed to topiramate in utero have

increased

risk

congenital

malformations

(e.g.,

craniofacial

defects,

such as cleft lip/palate, hypospadias, and

anomalies involving various body systems).

This

been

reported

with

topiramate

monotherapy and topiramate as part of a

USE DURING PREGNANCY

Studies in animals have shown reproductive toxicity

(see PRECLINICAL SAFETY DATA Section ). In

rats, topiramate crosses the placental barrier.

There are no adequate and well-controlled studies

using TOPAMAX

in pregnant women.

TOPAMAX

cause

fetal

harm

when

administered

pregnant

woman.

Data

from

pregnancy registries indicate that infants exposed

to topiramate in utero have an increased risk of

congenital malformations (e.g., craniofacial defects,

such

cleft

lip/palate,

hypospadias,

anomalies involving various body systems). This

has been reported

with topiramate monotherapy

and topiramate as part of a polytherapy regimen.

Compared

with

reference

group

taking

antiepileptic drugs, registry

data for

TOPAMAX

monotherapy showed a higher prevalence of low

polytherapy regimen.

Compared with a reference group not taking

antiepileptic

drugs,

registry

data

TOPAMAX

monotherapy showed a higher

prevalence

birth

weight

(<2500

grams). A causal relationship has not been

established.

In addition, data from these registries and

other studies indicate that, compared with

monotherapy, there is an increased risk of

teratogenic effects associated with the use

anti-epileptic

drugs

combination

therapy.

TOPAMAX

should

used

during

pregnancy

only

potential

benefit

justifies the potential risk to the fetus. In

treating

counseling

women

childbearing

potential,

prescribing

physician

should

weigh

benefits

therapy

against

risks

consider

alternative therapeutic options. If this drug is

used

during

pregnancy

patient

becomes pregnant while taking this drug,

patient

should

apprised

potential hazard to the fetus.

Topiramate is contraindicated in pregnancy

birth weight (<2500 grams). A causal relationship

has not been established.

In addition, data from these registries and other

studies indicate that, compared with monotherapy,

there is an increased risk of teratogenic effects

associated with the use of anti-epileptic drugs in

combination therapy.

TOPAMAX

should be used during pregnancy only

if the potential benefit justifies the potential risk to

fetus.

treating

counseling

women

childbearing

potential,

prescribing

physician

should weigh the benefits of therapy against the

risks and consider alternative therapeutic options. If

this drug is used during pregnancy or if the patient

becomes

pregnant

while

taking

this

drug,

patient should be apprised of the potential hazard to

the fetus.

Topiramate is contraindicated in pregnancy and in

women

childbearing

potential

effective

method of contraception is not used .

Pregnancy

Risk related to epilepsy and AEDs in general

Specialist advice should be given to women who

are of childbearing potential. The need for treatment

and in women of childbearing potential if an

effective

method

contraception

used .

with AEDs should be reviewed when a woman is

planning

become

pregnant.

women

being

treated for epilepsy, sudden discontinuation of AED

therapy should be avoided as this may lead to

breakthrough

seizures

that

could

have

serious

consequences for the woman and the unborn child.

Monotherapy

should

preferred

whenever

possible because therapy with multiple AEDs could

associated

with

higher

risk

congenital

malformations than monotherapy, depending on the

associated antiepileptics.

Risk related to topiramate

Topiramate was teratogenic in mice, rats and

rabbits (see section 5.3). In rats, topiramate

crosses the placental barrier.

Clinical data from pregnancy registries indicate that

infants exposed to topiramate monotherapy have:

An increased risk of congenital malformations

(particularly cleft lip/palate, hypospadias, and

anomalies involving various body systems)

following exposure during the first trimester. The

North American Antiepileptic Drug pregnancy

registry data for topiramate monotherapy showed

an approximate 3-fold higher incidence of major

congenital malformations, compared with a

reference group not taking AEDs. In addition, data

from other studies indicate that, compared with

monotherapy, there is an increased risk of

teratogenic effects associated with the use of

AEDs in combination therapy.

A higher prevalence of low birth weight (<2500

grams) compared with a reference group.

An increased prevalence of being small for

gestational age (SGA; defined as birth weight

below the 10

percentile corrected for their

gestational age, stratified by sex). The long term

consequences of the SGA findings could not be

determined.

It is recommended that women of child bearing

potential use highly effective contraception (see

section 4.5) and consider alternative therapeutic

options.

Indication epilepsy

It is recommended to consider alternative

therapeutic options in women of child bearing

potential. If topirmate is used in women of child

bearing potential, it is recommended that highly

effective contraception be used (see section 4.5),

and that the woman is fully informed of the known

risks of uncontrolled epilepsy to the pregnancy and

the potential risks of the medicinal product to the

foetus. If a woman plans a pregnancy, a

preconceptional visit is recommended in order to

reassess the treatment, and to consider other

therapeutic options. In case of administration

during the first trimester, careful prenatal

monitoring should be performed.

Indication migraine prophylaxis

Topiramate is contraindicated in pregnancy and in

women of childbearing potential if a highly effective

method of contraception is not used (see sections

4.3 and 4.5).

USE DURING LACTATION

Breast-feeding

Topiramate is excreted in the milk of lactating

rats. Animal studies have shown excretion of

topiramate in milk. The excretion of topiramate in

human milk has not been evaluated in controlled

studies. Limited observations in patients suggest

an extensive excretion of topiramate into breast

milk. Since many medicinal products drugs are

excreted in human milk, a decision should be

made whether to suspend discontinue breast

feeding or to discontinue/ / abstain from topiramate

therapy taking into account the importance of the

medicinal product to the mother (see section 4.4).

the drug, taking into account the importance of the

drug to the mother.

Fertility

Animal studies did not reveal impairment of fertility

by topiramate (see section 5.3). The effect of

topiramate on human fertility has not been

established.

Effects On Ability

To Drive And Use

Machines

TOPAMAX

acts

central

nervous

system

produce

drowsiness,

dizziness or other related symptoms.It may

also

cause

visual

disturbances

and/or

blurred vision. These adverse events could

potentially be dangerous in patients driving

vehicle

operating

machinery,

particularly until such time as the individual

patient's

experience

with

drug

established.

Topamax has minor or moderate influence on the

ability to drive and use machines.TOPAMAX

acts

on the central nervous system and may produce

drowsiness, dizziness or other related symptoms.It

may also cause visual disturbances and/or blurred

vision. These adverse events could potentially be

dangerous in patients driving a vehicle or operating

machinery,

particularly

until

such

time

individual patient's experience with the medicinal

product drug is established.

Overdose

The highest topiramate overdose reported

was calculated to be between 96 and 110 g

and resulted in coma lasting 20 to 24 hours

followed by full recovery after 3 to 4 days.

highest

topiramate

overdose

reported

calculated to be between 96 and 110 g and resulted

in coma lasting 20 to 24 hours followed by full

recovery after 3 to 4 days.

Adverse events:

Undesirable Effects

Throughout this section, adverse reactions are presented. Adverse reactions are adverse events that were considered to be reasonably

associated with the use of topiramate based on the comprehensive assessment of the available adverse event information. A causal

relationship with topiramate cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely

varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials

of another drug and may not reflect the rates observed in clinical practice.

Clinical Trial Data

The safety of TOPAMAX

was evaluated from a clinical trial database consisting of 4111 patients (3182 on TOPAMAX

and 929 on

placebo) who participated in 20 double-blind trials and 2847 patients who participated in 34 open-label trials, respectively, for the treatment

of primary generalized tonic-clonic seizures, partial onset seizures, seizures associated with Lennox-Gastaut syndrome, newly or recently

diagnosed epilepsy or migraine. The information presented in this section was derived from pooled data.

The majority of all adverse reactions were mild to moderate in severity.

Double-Blind, Placebo-Controlled Data, Adjunctive Epilepsy Trials – Adult Patients

Adverse Drug Reactions (ADRs) reported in

1% of TOPAMAX

-treated adult patients in double-blind, placebo-controlled adjunctive epilepsy trials

are shown in Table 1. ADRs that had an incidence >5% in the recommended dose range (200 to 400 mg/day) in adults in double-blind, placebo-

controlled adjunctive epilepsy studies in descending order of frequency included somnolence, dizziness, fatigue, irritability, weight decreased,

bradyphrenia, paresthesias, diplopia, coordination abnormal, nausea, nystgamus, lethargy, anorexia, dysarthria, vision blurred, decreased appetite,

memory impairment and diarrhoea.

The recommended dose for adjunctive epilepsy therapy in adults is 200-400 mg/day

Double-Blind, Placebo-Controlled Data, Adjunctive Epilepsy Trials – Pediatric Patients

ADRs reported in >2% of TOPAMAX

-treated pediatric patients (2 to 16 years of age) in double-blind, placebo-controlled adjunctive

epilepsy trials are shown in Table 2. ADRs that had an incidence >5% in the recommended dose range (5 to 9 mg/kg/day) in descending

order of frequency included decreased appetite, fatigue, somnolence, lethargy, irritability, disturbance in attention, weight decreased,

aggression, rash, abnormal behavior, anorexia, balance disorder, and constipation.

Table 2: Adverse Drug Reactions Reported by ≥2% of TOPAMAX

-Treated Pediatric patients in

Double-Blind, Placebo-Controlled, Adjunctive Epilepsy Trials

TOPAMAX

PLACEBO

System/Organ Class

(N=104)

(N=102)

Adverse Reaction

%

%

Metabolism and Nutrition Disorders

Decreased appetite

19.2

12.7

Anorexia

Psychiatric Disorders

Aggression

Abnormal behavior

Confusional state

Mood altered

Nervous System Disorders

Somnolence

15.4

Lethargy

13.5

Disturbance in attention

10.6

Balance disorder

Dizziness

Memory impairment

Respiratory, Thoracic and Mediastinal

Disorders

Epistaxis

Gastrointestinal Disorders

Constipation

Skin and Subcutaneous Tissue Disorders

Rash

General Disorders and Administration Site

Conditions

Fatigue

16.3

Irritability

11.5

Gait disturbance

Investigations

Weight decreased

The recommended dose for adjunctive epilepsy therapy in children (2-16 years of age) is 5 to 9

mg/kg/day.

Double-Blind, Controlled Data, Monotherapy Epilepsy Trials – Adult Patients

ADRs reported in

1% of TOPAMAX

-treated adult patients in double-blind, controlled monotherapy epilepsy trials are shown in Table 3.

ADRs that had an incidence >5% at the recommended dose (400 mg/day) in descending order of frequency included paraesthesia, weight

decreased, fatigue, anorexia, depression, memory impairment, anxiety, diarrhoea, asthenia, dysguesia, and hypoesthesia.

Table 3: Adverse Drug Reactions Reported by ≥1% of TOPAMAX

-Treated Adult Patients in Double-

Blind, Controlled Monotherapy Epilepsy Trials

TOPAMAX

50 mg/day

TOPAMAX

400 mg/day

System/Organ Class

(N=257)

(N=153)

Adverse Reaction

%

%

Blood and Lymphatic System Disorders

Anemia

Metabolism and Nutrition Disorders

Anorexia

12.4

Decreased appetite

Psychiatric Disorders

Depression

Anxiety

Bradyphrenia

Expressive language disorder

Depressed mood

Mood altered

Mood swings

Nervous System Disorders

Paresthesia

18.7

40.5

Memory impairment

Dysgeusia

Hypoesthesia

Balance disorder

Dysarthria

Cognitive disorder

Lethargy

Mental impairment

Psychomotor skills impaired

Sedation

Visual field defect

Eye Disorders

Dry eye

Ear and Labyrinth Disorders

Ear pain

Tinnitus

Respiratory, Thoracic and Mediastinal Disorders

Dyspnea

Rhinorrhea

Gastrointestinal Disorders

Diarrhea

Paresthesia oral

Dry mouth

Gastritis

Abdominal pain

Gastroesophageal reflux disease

Gingival bleeding

Skin and Subcutaneous Tissue Disorders

Rash

Alopecia

Pruritus

Hypoesthesia facial

Pruritus generalized

Double-Blind,

Controlled Data,

Monotherapy

Epilepsy Trials –

Pediatric

Patients

ADRs reported in

TOPAMAX

treated

pediatric

patients (10 to 16

years

age)

double-blind,

controlled

monotherapy

epilepsy trials are

shown in Table 4.

ADRs that had an

incidence >5% at

recommended

dose

(400

mg/day) in descending order of frequency included weight decreased, paraesthesia, diarrhoea, disturbance in attention, pyrexia, and

alopecia.

Table 3: Adverse Drug Reactions Reported by ≥1% of TOPAMAX

-Treated Adult Patients in Double-

Blind, Controlled Monotherapy Epilepsy Trials

TOPAMAX

50 mg/day

TOPAMAX

400 mg/day

System/Organ Class

(N=257)

(N=153)

Adverse Reaction

%

%

Musculoskeletal

and

Connective

Tissue

Disorders

Muscle spasms

Arthralgia

Muscle twitching

Renal and Urinary Disorders

Nephrolithiasis

Dysuria

Pollakiuria

Reproductive System and Breast Disorders

Erectile dysfunction

General Disorders and Administration Site

Conditions

Fatigue

15.2

14.4

Asthenia

Irritability

Investigations

Weight decreased

17.0

The recommended dose for monotherapy therapy in adults is 400 mg/day.

Table 4: Adverse Drug Reactions Reported by

2% of TOPAMAX

-Treated Pediatric Patients in

Double-Blind, Controlled Monotherapy Epilepsy Trials

TOPAMAX

50 mg/day

TOPAMAX

400 mg/day

System/Organ Class

(N=77)

(N=63)

Adverse Reaction

%

%

Metabolism and Nutrition Disorders

Decreased appetite

Psychiatric Disorders

Bradyphrenia

Mood altered

Depression

Nervous System Disorders

Paresthesia

15.9

Disturbance in attention

Ear and Labyrinth Disorders

Vertigo

Respiratory, Thoracic and Mediastinal Disorders

Epistaxis

Gastrointestinal Disorders

Diarrhea

Vomiting

Skin and Subcutaneous Tissue Disorders

Alopecia

General Disorders and Administration Site

Conditions

Pyrexia

Asthenia

Investigations

Weight decreased

20.6

Social Circumstances

Learning disability

The recommended dose for monotherapy therapy in children 10 years and older is 400 mg/day.

Double-Blind, Placebo-Controlled Data, Migraine Prophylaxis Trials – Adult Patients

ADRs reported in

1% of TOPAMAX®-treated adult patients in double-blind, placebo-controlled migraine prophylaxis trials are shown in Table 5.

ADRs that had an incidence >5% at the recommended dose (100 mg/day) in descending order of frequency included paresthesia, fatigue, nausea,

diarrhea, weight decreased, dysguesia, anorexia, decreased appetite, insomnia, hypoesthesia, disturbance in attention, anxiety, somnolence, and

expressive language disorder.

Table 5: Adverse Drug Reactions Reported by ≥1% of TOPAMAX

-Treated Adult Patients in Double-

Blind, Placebo-Controlled Migraine Prophylaxis Trials

TOPAMAX 50

mg/day

TOPAMAX 100

mg/day

TOPAMAX 200

mg/day

PLACEBO

System/Organ Class

(N=227)

(N=374)

(N=501)

(N=436)

Adverse Reaction

%

%

%

%

Metabolism and Nutrition

Disorders

Anorexia

Decreased appetite

Psychiatric Disorders

Insomnia

Anxiety

Expressive language disorder

Depression

Depressed mood

Confusional state

Mood swings

Affect lability

Bradyphrenia

Nervous System Disorders

Paresthesia

35.7

50.0

48.5

Dysgeusia

15.4

12.6

Hypoesthesia

Disturbance in attention

Somnolence

Memory impairment

Amnesia

Tremor

Balance disorder

Mental impairment

Eye Disorders

Vision blurred

Ear and Labyrinth Disorders

Tinnitus

Respiratory, Thoracic and

Mediastinal Disorders

Dyspnea

Epistaxis

Table 5: Adverse Drug Reactions Reported by ≥1% of TOPAMAX

-Treated Adult Patients in Double-

Blind, Placebo-Controlled Migraine Prophylaxis Trials

TOPAMAX 50

mg/day

TOPAMAX 100

mg/day

TOPAMAX 200

mg/day

PLACEBO

System/Organ Class

(N=227)

(N=374)

(N=501)

(N=436)

Adverse Reaction

%

%

%

%

Gastrointestinal Disorders

Nausea

13.6

14.6

Diarrhea

11.2

10.0

Dry mouth

Paresthesia oral

Constipation

Abdominal distension

Stomach discomfort

Gastroesophageal reflux disease

Musculoskeletal and Connective

Tissue Disorders

Muscle twitching

General Disorders and

Administration Site Conditions

Fatigue

15.0

15.2

19.2

11.2

Asthenia

Irritability

Thirst

Investigations

Weight decreased

10.8

The recommended dose for migraine prophylaxis is 100 mg/day.

Other Clinical Trial Data

ADRs reported in double-blind controlled clinical trials in <1% of TOPAMAX®-treated adult patients or at any rate in open-label clinical

trials of TOPAMAX®-treated adult patients are shown in Table 6.

Table 6. Adverse Drug Reactions Reported in Double-Blind Controlled Clinical Trials in

<1% of TOPAMAX

-Treated Adult Patients or at Any Rate in Open-Label Clinical Trials of

TOPAMAX

-Treated Adult Patients

Table 6. Adverse Drug Reactions Reported in Double-Blind Controlled Clinical Trials in

<1% of TOPAMAX

-Treated Adult Patients or at Any Rate in Open-Label Clinical Trials of

TOPAMAX

-Treated Adult Patients

Blood and Lymphatic System Disorders

Leukopenia, lymphadenopathy, thrombocytopenia

Immune System Disorders

Hypersensitivity

Metabolism and Nutrition Disorders

Acidosis hyperchloremic, hypokalemia, increased appetite, metabolic acidosis, polydipsia

Psychiatric Disorders

Abnormal behavior, anorgasmia, apathy, crying, distractibility, disturbance in sexual arousal,

dysphemia, early morning awakening, elevated mood, euphoric mood, flat affect, hallucination,

hallucination-auditory, hallucination--visual,

hypomania, initial insomnia, lack of spontaneous

speech, libido decreased, listless, loss of libido, mania, middle insomnia, orgasmic sensation

decreased, panic attack, panic disorder, panic reaction, paranoia, perseveration, reading disorder,

restlessness, sleep disorder, suicidal ideation, suicide attempt, tearfulness, thinking abnormal

Nervous System Disorders

Ageusia, akinesia, anosmia, aphasia, apraxia, aura, burning sensation, cerebellar syndrome,

circadian rhythm sleep disorder, clumsiness, complex partial seizure, convulsion, depressed level

of consciousness, dizziness postural, drooling, dysesthesia, dysgraphia, dyskinesia, dysphasia,

dystonia,

essential

tremor,

formication,

grand

convulsion,

hyperesthesia,

hypersomnia,

hypogeusia,

hypokinesia,

hyposmia,

neuropathy

peripheral,

parosmia,

poor

quality

sleep,

presyncope, repetitive speech, sensory disturbance, sensory loss, stupor, syncope, unresponsive

to stimuli

Eye Disorders

Accommodation disorder, altered visual depth perception, amblyopia, blepharospasm, blindness

transient,

blindness

unilateral,

glaucoma,

lacrimation

increased,

mydriasis,

night

blindness,

photopsia, presbyopia, scintillating scotoma, scotoma, visual acuity reduced

Ear and Labyrinth Disorders

Deafness, deafness neurosensory, deafness unilateral, ear discomfort, hearing impaired

Cardiac Disorders

Bradycardia, sinus bradycardia, palpitations

Vascular Disorders

Flushing, hot flush, orthostatic hypotension, Raynaud's phenomenon

Respiratory, Thoracic, and Mediastinal Disorders

Dysphonia, dyspnoea exertional, nasal congestion, paranasal sinus hypersecretion

Gastrointestinal Disorders

Abdominal discomfort, abdominal pain lower, abdominal tenderness, breath odour, epigastric

discomfort,

flatulence,

glossodynia,

hypoaesthesia

oral,

oral

pain,

pancreatitis,

salivary

Table 6. Adverse Drug Reactions Reported in Double-Blind Controlled Clinical Trials in

<1% of TOPAMAX

-Treated Adult Patients or at Any Rate in Open-Label Clinical Trials of

TOPAMAX

-Treated Adult Patients

hypersecretion

Skin and Subcutaneous Tissue Disorders

Anhidrosis, dermatitis allergic, erythema, rash macular, skin discolouration, skin odour abnormal,

swelling face, urticaria, urticaria localized

Musculoskeletal and Connective Tissue Disorders

Flank pain, muscle fatigue, muscular weakness, musculoskeletal stiffness

Renal and Urinary Disorders

Calculus ureteric, calculus urinary, hematuria, incontinence, micturition urgency, renal colic, renal

pain, urinary incontinence

Reproductive System and Breast Disorders

Sexual dysfunction

General Disorders

Calcinosis, face edema,

feeling abnormal,

feeling drunk, feeling jittery,

malaise, peripheral

coldness, sluggishness

Investigations

Blood bicarbonate decreased, crystal urine present, tandem gait test abnormal, white blood cell

count decreased

ADRs reported in double-blind controlled clinical trials in <2% of TOPAMAX

-treated pediatric patients or at any rate in open-label clinical

trials of TOPAMAX

-treated pediatric patients are shown in Table 7.

Table 7. Adverse Drug Reactions Reported in Double-Blind Controlled Clinical Trials in

<2% of TOPAMAX

-Treated Pediatric Patients or at Any Rate in Open-Label Clinical Trials

of TOPAMAX

-Treated Pediatric Patients

Blood and Lymphatic System Disorders

Eosinophilia, leukopenia, lymphadenopathy, thrombocytopenia

Immune System Disorders

Table 7. Adverse Drug Reactions Reported in Double-Blind Controlled Clinical Trials in

<2% of TOPAMAX

-Treated Pediatric Patients or at Any Rate in Open-Label Clinical Trials

of TOPAMAX

-Treated Pediatric Patients

Hypersensitivity

Metabolism and Nutrition Disorders

Acidosis hyperchloremic, hypokalemia, increased appetite

Psychiatric Disorders

Anger, apathy, crying, distractibility, expressive language disorder, initial insomnia, insomnia,

middle insomnia, mood swings, perseveration, sleep disorder, suicidal ideation, suicide attempt

Nervous System Disorders

Circadian

rhythm

sleep

disorder,

convulsion,

dysarthria,

dysgeusia,

grand

convulsion,

hypoesthesia,

mental

impairment,

nystagmus,

parosmia,

poor

quality

sleep,

psychomotor

hyperactivity, psychomotor skills impaired, syncope, tremor

Eye Disorders

Diplopia, lacrimation increased, vision blurred

Ear and Labyrinth Disorders

Ear pain

Cardiac Disorders

Palpitations, sinus bradycardia

Vascular Disorders

Orthostatic hypotension

Respiratory, Thoracic, and Mediastinal Disorders

Nasal congestion, paranasal sinus hypersecretion, rhinorrhea

Gastrointestinal Disorders

Abdominal discomfort, abdominal pain, dry mouth, flatulence, gastritis, gastroesophageal reflux

disease, gingival bleeding, glossodynia, pancreatitis, paresthesia oral, stomach discomfort

Musculoskeletal and Connective Tissue Disorders

Arthralgia, musculoskeletal stiffness, myalgia

Renal and Urinary Disorders

Incontinence, micturition urgency, pollakiuria

General Disorders

Feeling abnormal, hyperthermia, malaise, sluggishness

Postmarketing Data

Adverse events first identified as ADRs during postmarketing experience with TOPAMAX® are included in Table 8. The frequencies are

provided according to the following convention:

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, including isolated reports

In Table 8, ADRs are presented by frequency category based on spontaneous reporting rates.

Table 8: Adverse Drug Reactions Identified During Postmarketing Experience with

TOPAMAX

by

Frequency

Category

Estimated

from

Spontaneous

Reporting Rates

Infections and Infestations

Very rare Nasopharyngitis

Blood and Lymphatic System Disorders

Very rare Neutropenia

Immune System Disorders

Very rare Allergic edema

Very rare Conjuctival edema

Psychiatric Disorders

Very rare Feeling of despair

Eye Disorders

Very rare Abnormal sensation in eye

Very rare Angle closure glaucoma

Very rare Eye movement disorder

Very rare Eyelid edema

Very rare Maculopathy

Very rare Myopia

Respiratory, Thoracic and Mediastinal Disorders

Very rare Cough

Skin and Subcutaneous Tissue Disorders

Very rare Erythema multiforme

Very rare Periorbital edema

Very rare Stevens-Johnson syndrome

Very rare Toxic epidermal necrolysis

Musculoskeletal and Connective Tissue Disorders

Very rare Joint swelling

Very rare Limb discomfort

Renal and Urinary Disorders

Very rare Renal tubular acidosis

General Disorders and Administration Site Reactions

Very rare Generalized edema

Very rare Influenza like illness

Investigations

Very rare Weight increased

Additional adverse events:

Psychotic disorder, photophobia, hepatitis, hepatic failure, increased liver enzyms

The safety of topiramate was evaluated from a clinical trial database consisting of 4,111 patients (3,182 on topiramate and 929 on

placebo) who participated in 20 double-blind trials and 2,847 patients who participated in 34 open-label trials, respectively, for topiramate

as adjunctive treatment of primary generalized tonic-clonic seizures, partial onset seizures, seizures associated with Lennox-Gastaut

syndrome, monotherapy for newly or recently diagnosed epilepsy or migraine prophylaxis. The majority of adverse reactions were mild to

moderate in severity. Adverse reactions identified in clinical trials, and during post-marketing experience (as indicated by “*”) are listed by

their incidence in clinical trials in Table 1. Assigned frequencies are as follows:

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

Not known cannot be estimated from the available data

The most common adverse reactions (those with an incidence of >5% and greater than that observed in placebo in at least 1 indication in

double-blind controlled studies with topiramate) include: anorexia, decreased appetite, bradyphrenia, depression, expressive language

disorder, insomnia, coordination abnormal, disturbance in attention, dizziness, dysarthria, dysgeusia, hypoesthesia, lethargy, memory

impairment, nystagmus, paresthesia, somnolence, tremor, diplopia, vision blurred,diarrhoea, nausea, fatigue, irritability, and weight

decreased.

Table 1: Topiramate Adverse Reactions

System Organ

Very common

Common

Uncommon

Rare

Not known

Infections and

infestations

Nasopharyngitis*

Blood and

lymphatic system

disorders

Anaemia

Leucopenia,

Thrombocytopenia

lymphadenopathy,

eosinophilia

Neutropenia*

Immune system

disorders

Hypersensitivity

Allergic

oedema*

Metabolism and

nutrition

disorders

Anorexia,

decreased appetite

Metabolic

acidosis,

hypokalaemia,

increased

appetite,

polydipsia

Acidosis

hyperchloraem

Psychiatric

disorders

Depression

Bradyphrenia,

insomnia,

expressive

language disorder,

anxiety,

confusional state,

disorientation,

aggression, mood

altered, agitation,

mood swings,

depressed mood,

anger, abnormal

behaviour

Suicidal ideation,

suicide attempt,

hallucination,

psychotic disorder,

hallucination

auditory,

hallucination

visual,

apathy, lack of

spontaneous

speech,

sleep disorder,

affect lability, libido

decreased,

restlessness,

crying,

dysphemia,

euphoric

mood, paranoia,

perseveration,

panic

attack, tearfulness,

reading disorder,

initial insomnia,

Mania, panic

disorder,

feeling of

despair*,

hypomania

flat

affect, thinking

abnormal, loss of

libido, listless,

middle insomnia,

distractibility, early

morning

awakening,

panic reaction,

elevat

mood

Nervous system

disorders

Paraesthesia,

somnolence

Dizziness

Disturbance in

attention, memory

impairment,

amnesia, cognitive

disorder, mental

impairment,

psychomotor skills

impaired,

convulsion,

coordination

abnormal, tremor,

lethargy,

hypoaesthesia,

nystagmus,

dysgeusia, balance

disorder,

dysarthria,

intention tremor,

sedation

Depressed level of

consciousness,

grand mal

convulsion, visual

field defect,

complex partial

seizures, speech

disorder,

psychomotor

hyperactivity,

syncope, sensory

disturbance,

drooling,

hypersomnia,

aphasia, repetitive

speech,

hypokinesia,

dyskinesia,

dizziness

postural, poor

quality sleep,

burning sensation,

sensory loss,

parosmia,

cerebellar

syndrome,

dysaesthesia,

hypogeusia,

stupor,

clumsiness, aura,

ageusia,

Apraxia,

circadian

rhythm sleep

disorder,

hyperaesthesi

hyposmia,

anosmia,

essential

tremor,

akinesia,

unresponsive

stimuli

dysgraphia,

dysphasia,

neuropathy

peripheral,

presyncope,

dystonia,

formication

disorders

Vision blurred,

diplopia, visual

disturbance

Visual acuity

reduced, scotoma,

myopia*, abnormal

sensation in eye*,

dry eye,

photophobia,

blepharospasm,

lacrimation

increased,

photopsia,

mydriasis,

presbyopia

Blindness

unilateral,

blindness

transient,

glaucoma,

accommodatio

disorder,

altered

visual depth

perception,

scintillating

scotoma,

eyelid

oedema*,

night

blindness,

amblyopia

Angle closure

glaucoma*,

Maculopathy*,

eye movement

disorder*,

conjunctival

oedema*

Ear and labyrinth

disorders

Vertigo, tinnitus,

ear pain

Deafness,

deafness

unilateral,

deafness

neurosensory, ear

discomfort,

hearing

impaired

Cardiac

disorders

Bradycardia, sinus

bradycardia,

palpitations

Vascular

Hypotension,

orthostatic

hypotension,

Raynaud's

phenomenon

disorders

flushing, hot flush

Respiratory,

thoracic and

mediastinal

disorders

Dyspnoea,

epistaxis, nasal

congestion,

rhinorrhoea,

cough*

Dyspnoea

exertional,

Paranasal

sinus

hypersecretion,

dysph

onia

Gastrointestinal

disorders

Nausea,

diarrhoea

Vomiting,

constipation,

abdominal pain

upper, dyspepsia,

abdominal pain,

dry mouth,

stomach

discomfort,

paraesthesia oral,

gastritis, abdominal

discomfort

Pancreatitis,

flatulence,

gastrooesophagea

reflux disease,

abdominal pain

lower,

hypoaesthesia

oral, gingival

bleeding,

abdominal

distension,

epigastric

discomfort,

abdominal

tenderness,

salivary

hypersecretion,

oral

pain, breath odour,

glosso

dynia

Hepatobiliary

disorders

Hepatitis,

Hepatic

failure

Skin and

subcutaneous tissue

Alopecia, rash,

Anhidrosis,

hypoaesthesia

facial,

Stevens-

Johnson

syndrome*

Toxic

epidermal

disorders

pruritus

urticaria,

erythema,

pruritus

generalised,

rash macular, skin

discolouration,

dermatitis allergic,

swelling face

erythema

multiforme*,

skin

odour

abnormal,

periorbital

oedema*,

urticaria

localised

necrolysis*

Musculoskeletal

and connective

tissue

disorders

Arthralgia, muscle

spasms, myalgia,

muscle twitching,

muscular

weakness,

musculoskeletal

chest pain

Joint swelling*,

musculoskeletal

stiffness, flank

pain,

muscle fatigue

Limb

discomfort*

Renal and urinary

disorders

Nephrolithiasis,

pollakiuria, dysuria

Calculus urinary,

urinary

incontinence,

haematuria,

incontinence,

micturition

urgency,

renal colic, renal

pain

Calculus

ureteric,

renal tubular

acidosis*

Reproductive

system and breast

disorders

Erectile

dysfunction,

sexual dysfunction

General disorders

and administration

site

conditions

Fatigue

Pyrexia, asthenia,

irritability, gait

disturbance, feeling

abnormal, malaise

Hyperthermia,

thirst,

influenza like

illness*,

sluggishness,

peripheral

coldness,

feeling drunk,

feeling jittery

Face oedema,

calcinosis

Investigati

Weight

decreased

Weight increased*

Crystal urine

present, tandem

gait

test abnormal,

white

blood cell count

decreased,

Increase

in liver enzymes

Blood

bicarbonate

decreased

Social

circumstan

Learning

disability

* identified as an adverse reaction from postmarketing spontaneous reports. Its frequency was calculated based on clinical trial data.

Paediatric population

Adverse reactions reported more frequently (≥2-fold) in children than in adults in double-blind

controlled studies include:

aemic acidosis

ng abnormal

Adverse reactions that were reported in children but not in adults in double-blind controlled studies

include:

Eosinophilia

Psychomotor hyperactivity

Vertigo

Vomiting

Hyperthermia

Pyrexia

Learning disability.

Similar products

Search alerts related to this product

View documents history

Share this information