Topiramate Actavis 50

New Zealand - English - Medsafe (Medicines Safety Authority)

Active ingredient:
Topiramate 50 mg;  
Available from:
Teva Pharma (New Zealand) Limited
INN (International Name):
Topiramate 50 mg
Dosage:
50 mg
Pharmaceutical form:
Film coated tablet
Composition:
Active: Topiramate 50 mg   Excipient: Colloidal silicon dioxide Croscarmellose sodium Opadry Yellow 85G32312 Magnesium stearate Mannitol Microcrystalline cellulose Pregelatinised maize starch
Prescription type:
Prescription
Manufactured by:
Hetero Drugs Limited
Therapeutic indications:
Topiramate Actavis is indicated in adults and children. Topiramate Actavis tablet range is not suitable for any children weighing less than 25 Kg and is not suitable as monotherapy for children or adolescents weighing less than 50 kg. - as monotherapy in patients with newly diagnosed epilepsy - for conversion to monotherapy in patients with epilepsy - as add-on therapy in partial onset seizures, generalised tonic-clonic seizures or seizures associated with Lennox-Gastaut syndrome.
Product summary:
Package - Contents - Shelf Life: Blister pack, Alu/Alu bottom strip with Alu/PVC/PVDC blisters in printed carton - 10 tablets - 36 months from date of manufacture stored at or below 25°C - Blister pack, Alu/Alu bottom strip with Alu/PVC/PVDC blisters in printed carton - 60 tablets - 36 months from date of manufacture stored at or below 25°C - Blister pack, Alu/Alu bottom strip with Alu/PVC/PVDC blisters in printed carton - 200 tablets - 36 months from date of manufacture stored at or below 25°C - Bottle, plastic, HDPE with HDPE twist off cap with integrated dessicant - 10 tablets - 36 months from date of manufacture stored at or below 25°C - Bottle, plastic, HDPE with HDPE twist off cap with integrated dessicant - 60 tablets - 36 months from date of manufacture stored at or below 25°C - Bottle, plastic, HDPE with HDPE twist off cap with integrated dessicant - 200 tablets - 36 months from date of manufacture stored at or below 25°C
Authorization number:
TT50-9306a
Authorization date:
2013-06-05

Read the complete document

NEW ZEALAND CONSUMER MEDICINE INFORMATION

Topiramate Actavis

Topiramate

Topiramate Tablets 25 mg, 50 mg, 100 mg and 200 mg

What is in this leaflet

This leaflet answers some common questions about TOPIRAMATE - ACTAVIS Tablets.

It does not contain all of the available information. It does not take the place of talking to your

doctor or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of you taking

TOPIRAMATE - ACTAVIS against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, talk to your doctor or pharmacist.

Keep this leaflet with your medicine. You may need to read it again.

What TOPIRAMATE - ACTAVIS is used for

TOPIRAMATE, the active ingredient in TOPIRAMATE - ACTAVIS Tablets, is used for the

treatment of various types of epilepsy in adults and children over 2 years of age**, and for the

prevention of migraine in adults. It prevents seizures and migraines by acting on the nerves

and chemicals in the brain.

Your doctor may prescribe TOPIRAMATE - ACTAVIS on its own, or in addition to another

medicine for controlling your seizures or migraines.

Your doctor may have prescribed TOPIRAMATE - ACTAVIS for another reason. Ask your

doctor if you have any questions about why TOPIRAMATE - ACTAVIS has been prescribed

for you.

There is no evidence that TOPIRAMATE - ACTAVIS is addictive.

TOPIRAMATE - ACTAVIS is available only with a doctor’s prescription.

** Topiramate Actavis tablet range cannot deliver lower doses required for younger paediatric

patients (See the data sheet for further information on this).

Before you take TOPIRAMATE - ACTAVIS

When you must not take it

Do not take TOPIRAMATE - ACTAVIS if you are allergic to medicines containing

topiramate, or any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

shortness of breath, wheezing or difficulty breathing

swelling of the face, lips, tongue or other parts of the body

lumpy skin rash (“hives”), hayfever or fainting.

Do not take TOPIRAMATE - ACTAVIS if the expiry date (Exp.) printed on the pack has

passed. It may not work well if you do.

Do not take TOPIRAMATE - ACTAVIS if the packaging is torn or shows signs of

tampering.

Before you start to take it

Certain people must use TOPIRAMATE - ACTAVIS with caution. Ask your doctor for

advice.

Tell your doctor if you are allergic to any other medicines, foods, dyes or

preservatives.

Tell your doctor if you are pregnant or intend to become pregnant.

Topiramate can cause harm to the developing foetus in pregnant women. Information

available indicates that infants exposed to topiramate in their mothers’ womb have an

increased risk of birth defects including cleft lip/palate. However, it is very important to control

your fits while you are pregnant. If it is necessary for you to take topiramate, your doctor can

help you decide whether or not to take it during pregnancy.

Tell your doctor if you are breastfeeding or intend to breastfeed.

Topiramate may appear in breast milk and it is not recommended to breastfeed while taking

TOPIRAMATE - ACTAVIS.

Tell your doctor if you have, or have had, the following medical problems:

kidney disease, kidney stones or have a family history of kidney stones

liver disease

eye problem or high pressure in the eye

personality disorder or mental illness.

Taking other medicines

Tell your doctor if you are taking any other medicines, including those you buy without

a prescription from a pharmacy, supermarket or health food shop.

Some medicines may be affected by TOPIRAMATE - ACTAVIS, or may affect how well it

works. These include:

other medicines for epilepsy, such as phenytoin or carbamazepine

valproic acid (used to control epilepsy or treat mood disorder like mania)

lithium, risperidone (used to treat bipolar disorder and schizophrenia)

oral contraceptives (the pill)

digoxin (used to treat heart disease)

hydrochlorothiazide (used to treat swelling or high blood pressure)

propranolol (used to lower blood pressure or treat tremor)

diltiazem (used to lower blood pressure and prevent angina)

metformin, pioglitazone, glibenclamide (used to treat diabetes)

acetazolamide (used to treat glaucoma)

any medicine which slows your reactions. This may include medicines to help you sleep

or relieve pain such as antidepressants, tranquillisers or antihistamines, which all can

make you drowsy.

Your doctor can tell you what to do if you are taking any of these medicines. If you are not

sure whether you are taking any of these medicines, check with your doctor or pharmacist.

Your doctor and pharmacist have more information on medicines to be careful with or avoid

while taking TOPIRAMATE - ACTAVIS.

If you have not told your doctor about any of the above, tell them before you start

taking TOPIRAMATE - ACTAVIS.

How to take TOPIRAMATE - ACTAVIS

Follow all directions given to you by your doctor and pharmacist carefully.

How much to take

The doses shown below are the usual recommended doses. However, your doctor may tell

you to take higher or lower doses. Your doctor will start with a low dose and slowly increase

the dose to the lowest amount needed to control your condition.

Adults

Epilepsy - Treatment starts at a low dose of 25 mg to 50 mg per day. The dose is then

gradually increased by 25 mg to 100 mg over weekly periods or longer, until the most suitable

dose is reached. Daily doses above 1000 mg are not recommended.

Migraine - Treatment starts at a low dose of 25 mg nightly for one week. The dose is then

increased over weekly periods or longer by 25mg/day, until the most suitable dose is reached.

Children (2 years and over)**

Epilepsy only - Treatment starts at 25 mg or less per day, depending on the body weight.

This dose is then gradually increased over weekly periods or longer, until the most suitable

dose is reached.

** Topiramate Actavis tablet range cannot deliver lower doses required for younger paediatric

patients (See the data sheet for further information on this).

How to take it

Swallow TOPIRAMATE - ACTAVIS Tablets whole with plenty of water. You can take them

with or without food.

When to take it

At the start of treatment, TOPIRAMATE - ACTAVIS may be taken once a day, preferably at

night. After the dose is increased, it is taken twice a day.

Take TOPIRAMATE - ACTAVIS at about the same time of each day.

Taking your medicine at the same time each day will have the best effect on your condition. It

will also help you to remember when to take it.

How long to take it

You should continue taking TOPIRAMATE - ACTAVIS until your doctor tells you to stop.

Before stopping, it is recommended that the dose be reduced gradually.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next

dose when you are meant to.

Otherwise, take the missed dose as soon as you remember, and then go back to taking

your tablets as you would normally.

Do not take a double dose to make up for the dose you missed.

If you have missed more than one dose, or are not sure what to do, ask your doctor or

pharmacist.

If you have trouble remembering when to take your medicine, ask your pharmacist for

some hints.

If you take too much (overdose)

Immediately telephone your doctor, or the National Poisons Information Centre (0800

POISON or 0800 764 766), or go to Accident and Emergency department at your

nearest hospital, if you think that you or anyone else may have taken too many

TOPIRAMATE - ACTAVIS Tablets.

Do this even if there are no signs of discomfort or poisoning. You may need urgent

medical attention.

Keep the telephone numbers for these places handy.

If you take too much TOPIRAMATE - ACTAVIS, you may experience headache, dizziness,

light-headedness, drowsiness, convulsions, speech disturbances, double or blurred vision,

difficulty with thinking, abnormal coordination, stomach pain, depression, agitation, faster

breathing or you may lose consciousness.

While you are taking TOPIRAMATE - ACTAVIS

Things you must do

Before starting any new medicine, tell your doctor or pharmacist that you are taking

TOPIRAMATE - ACTAVIS.

Drink plenty of water.

Topiramate has been known to cause kidney stones and drinking water may help prevent

this.

If you become pregnant while taking TOPIRAMATE - ACTAVIS, tell your doctor

immediately.

Tell your doctor if, for any reason, you have not taken your medicine exactly as

directed.

Otherwise, your doctor may think that it is not working and change your treatment

unnecessarily.

Always follow your doctor's instructions carefully.

Things you must not do

Do not use TOPIRAMATE - ACTAVIS to treat any other conditions unless your doctor

tells you to.

Do not change the dose of your TOPIRAMATE - ACTAVIS without checking with your

doctor.

Do not suddenly stop taking TOPIRAMATE - ACTAVIS without checking with your

doctor.

Do not give TOPIRAMATE - ACTAVIS to anyone else, even if they have the same

condition or similar symptoms as you.

Things to be careful of

Be careful driving, operating machinery or doing jobs that require you to be alert while

you are taking TOPIRAMATE - ACTAVIS until you know how it affects you.

TOPIRAMATE - ACTAVIS can cause drowsiness, dizziness or other symptoms that can

affect your ability to drive or operate machinery. It may also cause visual disturbances and/or

blurred vision. Make sure you know how you are affected by this medicine before you drive or

use machinery.

Particular care is recommended when you first start taking TOPIRAMATE - ACTAVIS or if the

amount of TOPIRAMATE - ACTAVIS or any other medicine you are taking is increased or

decreased.

Avoid alcohol while taking TOPIRAMATE - ACTAVIS.

Alcohol may increase the risk of unwanted side effects, such as drowsiness.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are

taking TOPIRAMATE - ACTAVIS.

Like other medicines, TOPIRAMATE - ACTAVIS can cause some side effects. Sometimes

they are serious, most of the time they are not. You may need medical treatment if you get

some of the side effects.

Do not be alarmed by this list of possible side effects.

You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following and they worry you:

unusual tiredness, drowsiness, weakness, dizziness

decrease in appetite or weight loss

itchy skin or skin rash

inability to sleep

faster breathing

headache

unsteady or abnormal way of walking

tingling and numbness in fingers and toes

nose bleed

nausea, diarrhoea, increased saliva, altered sense of taste, stomach pain

difficulty in controlling emotions.

Tell your doctor as soon as possible if you notice any of the following, as you may

need medical care:

difficulty with concentration or attention; confusion

difficulty with memory and/or thinking

depression, mood problems, abnormal thoughts, thoughts of harming yourself

reduced sweating or overheating (mainly in children) - feeling flushed or overheated more

than usual, particularly during exercise or hot weather

agitation or unusual nervousness

co-ordination problems, tremor or slow reaction

unusual hair loss or thinning

abnormal frequent urination

speech or language problems

effects on eyes or vision (e.g. double vision)

frequent infections with symptoms such as fever, severe chills, sore throat or mouth

ulcers.

If any of the following happen after taking TOPIRAMATE - ACTAVIS, stop taking it and

tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

allergic reactions such as swelling of the face, lips, mouth, tongue or throat that may cause

difficulty in swallowing or breathing; pinkish or itchy swellings on the skin (hives or nettle

rash)

blood in your urine or severe lower back pain that spreads towards the groin area

sudden severe pain in the chest, arms or legs

sudden changes in your eyesight (e.g. blurred or loss of vision), red eye or eye pain

abnormal tiredness, dark urine, pale stools, yellowing of the skin or eyes.

These are rare but very serious side effects. You may need urgent medical attention or

hospitalisation.

This is not a complete list of all possible side effects. Other side effects not listed above may

also occur in some patients. Tell your doctor if you notice anything that is making you feel

unwell.

After using TOPIRAMATE - ACTAVIS

Storage

Keep TOPIRAMATE - ACTAVIS where children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store

medicines.

Keep TOPIRAMATE - ACTAVIS in a cool, dry place where the temperature stays below

25

C.

Keep your tablets in the packs until it is time to take them.

If you take the tablets out of the pack, they may not keep well.

Do not store TOPIRAMATE - ACTAVIS or other medicines in the bathroom or near a

sink. Do not leave the medicines in the car or on window sills.

Heat, light and dampness can destroy some medicines.

Disposal

If your doctor tells you to stop taking TOPIRAMATE - ACTAVIS, or your medicine has passed

its expiry date, ask your pharmacist what to do with any that are left over.

Product Description

What TOPIRAMATE - ACTAVIS looks like

TOPIRAMATE - ACTAVIS Tablets are available in four strengths, supplied in both opaque

bottles and foil blister packs of 60 tablets. TOPIRAMATE ACTAVIS 25 mg tablets are also

available as sample packs- bottles of 20 tablets. (Not all pack sizes may be available in

market)

25 mg – white, round, biconvex, film marked with ‘V1’.

50 mg – light yellow, round biconvex, film coated tablet marked with ‘V3’.

100 mg – yellow, round biconvex, film coated tablet marked with ‘V4’.

200 mg – salmon, oval biconvex, film coated tablet marked with ‘V5’.

Ingredients

Each TOPIRAMATE - ACTAVIS Tablet contains:

25 mg, 50 mg, 100 mg or 200 mg as the active ingredient

excipients including mannitol, microcrystalline cellulose, pregelatinised maize starch,

magnesium stearate, croscarmellose sodium

colouring agent Opadry II White 85F18422 for 25 mg Tablets, Opadry II Yellow 85G32312

for 50 mg Tablets, Opadry II Yellow 85G32313 for 100 mg Tablets, and Opadry II Pink

85G34776 for 200 mg Tablets.

Supplier

Teva Pharma (New Zealand) Limited

P O Box 128 244

Remuera

Auckland 1541

Telephone: 0800 800 097

Date of preparation

July 2017

Read the complete document

Version 1.1

NEW ZEALAND DATA SHEET

1.

PRODUCT NAME

Topiramate Actavis 25, film-coated tablets 25 mg

Topiramate Actavis 50, film-coated tablets, 50 mg

Topiramate Actavis 100, film-coated tablets, 100 mg

Topiramate Actavis 200, film-coated tablets, 200 mg

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 25 mg, 50 mg, 100 mg or 200 mg topiramate.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

25 mg – White, round, biconvex, film coated tablet marked with ‘V1’.

50 mg – Light yellow, round biconvex, film coated tablet marked with ‘V3’.

100 mg – Yellow, round biconvex film, coated tablet marked with ‘V4’.

200 mg – Salmon, oval biconvex, film coated tablet marked with ‘V5’.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Epilepsy

Topiramate Actavis is indicated in adults and children 2 years and over**:

as monotherapy in patients with newly diagnosed epilepsy

for conversion to monotherapy in patients with epilepsy

as add-on therapy in partial onset seizures, generalised tonic-clonic seizures or seizures associated

with Lennox-Gastaut syndrome.

** Topiramate Actavis tablet range cannot deliver lower doses required for younger paediatric

patients (See section 4.2

Dose and method of administration

Migraine

Topiramate Actavis is indicated in adults for the prophylaxis of migraine headache. The usefulness of

Topiramate Actavis in the acute treatment of migraine headache has not been studied.

4.2

Dose and method of administration

Topiramate Actavis Tablets should be swallowed whole. Topiramate Actavis Tablets can be taken

with or without food.

For optimum seizure control in both adults and children, it is recommended that therapy should be

initiated at a low dose followed by slow titration to an effective dose. Dose titration should be guided

by clinical outcome.

The recommended dosages of Topiramate Actavis in adults and children with epilepsy are listed as

follows and summarised in Table 1.

Epilepsy - Monotherapy

In newly diagnosed epileptic patients, Topiramate Actavis monotherapy should be initiated at a low

dose (see Table 1).

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In patients who are being converted to Topiramate Actavis monotherapy, consideration should be

given to the effects of seizure control when withdrawing concomitant antiepileptic agents (AEAs).

Unless

safety

concerns

require

abrupt

withdrawal

concomitant

AEA,

gradual

discontinuation at the rate of approximately one-third of the concomitant AEA dose every 2 weeks is

recommended. When enzyme inducing medicines are withdrawn, topiramate levels will increase. A

decrease in topiramate dosage may be required if clinically indicated.

Adults

Titration for monotherapy should begin at 25 mg as a single (nightly) dose for one week or longer.

The dosage should then be increased by 25 to 50 mg/day at weekly or longer intervals to the

recommended target dose of 100 mg/day. The maximum recommended dose is 500 mg/day. Some

patients with refractory forms of epilepsy have tolerated doses of 1,000 mg/day. The daily dosage

should be taken as two divided doses.

Children**

Titration for monotherapy should begin at 0.5 to 1 mg/kg as a single (nightly) dose for the first week.

The dosage should then be increased by 0.5 to 1 mg/kg/day at weekly or longer intervals to the

recommended target dose of 100 to 400 mg/day. The daily dosage should be given as two divided

doses.

** Topiramate Actavis tablet range cannot deliver lower doses required for younger paediatric

patients (See section 4.2

Dose and method of administration

Epilepsy - Add-on therapy

Adults

Titration for add-on therapy should begin at 25 to 50 mg as a single (nightly) or divided dose for one

week or longer. The dosage should then be increased by 25 to 100 mg/day at weekly or longer

intervals to the target dose of 200 to 400 mg/day. The maximum recommended dose should not

exceed 1000 mg/day. The daily dosage should be taken as two divided doses.

Children**

Titration for add-on therapy should begin at 1 to 3 mg/kg/day up to 25 mg/day as a single (nightly)

dose for the first week. The dosage should then be increased by 1 to 3 mg/kg/day at weekly or longer

intervals to the recommended total daily dose of 5 to 9 mg/kg/day. Daily doses up to 30 mg/kg have

been studied and were generally well tolerated. The daily dosage should be given as two divided

doses.

** Topiramate Actavis tablet range cannot deliver lower doses required for younger paediatric

patients (see section 4.2

Dose and method of administration

Version 1.1

Table 1 Recommended dosages of Topiramate Actavis in adults and children

Monotherapy

Add-on therapy

ADULTS

Starting dose

25 mg as a single (nightly) dose for one

week (or longer)

25 to 50 mg as a single (nightly) or

divided dose for one week (or longer)

Escalation dose

Increase by 25 to 50 mg/day at weekly

or longer intervals

Increase

mg/day

weekly or longer intervals

Target dose

100 mg/day

200 to 400 mg/day

Maximum dose

Up to 500 mg/day

Up to 1000 mg/day

CHILDREN **

Starting dose

0.5 to 1 mg/kg as a single (nightly)

dose for the first week

1 to 3 mg/kg/day up to 25 mg/day as a

single (nightly) dose for the first week

Escalation dose

Increase

mg/kg/day

weekly or longer intervals

Increase by 1 to 3 mg/kg/day at weekly

or longer intervals

Target dose

3 to 6 mg/kg/day

5 to 9 mg/kg/day

Maximum dose

Up to 500 mg/day

Up to 30 mg/kg/day

Note:

Daily doses greater or equal to 50 mg should be taken as two divided doses.

Some patients with refractory epilepsy have tolerated doses of 1000 mg/day.

** Topiramate Actavis tablet range cannot deliver lower doses required for younger paediatric

patients (See section 4.2

Dose and method of administration

It is not necessary to monitor topiramate plasma concentrations to optimise topiramate therapy. For

patients receiving concomitant phenytoin and carbamazepine, dosage adjustment for Topiramate

Actavis may be required (see section 4.5

Interactions with other medicines and other forms of

interactions

Migraine

Adults

Titration should begin at 25 mg nightly for 1 week. The dosage should then be increased weekly in

increments of 25 mg/day. If the patient is unable to tolerate the titration regimen, longer intervals

between dose adjustments can be used.

The recommended total daily dose of Topiramate Actavis as treatment for prophylaxis of migraine

headache is 100 mg/day administered in two divided doses. 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 should be guided by clinical outcome.

Use in patients with hepatic and/or renal impairment

Caution is advised during titration in the elderly and in patients with renal disease and/or hepatic

impairment (see Warnings and Precautions). Patients with moderate and severe renal impairment may

require a dose reduction. Half of the usual starting and maintenance dose is recommended (see section

Pharmacokinetic Properties).

Version 1.1

Use in patients undergoing haemodialysis

Topiramate is cleared by haemodialysis. To avoid rapid reduction in topiramate plasma concentration

during haemodialysis, a supplemental dose of topiramate equal to approximately one-half the daily

dose should be administered on hemodialysis days. The supplemental dose should be administered in

divided doses at the beginning and completion of the hemodialysis procedure. The supplemental dose

may differ based on the characteristics of the dialysis equipment being used (see section 5.2

Pharmacokinetic properties).

Drug withdrawal and dosage reduction

In patients with or without a history of seizures or epilepsy, antiepileptic drugs, including Topiramate

Actavis, should be gradually withdrawn to minimize the potential for seizures or of increased seizure

frequency (see section 4.4

Special warnings and precautions for use

). In situations where rapid

withdrawal of Topiramate Actavis is medically required, appropriate monitoring is recommended.

4.3

Contraindications

Hypersensitivity to topiramate and the excipients listed under 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

Drug withdrawal

In patients with or without a history of seizures or epilepsy, antiepileptic agents, including Topiramate

Actavis, should be gradually withdrawn to minimise the potential for seizures or increased seizure

frequency.

In clinical trials, daily dosages were decreased in weekly intervals by 50 to 100 mg in adults with

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

prophylaxis. In clinical trials of children, topiramate was gradually withdrawn over a 2- to 8-week

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

monitoring is recommended.

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 or nephrolithiasis and

hypercalciuria. None of these risk factors can reliably predict stone formation during topiramate

treatment. In addition, patients taking other medication associated with nephrolithiasis may be at

increased risk.

Hydration

Adequate hydration while using Topiramate Actavis is very important. Hydration can reduce the risk

of nephrolithiasis. Proper hydration prior to and during activities such as exercise or exposure to

warm temperatures may reduce the risk of heat-related adverse events.

Serious skin reactions

Serious skin reactions (Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN))

have been reported in patients receiving topiramate (see section 4.8

Undesirable effects

). The

majority of cases have occurred in patients concurrently taking other medications that are known to be

associated with SJS and TEN. There have also been several cases in patients receiving monotherapy.

It is recommended that patients be informed about the signs of serious skin reactions. If SJS or TEN

are suspected, use of Topiramate Actavis should be discontinued.

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Suicidality (suicidal behaviour and ideation)

An analysis of reports of suicidality (suicidal behaviour or ideation) from placebo controlled clinical

studies of eleven medicines used to treat epilepsy as well as psychiatric disorders, and other

conditions revealed that patients receiving anti-epileptic drugs had approximately twice the risk of

suicidal behaviour or ideation (0.43%) compared to patients receiving placebo (0.24%). The increased

risk of suicidal behaviour and suicidal ideation was observed as early as one week after starting the

anti-epileptic medicine and continued through 24 weeks. The results were generally consistent among

the eleven medicines. As most trials included in the analysis did not extend beyond 24 weeks, the risk

of suicidal thoughts or behaviour beyond 24 weeks could not be assessed.

Patients who were treated for epilepsy, psychiatric disorders, and other conditions were all at

increased risk for suicidality when compared to placebo, and there did not appear to be a specific

demographic subgroup of patients to which the increased risk could be attributed. The relative risk for

suicidality was higher in the patients with epilepsy compared to patients who were given one of the

medicines in the class for psychiatric or other conditions.

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

occurred at a frequency of 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). One completed suicide was

reported in a bipolar disorder double-blind trial in a patient on topiramate.

All patients who are currently taking or starting on any anti-epileptic drug should be closely

monitored for notable changes in behaviour that could indicate the emergence or worsening of

suicidal thoughts or behaviour or depression.

Healthcare professionals should inform patients, their families, and caregivers of the potential for an

increase

risk

suicidality.

Prescribers

should

advise

patients

seek

medical

advice

immediately if they develop any symptoms suggestive of suicidality.

Rapid dose reduction, discontinuation or substitution of topiramate

In patients who are seizure-free or whose seizures are well controlled, the need for dosage reduction,

discontinuation or substitution should be assessed by a healthcare professional and any changes

should be implemented gradually.

Oligohydrosis and Hyperthermia

Oligohydrosis (decreased sweating), infrequently resulting in hospitalization, has been reported in

association with topiramate use. Decreased sweating and an elevation in body temperature above

normal characterized these cases. Some of the cases were reported after exposure to elevated

environmental temperature.

The majority of the reports have been in children. Patients, especially paediatric patients, treated with

topiramate should be monitored closely for evidence of decreased sweating and increased body

temperature, especially in hot weather. Caution should be used when Topiramate Actavis is

prescribed with other drugs that predispose patients to heat-related disorders; these drugs include, but

are not limited to, other carbonic anhydrase inhibitors and drugs with anticholinergic activity.

Decreased hepatic function

In patients with hepatic impairment, 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 topiramate. Symptoms include acute onset of decreased visual acuity

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

Version 1.1

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

present.

This

syndrome

associated

with

supraciliary

effusion

resulting

anterior

displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur

within 1 month of initiating topiramate 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 topiramate, as

rapidly as possible in the judgement 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.

Visual field defects

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

intraocular

pressure.

clinical

trials,

most

these

events

were

reversible

after

topiramate

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

should be given to discontinuing the drug.

Metabolic acidosis and sequelae

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

normal

reference

range

absence

respiratory

alkalosis)

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

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 drugs) may be additive to the

bicarbonate lowering effects of topiramate .

Chronic, untreated metabolic acidosis may increase the risk of nephrolithiasis or nephrocalcinoisis

(see section 4.4 Nephrolithiasis).

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

growth and bone-related sequelae has not been systematically investigated in adult populations. A

one year, open-label study in pediatric patients aged 6 to 15 years including 63 subjects with recent or

new onset of epilepsy was conducted to assess the effects of topiramate (28 subjects) versus

levetiracetam on growth, development, and bone mineralization. Continued growth was observed in

both treatment groups but the topiramate group showed statistically significant reductions in mean

annual change from baseline in body weight and bone mineral density compared to the levetiracetam

group. A similar trend was also observed for height and height velocity but were not statistically

significant. Growth-related changes were not clinically significant nor treatment limiting. Other

confounding factors cannot be excluded.

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

recommended

with

Topiramate

Actavis

therapy.

metabolic

acidosis

develops

persists,

consideration should be given to reducing the dose or discontinuing Topiramate Actavis (using dose

tapering).

Hyperammonemia and encephalopathy

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

section 4.8

Undesirable effects

). The risk for hyperammonemia with topiramate appears dose-

related. Hyperammonemia has been reported more frequently when topiramate is used concomitantly

Version 1.1

with valproic acid (see section 4.5

Interactions with other medicines and other forms of

interactions

Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of

consciousness

and/or

cognitive

function

with

lethargy.

most

cases,

hyperammonemic

encephalopathy abated with discontinuation of treatment. 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.

Mood disturbances and depression

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

treatment. Psychiatric or behavioural disturbances (depression or mood problems) in majority of

affected patients were dose related for both the add-on epilepsy and migraine populations.

Suicide attempt

double-blind

phases

clinical

trials

with

topiramate

approved

investigational

indications, suicide attempts occurred at a rate of 0.003 on topiramate (13 events/3999 patient years)

versus 0 on placebo (0 events/1430 patient years). One completed suicide was reported in a bipolar

disorder trial in a patient on topiramate.

Women of childbearing potential

Topiramate may cause foetal harm when administered to a pregnant woman. There is an increased

risk of pre-term labour and premature delivery associated with the use of AEDs, including topiramate.

Topiramate should be used during pregnancy only if the potential benefit justifies the potential risk to

the foetus (see section 4.6

Fertility, pregnancy and lactation

Nutritional supplementation

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

on this medication.

Decreased renal function

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 or

severe renal impairment may take 10 to 15 days to reach steady state plasma concentrations as

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.

4.5

Interaction with other medicines and other forms of interaction

Effects of topiramate on other antiepileptic agents

The addition of topiramate to other antiepileptic agents (phenytoin, carbamazepine, valproic acid,

phenobarbitone, primidone) has no effect on their steady-state plasma concentrations. However, the

addition of topiramate to phenytoin may occasionally result in an increase of plasma concentrations of

phenytoin in some patients. This is possibly due to inhibition of a specific enzyme polymorphic

isoform (CYP2C19). Thus, any patient on phenytoin showing clinical signs or symptoms of toxicity

should have phenytoin levels monitored.

Effects of other antiepileptic agents on topiramate

Topiramate is metabolised up to 50% in patients receiving concomitant antiepileptic therapy with

known inducers of enzymes, which metabolise medicines.

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Phenytoin and carbamazepine decrease the plasma concentration of topiramate. The addition or

withdrawal of phenytoin or carbamazepine to topiramate 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 topiramate and, therefore, does not warrant dosage adjustment of topiramate.

The results of these interactions are summarised as below:

Table 2: Interactions between antiepileptic agents (AEA) and topiramate

AEA co-administered

AEA plasma concentration

Topiramate plasma concentration

Phenytoin

Decrease (48%)

Carbamazepine

Decrease (40%)

Valproic Acid

Phenobarbitone

Not studied

Primidone

Not studied

Lamotrigine

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

* Plasma concentrations increase occasionally in some patients.

No data are available on the use of topiramate with vigabatrin.

Other interactions

Digoxin:

In a single dose study, the serum digoxin area under plasma concentration curve (AUC)

decreased 12% due to concomitant administration of topiramate. The clinical relevance of this

observation has not been established. When topiramate is added or withdrawn in patients on digoxin

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

CNS depressants:

Concomitant administration of topiramate and alcohol or other CNS depressant

medicines has not been evaluated in clinical studies. It is recommended that topiramate not be used

concomitantly with alcohol or other CNS depressant medicines.

Oral

contraceptives:

pharmacokinetic

interaction

study

healthy

volunteers

with

concomitantly administered combination oral contraceptive product containing 1 mg norethindrone

plus 35 microgram ethinyl oestradiol, topiramate 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 ethinyl oestradiol 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. In both studies, topiramate (50 mg/day to 800 mg/day) did not

significantly affect exposure to norethindrone. Although there was a dose dependent decrease in

ethinyl oestradiol exposure for doses between 200 to 800 mg/day, there was no significant dose

dependent change in ethinyl oestradiol exposure for doses of 50 to 200 mg/day. 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 topiramate. Patients taking oestrogen containing contraceptives

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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 and multiple dose conditions in

healthy volunteers and 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) with systemic exposure (16% and

33% for steady-state AUC at the 250 and 400 mg/day doses, respectively). 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 clinically significant changes in the systemic

exposure of the risperidone total active moiety or of topiramate, therefore this interaction is not likely

to be of clinical significance.

Hydrochlorothiazide (HCTZ):

A drug-drug interaction study conducted in healthy volunteers

evaluated the steady-state pharmacokinetics of HCTZ (25 mg 24-hourly) and topiramate (96 mg 12-

hourly) when administered alone and concomitantly. The results of this study indicate that topiramate

increased by 27% and AUC increased by 29% when HCTZ was added to topiramate. The

clinical significance of this change is unknown. The addition of HCTZ to topiramate therapy may

require an adjustment of the topiramate dose. The steady-state pharmacokinetics of HCTZ was 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 but the extent of change in the clearance is not known. Similarly, the clinical significance

of the effect of metformin on topiramate pharmacokinetics is also not clear. Thus, when topiramate 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

t,ss

of pioglitazone with no alteration in C

max,ss

was observed. This finding

was however not statistically significant. In addition, a 13% and 16% decrease in C

max,ss

and AUC

t,ss

respectively, of the active hydroxy-metabolite was noted as well as a 60% decrease in C

max,ss

t,ss

of the active keto-metabolite. The clinical significance of these findings is not known. When

topiramate is added to pioglitazone therapy or pioglitazone is added to topiramate therapy, careful

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

disease state.

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Glibenclamide:

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

steady-state

pharmacokinetics

glibenclamide

mg/day)

alone

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-glibenclamide and 3-

cis

-hydroxyglibenclamide, 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:

When topiramate is used concomitantly with other agents

predisposing to nephrolithiasis, the risk of nephrolithiasis may be increased. Thus, while on

topiramate

therapy,

agents

like

these

should

avoided,

they

create

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 drug alone. In

most cases, symptoms and signs abated with discontinuation of either drug (see sections 4.4

Special

warnings and precautions for

use

and 4.8

Undesirable effects

). This adverse event 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 the 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.

Vitamin K-antagonist anticoagulant medications

Decreased Prothrombin Time/International Normalised Ratio (PT/INR) responses have been reported

following

concomitant

administration

topiramate

with

vitamin

K-antagonist

anticoagulant

medications. Closely monitor INR during concomitant administration of topiramate therapy with

vitamin K-antagonist anticoagulant medications.

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 in Table 3. 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 co-administration of a drug listed in the first column modifies the concentration of

topiramate.

Version 1.1

Table 3: Pharmacokinetic drug interaction studies

Concomitant drug

Concomitant drug concentration

Topiramate concentration

Amitriptyline

increase

nortriptyline metabolite

Not studied

Dihydroergotamine

(oral and subcutaneous)

Haloperidol

increase

reduced

metabolite

Not studied

Propranolol

17% Increase in C

for 4-OH propranolol

(topiramate 50 mg 12-hourly)

9% and 16% Increase in C

9% and 17% increase in AUC

(40 mg and 80 mg propranolol

12-hourly respectively)

Sumatriptan

(oral and subcutaneous)

Not studied

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 (topiramate 50 mg 12-

hourly)

= No effect on C

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

* 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.

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.

Topiramate should be used during pregnancy only if potential benefit justifies the potential risk to the

fetus. In treating and counseling women of childbearing potential, the prescribing physician should

weigh the benefits of therapy against the risks, particularly when topiramate is considered for a

condition not usually associated with permanent injury or death. If this drug is used during pregnancy

or if the patient becomes pregnant while taking this drug, the patient should be apprised of the

potential hazard to the fetus.

The risk of having an abnormal child as a result of antiepileptic medication is far outweighed by the

danger to the mother and fetus of uncontrolled epilepsy.

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It is recommended that:

Women on antiepileptic drugs (AEDs) receive pregnancy counselling with regard to the risk of

foetal abnormalities;

AEDs should be continued during pregnancy and monotherapy should be used if possible at the

lowest effective dose as risk of abnormality is greater in women taking combined medication;

Folic acid supplementation (5mg) should be commenced four weeks prior to and continue for

twelve weeks after conception;

Specialist prenatal diagnosis including detailed mid-trimester ultrasound should be offered.

Risk related to topiramate

As with other antiepileptic medicines, topiramate was teratogenic in mice, rats and rabbits. In rats,

topiramate crosses the placental barrier. There are no adequate and well-controlled studies using

topiramate in pregnant women.

Topiramate can cause fetal harm when administered to a 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.

Data from the North American AED (NAAED) Pregnancy Registry indicate an increased risk of oral

clefts in infants exposed to topiramate monotherapy during the first trimester of pregnancy. The

prevalence of oral clefts was 1.4% compared to a prevalence of 0.38% - 0.55% in infants exposed to

other AEDs, and a prevalence of 0.07 % in infants of mothers without epilepsy or treatment with other

AEDs. For comparison, the Centers for Disease Control and Prevention (CDC) reviewed available

data on oral clefts in the United States and found a background rate of 0.17%. The relative risk of oral

clefts

topiramate-exposed

pregnancies

NAAED

Pregnancy

Registry

21.3

(95%

Confidence Interval=CI 7.9 – 57.1) as compared to the risk in a background population of untreated

women. The UK Epilepsy and Pregnancy Register reported a similarly increased prevalence of oral

clefts of 3.2% among infants exposed to topiramate monotherapy. The observed rate of oral clefts was

16 times higher than the background rate in the UK, which is approximately 0.2%.

The background incidence rate of oral clefts is higher for Maori (2.37 per 1000 live births) compared

with the overall New Zealand population (1.79 per 1000 live births).

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

observed in all doses and effects were reported to be dose-dependent. 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. There is an increased risk of

pre-term labour and premature delivery associated with the use of AEDs, including topiramate.

Compared

with

reference

group

taking

antiepileptic

drugs,

registry

data

topiramate

monotherapy showed a higher prevalence of low birth weight (<2500 grams). One pregnancy registry

reported an increased frequency of infants who were small for gestational age (SGA: defined as birth

weight below the 10

percentile corrected for their gestational age, stratified by sex) among those

exposed to topiramate monotherapy

in utero.

SGA has been observed in all doses and is dose-

dependent. The prevalence of SGA is greater in women who received higher doses of topiramate

during pregnancy. In addition, the prevalence of SGA for women who continued topiramate use later

in pregnancy is higher compared to women who stopped its use before the third trimester. The long-

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term consequences of the SGA findings could not be determined. A causal relationship for low birth

weight and SGA has not been established.

Indication epilepsy

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

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

contraception be used (see section 4.5

Interactions with other medicines and other forms of

interactions

), 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.

case

administration

during

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

Contraindications

and section 4.5

Interactions with other medicines and other forms of interactions

Lactation

Topiramate is excreted in the milk of lactating rats. The excretion of topiramate in human milk has

not been evaluated in controlled studies. Limited observation in patients suggests an extensive

excretion of topiramate into breast milk. Diarrhoea and somnolence have been reported in breastfed

infants

whose

mothers

receive

topiramate

treatment.

Therefore

decision

discontinue

breastfeeding or to discontinue the medicine, taking into account the benefit of breastfeeding for the

child and the benefit of the medicine to the mother.

4.7

Effects on ability to drive and use machines

Topiramate 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 otherwise mild or

moderate

adverse

events

potentially

dangerous

patients

driving

vehicle

operating

machinery, particularly until the individual patient's experience with the medicine is established.

4.8

Undesirable effects

The safety of topiramate

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

on topiramate

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 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 topiramate-treated adult patients in double-blind,

placebo-controlled adjunctive epilepsy trials are shown in Table 4. 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.

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Table 4: Adverse Drug Reactions Reported by ≥1% of Topiramate-treated Adult Patients in

Double-Blind, Placebo-Controlled, Adjunctive Epilepsy Trials

System/Organ Class

Adverse Reaction

Topiramate

200-400

mg/day

(N=354)

%

Topiramate

600-1000

mg/day

(N=437)

%

Placebo

(N=382)

%

Metabolism and Nutrition Disorders

Anorexia

Decreased appetite

Psychiatric Disorders

Bradyphrenia

19.5

Expressive language disorder

Confusional state

Depression

11.7

Insomnia

Aggression

Agitation

Anger

Anxiety

Disorientation

Mood altered

Nervous System Disorders

Somnolence

17.8

17.4

Dizziness

16.4

34.1

13.6

Paraesthesia

17.2

Coordination abnormal

11.4

Nystagmus

11.7

Lethargy

Dysarthria

Memory impairment

10.8

Disturbance in attention

11.9

Tremor

Amnesia

Balance disorder

Hypoaesthesia

Intention tremor

Dysgeusia

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Mental impairment

Speech disorder

Eye Disorders

Diplopia

12.1

Vision blurred

Visual disturbance

Gastrointestinal Disorders

Nausea

15.1

Diarrhoea

14.0

Abdominal pain upper

Constipation

Stomach discomfort

Dyspepsia

Dry mouth

Abdominal pain

Musculoskeletal

and

Connective

Tissue

Disorders

Myalgia

Muscle spasms

Musculoskeletal chest pain

General

Disorders

and

Administration

Site

Conditions

Fatigue

13.0

30.7

11.8

Irritability

14.6

Asthenia

Gait disturbance

Investigations

Weight decreased

11.9

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 topiramate-treated paediatric patients (2 to 16 years of age) in double-blind,

placebo-controlled adjunctive epilepsy trials are shown in Table 5. 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

attention,

weight

decreased, aggression, rash, abnormal behaviour, anorexia, balance disorder, and constipation.

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Table 5: Adverse Drug Reactions Reported by ≥2% of Topiramate-treated Paediatric Patients

in Double-Blind, Placebo-Controlled, Adjunctive Epilepsy Trials

System/Organ Class

Adverse Reaction

Topiramate

(N=104)

%

Placebo

(N=102)

%

Metabolism and Nutrition Disorders

Decreased appetite

19.2

12.7

Anorexia

Psychiatric Disorders

Aggression

Abnormal behaviour

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.

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

ADRs reported in ≥1% of topiramate-treated adult patients in double-blind, controlled monotherapy

epilepsy trials are shown in Table 6. 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 6: Adverse Drug Reactions Reported by ≥1% of Topiramate-treated Adult Patients in

Double-Blind, Controlled Monotherapy Epilepsy Trials

System/Organ Class

Adverse Reaction

Topiramate

50 mg/day

(N=257)

%

Topiramate

400 mg/day

(N=153)

%

Blood and Lymphatic System Disorders

Anaemia

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

Paraesthesia

18.7

40.5

Memory impairment

Dysgeusia

Hypoaesthesia

Balance disorder

Dysarthria

Cognitive disorder

Lethargy

Mental impairment

Psychomotor skills impaired

Sedation

Visual field defect

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Eye Disorders

Dry Eye

Ear and Labyrinth Disorders

Ear pain

Tinnitus

Respiratory, Thoracic and Mediastinal Disorders

Dyspnoea

Rhinorrhoea

Gastrointestinal Disorders

Diarrhoea

Paraesthesia oral

Dry mouth

Gastritis

Abdominal pain

Gastrooesophageal reflux disease

Gingival bleeding

Skin and Subcutaneous Tissue Disorders

Rash

Alopecia

Pruritus

Hypoaesthesia facial

Pruritus generalised

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

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Investigations

Weight decreased

17.0

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

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

ADRs reported in ≥2% of topiramate-treated paediatric patients (10 to 16 years of age) in double-

blind, controlled monotherapy epilepsy trials are shown in Table 7. ADRs that had an incidence >5%

at the recommended dose (400 mg/day) in descending order of frequency included weight decreased,

paraesthesia, diarrhoea, disturbance in attention, pyrexia, and alopecia.

Table 7: Adverse Drug Reactions Reported by ≥2% of Topiramate-treated Paediatric Patients

in Double-Blind, Controlled Monotherapy Epilepsy Trials

System/Organ Class

Adverse Reaction

Topiramate

50 mg/day

(N=77)

%

Topiramate

400 mg/day

(N=63)

%

Metabolism and Nutrition Disorders

Decreased appetite

Psychiatric Disorders

Bradyphrenia

Mood altered

Depression

Nervous System Disorders

Paraesthesia

15.9

Disturbance in attention

Ear and Labyrinth Disorders

Vertigo

Respiratory, Thoracic and Mediastinal Disorders

Epistaxis

Gastrointestinal Disorders

Diarrhoea

Vomiting

Skin and Subcutaneous Tissue Disorders

Alopecia

General Disorders and Administration Site Conditions

Pyrexia

Asthenia

Investigations

Weight decreased

20.6

Social Circumstances

Version 1.1

Learning disability

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

Migraine Prophylaxis

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

ADRs reported in ≥1% of topiramate-treated adult patients in double-blind, placebo-controlled

migraine prophylaxis trials are shown in Table 8. ADRs that had an incidence >5% at the

recommended dose (100 mg/day) in descending order of frequency included paraesthesia, fatigue,

nausea, diarrhoea, weight decreased, dysguesia, anorexia, decreased appetite, insomnia, hypoesthesia,

disturbance in attention, anxiety, somnolence, and expressive language disorder.

Table 8: Adverse Drug Reactions Reported by ≥1% of Topiramate-treated Adult Patients in

Double-Blind, Placebo-Controlled Migraine Prophylaxis Trials

System/Organ Class

Adverse Reaction

Topiramate

50 mg/day

(N=227)

%

Topiramate

100 mg/day

(N=374)

%

Topiramate

200 mg/day

(N=501)

%

Placebo

(N=436)

%

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

Paraesthesia

35.7

50.0

48.5

Dysgeusia

15.4

12.6

Hypoaesthesia

Disturbance in attention

Somnolence

Memory impairment

Amnesia

Tremor

Balance disorder

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Mental impairment

Eye Disorders

Vision blurred

Ear and Labyrinth Disorders

Tinnitus

Respiratory,

Thoracic

and

Mediastinal Disorders

Dyspnoea

Epistaxis

Gastrointestinal Disorders

Nausea

13.6

14.6

Diarrhoea

11.2

10.0

Dry mouth

Paraesthesia oral

Constipation

Abdominal distension

Stomach discomfort

Gastrooesophageal 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 topiramate-treated adult patients or

at any rate in open-label clinical trials of topiramate-treated adult patients are shown in Table 9.

Version 1.1

Table 9: Adverse Drug Reactions Reported in Double-Blind Controlled Clinical Trials in <1%

of

Topiramate-treated

Adult

Patients

or

at

Any

Rate

in

Open-Label

Clinical

Trials

of

Topiramate-treated Adult Patients

Blood and Lymphatic System Disorders

Leukopenia, lymphadenopathy, thrombocytopenia

Immune System Disorders

Hypersensitivity

Metabolism and Nutrition Disorders

Acidosis hyperchloraemic, hypokalaemia, increased appetite, metabolic acidosis, polydipsia

Psychiatric Disorders

Abnormal behaviour, 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, dysaesthesia, dysgraphia, dyskinesia, dysphasia, dystonia, essential tremor, formication,

grand

convulsion,

hyperaesthesia,

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

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Gastrointestinal Disorders

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

flatulence, glossodynia, hypoaesthesia oral, oral pain, pancreatitis, salivary hypersecretion

Skin and Subcutaneous Tissue Disorders

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

face, urticaria, urticaria localised

Musculoskeletal and Connective Tissue Disorders

Flank pain, muscle fatigue, muscular weakness, musculoskeletal stiffness

Renal and Urinary Disorders

Calculus ureteric, calculus urinary, haematuria, incontinence, micturition urgency, renal colic, renal pain,

urinary incontinence

Reproductive System and Breast Disorders

Sexual dysfunction

General Disorders

Face oedema, 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 topiramate-treated paediatric

patients or at any rate in open-label clinical trials of topiramate-treated paediatric patients are shown

in Table 10.

Table 10: Adverse Drug Reactions Reported in Double-Blind Controlled Clinical Trials in <2%

of Topiramate-treated Paediatric Patients or at Any Rate in Open-Label Clinical Trials of

Topiramate-Treated Paediatric Patients

Blood and Lymphatic System Disorders

Eosinophilia, leukopenia, lymphadenopathy, thrombocytopenia

Immune System Disorders

Hypersensitivity

Metabolism and Nutrition Disorders

Acidosis hyperchloraemic, hypokalaemia, 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

Version 1.1

Nervous System Disorders

Circadian rhythm sleep disorder, convulsion, dysarthria, dysgeusia, grand mal convulsion, hypoaesthesia,

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, rhinorrhoea

Gastrointestinal Disorders

Abdominal discomfort, abdominal pain, dry mouth, flatulence, gastritis, gastrooesophageal reflux disease,

gingival bleeding, glossodynia, pancreatitis, paraesthesia 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 topiramate, presented

by frequency category based on incidence in clinical trials, are included in Table 11. 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

Version 1.1

Table

11:

Adverse

Drug

Reactions

Identified

During

Postmarketing

Experience

with

Topiramate by Frequency Category Estimated from Clinical Trials

Infections and Infestations

Very rare

Nasopharyngitis

Blood and Lymphatic System Disorders

Very rare

Neutropenia

Immune System Disorders

Very rare

Allergic oedema

Metabolism and Nutrition Disorders

Very rare

Hyperammonemia

Very rare

Hyperammonemic encephalopathy

Psychiatric Disorders

Very rare

Feeling of despair

Eye Disorders

Very rare

Abnormal sensation in eye

Very rare

Angle closure glaucoma

Very rare

Conjunctival oedema

Very rare

Eye movement disorder

Very rare

Eyelid oedema

Very rare

Maculopathy

Very rare

Myopia

Respiratory, Thoracic and Mediastinal Disorders

Very rare

Cough0

Skin and Subcutaneous Tissue Disorders

Very rare

Erythema multiforme

Very rare

Periorbital oedema

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

Very rare

Nephrocalcinosis

General Disorders and Administration Site Conditions

Very rare

Influenza like illness

Very rare

Generalised oedema

Version 1.1

Investigations

Very rare

Weight increased

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows

continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked

to report any suspected adverse reactions https://nzphvc.otago.ac.nz/reporting/

4.9

Overdose

Signs and symptoms

Ingestion of between 6 and 40 g topiramate have been reported in a few patients. Signs and

symptoms included: headache, agitation, drowsiness, lethargy, convulsions, speech disturbances,

blurred vision, diplopia, impaired mentation, abnormal coordination, stupor, hypotension, abdominal

pain, dizziness, depression and hypokalaemia. The clinical consequences were not severe in most

cases, but deaths have been reported after polydrug overdoses involving topiramate.

Topiramate overdose can result in severe metabolic acidosis (see

Metabolic acidosis

under section

Special warnings and precautions for use

The highest topiramate overdose reported was calculated to be between 96 and 110 g and resulted

coma lasting 20 to 24 hours, followed by full recovery after 3 to 4 days.

Treatment

In the event of overdose, topiramate should be discontinued and general supportive treatment given

until clinical toxicity has been diminished or resolved. Haemodialysis has been shown to be an

effective means of removing topiramate from the body. The patient should be well hydrated.

For advice on the management of overdose please contact the National Poisons Centre on 0800

POISON (0800 764766).

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

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

code: N03AX11

Topiramate is a white crystalline powder with a bitter taste. It is most soluble in alkaline solutions

containing sodium hydroxide or sodium phosphate and has a pH of 9 to 10. It is freely soluble in

acetone, chloroform, dimethylsulfoxide and ethanol. The solubility in water is 9.8 mg/mL. Its

saturated solution has a pH of 6.3.

Topiramate is classified as a sulfamate-substituted monosaccharide.

precise

mechanism

which

topiramate

exerts

antiseizure

effect

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 depolarisation of the neurons were blocked by

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

action.

Topiramate

increased

frequency

which

gamma-aminobutyrate

(GABA)

activated

GABA

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.

Version 1.1

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 antagonised the

ability of kainate to activate the kainate/AMPA (a-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 micromol to 200 micromols, with minimum activity

observed at 1 micromol to 10 micromols.

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

mice

receiving

concomitant

administration

topiramate

carbamazepine

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.

evidence

tolerance has been demonstrated in humans.

5.2

Pharmacokinetic properties

The pharmacokinetic profile of topiramate compared to other antiepileptic medicines 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 metabolising enzymes. It 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.

Absorption

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

healthy subjects, a mean peak plasma concentration (Cmax) of 1.5 micrograms/mL was achieved

within 2 to 3 hours (Tmax). 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 micrograms/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. There is an effect of

gender on the volume of distribution. Values for females are about 50% lower than those for males.

This was attributed to the higher percentage body fat in female patients and is of no clinical

consequence.

Version 1.1

Metabolism

It is metabolised up to 50% in patients receiving concomitant antiepileptic therapy with known

inducers of drug metabolising enzymes. Six metabolites, formed through hydroxylation, hydrolysis

and glucuronidation, have been isolated, characterised 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

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.

Topiramate

exhibits

intersubject

variability

plasma

concentrations

therefore

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 micrograms/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.

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.

Special Populations

Patients with renal impairment

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

impaired renal function (CL

< 70 mL/min). As a result, higher steady state topiramate plasma

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

maintenance

dose

recommended

(see

section

4.2

Dose

and

method

of

administration

Topiramate

effectively

removed

from

plasma

haemodialysis.

prolonged

period

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 dialysed.

Patients with 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.

Version 1.1

Elderly

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

disease.

Paediatric 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 antiepileptic medicines decrease the steady state

plasma concentrations.

5.3

Preclinical safety data

Teratogenicity and embryotoxicity

As with other antiepileptic agents, topiramate was teratogenic in mice, rats and rabbits. Overall

numbers of foetal malformations in mice were increased for all topiramate treated groups, but no

significant

differences

dose-response

relationships

were

observed

overall

specific

malformations, suggesting that other factors such as maternal toxicity may be involved.

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.

Mutagenicity

In a battery of

in vitro

in vivo

mutagenicity assays, topiramate did not show genotoxic potential.

Carcinogenicity

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 and slight urothelial hyperplasia in the urinary bladder).

There were no relevant effects on long bone (tibia) growth or bone (femur) mineral density,

preweaning and reproductive development, neurological development (including assessments on

memory and learning), mating and fertility or hysterotomy parameters.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Topiramate Actavis Tablets contain the following excipients: mannitol, microcrystalline cellulose,

pregelatinised maize starch, magnesium stearate, croscarmellose sodium, and the colouring Opadry II

White 85F18422for 25 mg Tablets, Opadry II Yellow 85G32312 for 50 mg Tablets, Opadry II Yellow

85G32313 for 100 mg Tablets, and Opadry II Pink 85G34776 for 200 mg Tablets.

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

3 years for both blister packs and bottles.

6.4

Special precautions for storage

Store at or below 25°C.

6.5

Nature and contents of container

Topiramate Actavis Tablets are available in opaque bottles and foil blister packs of 10, 60 and 200

tablets.

Version 1.1

Topiramate Actavis 25 mg tablets are also available as a sample pack of 20 tablets in an opaque

bottle.

Not all pack types and sizes may be marketed.

6.6

Special precautions for disposal

No special requirements for disposal.

7.

MEDICINE SCHEDULE

Prescription medicine

8.

SPONSOR

Teva Pharma (New Zealand) Limited

P O Box 128 244

Remuera

Auckland 1541

Telephone: 0800 800 097

9.

DATE OF FIRST APPROVAL

03 April 2014

10.

DATE OF REVISION OF THE TEXT

18 May 2021

SUMMARY TABLE OF CHANGES

Section changed

Summary of new information

Topiramate Actavis contraindicated for migraine prophylaxis in

pregnancy and in women of childbearing potential if not using a

highly effective method of contraception added.

Information relating to serious skin reactions and the risk of

nephrolithiasis or nephrocalcinoisis has been added.

Revision to the existing metabolic acidosis warning to add

information on paediatric growth changes.

Vitamin K-antagonist anticoagulant medications added.

Updated pregnancy and lactation information.

Information

relating

adverse

drug

reactions

identified

during

postmarketing experience with topiramate updated.

Updated information relating to treatment of topiramate overdose.

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