Consumer medicine information

RBX Topiramate

Topiramate

BRAND INFORMATION

Brand name

RBX Topiramate

Active ingredient

Topiramate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using RBX Topiramate.

What is in this leaflet

This leaflet answers some common questions about RBX TOPIRAMATE (topiramate). It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

This leaflet was last updated on the date at the end of this leaflet. More recent information may be available. The latest Consumer Medicine Information is available from https://www.ebs.tga.gov.au/ and may contain important information about the medicine and its use of which you should be aware.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking RBX TOPIRAMATE against the benefits it is expected to have for you.

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

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

What RBX Topiramate is used for

The name of your medicine is RBX TOPIRAMATE. RBX TOPIRAMATE contains topiramate.

Topiramate belongs to a group of medicines called antiepileptics. Topiramate prevents seizures and migraines by affecting chemicals in the brain that are involved in sending signals to the nerves.

RBX TOPIRAMATE is used for the treatment of various types of epilepsy in adults and children over 2 years of age.

RBX TOPIRAMATE is also used for the prevention of migraines in adults.

Your doctor may prescribe RBX TOPIRAMATE on its own, or in combination with other medicine for controlling your seizures or migraines. Your doctor may have prescribed RBX TOPIRAMATE for another reason.

Ask your doctor if you have any questions about why RBX TOPIRAMATE has been prescribed for you.

RBX TOPIRAMATE is available only with a doctor’s prescription.

Before you take RBX Topiramate

When you must not take it

  • Do not take RBX TOPIRAMATE if you are allergic to topiramate or any of the inactive ingredients listed at the end of this leaflet. Symptoms of an allergic reaction may include: wheezing, swelling of the lips/mouth, difficulty in breathing, hay fever, lumpy rash (hives) or fainting.
  • Do not take RBX TOPIRAMATE after the expiry date printed on the pack. If you take it after the expiry date has passed, it may not work as well.
  • Do not take RBX TOPIRAMATE if the tablets do not look quite right or if the packaging is torn or shows signs of tampering.

If you are not sure whether you should start taking RBX TOPIRAMATE, talk to your doctor or pharmacist.

Before you start to take it

You must tell your doctor if you:

  • have allergies to any medicine, foods, dyes or preservatives.
  • are pregnant or intend to become pregnant. Topiramate has caused harm to the developing foetus when administered to a pregnant woman. Its safety has not been verified in pregnant women. Information available suggests there may be an association between the use of topiramate during pregnancy and birth defects. However, it is very important to control your fits while you are pregnant. If it is necessary for you to take RBX TOPIRAMATE your doctor will discuss with you whether you should continue to take it during pregnancy.
  • are breast-feeding or intend to breast-feed. Lactating women should be advised not to breast-feed during treatment with RBX TOPIRAMATE. Your doctor will discuss the possible risks and benefits of taking/using RBX TOPIRAMATE while breast-feeding.
  • have or have had mental disorders such as depression or personality disorder.
  • have or have had kidney stones, kidney disease or have a family history of kidney stones.
  • have or have had liver problems.
  • have or have had eye problem or high pressure in the eye.
  • have a history of metabolic acidosis (too much acid in the blood, which may cause an increased rate of breathing).

If you have not told your doctor or pharmacist about any of the above, do so before you take RBX TOPIRAMATE.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including medicines you buy without a prescription from your pharmacy, supermarket or health food shop.

In particular, tell your doctor or pharmacist if you are taking:

  • other medicines for epilepsy (fits), such as phenytoin, carbamazepine or valproic acid
  • digoxin (used to treat heart disease)
  • oral contraceptives (the pill)
  • metformin, pioglitazone, glibenclamide (used to treat sugar diabetes)
  • acetazolamide used to treat glaucoma (increased intraocular pressure)
  • lithium, risperidone (used to treat bipolar disorder and schizophrenia)
  • haloperidol (used to treat psychoses)
  • hydrochlorothiazide (used to treat swelling or high blood pressure)
  • diltiazem or propranolol used to treat high blood pressure and or severe chest pain (angina)
  • venlafaxine and amitriptyline (used to treat depression)
  • flunarizine (used to treat migraine headache)
  • any medicine which slows your reactions. This may include medicines to help you sleep or relieve pain, antidepressants, tranquillisers, alcohol or antihistamines which can make you drowsy

These medicines may be affected by RBX TOPIRAMATE or may affect how well RBX TOPIRAMATE works. Your doctor or pharmacist can tell you what to do if you are taking any of these medicines.

How to take RBX Topiramate

Follow all directions given to you by your doctor or pharmacist carefully. This may differ from the information contained in this leaflet.

How to take it

You can take RBX TOPIRAMATE with or without food. Always swallow the tablets whole with plenty of water.

When to take it

At the start of treatment RBX TOPIRAMATE may be taken once a day, preferably at night. After the dose is increased, it is taken twice a day.

You should continue taking RBX TOPIRAMATE until your doctor tells you to stop. Before stopping, it is recommended that the dose be reduced gradually.

How much and how long 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 most suitable dose needed to control your epilepsy. Continue taking RBX TOPIRAMATE for as long as your doctor tells you to. Do not stop taking RBX TOPIRAMATE, or lower the dosage, without checking with your doctor.

Epilepsy

If you are taking only RBX TOPIRAMATE to treat your epilepsy:
For adults, treatment starts at a low dose of 25 mg/day as a single dose (nightly) for one week or longer. The dosage is then increased by 25 to 50 mg/day at weekly or longer intervals to the recommended target dose of 100 mg/day.

For children 2 years and over, treatment starts at a low dose of 0.5 to 1 mg/kg as a single dose (nightly) for the first week. The dosage is then increased by 0.5 to 1 mg/kg daily at weekly or longer intervals to the recommended target dose of 3 to 6 mg/kg/day.

If you are taking RBX TOPIRAMATE with other antiepileptic drugs:
For adults, treatment starts at a low dose of 25 to 50 mg as a single dose (nightly) or divided dose for one week or longer. The dosage is then increased by 25 to 100 mg/day at weekly or longer intervals to the recommended target dose of 200 to 400 mg/day.

For children 2 years and over, treatment starts at 1 to 3 mg/kg/day up to 25 mg/day as a single dose (nightly) for the first week. The dosage is then increased by 1 to 3 mg/kg/day at weekly or longer intervals to the recommended target dose of 5 to 9 mg/kg/day.

Migraine

Treatment starts at a low dose of 25 mg as a single dose (nightly) for one week. The dose is then increased over weekly periods or longer by 25 mg/day, until the most suitable dose is reached (only for adults).

If you forget to take it

  • Take your dose as soon as you remember, and then go back to taking your medicine as you would normally.
  • If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.
  • Do not take a double dose to make up for the dose you missed. This may increase the chance of you getting an unwanted side effect.

If you 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 have taken too much (overdose)

If you have taken too much, immediately telephone your doctor or the Poisons Information Centre (Tel. No. 131126) for advice, or go to Accident & Emergency at your nearest hospital.

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

Keep these numbers handy in case of an emergency.

If you take too much RBX TOPIRAMATE, you may experience headache, lightheadedness, agitation, drowsiness, lethargy, convulsions, speech disturbances, double or blurred vision, difficulty with thinking, abnormal coordination, reduced responsiveness and awareness, hypotension, abdominal pain, dizziness and depression, muscular weakness, muscle cramps and change in heart rhythm (apart from that you may also experience other symptoms due to low levels of potassium in blood.

While you are using RBX Topiramate

Things you must do

  • Drink plenty of water while taking RBX TOPIRAMATE. RBX TOPIRAMATE has been known to cause kidney stones and drinking water may help to prevent this.
  • Always follow your doctor's instructions carefully.
  • If you are about to start taking a new medicine, tell your doctor or pharmacist that you are taking RBX TOPIRAMATE.
  • Tell your doctor if you become pregnant while taking RBX TOPIRAMATE.

Things you must not do

  • Do not suddenly stop taking RBX TOPIRAMATE without checking with your doctor.
  • Do not drink alcohol.
  • Do not drive or operate machinery until you know how the medicine affects you.
  • Do not use RBX TOPIRAMATE to treat any other complaint unless your doctor says so.
  • Do not give this medicine to anyone else to use.

Things to be careful of

Changes to your medication
If you are seizure free or your seizures are well controlled, a reduction in your dose, discontinuation or substitution of your current medication should first be assessed by your doctor and pharmacist, and any changes should be implemented gradually.

Effects on thoughts and behaviour
Medicines used to treat epilepsy can increase the risk of suicidal thoughts and behaviour. If you experience feelings of deep sadness and unworthiness (depression) or a worsening of these feelings, any unusual changes in your mood, or the emergence of suicidal thoughts, behaviour or thoughts of self harm, you should report this to your doctor immediately.

Decreased sweating and elevation in body temperature
RBX Topiramate may cause decreased sweating and increased body temperature (fever). People, especially children, should be watched for signs of decreased sweating and fever, especially in hot temperatures. Some people may need to be hospitalized for this condition. Call your healthcare provider right away if you have a high fever, a fever that does not go away, or decreased sweating.

Effects on driving and operating machinery
RBX TOPIRAMATE may cause drowsiness, dizziness or other symptoms which could 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 RBX TOPIRAMATE or if the amount of RBX TOPIRAMATE or any other medicine you are taking is increased or decreased.

Effects of food and alcohol
RBX TOPIRAMATE can be taken with or without food. Do not drink alcohol while taking RBX TOPIRAMATE. 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 RBX TOPIRAMATE. RBX TOPIRAMATE helps most people with epilepsy/migraine, but it may have unwanted side effects in a few people.

All medicines can have 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 or pharmacist if you notice any of the following and they worry you:

  • dizziness
  • decrease in appetite or weight loss
  • itchy skin or skin rash
  • sleeplessness
  • tingling and numbness in fingers and toes
  • nausea (feeling sick), loose stool (diarrhoea), vomiting or constipation
  • abdominal pain or discomfort
  • ear pain, buzzing or ringing in ears, deafness

Tell your doctor as soon as possible if you notice any of the following as you may need medical attention:

  • depression
  • nervousness or anxiety
  • mood alterations such as aggression, agitation or anger
  • difficulty with memory and slowing of thought processes
  • abnormal behaviour
  • speech or language problems
  • difficulty with concentration or attention
  • fever
  • decreased or lack of sweating or overheating (mainly in children)
  • reduced sense of touch or sensation
  • reduced co-ordination
  • balance disorder
  • unusual hair loss or thinning
  • abnormal frequent urination
  • unusual weakness
  • taste disturbance or loss of taste

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you notice any of the following

  • unusual tiredness, drowsiness, irritability or lack of energy
  • difficulty breathing, fast or irregular heartbeat or tightening of chest
  • thoughts of harming yourself or thoughts of suicide
  • sudden signs of allergy such as rash, itching or hives, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or difficulty breathing
  • kidney stones
  • sudden severe back or side pain, difficult or painful to pass urine
  • blood in your urine or severe pain in the lower back or genital area
  • sudden changes in your eyesight (eg. blurred, double vision or loss of vision) or uncontrollable eye movements
  • eye pain or increased pressure in the eye
  • severe blisters and bleeding in mucosal sites (such as lips, eyes, mouth, nose, genitals)

These are serious side effects. You may need urgent medical attention. Serious side effects are rare.

Other side effects not listed above may also occur in some people. Tell your doctor if you notice any other effects.

After using RBX Topiramate

Storage

Keep RBX TOPIRAMATE in the original pack until it is time to take it.

Keep RBX TOPIRAMATE in a cool, dry place where the temperature is below 25 degrees C. Protect from light.

Do not store RBX TOPIRAMATE or any medicine in the bathroom or near a sink. Do not leave medicines in the car or on window sills. Heat and dampness can destroy some medicines.

Keep RBX TOPIRAMATE 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.

Disposal

If your doctor tells you to stop taking RBX TOPIRAMATE, or your medicine has passed its expiry date, ask your pharmacist what to do with any tablets which may be left over.

Product description

What it looks like

RBX TOPIRAMATE 25 mg tablets are white, film-coated, circular tablets debossed with ‘TP1’ on one side and plain on the other side. Available in packs of 60 tablets.

RBX TOPIRAMATE 50 mg tablets are yellow, film-coated, circular tablets debossed with ‘TP2’ on one side and plain on the other side. Available in packs of 60 tablets.

RBX TOPIRAMATE 100 mg tablets are yellow, film-coated, circular tablets debossed with ‘TP3’ on one side and plain on the other side. Available in packs of 60 tablets.

RBX TOPIRAMATE 200 mg tablets are peach-coloured, film-coated, circular tablets debossed with ‘TP4’ on one side and plain on the other side. Available in packs of 60 tablets.

Ingredients

Active ingredient:

RBX TOPIRAMATE 25 mg tablets - 25 mg of topiramate

RBX TOPIRAMATE 50 mg tablets - 50 mg of topiramate

RBX TOPIRAMATE 100 mg tablets - 100 mg of topiramate

RBX TOPIRAMATE 200 mg tablets - 200 mg of topiramate

Inactive ingredients:

Microcrystalline cellulose, lactose, pregelatinised maize starch, sodium starch glycolate (Type A), and magnesium stearate. In addition the 25 mg tablet contains Opadry 12 B 58956 (White), the 50 mg and 100 mg tablets contain Opadry 12 B 52749 (Yellow), and the 200 mg tablet contains Opadry 12 B 56662 (Brown). Opadry 12 B 58956 (White) contains hypromellose 5 cp, titanium dioxide, macrogol PEG 400 and polysorbate 80. Opadry 12 B 52749 (Yellow) contains hypromellose 5 cp, titanium dioxide, macrogol PEG 400, polysorbate 80 and iron oxide yellow. Opadry 12 B 56662 (Brown) contains hypromellose 5 cp, titanium dioxide, macrogol PEG 400, polysorbate 80 and iron oxide red.

Sponsor

RBX TOPIRAMATE is supplied in Australia by:

Sun Pharma ANZ Pty Ltd
12 Waterloo Road
MACQUARIE PARK NSW 2113
Australia
Tel: 1800 726 229
[email protected]

Australian Registration Numbers

RBX TOPIRAMATE 25 mg tablets: AUST R 157964

RBX TOPIRAMATE 50 mg tablets: AUST R 157971

RBX TOPIRAMATE 100 mg tablets: AUST R 157966

RBX TOPIRAMATE 200 mg tablets: AUST R 157973

This leaflet was prepared in December 2019.

Published by MIMS March 2020

BRAND INFORMATION

Brand name

RBX Topiramate

Active ingredient

Topiramate

Schedule

S4

 

1 Name of Medicine

Topiramate.

6.7 Physicochemical Properties

Molecular formula: C12H21NO8S.
Chemical name: 2,3:4,5-bis-O- (1-methylethylidene)-beta-D- fructopyranose sulfamate.
Molecular weight: 339.36.

Chemical structure.


CAS number.

CAS Number: 97240-79-4.

2 Qualitative and Quantitative Composition

Topiramate is a white crystalline powder with a bitter taste. It is most soluble in alkaline solutions containing sodium hydroxide or sodium phosphate and having 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.
Each film-coated tablet of RBX Topiramate contains 25 mg, 50 mg, 100 mg or 200 mg of topiramate.

Excipient with known effect.

Lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

RBX Topiramate 25 mg tablets are available as white, film-coated, circular tablets debossed with 'TP1' on one side and plain on the other side.
RBX Topiramate 50 mg tablets are available as yellow-coloured, film-coated, circular tablets debossed with 'TP2' on one side and plain on the other side.
RBX Topiramate 100 mg tablets are available as yellow-coloured, film-coated, circular tablets debossed with 'TP3' on one side and plain on the other side.
RBX Topiramate 200 mg tablets are available as peach-coloured, film-coated, circular tablets debossed with 'TP4' on one side and plain on the other side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Topiramate is classified as a sulfamate 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 neurons are subjected to a sustained depolarisation, which is indicative of a state dependent blockade of voltage sensitive sodium channels.
Topiramate markedly enhances the activity of GABA at some types of GABAA receptors. 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 GABAA receptors. Because the antiepileptic profile of topiramate differs markedly from that of the benzodiazepines, it may modulate a benzodiazepine insensitive subtype of GABAA receptor.
Topiramate antagonises the ability of kainate to activate the kainate/ AMPA subtype of excitatory amino acid (glutamate) receptors 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 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.
The mechanism(s) of action of topiramate in migraine prophylaxis is unknown.

Clinical trials.

Monotherapy epilepsy.

Three double blind, randomised, parallel group clinical trials were conducted to evaluate the efficacy and safety of topiramate given as monotherapy. Study YI and EPMN-104 evaluated the safety and efficacy of topiramate monotherapy using a dose response design by comparing the low dose regimen with the high dose regimen. Study EPMN-105 compared topiramate monotherapy to carbamazepine or valproate in patients with newly diagnosed epilepsy.
In study YI, adults with refractory partial onset seizures (n = 48) were converted from their existing treatment to topiramate 100 mg/day or 1000 mg/day as monotherapy. The high dose group was statistically superior to the low dose group for efficacy variables. 54% of high dose patients achieved monotherapy compared with 17% in the low dose group with the difference between the doses being statistically significant (p = 0.005). The mean time to exit was significantly greater in the high dose group (p = 0.002). The investigator and subject global evaluations of clinical response statistically favoured the high dose group (≤ 0.002). In study EPMN-104, adult and paediatric patients with recently diagnosed epilepsy (n = 252) were randomised into the low dose (25 or 50 mg/day) or the high dose group (200 or 500 mg/day) based on their body weight. Overall, 54% of high dose patients and 39% of low dose patients were reported to be seizure free during the double blind phase (p = 0.022). The high dose group was also superior to the low dose group with respect to seizure frequency distribution (p = 0.008) and the difference in time to first seizure across three plasma topiramate concentration strata (p = 0.015).
In study EPMN-105, patients with newly diagnosed epilepsy (n = 613) were randomised to receive either 100 or 200 mg/day of topiramate or standard antiepileptic treatment (carbamazepine or valproate). Topiramate was at least as efficacious as carbamazepine or valproate in reducing seizures in these patients; the 95% confidence intervals for the difference between the two treatment groups were narrow and included zero, indicating that there were no statistically significant between group difference. The two treatment groups were also comparable with respect to all clinical utility and efficacy endpoints including time to exit, proportion of seizure free subjects and time to first seizure.
Patients (n = 207; 32 were aged ≤ 16 years) who completed the double blind phase of studies YI and EPMN-104 were enrolled in long-term extension studies with the majority of patients receiving topiramate for 2 to 5 years. In these studies, sustained efficacy was demonstrated with long-term administration of topiramate as monotherapy. There was no significant change in dosage during the extension period and no indication that effectiveness of topiramate monotherapy diminished with continued exposure.
The safety profile of topiramate in monotherapy trials is consistent with that of the add-on trials.

Add-on therapy epilepsy.

Over 2000 patients worldwide were involved in the clinical trials of topiramate as an add-on treatment in adults and children with the following type of epilepsy: partial onset seizures with or without secondary generalised seizures, primary generalised tonic-clonic seizures and seizures associated with Lennox-Gastaut syndrome. These trials were randomised, placebo controlled, double blind, multicentre, parallel group studies in which patients were given topiramate or placebo as add-on treatment while they were receiving phenytoin, carbamazepine, primidone, phenobarbitone or valproic acid, as concomitant therapy.
These trials had 4 to 12 weeks as the 'run in' phases, several weeks of titration and then up to 12 weeks of stabilisation. Topiramate reduced monthly seizure rates and increased responder rates (fraction of patients with at least 50% seizure reduction) significantly compared to placebo. In addition, topiramate significantly reduced seizure severity in patients with Lennox-Gastaut syndrome. No evidence of tolerance to topiramate has been demonstrated in humans.
In a pooled analysis of two clinical trials involving patients with primary generalised tonic-clonic epilepsy, topiramate (n = 79) was statistically better than placebo (n = 81) (p = 0.004). In these two trials, 17 patients who were 16 years or younger received topiramate. There is limited clinical experience with topiramate at or above a daily dose of 1000 mg. Comparative data or data on the safety and efficacy of using topiramate with lamotrigine, vigabatrin or gabapentin are not available. Geriatric patients and patients with known or suspected coronary artery disease did not participate in these studies.

Migraine.

The clinical development programme to evaluate the efficacy of topiramate in the prophylaxis of migraine included four double blind, placebo controlled, parallel group trials. Each trial started with a washout period (14 to 28 days) for subjects already taking prophylactic drugs, followed by a 28 day 'run in' phase, an eight week dose titration phase and a 12 or 18 week maintenance phase.
The pooled results of the two pivotal trials, evaluating topiramate doses of 50 mg/day (N = 233), 100 mg/day (N = 244), and 200 mg/day (N = 228), found a median percent reduction in average monthly migraine period rate of 35%, 51% and 49% respectively, compared to 21% for the pooled placebo group (N = 229). Notably 27% of patients administered topiramate 100 mg/day achieved at least a 75% reduction in migraine frequency, whilst 52% achieved at least a 50% reduction.
Study MIGR-003 demonstrated that topiramate 100 mg/day was comparable in terms of efficacy to propranolol 160 mg/day. There was no statistically significant difference between the two groups in the primary efficacy endpoint or clinically significant 50% responder rate (43% for propranolol 160 mg/day, 37% for topiramate 100 mg/day (-6% difference, 95% CI [-17%,+6%], p = 0.28), 35% for topiramate 200 mg/day (-7% difference, 95% CI [-19%,+4%], p=0. 17)).
Results from each trial are summarised in Table 13.
The overall safety profile of topiramate observed in the migraine studies was generally consistent with that established for epilepsy therapy.

5.2 Pharmacokinetic Properties

The pharmacokinetic profile of topiramate compared to other antiepileptic drugs shows a long plasma elimination 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.
Topiramate was rapidly and well absorbed and distributed in total body water following oral administration in animals. The same metabolic and elimination pathways were present as in human subjects. Cmax values were similar to those obtained in human subjects but topiramate was more rapidly cleared in animals resulting in lower overall systemic exposure.

Absorption.

Based on recovery of radioactivity from urine in humans, the mean extent of absorption of a 100 mg dose of 14C-topiramate was at least 81%. Following oral administration of 100 mg topiramate to healthy subjects, a mean peak plasma concentration (Cmax) of approximately 2 microgram/mL was achieved within 2 or 3 hours (Tmax). The bioavailability of topiramate is not significantly affected by food.

Distribution.

Generally 13-17% of topiramate is bound to plasma proteins. A low capacity binding site for topiramate in/on erythrocytes that is saturated at steady state has been observed. Following single dose administration, the volume of distribution varies inversely with dose. The mean apparent volume of distribution has been measured as 0.8-0.55 L/kg for a single dose range of 100 mg 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 is attributed to the higher percent body fat in females and is of no clinical consequence.

Metabolism.

Topiramate is not extensively metabolised (~20%) in healthy volunteers. 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 14C-topiramate. Two metabolites, which retained most of the structure of topiramate, were tested and found to have little or no anticonvulsant activity.

Excretion.

In humans, the major route of elimination of unchanged topiramate and its metabolites is via the kidney (at least 81% of the dose). Approximately 66% of a dose of 14C-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 coadministered 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. 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.
Topiramate exhibits low intersubject variability in plasma concentrations and, therefore, has predictable pharmacokinetics. The pharmacokinetics of topiramate are linear at steady state with plasma clearance remaining constant and area under the plasma concentration curve increasing in a dose proportional manner over a 200 to 800 mg daily oral dose range. Patients with normal renal function may take 4 to 8 days to reach steady-state plasma concentrations. The mean Cmax following multiple, twice daily oral doses of 100 mg to healthy subjects was 6.76 microgram/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.

Patients with renal impairment.

The plasma and renal clearance of topiramate are decreased in patients with moderate and severe impaired renal function (CLCR < 70 mL/min). As a result, higher steady-state 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.
Topiramate is effectively removed from plasma by haemodialysis. A prolonged period of haemodialysis may cause topiramate concentration to fall below levels that are required to maintain an antiseizure effect. To avoid rapid drops in topiramate plasma concentration during haemodialysis, 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.

Elderly.

Plasma clearance of topiramate is unchanged in elderly subjects in the absence of underlying renal disease or hepatic impairment. Patients over 71 years of age have not been studied.

Paediatric up to 12 years of age.

The pharmacokinetics of topiramate in children receiving the drug as add-on therapy are linear. The clearance is independent of dose and steady-state plasma concentrations increase in proportion to dose. Hepatic enzyme inducing antiepileptic drugs decrease the steady-state plasma concentrations. In comparison to adults, however, children have a higher clearance and shorter elimination half-life when topiramate is used as adjunctive therapy to both enzyme inducing and nonenzyme inducing antiepileptic drugs. Consequently, the plasma concentrations of topiramate for the same mg/kg dose may be lower in children compared to adults.
A bioequivalence study was conducted comparing RBX Topiramate 25 mg tablets and Topamax 25 mg tablets (Janssen-Cilag Pty Ltd, Australia) in healthy, adult male subjects, under fasting conditions. Summary of results is tabulated in Table 14.

5.3 Preclinical Safety Data

Genotoxicity.

Topiramate was not genotoxic in a series of assays for gene mutations, chromosomal damage or DNA damage.

Carcinogenicity.

No evidence of carcinogenicity was seen in rats following oral administration of topiramate for 2 years at doses of 120 mg/kg/day. An increased incidence of urinary bladder tumours of a proliferative nature was observed in mice following oral administration of topiramate for 22 months at doses of 300 mg/kg/day. These tumours probably resulted from chronic irritation and may lack clinical significance. The plasma concentration exposure obtained in the animal studies was less than the likely clinical exposure at the maximum recommended dose.

4 Clinical Particulars

4.1 Therapeutic Indications

Epilepsy.

RBX Topiramate tablets are 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 (with or without secondary generalised seizures), primary generalised tonic-clonic seizures or drop attacks associated with Lennox-Gastaut syndrome.

Migraine.

RBX Topiramate tablets are indicated for the prophylaxis of migraine headache in adults.

4.3 Contraindications

Hypersensitivity to any component of this product.

4.4 Special Warnings and Precautions for Use

In patients with or without a history of seizures or epilepsy, antiepileptic drugs including topiramate 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 50-100 mg in adults with epilepsy and by 25-50 mg in adults receiving topiramate at doses up to 100 mg/day for migraine prophylaxis. In clinical trials of children, topiramate was gradually withdrawn over a 2-8 week period. In situations where rapid withdrawal of topiramate is medically required, appropriate monitoring is recommended.
Topiramate has not been studied in patients with a history of psychiatric disorders. Given the reported association of certain antiepileptic agents and psychiatric disturbances, topiramate should be used with caution in patients with a prior psychiatric history.
Adequate hydration while using topiramate 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.

Suicidal behaviour and ideation.

Antiepileptic drugs (AEDs), including topiramate, increase the risk of suicidal thoughts or behaviour in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behaviour, and/or any unusual changes in mood or behaviour.
Pooled analyses of 199 placebo controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomised to one of the AEDs had approximately twice the risk (adjusted relative risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behaviour compared to patients randomised to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behaviour or ideation among 27,863 AED treated patients was 0.43%, compared to 0.24% among 16,029 placebo treated patients, representing an increase of approximately one case of suicidal thinking or behaviour for every 530 patients treated. There were four suicides in drug treated patients in the trials and none in placebo treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behaviour with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because 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.
The risk of suicidal thoughts or behaviour was generally consistent among drugs in the data analysed. The finding of increased risk with AEDs of varying mechanisms of actions and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analysed.
Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
The relative risk for suicidal thoughts or behaviour was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
In double blind clinical trials with topiramate in approved and investigational indications, 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% in placebo treated patients (8 out of 4,045). One completed suicide of a patient treated with topiramate was reported in a bipolar disorder double blind trial.
Anyone considering prescribing topiramate or any other AED must balance the risk of suicidal thoughts or behaviour with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behaviour. Should suicidal thoughts and behaviour emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, and when appropriate, their caregivers and families, should be informed that AEDs increase the risk of suicidal thoughts and behaviour and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behaviour, or the emergence of suicidal thoughts, behaviour or thoughts about self harm. Behaviours of concern should be reported immediately to the treating doctor.

Nephrolithiasis.

Patients, especially those with a predisposition to nephrolithiasis, may be at increased risk for renal stone formation (none of 216 placebo patients versus 1.6% of 1446 patients who had received topiramate were reported to have nephrolithiasis) and associated signs and symptoms such as renal colic, renal pain or flank pain.
Risk factors for nephrolithiasis include prior stone formation, a family history of nephrolithiasis and hypercalciuria (see Section 4.4 Special Warnings and Precautions for Use, Metabolic acidosis), and gender (male). 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.

Oligohydrosis and hyperthermia.

Oligohydrosis (decreased sweating) and anhidrosis, infrequently resulting in hospitalisation, has been reported in association with topiramate use. Decreased sweating and an elevation in body temperature above normal characterised 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 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.
Patients, especially paediatric patients, treated with topiramate should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather.

Use in patients with hepatic impairment.

In hepatically impaired patients, topiramate should be administered with caution as the clearance of topiramate may be decreased.

Use in patients with renal impairment.

The major route of elimination of unchanged topiramate and its metabolites is via the kidney. Renal elimination is dependent on renal function and is independent of age. Patients with moderate 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.
In all patients the titration schedule should be guided by clinical outcome (i.e. seizure control, avoidance of side effects) and the knowledge that subjects with known renal impairment may require a longer time to reach steady state at each dose.

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. Ophthalmological findings can include myopia, anterior chamber shallowing, ocular hyperaemia (redness) and increased intraocular pressure.
Mydriasis may or may not be present. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating 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. In clinical trials, most of these events were reversible after topiramate discontinuation, however some cases were not. In a large proportion of postmarketing case reports reversibility was unknown, but in cases where an outcome was reported, the majority were reversible. If visual problems occur at any time during topiramate treatment, consideration should be given to discontinuing the drug.

Metabolic acidosis.

Hyperchloremic, nonanion 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 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 nephrocalcinosis (see Section 4.4 Special Warnings and Precautions for Use, Nephrolithiasis).
In adults, the incidence of persistent treatment emergent decreases in serum bicarbonate (levels of < 20 mmol/L at two consecutive visits or at the final visit) in controlled clinical trials for adjunctive treatment of epilepsy was 32% for 400 mg/day, and 1% for placebo. Metabolic acidosis has been observed at doses as low as 50 mg/day. The incidence of a markedly abnormally low serum bicarbonate (i.e. absolute value < 17 mmol/L and > 5 mmol/L decrease from pretreatment) in these trials was 3% for 400 mg/day, and 0% for placebo. Serum bicarbonate levels have not been systematically evaluated at daily doses greater than 400 mg/day.
The incidence of persistent treatment emergent decreases in serum bicarbonate in placebo controlled trials for adults for prophylaxis of migraine was 44% for 200 mg/day, 39% for 100 mg/day, 23% for 50 mg/day, and 7% for placebo. The incidence of a markedly abnormally low serum bicarbonate (i.e. absolute value < 17 mmol/L and > 5 mmol/L decrease from pretreatment) in these trials was 11% for 200 mg/day, 9% for 100 mg/day, 2% for 50 mg/day, and < 1% for placebo.
In paediatric patients (< 16 years of age), the incidence of persistent treatment emergent decreases in serum bicarbonate in placebo controlled trials for adjunctive treatment of Lennox-Gastaut syndrome or refractory partial onset seizures was 67% for topiramate (at approximately 6 mg/kg/day), and 10% for placebo. The incidence of a markedly abnormally low serum bicarbonate (i.e. absolute value < 17 mmol/L and > 5 mmol/L decrease from pretreatment) in these trials was 11% for topiramate and 0% for placebo. Cases of moderately severe metabolic acidosis have been reported in patients as young as 5 months old, especially at daily doses above 5 mg/kg/day.
Some manifestations of acute or chronic metabolic acidosis may include hyperventilation, nonspecific symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or stupor. Chronic, untreated metabolic acidosis may increase the risk for neprolithiasis or nephrocalcinosis, and may also result in osteomalacia (referred to as rickets in paediatric patients) and/or osteoporosis with an increased risk for fractures. Chronic metabolic acidosis in paediatric patients can reduce growth rates. A reduction in growth rate may eventually decrease the maximal height achieved. The effect of topiramate on growth and bone related sequelae has not been systematically investigated in paediatric or adult populations.
Depending on underlying conditions, appropriate evaluation including serum bicarbonate levels is recommended with topiramate therapy. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing topiramate (using dose tapering).

Hyperammonaemia and encephalopathy.

Hyperammonaemia with or without encephalopathy has been reported with topiramate treatment (see Section 4.8 Adverse Effects (Undesirable Effects)). The risk for hyperammonaemia with topiramate appears dose-related. Hyperammonaemia has been reported more frequently when topiramate is used concomitantly with valproic acid (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Clinical symptoms of hyperammonaemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy. In most cases, hyperammonaemic 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 hyperammonaemic encephalopathy and measuring ammonia levels.

Mood disturbances/ depression.

An increased incidence of mood disturbances and depression has been observed during topiramate treatment. Psychiatric/ behavioural disturbances (depression or mood problems) in majority of affected patients were dose related for both the add-on epilepsy and migraine populations.

Women of childbearing potential.

Topamax may cause foetal harm when administered to a pregnant woman. There is an increased risk of pre-term labour, premature delivery and congenital malformations associated with the use of AEDs, including topiramate.
Topamax 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).

Use in the elderly.

See Section 4.2 Dose and Method of Administration, Use in the elderly.

Paediatric use.

See Section 4.2 Dose and Method of Administration, Children (2 years and over).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Studies in mice receiving concomitant administration of topiramate and carbamazepine or phenobarbitone showed synergistic anticonvulsant activity, while combination with phenytoin showed additive anticonvulsant activity.

Effects of topiramate on other antiepileptic drugs.

The addition of topiramate to other antiepileptic drugs (phenytoin, carbamazepine, valproic acid, phenobarbitone, 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.

Effects of other antiepileptic drugs on topiramate.

The metabolic breakdown of topiramate is increased in patients receiving concomitant antiepileptic therapy with agents that are inducers of drug metabolising enzymes. The increased metabolic breakdown results in up to 1.5 times higher clearance of topiramate.
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 in Table 3.
No data are available on the use of topiramate with vigabatrin.

Other drug interactions.

Digoxin.

In a single dose study, 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 drugs has not been evaluated in clinical studies. It is recommended that topiramate not be used concomitantly with alcohol or other CNS depressant drugs.

Oral contraceptives.

In a pharmacokinetic interaction study in healthy volunteers with a concomitantly administered combination oral contraceptive product containing 1 mg norethisterone (NET) plus 35 microgram ethinyl oestradiol (EO), 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 EO 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 NET. Although there was a dose dependent decrease in EO exposure for doses between 200-800 mg/day, there was no significant dose dependent change in EO exposure for doses of 50-200 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 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 coadministered 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) 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. The clinical relevance of the observed, apparently not statistically significant, changes in the systemic exposure of the total active moiety (risperidone plus 9-hydroxyrisperidone) or of topiramate is not known.

Hydrochlorothiazide (HCTZ).

A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of HCTZ (25 mg q24h) and topiramate (96 mg q12h) when administered alone and concomitantly. The results of this study indicate that topiramate Cmax 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. 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 Cmax and mean AUC0-12h increased by 18% and 25%, respectively, while mean CL/F decreased 20% when metformin was coadministered with topiramate. Topiramate did not affect metformin Tmax. The clinical significance of the effect of topiramate on metformin pharmacokinetics is unclear. Oral plasma clearance of topiramate appears to be reduced when administered with metformin. The extent of change in the clearance is unknown. The clinical significance of the effect of metformin on topiramate pharmacokinetics is unclear. When 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 AUCt,ss, of pioglitazone with no alteration in Cmax,ss was observed. This finding was not statistically significant. In addition, a 13% and 16% decrease in Cmax,ss and AUCt,ss respectively, of the active hydroxymetabolite was noted as well as a 60% decrease in Cmax,ss and AUCt,ss, of the active ketometabolite. 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.

Glibenclamide.

A drug-drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state pharmacokinetics of glibenclamide (5 mg/day) alone and concomitantly with topiramate (150 mg/day). There was a 25% reduction in glibenclamide AUC24 during topiramate administration. Systemic exposure of the active metabolites, 4-trans-hydroxy- glibenclamide (M1) and 3-cis- hydroxyglibenclamide (M2), were also reduced by 13% and 15%, respectively. The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glibenclamide. When topiramate is added to glibenclamide therapy or glibenclamide is added to topiramate therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.

Other forms of interactions.

Agents predisposing to nephrolithiasis.

Topiramate, when used concomitantly with other agents predisposing to nephrolithiasis, may increase the risk of nephrolithiasis. While using topiramate, agents like these should be avoided since they may create a physiological environment that increases the risk of renal stone formation.

Valproic acid.

Concomitant administration of topiramate and valproic acid has been associated with hyperammonaemia with or without encephalopathy in patients who have tolerated either drug alone. In most cases, symptoms and signs abated with discontinuation of either drug. This adverse event is not due to a pharmacokinetic interaction. An association of hyperammonaemia with either topiramate or valproic acid monotherapy has not been established.

Vitamin K-antagonist anticoagulant medications.

Decreased Prothrombin Time/International Normalized Ratio (PT/INR) responses have been reported following concomitant administration of 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 Cmax or AUC as a result of the interactions are summarised in Table 4. The second column (concomitant drug concentration) describes what happens to the concentration of the concomitant drug listed in the first column when topiramate is added. The third column (topiramate concentration) describes how the coadministration of a drug listed in the first column modifies the concentration of topiramate.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There were no effects on fertility or reproductive parameters in rats following oral administration of topiramate at doses up to 100 mg/kg/day, with estimated exposures (plasma AUC) less than human exposure at the maximal recommended clinical dose. Oral administration of topiramate to juvenile rats did not affect subsequent reproductive development, mating or fertility (see Growth and development).
(Category D)
Category D. When administered orally during organogenesis, topiramate was teratogenic in mice, rats and rabbits at maternal exposures (plasma AUC) less than clinical exposure at the maximal recommended dose. In mice, the numbers of foetal malformations (primarily craniofacial abnormalities) were increased at all dose levels tested. The malformations in rats (limb reduction defects) and rabbits (axial and costal skeletal defects) were similar to those seen with carbonic anhydrase inhibitors in these species. Carbonic anhydrase inhibitors have not been associated with malformations in human beings. There are no studies using topiramate in pregnant women. In postmarketing experience, cases of hypospadias have been reported in male infants exposed in utero to topiramate, with or without other anticonvulsants. A causal relationship with topiramate has not been established.
There are no adequate and well-controlled studies using topiramate in pregnant women.
Topiramate can cause foetal 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 as cleft lip/ palate, hypospadias, and 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. The relative risk of oral clefts in topiramate exposed pregnancies in the NAAED Pregnancy Registry was 21.3 (95% confidence interval 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%.
In addition, data from other studies indicate that, compared with monotherapy, there may be an increased risk of teratogenic effects associated with the use of antiepileptic drugs 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 a reference group not taking antiepileptic drugs, registry data for 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 10th 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 topirmate 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-term consequences of the SGA findings could not be determined. A causal relationship for low birth weight and SGA has not been established.
Topiramate should be used during pregnancy only if potential benefit justifies the potential risk to the foetus. In treating and counseling women of childbearing potential, the prescribing physician should weigh the benefits of therapy against the risks. 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 foetus.
The risk of having an abnormal child as a result of antiepileptic medication is far outweighed by the danger to the mother and foetus of uncontrolled epilepsy.
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 (5 mg) should be commenced four weeks prior to and continue for twelve weeks after conception;
specialist prenatal diagnosis including detailed midtrimester ultrasound should be offered.
Radioactivity was detected in milk following oral administration of radiolabelled topiramate to lactating rats. About 1.5% of the dose was recovered in milk in 24 hours, and milk and maternal plasma radioactivity concentrations were similar. The excretion of topiramate has not been evaluated in controlled studies. Limited observation in patients suggests an extensive excretion of topiramate in breast milk. Diarrhoea and somnolence have been reported in breastfed infants whose mothers receive topiramate treatment. Lactating women should be advised not to breastfeed during treatment with topiramate.

Growth and development.

In juvenile rats, 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, pre-weaning and reproductive development, neurological development (including assessments on memory and learning), mating and fertility or hysterotomy parameters. Exposure (plasma AUC) was up to 2-fold human exposure at the maximal recommended clinical dose.

4.8 Adverse Effects (Undesirable Effects)

Clinical study data.

The safety of topiramate was evaluated from a clinical study database consisting of 4,111 patients (3,182 on topiramate and 929 on placebo) who participated in 20 double blind studies and 2,847 patients who participated in 34 open label studies for the treatment of primary generalised tonic-clonic seizures, partial onset seizures, seizures associated with Lennox-Gastaut syndrome, newly or recently diagnosed epilepsy or migraine. The information presented in this section was derived from pooled data. The majority of all adverse drug reactions (ADRs) were mild to moderate in severity.

Increased risk for bleeding.

Topiramate treatment is associated with an increased risk for bleeding. In a pooled analysis of placebo-controlled studies of approved and unapproved indications, bleeding was more frequently reported as an adverse event for Topamax than for placebo (4.5% versus 3.0% in adult patients, and 4.4% versus 2.3% in paediatric patients). In this analysis, the incidence of serious bleeding events for Topamax and placebo was 0.3% versus 0.2% for adult patients, and 0.4% versus 0% for paediatric patients.
Adverse bleeding reactions reported with Topamax ranged from mild epistaxis, ecchymosis, and increased menstrual bleeding to life-threatening haemorrhages. In patients with serious bleeding events, conditions that increased the risk for bleeding were often present, or patients were often taking drugs that cause thrombocytopenia (other antiepileptic drugs) or affect platelet function or coagulation (e.g. aspirin, nonsteroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, or warfarin or other anticoagulants).

Double blind, placebo controlled, adjunctive epilepsy studies in adults.

ADRs reported in ≥ 1% of topiramate treated adult patients in double blind placebo controlled adjunctive epilepsy studies are shown in Table 5. 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, nystagmus, lethargy, anorexia, dysarthria, vision blurred, decreased appetite, memory impairment and diarrhoea.

Double blind placebo controlled adjunctive epilepsy studies in paediatric patients.

ADRs reported in > 2% of topiramate treated paediatric patients (2 to 16 years of age) in double blind placebo controlled adjunctive epilepsy studies are shown in Table 6. ADRs that had an incidence > 5% in the recommended dose range of 5 to 9 mg/kg/day in descending order of frequency included decreased appetite, fatigue, somnolence, lethargy, irritability, disturbance in attention, weight decreased, aggression, rash, abnormal behaviour, anorexia, balance disorder and constipation.

Double blind, controlled, monotherapy epilepsy studies in adult patients.

ADRs reported in ≥ 1% of topiramate treated adult patients 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 paraesthesia, weight decreased, fatigue, anorexia, depression, memory impairment, anxiety, diarrhoea, asthenia, dysgeusia, and hypoesthesia.

Double blind, controlled, monotherapy epilepsy studies in paediatric 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 8. 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.

Double blind, placebo controlled, migraine prophylaxis studies in adult patients.

ADRs reported in ≥ 1% of topiramate treated adult patients in double blind, placebo controlled migraine prophylaxis trials are shown in Table 9. 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, dysgeusia, anorexia, decreased appetite, insomnia, hypoesthesia, disturbance in attention, anxiety, somnolence, and expressive language disorder.

Other clinical trial data.

ADRs reported, rate unspecified, in open label clinical trials of topiramate treated adult patients are shown in Table 10.
ADRs reported, rate unspecified, in open-label clinical trials of topiramate-treated paediatric patients are shown in Table 11.

Postmarketing data.

Adverse events first identified as ADRs during postmarketing experience with topiramate, presented by frequency category based on spontaneous reporting rates are included in Table 12. 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).
No adverse events were reported during the bioequivalence study comparing RBX Topiramate 25 mg tablets and Topamax 25 mg tablets (Janssen-Cilag Pty Ltd) in healthy, adult, human, male, subjects, under fasting conditions.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

RBX Topiramate tablets should be swallowed whole.
RBX Topiramate tablets can be taken without regard to meals.
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 in adults and children for epilepsy are summarized in Table 1.

Monotherapy epilepsy.

In newly diagnosed epileptic patients, monotherapy should be initiated at a low dose (see Table 1).
In patients who are being converted to topiramate monotherapy, consideration should be given to the effects of seizure control when withdrawing concomitant antiepileptic agents (AEDs). Unless safety concerns require an abrupt withdrawal of the concomitant AED, a gradual discontinuation at the rate of approximately one-third of the concomitant AED dose every 2 weeks is recommended. When enzyme inducing drugs are withdrawn, topiramate levels will increase. A decrease in 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. If the patient is unable to tolerate the titration regimen, smaller increments or longer intervals between increments can be used. 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 (2 years and over).

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 3 to 6 mg/kg/day. If the child is unable to tolerate the titration regimen, smaller increments or longer intervals between dose increments can be used. Some children with recently diagnosed partial onset seizures have received doses of up to 500 mg/day. The daily dosage should be given as two divided doses.

Add-on therapy epilepsy.

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 (2 years and over).

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.
It is not necessary to monitor topiramate plasma concentrations to optimize topiramate therapy. For patients receiving concomitant phenytoin and carbamazepine, dosage adjustment for topiramate 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 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 the elderly.

Caution is advised during titration in the elderly with renal disease and/or hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use).

Use in patients with hepatic and/or renal impairment.

Caution is advised during titration in patients with renal disease and/or hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use).

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 should be added to the patient's normal daily dose as follows.

Patients on concomitant enzyme inducers (phenytoin, carbamazepine, phenobarbitone and other barbiturates).

A supplemental dose equal to 1/3 the patient's normal daily dose should be given on the day of haemodialysis. The supplemental dose should be divided so as to allow for administration of 1/4 of the supplemental dose at the start of haemodialysis. The remaining 3/4 of the supplemental dose should be administered at the completion of the haemodialysis.

Patients not on concomitant enzyme inducers.

A supplemental dose equal to 1.6 times the patient's normal daily dose should be given on the day of haemodialysis. The supplemental dose should be divided so as to allow for administration of 1/3 of the supplemental dose at the start of haemodialysis. The remaining 2/3 of the supplemental dose should be administered at the completion of the haemodialysis.

Drug withdrawal and dosage reduction.

In patients with or without a history of seizures or epilepsy, antiepileptic drugs, including topiramate, should be gradually withdrawn to minimise the potential for seizures or of increased seizure frequency. In situations where rapid withdrawal of topiramate is medically required, appropriate monitoring is recommended.

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 adverse events are potentially dangerous in patients driving a vehicle or operating machinery, particularly until the individual patient's experience with the drug is established.

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, mentation impaired, 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 Section 4.4 Special Warnings and Precautions for Use).
The highest topiramate overdose reported was calculated to be between 96 and 110 g and resulted in coma lasting 20-24 hours followed by full recovery after 3 to 4 days.

Treatment.

General supportive measures are indicated and an attempt should be made to remove undigested drug from the gastrointestinal tract using activated charcoal. Treatment should be appropriately supportive. Haemodialysis has been shown to be an effective means of removing topiramate from the body. The patient should be well hydrated.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each film-coated tablet of RBX Topiramate contains the inactive ingredients microcrystalline cellulose, lactose, pregelatinised maize starch, sodium starch glycollate type A and magnesium stearate. In addition the 25 mg tablet contains Opadry complete film coating system 12B58956 White (proprietary ingredient no. 13153), the 50 mg and 100 mg tablets contain Opadry complete film coating system 12B52749 Yellow (proprietary ingredient no. 13152), and the 200 mg tablet contains Opadry complete film coating system 12B56662 Brown (proprietary ingredient no. 13151). Opadry complete film coating system 12B58956 White contains hypromellose, titanium dioxide, macrogol 400 and polysorbate 80. Opadry complete film coating system 12B52749 Yellow contains hypromellose, titanium dioxide, macrogol 400, polysorbate 80 and iron oxide yellow. Opadry complete film coating system 12B56662 Brown contains hypromellose, titanium dioxide, macrogol 400, polysorbate 80 and iron oxide red.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C in the original container. Protect from light.

6.5 Nature and Contents of Container

The tablets are supplied in cold form blisters with embedded desiccant* and HDPE bottle containing 60 tablets of 25 mg, 50 mg, 100 mg and 200 mg tablets.
* Not currently distributed in Australia.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes