Topiramate 100mg tablets

United Kingdom - English - eMC (Electronic Medicines Compendium)

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Active ingredient:
Topiramate
Available from:
Ennogen Healthcare Ltd
ATC code:
N03AX11
INN (International Name):
Topiramate
Dosage:
100mg
Pharmaceutical form:
Tablet
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 04080100; GTIN: 05060254924403

Topiramate Accord Healthcare

25mg, 50mg, 100mg and 200mg

Film-coated Tablets

(Topiramate)

Continued on next page

Read all of this leaflet carefully before you start

taking this medicine because it contains important

information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or

pharmacist.

This medicine has been prescribed for you only. Do

not pass it on to others. It may harm them, even if

their signs of illness are the same as yours.

If you get any side effects, talk to your doctor or

pharmacist. This includes any possible side effects not

listed in this leaflet. See section 4.

The full name of this medicine is Topiramate Accord

Healthcare 25mg, 50mg, 100mg and 200mg

Film-coated Tablets but within the leaflet it will be

referred to as Topiramate tablets.

What is in this leaflet:

1

What Topiramate tablets are and what they

are used for

2

What you need to know before you take

Topiramate tablets

3

How to take Topiramate tablets

4

Possible side effects

5

How to store Topiramate tablets

6

Contents of the pack and other information

1

What Topiramate tablets are and what they

are used for

Topiramate belongs to a group of medicines called

antiepileptic medicines. It is used:

alone to treat seizures in adults and children over age 6

with other medicines to treat seizures in adults and

children aged 2 years and above

to prevent migraine headaches in adults.

2

What you need to know before you take

Topiramate tablets

Do not take Topiramate tablets

if you are allergic to topiramate or any of the other

ingredients of this medicine (listed in section 6).

for migraine prevention do not take if you are pregnant

or if you are a woman of childbearing potential unless you

are using effective contraception (see ‘Pregnancy and

breast-feeding’ for further information). You should talk to

your doctor about the best kind of contraception to use

while you are taking Topiramate tablets.

Warnings and precautions

Talk to your doctor or pharmacist before taking

Topiramate tablets if you

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

much calcium in the urine

have other kidney problems, or are having kidney

dialysis

have a history of blood and body fluid abnormality

(metabolic acidosis)

have liver problems

have eye problems, especially glaucoma

have a growth problem

are on a high fat diet (ketogenic diet)

are taking Topiramate tablets to treat epilepsy and you

are pregnant or a woman of childbearing potential

(see section ‘Pregnancy and breast-feeding’ for further

information).

If you are not sure if any of the above applies to you, talk to

your doctor or pharmacist before

using Topiramate tablets.

It is important that you do not stop taking your medicine

without first consulting your doctor.

You should also talk to your doctor before taking any other

medicine containing topiramate that is given to you as an

alternative to Topiramate tablets.

You may experience weight loss while taking Topiramate

tablets. Therefore, your weight should be checked regularly

when using this medicine. If you are losing too much

weight or if a child using this medicine is not gaining

enough weight, you should consult your doctor.

You should drink plenty of fluids while taking Topiramate

tablets, especially prior to and during activities such as

exercise or being exposed to warm temperatures, as this

may reduce the risk of heat-related side effects.

A small number of people being treated with anti-epileptic

medicines such as Topiramate tablets have had thoughts

of harming or killing themselves. If at any time you have

these thoughts, immediately contact your doctor.

Topiramate tablets may in rare cases cause high levels of

ammonia in the blood (seen in blood tests) which can lead

to a change in brain function, especially if you are also

taking a medicine called valproic acid or sodium valproate.

Since this may be a severe condition, tell your doctor

immediately if the following symptoms occur (see also

section 4 ‘Possible side effects’):

difficulty thinking, remembering information, or solving

problems

being less alert or aware

feeling very sleepy with low energy

At higher doses of Topiramate tablets, the risk of

developing these symptoms may increase.

Other medicines and Topiramate tablets

Tell your doctor or pharmacist if you are taking, have

recently taken or might take any other medicines.

Topiramate and certain other medicines can affect

each other. Sometimes the dose of some of your other

medicines or Topiramate tablets will have to be adjusted.

Especially, tell your doctor or pharmacist if you are taking:

other medicines that impair or decrease your thinking,

concentration, or muscle coordination (e.g. central

nervous system depressant medicines such as muscle

relaxants and sedatives)

birth control pills. Topiramate may make these pills

less effective. You should talk to your doctor about the

best kind of contraception to use while you are taking

Topiramate tablets. If your menstrual bleeding changes,

you have breakthrough bleeding or spotting, tell your

doctor

other antiepileptic medicines (e.g. carbamazepine or

phenytoin, which can reduce the effect of topiramate)

risperidone, lithium, amitriptyline, venlafaxine,

moclobamide, imipramine, St John’s Wort (for

depression)

warfarin (used to thin the blood)

hydrochlorothiazide, propranolol, diltiazem (for angina

and high blood pressure)

metformin, pioglitazone, glibenclamide (antidiabetic

medicines)

flunarazine (for migraines)

digoxin (for heart problems)

haloperidol (for mental health problems)

proguanil (for malaria)

omeprazole (for stomach acid).

Topiramate tablets with food, drink and alcohol

You can take Topiramate tablets with or without food. To

prevent kidney stones whilst being treated with Topiramate

tablets, drink plenty of fluids during the day. You should

avoid drinking alcohol when taking Topiramate tablets.

Pregnancy and breast-feeding

Pregnancy

Migraine prevention:

Topiramate tablets can harm an unborn baby. You must

not take Topiramate tablets if you are pregnant. You must

not take Topiramate tablets for migraine prevention if you

are a woman of childbearing potential unless you are using

effective contraception. Talk to your doctor about the best

kind of contraception and whether Topiramate tablets

are suitable for you. Before the start of treatment with

Topiramate tablets, a pregnancy test should be performed.

Treatment of epilepsy:

If you are a woman of childbearing potential you should

talk to your doctor about other possible treatments instead

of Topiramate tablets. If the decision is made to take

Topiramate tablets, you should use effective contraception.

Talk to your doctor about the best kind of contraception

to use while you are taking Topiramate tablets. Before the

start of treatment with Topiramate tablets a pregnancy test

should be performed.

Talk to your doctor if you wish to become pregnant. As

with other antiepileptic medicines, there is a risk of harm

to the unborn child if Topiramate tablets is used during

pregnancy. Make sure you are very clear about the risks

and the benefits of taking Topiramate tablets for epilepsy

during pregnancy.

If you take Topiramate tablets during pregnancy, your

baby has a higher risk for birth defects, particularly, cleft

lip (split in the top lip) and cleft palate (split in the roof of

the mouth). Newborn boys may also have a malformation

of the penis (hypospadia). These defects can develop

early in pregnancy, even before you know you are

pregnant.

If you take Topiramate tablets during pregnancy, your

baby may be smaller than expected at birth. Talk to

your doctor if you have questions about this risk during

pregnancy.

There may be other medicines to treat your condition

that have a lower risk of birth defects.

Tell your doctor straight away if you become pregnant

while taking Topiramate tablets. You and your doctor

should decide if you will continue to take Topiramate

tablets while you are pregnant.

Breast-feeding

The active substance in Topiramate tablets (topiramate)

passes into human milk. Effects have been seen in

breastfed babies of treated mothers, including diarrhoea,

feeling sleepy, feeling irritable, and poor weight gain.

Therefore, your doctor will discuss with you whether you

abstain from breast-feeding or whether to abstain from

treatment with Topiramate tablets. Your doctor will take

into account the importance of the medicine to the mother

and the risk for the baby.

Mothers who breastfeed while taking Topiramate tablets

must tell the doctor as soon as possible if the baby

experiences anything unusual.

Driving and using machines

Dizziness, tiredness and vision problems may occur whilst

taking Topiramate tablets. Do not drive or use any tools or

machines without talking to your doctor first.

Topiramate tablets contain lecithin (soya oil)

Topiramate 50mg, 100mg and 200mg tablets contain

lecithin (soya oil). If you are allergic to peanuts or soya, do

not use this medicinal product.

This medicine contains less than 1 mmol sodium

(23mg)

per film-coated tablet, that is to say

essentially ‘sodium-free’.

3

How to take Topiramate tablets

Always take this medicine exactly as your doctor has told

you. Check with your doctor or pharmacist if you are not

sure.

Your doctor will usually start you on a low dose and slowly

increase your dose until the best dose is found.

The recommended dose is

If you take Topiramate tablets only for epilepsy

Adults – starting dose of 25mg at night. The dose will

be slowly increased to a maintenance dose, usually 100-

200mg a day in 2 divided doses. Maximum dose of 500mg

a day in 2 divided doses.

Children over 6 years of age – starting dose of 0.5-1mg

per kg of body weight at night increasing slowly to a

maintenance dose, usually 100mg a day.

If you take Topiramate tablets with another epilepsy

medicine

Adults – starting dose of 25-50mg at night. The dose will

be slowly increased to a maintenance dose, usually 200-

400mg a day in 2 divided doses.

Children over 2 years of age – starting dose of 1-3mg

per kg of body weight at night increasing slowly to a

maintenance dose, usually 5-9mg per kg of body weight a

day in 2 divided doses.

Prevention of migraines

Adults – starting dose of 25mg at night. The dose will be

slowly increased to a maintenance dose of 100mg a day

in 2 divided doses.

Children – Not recommended for use in children.

Swallow whole. Do not chew. Take with or without food.

To prevent kidney stones while taking Topiramate tablets,

drink plenty of fluids during the day.

If you take more Topiramate tablets than you

should

See a doctor right away. Take the medicine pack with you.

Signs and symptoms of overdose may include: feeling

sleepy or tired, abnormal body movements, problems

standing and walking, feeling dizzy due to low blood

pressure, fits, double or blurred vision, changes in thinking

and alertness, loss of consciousness, speech problems,

changes in mood or behaviour (including anger or

depression), stomach pain.

Overdose can happen if you are taking other medicines

together with Topiramate tablets.

If you forget to take Topiramate tablets

If you forget to take a dose, take it as soon as you

remember it. However, if it is almost time for your next

dose, skip the missed dose and continue as usual. If you

miss two or more doses, contact your doctor. Do not take a

double dose to make up for a forgotten dose.

If you stop taking Topiramate tablets

Do not stop taking this medicine, even if you feel better,

unless your doctor tells you to as your symptoms may

return. If your doctor decides to stop this medication, your

dose may be decreased gradually over a few days.

If you have any further questions on the use of this

medicine, ask your doctor or pharmacist.

Package leaflet: Information for the user

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Topiramate All strengths Film-coated Tablets PIL - UK

Black

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Accord Healthcare Ltd, North Harrow, HA1 4HF, UK

4

Possible side effects

Like all medicines, this medicine can cause side effects,

although not everybody gets them.

Tell your doctor, or seek medical attention immediately

if you have the following side effects:

Very common (may affect more than 1 in 10 people)

Depression (new or worse).

Common (may affect up to 1 in 10 people)

Allergic reaction (such as skin rash, redness, itching, facial

swelling, hives)

Seizures (fits)

Anxiety, irritability, changes in mood, confusion,

disorientation

Problems with concentration, slowness of thinking, loss

of memory, problems with memory (new onset, sudden

change or increased severity)

Kidney stone, frequent or painful urination.

Uncommon (may affect up to 1 in 100 people)

Increased acid level in the blood (may cause troubled

breathing including shortness of breath, loss of appetite,

nausea, vomiting, excessive tiredness, and fast or uneven

heart beats)

Decreased or loss of sweating (particularly in young

children who are exposed to high temperatures)

Having thoughts of serious self-harm, trying to cause

serious self-harm

Loss of part of the field of vision.

Pancreatitis (inflammation of the pancreas)

Rare (may affect up to 1 in 1,000 people)

Glaucoma – blockage of fluid in eye causing increased

pressure in the eye, pain, or decreased vision

Stevens-Johnson syndrome, a potentially life-threatening

condition that may present with sores in multiple

mucosal sites (such as the mouth, nose, and eyes), a skin

rash, and blistering

Difficulty thinking, remembering information, or solving

problems, being less alert or aware, feeling very sleepy

with low energy – these symptoms may be a sign of a

high level of ammonia in the blood (hyperammonemia),

which can lead to a change in brain function

(hyperammonemic encephalopathy).

Not known (frequency cannot be estimated from the

available data)

Maculopathy is a disease of the macula, the small spot in

the retina where vision is keenest. You should call your

doctor if you notice a change or decrease in your vision.

Toxic epidermal necrolysis, a life-threatening condition

related to, yet more severe than, Stevens-Johnson

syndrome, characterised by widespread blistering and

sloughing of the outer layers of the skin (see rare side

effects).

Inflammation of the eye (uveitis) with symptoms such as

eye redness, pain, sensitivity to light, runny eyes, seeing

small dots or getting blurred vision.

Other side effects include the following, if they get

serious, please tell your doctor or pharmacist:

Very common (may affect more than 1 in 10 people)

Stuffy, runny nose or sore throat

Tingling, pain and/or numbness of various body parts

Sleepiness, tiredness, dizziness, nausea, diarrhoea,

weight loss.

Common (may affect up to 1 in 10 people)

Anaemia (low blood count)

Loss of appetite, decreased appetite

Aggression, agitation, anger, abnormal behaviour

Difficulty falling or staying asleep

Problems with speech or speech disorder, slurred speech

Clumsiness or lack of coordination, feeling of

unsteadiness when walking

Decreased ability to complete routine tasks

Decreased, loss of, or no sense of taste

Involuntary trembling or shaking; rapid, uncontrollable

movements of the eyes

Visual disturbance, 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 bleeds

Fever, not feeling well, weakness

Vomiting, constipation, abdominal pain or discomfort,

indigestion, stomach or intestinal infection

Dry mouth

Hair loss

Itching

Joint pain or swelling, muscle spasms or twitching,

muscle aches or weakness, chest pain

Weight gain.

Uncommon (may affect up to 1 in 100 people)

Decrease in platelets (blood cells that help stop

bleeding), decrease in white blood cells that help to

protect you against infection, decrease in potassium level

in the blood

Increase in liver enzymes, increase in eosinophils (a type

of white blood cell) in the blood

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)

Showing and/or feeling no emotion, unusual

suspiciousness, panic attack

Problems with reading, speech disorder, problems with

handwriting

Restlessness, hyperactivity

Slowed thinking, decreased wakefulness or alertness

Reduced or slow body movements, involuntary abnormal

or repetitive muscle movements

Fainting

Abnormal sense of touch; impaired sense of touch

Impaired, distorted, or no sense of smell

Unusual feeling or sensation that may precede a

migraine or a certain type of seizure

Dry eye, sensitivity of the eyes to light, eyelid twitching,

watery eyes

Decreased or loss of hearing, loss of hearing in one ear

Slow or irregular heartbeat, feeling your heart beating in

your chest

Low blood pressure, low blood pressure upon standing

(consequently, some people taking Topiramate tablets

may feel faint, dizzy, or may pass out when they stand up

or sit up suddenly)

Flushing, feeling warm

Excessive passing of gas or wind, heartburn, abdominal

fullness or bloating

Bleeding gums, increased saliva, drooling, breath odour

Excessive intake of fluids, thirst

Skin discolouration

Muscle stiffness, pain in side

Blood in urine, incontinence (lack of control) of urine,

urgent desire to urinate, flank or kidney pain

Difficulty getting or keeping an erection, sexual

dysfunction

Flu-like symptoms

Cold fingers and toes

Feeling drunk

Learning disability.

Rare (may affect up to 1 in 1,000 people)

Abnormally elevated mood

Loss of consciousness

Blindness in one eye, temporary blindness, night

blindness

Lazy eye

Swelling in and around the eyes

Numbness, tingling and colour change (white, blue then

red) in fingers and toes when exposed to the cold

Inflammation of the liver, liver failure

Abnormal skin odour

Discomfort in your arms or legs

Kidney disorder.

Children and adolescents

The side effects in children are generally similar to those

seen in adults, but the following side effects may be more

common in children than adults:

Problems with concentration, increased acid level in the

blood, having thoughts of serious self-harm, tiredness,

decreased or increased appetite, aggression, abnormal

behaviour, difficulty falling or staying asleep, feeling of

unsteadiness when walking, not feeling well, decrease in

potassium level in the blood, showing and/or feeling no

emotion, watery eyes, slow or irregular heartbeat

Other side effects that may occur in children are:

Common (may affect up to 1 in 10 people)

Sensation of spinning (vertigo), vomiting, fever.

Uncommon (may affect up to 1 in 100 people)

Increase in eosinophils (a type of white blood cell) in the

blood, hyperactivity, feeling warm, learning disability.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist

or nurse. This includes any possible side effects not listed in

this leaflet. You can also report side effects directly via the

Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

search for MHRA Yellow Card in the Google Play or Apple

App Store.

By reporting side effects you can help provide more

information on the safety of this medicine.

5

How to store Topiramate tablets

Keep out of the sight and reach of children.

Do not store above 25°C.

Do not use after the expiry date which is stated on the

label. The expiry date refers to the last day of that month.

Topiramate tablets which are supplied in bottles must be

used within 60 days of opening. There is a space provided

on the bottle for you to write the date that you opened

them.

Do not throw away any medicines via wastewater or

household waste. Ask your pharmacist how to throw away

medicines you no longer use. These measures will help

protect the environment.

6

Contents of the pack and other information

What Topiramate tablets contain

The active substance is topiramate. Each tablet contains

either 25mg, 50mg, 100mg or 200mg of topiramate.

The other ingredients are mannitol, starch (pregelatinised),

cellulose (microcrystalline), croscarmellose sodium, silica

(colloidal anhydrous), magnesium stearate, polyvinyl

alcohol, titanium dioxide, macrogols (macrogol 3350), talc.

The following ingredients are also in the:

50mg and 100mg tablets - lecithin (Soya) (E322) and iron

oxide yellow (E172).

200mg tablets - lecithin (Soya) (E322) and iron oxide red

(E172).

What Topiramate tablets look like and contents of

the pack

25mg tablets are round, biconvex, white tablets

50mg tablets are round, biconvex, light yellow tablets

100mg tablets are round, biconvex, yellow tablets

200mg tablets are oval, biconvex, salmon-coloured tablets

Pack size of 60 tablets.

Marketing Authorisation Holder

Accord Healthcare Limited

Sage House

319 Pinner Road

North Harrow

Middlesex

HA1 4HF

United Kingdom

Manufacturer

Balkanpharma-Dupnitsa AD

3 Samokovsko Schosse Str.

Dupnitsa 2600

Bulgaria

This leaflet was last revised in April 2020.

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Topiramate All strengths Film-coated Tablets PIL - UK

Black

BBBA8018

C.Grant

22/04/20

27/04/20

C.Grant

190x600

Teva Bulgaria Dupnitsa

22/04/20

24/04/20

03

Version 7

12.02.2020

German GTIN 14

(incorporating PZN):

Cartons and label leaflets only

(labels only when specified)

1

NAME OF THE MEDICINAL PRODUCT

Topiramate Torrent 100mg Film-Coated Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 100mg of Topiramate.

Excipient(s) with known effect: Also contains 0.53mg soya lecithin (E322).

For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM

Film-Coated Tablets

Topiramate 100mg Film-Coated Tablets are yellow, round, biconvex tablets with

10mm diameter and engraved with the marking “V4”.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

Monotherapy in adults, adolescents and children over 6 years of age with partial

seizures with or without secondary generalised seizures, and primary generalised

tonic-clonic seizures.

Adjunctive therapy in children aged 2 years and above, adolescents and adults with

partial onset seizures with or without secondary generalization or primary generalized

tonic-clonic seizures and for the treatment of seizures associated with Lennox-Gastaut

syndrome.

Topiramate is indicated in adults for the prophylaxis of migraine headache after

careful

evaluation

possible

alternative

treatment

options.

Topiramate

intended for acute treatment.

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 topiramate. On rare occasions, the addition of topiramate to phenytoin may

require an adjustment of the dose of phenytoin to achieve optimal clinical outcome.

Addition or withdrawal of phenytoin and carbamazepine to adjunctive therapy with

topiramate may require adjustment of the dose of topiramate.

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

(AEDs)

including

topiramate

should

gradually

withdrawn

minimize

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

adults

receiving

topiramate

doses

100 mg/day

migraine

prophylaxis. In paediatric clinical trials, topiramate was gradually withdrawn over a

2-8 week period.

Monotherapy epilepsy

General

When concomitant 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 medicinal products are withdrawn, topiramate levels will

increase. A decrease in topiramate 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.

recommended

initial

target

dose

topiramate

monotherapy

adults

100 mg/day to 200 mg/day in 2 divided doses. The maximum recommended daily

dose is 500 mg/day in 2 divided doses. 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.

Paediatric population (children over 6 years of age)

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

children over 6 years of age 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

over 6 years of age is 100 mg/day depending on clinical response, (this is about

2.0 mg/kg/day in children 6-16 years).

Adjunctive

therapy

epilepsy

(partial

onset

seizures

with

without

secondary

generalization, primary generalized tonic-clonic seizures, or seizures associated with

Lennox-Gastaut syndrome)

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 mg/day and taken in

two divided doses. Some patients may achieve efficacy with once-a-day dosing.

In clinical trials as adjunctive therapy, 200 mg was the lowest effective dose. The

usual daily dose is 200-400 mg in two divided doses.

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

absence of underlying renal disease (see section 4.4).

Paediatric population (children aged 2 years and above)

recommended

total

daily

dose

topiramate

adjunctive

therapy

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.

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

Migraine

Adults

recommended

total

daily

dose

topiramate

prophylaxis

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

Paediatric population

Topiramate is not recommended for treatment or prevention of migraine in children

due to insufficient data on safety and efficacy.

General dosing recommendations for topiramate in special patient populations

Renal impairment

In patients with impaired renal function (CL

60 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

each

dose.

Half

usual

starting

maintenance

dose

recommended (see section 5.2).

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

haemodialysis, a supplemental dose of topiramate 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.

supplemental

dose

differ

based

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

Hepatic impairment

patients

with

moderate

severe

hepatic

impairment

topiramate

should

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

Topiramate is available in film-coated tablets and it is recommended that the film-

coated tablets not be broken. Topiramate can be taken without regard to meals.

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 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.

North

American

Antiepileptic

Drug

pregnancy

registry

data

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%).

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

performed

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 rise in body temperature may occur

especially in young children exposed to high ambient temperature.

Mood disturbances/depression

increased

incidence

mood

disturbances

depression

been

observed during topiramate treatment.

Suicide/suicide ideation

Suicidal ideation and behaviour have been reported in patients treated with

anti-epileptic agents in several indications. A meta-analysis of randomised

placebo-controlled trials of AEDs drugs 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).

Patients therefore should be monitored for signs of suicidal ideation and

behaviour

appropriate

treatment

should

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

increased

risk

renal

stone

formation

associated

signs

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. 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 (CLCR

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

hepatically-impaired

patients,

topiramate

should

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

been

reported

patients

receiving

topiramate.

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

initiating topiramate therapy. In contrast to primary narrow angle glaucoma,

which

rare

under

40 years

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 judgment of the treating physician, and appropriate measures to reduce

intraocular

pressure.

These

measures

generally

result

decrease

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

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 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

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,

certain

medicinal

products)

additive

bicarbonate

lowering effects of topiramate.

Chronic metabolic acidosis increases the risk of renal stone formation 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

underlying

conditions,

appropriate

evaluation

including

measurement of 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

metabolic

acidosis,

measurement

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

used

with

caution

patients

with

conditions

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 anti-epileptic treatment.

There have been reports in the literature of impairment of cognitive function in

adults

topiramate

therapy

which

required

reduction

dosage

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

adjunctive

therapy,

recommended to consider hyperammonemic encephalopathy and measuring

ammonia levels.

Nutritional supplementation

Some

patients

experience

weight

loss

whilst

treatment

with

topiramate. It is recommended that patients on topiramate treatment should be

monitored for weight loss. A dietary supplement or increased food intake may

be considered if the patient is losing weight while on topiramate.

4.5

Interaction with other medicinal products and other forms of interaction

Effects of topiramate on other antiepileptic medicinal products

The addition of topiramate to other antiepileptic drugs (phenytoin, carbamazepine,

valproic acid, phenobarbital, primidone) has no effect on their steady-state plasma

concentrations, except in the occasional patient, where the addition of topiramate 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 topiramate

Phenytoin and carbamazepine decrease the plasma concentration of topimarate. 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

topiramate.

results

these

interactions

summarized below:

AED Co-administered

AED Concentration

Topiramate

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

NS = Not studied

AED = antiepileptic drug

Other medicinal product interactions

Digoxin

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

decreased

12 %

concomitant

administration

topiramate.

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.

Central Nervous System (CNS) depressants

Concomitant administration of topiramate and alcohol or other CNS depressant

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

topiramate

used

concomitantly

with

alcohol

other

depressant

medicinal products.

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

g ethinyl estradiol (EE), topiramate given in the absence of other

Public Assessment Report

Decentralised Procedure

Topiramate Accord 25 mg film-coated Tablets

Topiramate Accord 50 mg film-coated Tablets

Topiramate Accord 100 mg film-coated Tablets

Topiramate Accord 200 mg film-coated Tablets

(topiramate)

UK/H/1438/001-004/DC

UK licence numbers: PL 20075/0145-0148

Accord Healthcare Limited

Topiramate Accord 25mg, 50 mg, 100 mg & 200 mg film-coated tablets

UK/H/1438/001-004/DC

2

Lay Summary

Topiramate Accord 25 mg film-coated Tablets

Topiramate Accord 50 mg film-coated Tablets

Topiramate Accord 100 mg film-coated Tablets

Topiramate Accord 200 mg film-coated Tablets

(topiramate)

This is a summary of the Public Assessment Report (PAR) for Topiramate Accord

25 mg, 50 mg, 100 mg and 200 mg film-coated tablets (PL 20075/0145-0148).

Topiramate Accord 25 mg, 50 mg, 100 mg and 200 mg film-coated tablets will be

referred to as Topiramate tablets throughout this report, for ease of reading. It explains

how Topiramate tablets were assessed and their authorisation recommended, as well

as their conditions of use. It is not intended to provide practical advice on how to use

Topiramate tablets.

For practical information about using Topiramate tablets, patients should read the

package leaflet or contact their doctor or pharmacist.

What are Topiramate tablets and what are they used for?

Topiramate tablets are ‘generic medicines’. This means that they are similar to

‘reference medicines’, already authorised in the European Union (EU) called

Topamax 25mg, 50mg, 100mg, and 200mg film-coated tablets.

Topiramate tablets are used:

alone, to treat seizures in adults and children over age 6

with other medicines to treat seizures in adults and children over age 2

to prevent migraine headaches in adults

How do Topiramate tablets work?

Topiramate tablets contain the active substance topiramate, which belongs to a group

of medicines called “antiepileptic medicines”. The exact mechanism by which

topiramate treats seizures and prevents migraine headaches is not fully understood.

How are Topiramate tablets

used?

Topiramate tablets should be swallowed whole and can be taken before, during or

after meals. Patients are advised to drink plenty of fluids during the day to prevent

kidney stones.

The dose of Topiramate tablets should be taken as prescribed. The prescribing doctor

will usually start the patient on a low dose of Topiramate tablets and slowly increase

the dose until the most suitable dose for the patient is found.

Please read Section 3 of the package leaflet for further information.

Topiramate 25 mg, 50 mg, 100 mg and 200 mg tablets can only be obtained with a

prescription.

Topiramate Accord 25mg, 50 mg, 100 mg & 200 mg film-coated tablets

UK/H/1438/001-004/DC

3

What benefits of Topiramate tablets have been shown in studies?

Because Topiramate 25 mg, 50 mg, 100 mg and 200 mg tablets are generic medicines,

studies in patients have been limited to tests to determine that the highest strength

medicine, Topiramate 200 mg tablets, is bioequivalent to the reference medicine,

Topamax 200 mg film-coated tablets. Two medicines are bioequivalent when they

produce the same levels of the active substance in the body.

It was concluded, from these tests, that Topiramate 25 mg, 50 mg, 100 mg and

200 mg tablets are comparable to the equivalent strengths of the reference medicines

Topamax 25 mg, 50 mg and 100 mg film-coated tablets.

What are the possible side effects from Topiramate tablets?

Because Topiramate tablets are generic medicines, and are bioequivalent to the

reference medicines, their benefits and possible side effects are taken as being the

same as the reference medicines.

For information about side effects that may occur with using Topiranate tablets,

please refer to the package leaflet or the Summaries of Product Characteristics

(SmPCs) available on the Medicines and Healthcare products Regulatory Agency

(MHRA) website.

Why are Topiramate tablets approved?

It was concluded that, in accordance with EU requirements, Topiramate 25 mg,

50 mg, 100 mg and 200 mg tablets have been shown to have comparable quality and

to be bioequivalent to Topamax 25 mg, 50 mg, 100 mg and 200 mg film-coated

tablets, respectively. The MHRA, therefore, decided that, as for Topamax tablets, the

benefits are greater than the risks and recommended that Topiramate tablets can be

approved for use.

What measures are being taken to ensure the safe and effective use of

Topiramate tablets?

A Risk Management Plan (RMP) has been developed to ensure that Topiramate

tablets are used as safely as possible. Based on this plan, safety information has been

included in the SmPCs and the package leaflet for Topiramate tablets, including the

appropriate precautions to be followed by healthcare professionals and patients.

Known side effects are continuously monitored. Furthermore, new safety signals

reported by patients and healthcare professionals will be monitored and reviewed

continuously as well.

Other information about Topiramate tablets

Bulgaria, Germany, Italy, Lithuania, the Netherlands, Poland, Portugal, Spain and the

UK agreed to grant Marketing Authorisations for Topiramate tablets on 20 September

2009.

Marketing Authorisations were granted in the UK to Accord Healthcare Limited on

20 October 2009.

The Marketing Authorisations for Topiramate tablets have subsequently been

withdrawn in Germany and Poland.

Topiramate Accord 25mg, 50 mg, 100 mg & 200 mg film-coated tablets

UK/H/1438/001-004/DC

4

The full PAR for Topiramate tablets follows this summary.

For more information about taking Topiramate tablets, read the package leaflet, or

contact your doctor or pharmacist.

This summary was last updated in November 2015.

Topiramate Accord 25mg, 50 mg, 100 mg & 200 mg film-coated tablets

UK/H/1438/001-004/DC

5

Table of Contents

Introduction

Page 6

Quality aspects

Page 8

Non-clinical aspects

Page 11

Clinical aspects

Page 11

User consultation

Page 14

Overall conclusion, benefit/risk assessment and

recommendation

Page 14

Annex - Table of content of the PAR update for

MRP and DCP

Page 25

Topiramate Accord 25mg, 50 mg, 100 mg & 200 mg film-coated tablets

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I

Introduction

Based on the review of the data on quality, safety and efficacy, the MHRA granted

Accord Healthcare Limited Marketing Authorisations for the medicinal products

Topiramate 25 mg, 50 mg, 100 mg, and 200 mg film-coated tablets

(PL 20075/0145-0148, UK/H/1438/001-004/DC) on 20

October 2009. The products

are prescription-only medicines (POMs).

These are abridged applications for Topiramate 25 mg, 50 mg, 100 mg, and 200 mg

film-coated tablets, four strengths of topiramate, submitted under Article 10(1) of

2001/83 EC, as amended. The applications refer to the reference products, Topamax

25mg, 50mg, 100mg, and 200mg film-coated tablets (PL 00242/0301-0304

respectively), authorised to Janssen-Cilag Limited on 18

July 1995. These are the

innovator products. The innovator products have been authorised in the UK for more

than 10 years, so the period of data exclusivity has expired.

Topiramate tablets are indicated as monotherapy in adults, adolescents and children

over 6 years of age with partial seizures with or without secondary generalised

seizures, and primary generalised tonic-clonic seizures. The tablets are also indicated

as adjunctive therapy in children aged 2 years and above, adolescents and adults with

partial onset seizures with or without secondary generalization or primary generalized

tonic-clonic seizures, and for the treatment of seizures associated with Lennox-

Gastaut syndrome. Topiramate film-coated tablets are also indicated in adults for the

prophylaxis of migraine headache after careful evaluation of possible alternative

treatment options. Topiramate is not intended for acute treatment. Therapy is initiated

at a low dose followed by gradual titration to an effective dose. Dose and titration rate

should be guided by clinical response.

Topiramate belongs to the pharmacotherapeutic group, anti-epileptics (ATC code

N03A X11) and is classified as a sulphamate-substituted monosaccharide. Three

pharmacological properties of topiramate have been identified that may contribute to

its anticonvulsant activity. Topiramate reduces the frequency at which action

potentials are generated when neurones are subjected to sustained depolarisation,

indicative of state-dependent blockade of voltage-sensitive sodium channels.

Topiramate enhances the activity of GABA at some types of GABA receptors.

Topiramate weakly antagonises the excitatory activity of the kainate/AMPA subtype

of glutamate receptor, but has no apparent effect on the activity of N-methyl-D-

aspartate (NMDA) at the NMDA receptor subtype. In addition, topiramate inhibits

some isoenzymes of carbonic anhydrase. This effect is not thought to be a major

component of the antiepileptic activity of topiramate.

The pharmacokinetic profile of topiramate compared to other antiepileptic drugs

shows a long plasma half-life, linear pharmacokinetics, predominantly renal

clearance, absence of significant protein binding, and lack of clinically relevant active

metabolites.

No new non-clinical or clinical efficacy studies were conducted for these applications,

which is acceptable given that the applications were for generic versions of products

that have been licensed for over 10 years.

Topiramate Accord 25mg, 50 mg, 100 mg & 200 mg film-coated tablets

UK/H/1438/001-004/DC

7

The applications are supported by the bioequivalence study presented by the applicant

comparing the pharmacokinetic profile of the test product, Topiramate 200mg

film-coated tablets, to that of the reference product, Topamax 200mg film-coated

tablets (PL 00242/0304, Janssen-Cilag Limited). The bioequivalence study was

carried out in accordance with Good Clinical Practice (GCP).

The RMS has been assured that acceptable standards of Good Manufacturing Practice

(GMP) are in place for these product types at all sites responsible for the manufacture

and assembly of these products. Evidence of compliance with GMP has been provided

for the named manufacturing and assembly sites. For manufacturing sites within the

Community, the RMS has accepted copies of current manufacturer authorisations

issued by inspection services of the competent authorities as certification that

acceptable standards of GMP are in place at those sites.

For manufacturing sites outside the community, the RMS has accepted copies of

current GMP Certificates or satisfactory inspection summary reports, ‘close-out

letters’ or ‘exchange of information’ issued by the inspection services of the

competent authorities (or those countries with which the EEA has a Mutual

Recognition Agreement for their own territories) as certification that acceptable

standards of GMP are in place at those non-Community sites.

The RMS considers that the pharmacovigilance system as described by the applicant

fulfils the requirements and provides adequate evidence that the applicant has the

services of a qualified person responsible for pharmacovigilance and has the

necessary means for the notification of any adverse reaction suspected of occurring

either in the Community or in a third country.

The Marketing Authorisation holder has provided adequate justification for not

submitting an Environmental Risk Assessment (ERA). These were applications for

generic products and there is no reason to conclude that marketing of these products

will change the overall use pattern of the existing market. The Marketing

Authorisation holder has provided adequate justification for not submitting a Risk

Management Plan (RMP).

Topiramate Accord 25mg, 50 mg, 100 mg & 200 mg film-coated tablets

UK/H/1438/001-004/DC

8

II

Quality aspects

II.1

Introduction

The drug products are presented as round, biconvex film-coated tablets with bevelled

edges, each containing 25 mg, 50 mg, 100 mg, or 200 mg of the active ingredient

topiramate. Full descriptions of the colours and markings of the individual tablets may

be found by referring to the SmPCs / patient information leaflet.

Other ingredients consist of pharmaceutical excipients, namely microcrystalline

cellulose, croscarmellose sodium, pregelatinised starch, lactose monohydrate, and

magnesium stearate making up the tablet core. The film-coating comprises

hypromellose, titanium dioxide (E171), and macrogol 6000 for the 25mg strength

(white) tablets. For the 50mg (light yellow) and 100mg (dark yellow) strength tablets,

the film-coat is made up of Opadry yellow 03F52057 and Opadry yellow 03F52056,

respectively. Both Opadry yellow 03F52057 and Opadry yellow 03F52056 consist of

hypromellose, macrogol 6000, titanium dioxide (E171), and iron oxide yellow (E172).

For the 200mg strength (red) tablets, the film-coat is made up of Opadry pink

03F54045, which consists of hypromellose, macrogol 6000, titanium dioxide (E171),

and iron oxide red (E172). Appropriate justification for the inclusion of each excipient

has been provided.

The finished products are licensed for marketing in aluminium/aluminium foil blister

strips, which are placed with the Patient Information Leaflet (PIL) into cardboard

outer cartons. The tablets are packaged in pack sizes of 10, 14, 20, 28, 30, 50, 56, 60,

100, 120 and 200 film-coated. The tablets are also marketed in high density

polyethylene (HDPE) bottles fitted with a white opaque polypropylene child resistant

closure, supplied in cardboard cartons in pack sizes of 14, 30, 60, 100 and 200

film-coated tablets. The MA Holder has stated that not all pack sizes may be

marketed.

Specifications and Certificates of Analysis for all packaging components used have

been provided. These are satisfactory. All primary product packaging complies with

EU legislation, Directive 2002/72/EC, as amended, and is suitable for contact with

foodstuffs.

II.2

Drug Substance

Topiramate

Nomenclature:

INN:

Topiramate

Chemical name:

- 2,3:4,5-Bis-O-(1-methylethylidene)-ß-D-fructopyranose

sulfamate

- 2,3:4,5-di-O-isopropylidene-ß-D-fructopyranose sulfamate

Structure:

Topiramate Accord 25mg, 50 mg, 100 mg & 200 mg film-coated tablets

UK/H/1438/001-004/DC

9

Molecular formula:

Molecular weight:

339.36 g/mol

CAS No:

97240-79-4

Physical form:

White or off white crystalline powder

Solubility:

Soluble in methanol, acetone, dimethyl formamide, 0.1N

aqueous sodium hydroxide solution and slightly soluble in

water

The active substance, topiramate, is not the subject of a European Pharmacopeia

(Ph. Eur.) monograph.

Synthesis of the active substance from the designated starting materials has been

adequately described and appropriate in-process controls and intermediate

specifications are applied. Satisfactory specifications are in place for all starting

materials and reagents and these are supported by relevant Certificates of Analysis.

Confirmation has been provided that the raw materials, intermediates and auxiliary

agents used in synthesis of the active are not of animal, biological or genetically

modified origin.

An appropriate specification has been provided for the active substance. Analytical

methods have been appropriately validated and are satisfactory for ensuring

compliance with the relevant specifications. Batch analysis data are provided and

comply with the proposed specification. Satisfactory Certificates of Analysis have

been provided for any reference standards used by the active substance manufacturer

during validation studies.

The active substance is stored in appropriate packaging. It is packed in HDPE drums

lined with double polythene bags. Specifications and Certificates of Analysis have

been provided for the packaging materials used. The polyethylene bags in direct

contact with the active substance satisfy Directive 2002/72/EC (as amended), and are

suitable for contact with foodstuffs.

Appropriate stability data have been generated for the active substance stored in

containers representative of the proposed commercial packaging. These data

demonstrate the stability of the active substance and support a retest period of 24

months.

II.3

Medicinal Product

Pharmaceutical development

Details of the pharmaceutical development of the drug products have been supplied

and are satisfactory.

The excipients are all controlled to the requirements of the current European

Pharmacopoeia.

The coating dispersions are not compendial but the individual components comply

with the requirements of the European Pharmacopoeia. Copies of the routine tests and

specifications are provided. Satisfactory Certificates of Analysis have been provided

for all excipients.

Topiramate Accord 25mg, 50 mg, 100 mg & 200 mg film-coated tablets

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10

The magnesium stearate is of vegetable origin. The only excipient used that contains

material of animal or human origin is lactose monohydrate. The applicant has

provided a declaration that milk used in the production of lactose monohydrate is

sourced from healthy animals under the same conditions as that for human

consumption. Appropriate TSE/BSE documentation was provided for lactose

monohydrate.

There were no novel excipients used and no overages.

Comparative dissolution data were provided for each of the four strengths of the

generic topiramate tablets and appropriate reference tablet formulations. The

dissolution profiles were found to be similar.

Comparative impurity data were also provided for the test and appropriate reference

products. The impurity profiles were comparable and all impurities were within the

specification limits.

A bioequivalence study was presented comparing the test product, Topiramate 200mg

film-coated tablets, to the reference product, Topamax 200 mg film-coated tablets

(PL 00242/0304, Janssen-Cilag Limited).

An evaluation of the bioequivalence study is found in the Clinical Aspects section.

Manufacture of the product

A description and flow-chart of the manufacturing method has been provided.

In-process controls are appropriate considering the nature of the product and the

method of manufacture. Process validation studies were conducted on two production

scale batches for each of the strengths.

Finished Product Specification

The finished product specifications include tests and criteria to apply for both release

and end of shelf life testing and are satisfactory; they provide an assurance of the

quality and consistency of the finished products. Acceptance limits have been justified

with respect to conventional pharmaceutical requirements and, where appropriate,

safety. Test methods have been described and have been adequately validated, as

appropriate. Batch data have been provided for two production scale batches of each

of the strengths and they comply with the release specifications. Certificates of

Analysis have been provided for any reference standards used.

Stability of the product

Finished product stability studies have been conducted in accordance with current

guidelines and results were within the proposed specification limits. Based on the

results, a shelf-life of 2 years has been set, which is satisfactory. Storage conditions

are ‘Do not store above 25°C’. Additional instructions of ‘Keep in the original pack in

order to protect from moisture’ and ‘Keep the container tightly closed in order to

protect from moisture’ are applied to the packaging for the blister pack and HDPE

bottle pack respectively.

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II.4

Discussion on chemical and pharmaceutical aspects

The drug products correspond to the current EU definition of a generic medicinal

product because they comply with the criteria of having the same qualitative and

quantitative composition in terms of the active substance and pharmaceutical form.

On this basis, and considering the bioequivalence data provided, the applicant’s claim

that Topiramate 200 mg tablets are a generic medicinal product of Topamax 200 mg

film-coated tablets (PL 00242/0304, Janssen-Cilag Limited) appears justified.

Topiramate demonstrates linear pharmacokinetics over the therapeutic dose range of

100 mg to 400 mg. As the test products, Topiramate 25 mg, 50 mg, 100 mg, and

200 mg tablets, meet the criteria specified in the Note for Guidance on the

investigation of bioavailability and bioequivalence (CPMP/EWP/QWP/1401/98), the

results and conclusions of the bioequivalence study on the 200 mg strength were

extrapolated to the 25 mg, 50 mg, and 100 mg strength tablets.

All pharmaceutical issues have been resolved and the quality grounds for these

applications are considered adequate. Marketing Authorisations were, therefore,

granted.

III

Non-clinical aspects

Specific non-clinical studies have not been performed, which is acceptable for these

applications for generic versions of products that have been licensed for over 10

years. The non-clinical overview provides a satisfactory review of the

pharmacological and toxicological properties of topiramate, which is a widely used

and well-known active substance.

A satisfactory non-clinical overview is provided, and has been prepared by an

appropriately qualified expert. An appropriate CV for the expert has been supplied.

IV

Clinical aspects

IV.1 Introduction

Topiramate tablets are indicated as monotherapy in adults, adolescents and children

over 6 years of age with partial seizures with or without secondary generalised

seizures, and primary generalised tonic-clonic seizures. The tablets are also indicated

as adjunctive therapy in children aged 2 years and above, adolescents and adults with

partial onset seizures with or without secondary generalization or primary generalized

tonic-clonic seizures and for the treatment of seizures associated with Lennox-Gastaut

syndrome. Topiramate tablets are also indicated in adults for the prophylaxis of

migraine headache after careful evaluation of possible alternative treatment options.

Topiramate is not intended for acute treatment. Therapy is initiated at a low dose

followed by gradual titration to an effective dose. Dose and titration rate should be

guided by clinical response.

The indications are consistent with those for the reference products and are

satisfactory.

The posology is consistent with that for the reference products and is satisfactory.

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The clinical pharmacology of topiramate is well known. A satisfactory clinical

overview is provided, and has been prepared by an appropriately qualified expert. An

appropriate CV for the expert has been supplied.

No new clinical toxicology data have been submitted and none are required for these

types of application.

IV.2

Pharmacokinetics

The application is supported by the bioequivalence study presented by the applicant

comparing the pharmacokinetic profiles of Topiramate 200 mg tablets (test) and

Topamax 200 mg film-coated tablets (PL 00242/0304, Janssen-Cilag Limited;

reference). The study was of an appropriate design and was conducted to principles of

Good Clinical Practice (GCP). The use of the 200 mg strength only for the

bioequivalence study has been adequately justified.

This was a randomised, two-treatment, two-period, two sequence, single dose

crossover bioavailability and bioequivalence study conducted in 26 (24 + 2 alternates)

healthy adult male human subjects under fasting conditions. A single dose of the

investigational products was administered orally to each subject in each period. A

satisfactory washout period of 17 days was maintained between the two dosing days

in each group.

Blood samples were taken pre-dose (0.0) and at specified time points up to 144.0

hours after administration of test or reference product. The drug concentration levels

in plasma were determined by a validated LC/MS/MS method.

The primary pharmacokinetic parameters for this study were C

, AUC

, and

0-∞

. Bioequivalence of the test product versus the reference product was

concluded if the 90% CI fell within the acceptance range, 0.80-1.25 (80%-125%), for

log-transformed C

, AUC

, and AUC

0-∞

Twenty-five subjects completed the study and 24 were used in the statistical analysis.

There were no deaths or serious adverse events.

Results:

The summary of the results of the bioequivalence study are tabulated below:

Pharmacokinetic results for a randomised, two-treatment, two-period, single dose

crossover study between the test and reference products. n=24 healthy subjects, dosed

fasted; t=144 hours. Wash-out period: 17 days

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Conclusion on Bioequivalence

The results of the bioequivalence study show that the test product and reference

product are bioequivalent, under fasting conditions, as the confidence intervals for

, AUC

, and AUC

0-∞

fall within the acceptance criteria ranges of 80.00-125.00%

in line with current CHMP guidelines.

Satisfactory justification is provided for a bio-waiver for Topiramate 25 mg, 50 mg,

and 100 mg tablets. Topiramate demonstrates linear pharmacokinetics over the

therapeutic dose range of 100 mg to 400 mg. As Topiramate 25 mg, 50 mg, 100 mg,

and 200 mg tablets meet the criteria specified in the

Note for Guidance on the

investigation of bioavailability and bioequivalence

(CPMP/EWP/QWP/1401/98), the

results and conclusions of the bioequivalence study on the 200 mg strength were

extrapolated to the 25 mg, 50 mg, and 100 mg strength products.

IV.3

Pharmacodynamics

No novel pharmacodynamic data are supplied or required for this application.

IV.4

Clinical efficacy

No new data have been submitted and none are required. Efficacy is reviewed in the

clinical overview. The efficacy of topiramate is well established from its extensive use

in clinical practice.

IV.5

Clinical safety

No new data have been submitted and none are required for applications of this type.

Safety is reviewed in the clinical overview. The safety profile of topiramate is well-

known.

IV.6

Risk Management Plan (RMP)

This application was submitted, and approved, before implementation of the

Pharmacovigilance legislation on 21 July 2012 and, therefore, preceded the

mandatory requirement of an RMP for a new Marketing Authorisation. A suitable

justification for not submitting a Risk Management Plan was provided and this was

considered satisfactory.

The RMS considers that the pharmacovigilance system as described by the applicant

fulfils the requirements and provides adequate evidence that the applicant has the

services of a qualified person responsible for pharmacovigilance and has the

necessary means for the notification of any adverse reaction suspected of occurring

either in the Community or in a third country.

IV.7 Discussion on the clinical aspects

All issues have been adequately addressed by the applicant. The bioequivalence study

was of an appropriate design and demonstrates the bioequivalence of the test

(Topiramate 200 mg tablets, Accord Healthcare Limited) and reference (Topamax 200

mg film-coated tablets; PL 00242/0304, Janssen-Cilag Limited) products within

acceptance limits. Topiramate demonstrates linear pharmacokinetics over the

therapeutic dose range of 100 mg to 400 mg. The results and conclusions of the

bioequivalence study on the 200 mg strength were extrapolated to the 25 mg, 50 mg,

and 100 mg strength products.

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The approved SmPCs are consistent with those for the reference products, and are

acceptable.

The final PIL is in line with the approved SmPCs and is satisfactory.

The labelling is satisfactory.

Sufficient clinical information has been submitted to support these applications.

Marketing Authorisations were, therefore, granted on medical grounds.

V

User consultation

A package leaflet has been submitted to the MHRA along with results of consultations

with target patient groups ("user testing"), in accordance with Article 59 of Council

Directive 2001/83/EC. The results indicate that the package leaflet is well-structured

and organised, easy to understand and written in a comprehensive manner. The test

shows that the patients/users are able to act upon the information that the leaflet

contains.

VI

Overall conclusion, benefit/risk assessment and

recommendation

Quality

The important quality characteristics of Topiramate 25 mg, 50 mg, 100 mg, and

200 mg tablets are well-defined and controlled. The specifications and batch

analytical results indicate consistency from batch to batch. There are no outstanding

quality issues that would have a negative impact on the benefit/risk balance.

Non-clinical

No new non-clinical data were submitted and none are required for applications of

this type.

Efficacy

Bioequivalence has been demonstrated between the applicant’s Topiramate 200 mg

tablets, and the reference product, Topamax 200 mg film-coated tablets (PL

00242/0304, Janssen-Cilag Limited).

Topiramate demonstrates linear pharmacokinetics over the therapeutic dose range of

100 mg to 400 mg. As Topiramate 25 mg, 50 mg, 100 mg, and 200 mg tablets were

deemed to meet the criteria specified in the Note for Guidance on the investigation of

bioavailability and bioequivalence (CPMP/EWP/QWP/1401/98), the results and

conclusions of the bioequivalence study on the 200 mg strength were extrapolated to

the 25 mg, 50 mg, and 100 mg strength products, and omission of further

bioequivalence studies on the other strengths can be accepted.

No new or unexpected safety concerns arise from these applications.

Topiramate Accord 25mg, 50 mg, 100 mg & 200 mg film-coated tablets

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Product literature

The SmPCs, PIL and labelling are satisfactory and consistent with those for the

reference products.

The approved labelling artwork complies with statutory requirements. In line with

current legislation, the name of the product in Braille appears on the outer packaging

and sufficient space has been included for a standard UK pharmacy dispensing label.

Benefit/risk assessment

The quality of the products is acceptable and no new non-clinical or clinical safety

concerns have been identified. The bioequivalence study and its conclusions support

the claim that the applicant’s products and their respective reference products are

interchangeable. Extensive clinical experience with topiramate is considered to have

demonstrated the therapeutic value of the active substance. The benefit/risk is,

therefore, considered to be positive.

The Summaries of Product Characteristics (SmPCs), package leaflet text and labelling

are satisfactory, in line with current guidelines and consistent with the cross-reference

products. In accordance with Directive 2012/84/EU, as amended, the current approved

UK versions of the SmPCs and package leaflet text for these products are available on

the Medicines and Healthcare products Regulatory Agency website.

The currently approved labelling text is listed below:

Topiramate Accord 25mg, 50 mg, 100 mg & 200 mg film-coated tablets

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Topiramate Accord 25mg, 50 mg, 100 mg & 200 mg film-coated tablets

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Topiramate Accord 25mg, 50 mg, 100 mg & 200 mg film-coated tablets

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Topiramate Accord 25mg, 50 mg, 100 mg & 200 mg film-coated tablets

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19

Topiramate Accord 25mg, 50 mg, 100 mg & 200 mg film-coated tablets

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20

Topiramate Accord 25mg, 50 mg, 100 mg & 200 mg film-coated tablets

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21

Topiramate Accord 25mg, 50 mg, 100 mg & 200 mg film-coated tablets

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22

Topiramate Accord 25mg, 50 mg, 100 mg & 200 mg film-coated tablets

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Topiramate Accord 25mg, 50 mg, 100 mg & 200 mg film-coated tablets

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24

Topiramate Accord 25mg, 50 mg, 100 mg & 200 mg film-coated tablets

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Annex - Table of content of the PAR update for MRP and DCP

Steps taken after the initial procedure with an influence on the Public Assessment Report (Type II variations, PSURs, commitments)

Scope

Procedure number

Product

information

affected

Date of

start of the

procedure

Date of end of

procedure

Approval/

non

approval

Assessment

report

attached

Y/N

(version)

To update section 4.6 (pregnancy and lactation) and

4.7 (driving and machines) of the SmPC in line

with the reference product, Topamax 25 mg, 50 mg,

100 mg, 200 mg tablets. Consequential updates are

made to the PIL.

UK/H/1438/001-004

/IB/001/G

11 April

2011

28 October

2011

Approval

To update SmPC and PIL of Topiramate

25/50/100/200 mg Tablets following publication of

Paediatric Assessment Report for a EU

WorkSharing (WS) procedure on 11 March 2011.

UK/H/1438/001-

004/1B/003

18 August

2011

27 October

2011

Approved

To update the section 1 (name of the medicinal

product) of the SmPC in line with the advice to

include the MAH name, which was issued by the

Commission on Human Medicines (CHM) about

prescribing and dispensing of Anti-epileptic Drug

(AED) products.

National Type IB

Variation

December

2013

12 February

2014

Approved

Y – Annex 1

To submit a new bioequivalence study.

UK/H/1438/001-

004/II/014

23 April

2015

25 September

2015

Approved

Y – Annex 2

To introduce the Risk Management Plan (RMP).

UK/H/1438/001-

004/II/015

25 June

2015

22 September

2015

Approved

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Annex 1

Our Reference:

PL 20075/0145 - 0016

Product:

PL 20075/0145 Topiramate Accord 25

mg film-coated tablets

Marketing Authorisation Holder:

Accord Healthcare Limited

Active Ingredient(s):

Topiramate

Type of Procedure:

National

Submission Type:

Variation

Submission Category:

Type IB

Submission Complexity:

Standard

EU Procedure Number (if applicable):

Reason:

To update the section 1 (name of the medicinal product) in line with the advice to

include the MAH name, which was issued by the Commission on Human Medicines

(CHM) about prescribing and dispensing of

Anti-epileptic Drug (

AED) products.

Linked / Related Variation(s) or Case(s):

The Assessment Report refers to the Collection ID 146494 and covers the following

submissions PL 20075/0147 - 0016, PL 20075/0148 - 0017, PL 20075/0146 - 0017.

Supporting Evidence

Amended SmPC, labelling and PIL were provided.

Evaluation

This is a type IB variation number A.2.b to update the section 1 (name of the

medicinal product) in line with the advice to include the MAH name, which was

issued by the Commission on Human Medicines (CHM) about prescribing and

dispensing of AED products.

Conclusion

The proposed changes are acceptable.

In accordance with Directive 2010/84/EU, the Summary of Product Characteristics

(SmPC) for products granted Marketing Authorisations at a national level are

available on the MHRA website.

Decision:

Approved

Date:

12 February 2014

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Annex 2

Our Reference:

PL 20075/0145 - 0025

Product:

Topiramate Accord 25 mg film-coated

tablets

Marketing Authorisation Holder:

Accord Healthcare Limited

Active Ingredient(s):

Topiramate

Type of Procedure:

Mutual Recognition

Submission Type:

Variation

Submission Category:

Type II

Submission Complexity:

Complex

EU Procedure Number (if applicable):

UK/H/1438/001-004/II/014

Reason:

To submit a new bioequivalence study.

Linked / Related Variation(s) or Case(s):

The Assessment Report refers to the Collection ID 162608 and covers the following

submissions PL 20075/0147 - 0025, PL 20075/0146 - 0026, PL 20075/0148 - 0026.

Supporting Evidence

The Applicant wishes to file a Type II variation (C.I.4) to submit the new

bioequivalence (BE) study for the current product to meet the new BE guideline.

A complete BE study report has been enclosed in Module 5 of the Common Technical

Dossier (CTD).

No change to product information is part of this variation. No change in risk/benefit

balance has been proposed.

Evaluation

An open label, balanced, randomised, two-treatment, two sequence, two-period,

single oral dose, crossover, bioequivalence study of Topiramate Accord 200 mg

film-coated tablets (test product) versus Topamax 200 mg film-coated tablets

(reference product) in healthy, adult, male human subjects under fasting

conditions.

Pharmacokinetic study

After an overnight fast of at least 10 hours a single oral dose (200 mg) of either the

test or the reference product was administered with 240 ml of drinking water at

ambient temperature with the subjects in sitting posture. Blood samples were taken for

the measurement of pharmacokinetic parameters pre-dose and up to 72 hours

post-dose. The two treatment periods were separated by a 24-day washout period.

Design of the study was standard and acceptable. The blood sampling schedule was

appropriate to describe the selected PK parameters. The sampling was extended to 72

hours post dose. The washout period was sufficient in view of the half-life.

The main pharmacokinetic results are presented below:

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The 90% confidence intervals for the primary variables AUC

0-72

and C

are well

within the acceptance range of 80.00-125.00%. Based on the submitted

bioequivalence studies bioequivalence to the reference product may be concluded.

Conclusion

The results of the study can be accepted as valid. The bioequivalence has been shown.

There are no new safety signals emerging as the results of the study.

Decision:

Approved

Date:

25 September 2015

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