TOPAMAX 50

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).

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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

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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’.

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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.

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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

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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

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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.

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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

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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*

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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

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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

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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*

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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

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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

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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.

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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

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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

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(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