Consumer medicine information

Topamax tablets and sprinkle capsules [8820]

Topiramate

BRAND INFORMATION

Brand name

Topamax

Active ingredient

Topiramate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Topamax tablets and sprinkle capsules [8820].

What is in this leaflet

This leaflet answers some common questions about TOPAMAX® tablets and Sprinkle capsules. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking TOPAMAX against the benefits they expect it will 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 TOPAMAX is used for

The name of your medicine is TOPAMAX. It contains the active ingredient topiramate.

TOPAMAX belongs to a group of medicines known as antiepileptics. TOPAMAX is used for the treatment of various types of seizures in adults and children, aged 2 years and over. It can also be used for the prevention of migraines in adults. TOPAMAX is not used to treat severe migraines that come on suddenly (acute).

It prevents seizures and migraines by acting on the nerves and chemicals in the brain.

Your doctor may prescribe TOPAMAX on its own, or in addition to another medicine for controlling your seizures or migraines.

Your doctor may have prescribed TOPAMAX for another reason. Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Before you take TOPAMAX

When you must not take it

Do not take TOPAMAX if you have an allergy (hypersensitivity) to:

  • topiramate
  • any of the ingredients. See Product Description at the end of this leaflet for a list of ingredients.
  • if the tablets or capsules are not as described under Product Description at the end of this leaflet.

Symptoms of an allergic or hypersensitivity reaction may include:

  • rash, itching or hives on the skin
  • shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body

Do not take TOPAMAX if the packaging is torn or shows signs of tampering. Do not take TOPAMAX after the expiry date (month and year) printed on the pack has passed.

Before you start to take it

You must tell your doctor if you:

  • are pregnant or planning to become pregnant. Topamax has caused harm to the developing foetus when administered to a pregnant woman. Its safety has not been verified in pregnant humans. Information available indicates that there is an association between the use of Topamax in humans during pregnancy and birth defects including cleft lip/ palate. However, it is very important to control your fits while you are pregnant. If it is necessary for you to take Topamax, your doctor can help you decide whether or not to take it during pregnancy.
  • are breast feeding or wish to breastfeed. TOPAMAX may appear in breast milk and it is not recommended to breastfeed while taking TOPAMAX.
  • have or have ever had a personality disorder or mental illness
  • have or have ever had kidney stones, kidney disease or have a family history of kidney stones
  • have or have ever had liver disease
  • have 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, tell them before you start taking TOPAMAX.

Your doctor will advise you whether or not to take TOPAMAX or if you need to adjust the dose or adapt your treatment.

Taking other medicines

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

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

  • other medicines for epilepsy, such as phenytoin or carbamazepine
  • digoxin (used to treat heart disease)
  • oral contraceptives (the pill)
  • metformin, pioglitazone or glibenclamide (used to treat diabetes)
  • lithium or risperidone (used to treat bipolar disorder and schizophrenia)
  • haloperidol (used to treat psychoses)
  • hydrochlorothiazide (used to treat swelling or high blood pressure)
  • propranolol (used in high blood pressure, some heart conditions, tremors, tumor or migraine headaches)
  • diltiazem (used to treat hypertension and prevent angina)
  • valproic acid (used to treat epilepsy or mood disorders)
  • vitamin K-antagonist anticoagulant medications (such as warfarin)
  • amitriptyline (used to treat depression)
  • flunarizine
  • any medicine which slows your reactions (CNS depressants). This may include medicines to help you sleep or relieve pain, antidepressants, tranquillisers or antihistamines which can make you drowsy.

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

How to take TOPAMAX

How to take it

Follow your doctor's instructions about when and how to take TOPAMAX.

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

TOPAMAX Sprinkle capsules are available for people who cannot swallow tablets. These capsules can be opened and all of the contents sprinkled onto a teaspoon of soft food which does not require chewing. This mixture should be swallowed immediately and not chewed. It should not be stored for future use. The capsules can also be swallowed whole with water.

The doses shown below are the usual recommended doses. However, your doctor may tell you to take higher or lower doses. Your doctor will start with a low dose and slowly increase the dose to the lowest amount needed to control your epilepsy.

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

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

Adults

Epilepsy
Treatment starts at a low dose of 25 mg to 50 mg per day. The dose is then gradually increased by 25 mg to 100 mg over weekly periods or longer, until the most suitable dose is reached.

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

Children (2 years and over) - epilepsy only
Treatment starts at 25 mg or less per day, depending on the body weight. This dose is then gradually increased over weekly periods or longer, until the most suitable dose is reached.

If you forget to take it

  • Take your dose as soon as you remember, and then continue to take it 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.

If you have missed more than one dose, or are not sure what to do, check with your doctor or pharmacist.

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

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre 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.

Poisons Information Centre telephone numbers:

  • Australia: 13 11 26
  • New Zealand: 0800 POISON or 0800 764 766

Keep these numbers handy in case of an emergency.

If you take too much TOPAMAX, you may experience headache, dizziness, light-headedness, drowsiness, convulsions, speech disturbances, double or blurred vision, difficulty with thinking, abnormal coordination, stomach pain, depression, agitation, faster breathing or you may lose consciousness.

While you are using TOPAMAX

Things you must do

  • Drink plenty of water. TOPAMAX has been known to cause kidney stones and drinking water may help 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 TOPAMAX.
  • Tell your doctor if you become pregnant while taking TOPAMAX.

Things you must not do

  • Do not suddenly stop taking TOPAMAX 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 TOPAMAX 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
TOPAMAX 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
TOPAMAX 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 TOPAMAX or if the amount of TOPAMAX or any other medicine you are taking is increased or decreased.

Effects of food and alcohol
TOPAMAX can be taken with or without food.

Do not drink alcohol while taking TOPAMAX. Alcohol may increase the risk of unwanted side effects, such as drowsiness.

Side effects

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 side effects. Do not be alarmed by this list of possible side effects. You may not experience any of them.

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

Tell your doctor if any of the following continue or worry you:

  • dizziness
  • decrease in appetite or weight loss
  • itchy skin or skin rash
  • inability to sleep
  • tingling and numbness of hands and feet (pins and needles)
  • nausea, 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 have any of the following as you may need medical attention:

  • depression
  • nervousness or feeling anxious
  • mood alterations such as aggression, agitation or anger
  • disturbance in attention
  • difficulty with memory or memory impairment
  • slowing of thought processes
  • abnormal behaviour
  • expressive language disorder
  • difficulty in speaking
  • balance disorder
  • co-ordination problems
  • unusual hair loss or thinning
  • abnormal frequent urination
  • decreased feeling or sensitivity, especially in the skin
  • fever or high temperature
  • decreased or lack of sweating or overheating (mainly in children)
  • unusual weakness
  • taste disturbance or loss of taste

Tell your doctor immediately if you have:

  • 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
  • kidney stones
  • pain when passing urine
  • sudden changes in your eyesight (e.g. blurred vision, double vision or loss of vision) or rapid uncontrollable movements of the eyes
  • eye pain or increased pressure in eye
  • unexplained bleeding or bleeding more frequently
  • 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 TOPAMAX

Storage

  • Keep TOPAMAX tablets or capsules in the original pack until it is time to take them.
  • Keep TOPAMAX in a cool, dry place where the temperature is below 25°C. Protect from light.
  • For TOPAMAX Sprinkle capsules, do not store the drug/food mixture.
  • Do not store TOPAMAX 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 TOPAMAX where children cannot reach it. A locked cupboard at least one and a half metres (1.5 m) above the ground is a good place to store medicines.

Disposal

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

Product description

What it looks like

Tablets
TOPAMAX tablets are available in blister packs of 60:

  • 25 mg tablets are round and white and marked "TOP" on one side and "25" on the other.
  • 50 mg tablets are round and light yellow and marked "TOP" on one side and "50" on the other.
  • 100 mg tablets are round and yellow and marked "TOP" on one side and "100" on the other.
  • 200 mg tablets are round and salmon coloured and marked "TOP" on one side and "200" on the other.

Capsules
TOPAMAX Sprinkle capsules are available in bottles of 60. The capsules consist of a clear cap and a white body. They contain white to off-white spheres.

  • 15 mg capsules are marked "TOP" on the cap and "15 mg" on the body.
  • 25 mg capsules are marked "TOP" on the cap and "25 mg" on the body.
  • 50 mg capsules are marked "TOP" on the cap and "50 mg" on the body.

Ingredients

Tablets

  • contain 25, 50, 100 or 200 mg of topiramate per tablet.
  • the tablets also contain lactose, pregelatinised maize starch, carnauba wax, microcrystalline cellulose, sodium starch glycollate, magnesium stearate, titanium dioxide, hypromellose, lauromacrogol 400 and polysorbate 80. In addition, TOPAMAX 50 mg and 100 mg tablets contain iron oxide yellow, and the 200 mg tablets contain iron oxide red.

Capsules

  • contain 15, 25 or 50 mg of topiramate per capsule.
  • the capsules consist of sugar spheres containing topiramate, sucrose, povidone and cellulose acetate, enclosed in a gelatin capsule.
  • the capsule shells contain gelatin and titanium dioxide, and are imprinted with black ink.

Sponsor

JANSSEN-CILAG Pty Ltd
1-5 Khartoum Road, Macquarie Park NSW 2113
Australia
Telephone: 1800 226 334


NZ Office: Auckland New Zealand
Telephone: 0800 800 806

Australian Registration Numbers:

TOPAMAX Tablets.
Blister packs:

25mg - 62709
50mg - 62710
100mg - 62711
200mg - 62712

TOPAMAX Sprinkle Capsules
Bottle:

15mg - 167729
25mg - 167730
50mg - 167731

This leaflet was prepared in February 2019.

Published by MIMS April 2019

BRAND INFORMATION

Brand name

Topamax

Active ingredient

Topiramate

Schedule

S4

 

1 Name of Medicine

Topiramate.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

97240-79-4.

2 Qualitative and Quantitative Composition

Topiramate [2,3:4,5-bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate] is a white crystalline powder with a bitter taste. It is most soluble in alkaline solutions containing sodium hydroxide or sodium phosphate and has a pH of 9 to 10. It is freely soluble in acetone, chloroform, dimethylsulfoxide and ethanol. The solubility in water is 9.8 mg/mL. Its saturated solution has a pH of 6.3.

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

Each tablet contains 25 mg, 50 mg, 100 mg or 200 mg of topiramate.

Excipient(s) with known effect.

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

Topamax sprinkle 15 mg, 25 mg and 50 mg hard capsules.

Each capsule consists of sugar spheres enclosed in a gelatin capsule. The sugar spheres contain 15 mg, 25 mg or 50 mg of topiramate.

Excipient(s) with known effect.

Sugar.
For a full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tablets.

Topamax film-coated tablets are supplied in blisters:
25 mg, round and white, marked "TOP" on one side and "25" on the other;
50 mg, round and light-yellow, marked "TOP" on one side and "50" on the other;
100 mg, round and yellow, marked "TOP" on one side and "100" on the other;
200 mg, round and salmon, marked "TOP" on one side and "200" on the other.

Capsules.

Topamax Sprinkle capsules contain small, white to off-white spheres and are supplied in bottles. Each capsule consists of a clear capsule cap and a white capsule body:
15 mg, imprinted "TOP" on cap and "15 mg" on body;
25 mg, imprinted "TOP" on cap and "25 mg" on body;
50 mg, imprinted "TOP" on cap and "50 mg" on body.

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 Topamax given as monotherapy. Study YI and EPMN-104 evaluated the safety and efficacy of Topamax monotherapy using a dose response design by comparing the low dose regimen with the high dose regimen. Study EPMN-105 compared Topamax 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 Topamax 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 bodyweight. 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 Topamax or standard antiepileptic treatment (carbamazepine or valproate). Topamax 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 study YI and EPMN-104 were enrolled in long-term extension studies with the majority of patients receiving Topamax for 2 to 5 years. In these studies, sustained efficacy was demonstrated with long-term administration of Topamax as monotherapy. There was no significant change in dosage during the extension period and no indication that effectiveness of Topamax monotherapy diminished with continued exposure.
The safety profile of Topamax 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 Topamax 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 Topamax 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. Topamax reduced monthly seizure rates and increased responder rates (fraction of patients with at least 50% seizure reduction) significantly compared to placebo. In addition, Topamax significantly reduced seizure severity in patients with Lennox-Gastaut syndrome. No evidence of tolerance to Topamax has been demonstrated in humans.
In a pooled analysis of two clinical trials involving patients with primary generalised tonic-clonic epilepsy, Topamax (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 Topamax.
There is limited clinical experience with Topamax at or above a daily dose of 1000 mg. Comparative data or data on the safety and efficacy of using Topamax 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 Topamax 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 Topamax doses of 50 (N = 233), 100 (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 Topamax 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 Topamax 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 Topamax observed in the migraine studies was generally consistent with that established for epilepsy therapy.

5.2 Pharmacokinetic Properties

The tablet and capsule formulations of Topamax are bioequivalent at equivalent doses.
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.

Elimination.

In humans, the major route of elimination of unchanged topiramate and its metabolites is via the kidney (at least 81% of the dose). Approximately 66% of a dose of 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 a day 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 long time to reach steady state at each dose (see Section 4.2 Dose and Method of Administration).
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 is 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 Topamax 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.

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.

Topamax is indicated in adults and children, 2 years and over:
as monotherapy in patients with newly diagnosed epilepsy;
for conversion to monotherapy in patients with epilepsy;
as add-on therapy in partial onset seizures (with or without secondary generalised seizures), primary generalised tonic-clonic seizures or drop attacks associated with Lennox-Gastaut syndrome.

Migraine.

Topamax is indicated for the prophylaxis of migraine headache in adults. The usefulness of Topamax in the acute treatment of migraine headache has not been studied.

4.3 Contraindications

Hypersensitivity to any component of this product.

4.4 Special Warnings and Precautions for Use

Withdrawal of Topamax.

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

Hydration.

Adequate hydration while using Topamax 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 Topamax, 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 randomized 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 randomized 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 action 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 Topamax in approved and investigational indications, suicide related events (suicidal ideation, suicide attempts, and suicide) occurred at a frequency of 0.5% in Topamax treated patients (46 out of 8,652 patients treated) compared to 0.2% treated with placebo (8 out of 4,045 patients treated). One completed suicide was reported in a bipolar disorder double blind trial in a patient on topiramate.
Anyone considering prescribing Topamax 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.

Serious skin reactions.

Serious skin reactions (Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)) have been reported in patients receiving Topamax (see Section 4.8 Adverse Effects (Undesirable Effects)). The majority of cases have occurred in patients concurrently taking other medications that are known to be associated with SJS and TEN. There have also been several cases in patients receiving monotherapy. It is recommended that patients be informed about the signs of serious skin reactions. If SJS or TEN are suspected, use of Topamax should be discontinued.

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.

Oligohidrosis and hyperthermia.

Oligohidrosis (decreased sweating) and anhidrosis, infrequently resulting in hospitalization, has been reported in association with Topamax use. Decreased sweating and an elevation in body temperature above normal characterized these cases. Some of the cases were reported after exposure to elevated environmental temperature.
The majority of the reports have been in children. Patients, especially paediatric patients, treated with Topamax should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. Caution should be used when Topamax 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 Topamax should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather.

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.

Use in patients with hepatic impairment.

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

Acute myopia and secondary angle closure glaucoma.

A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving Topamax. Symptoms include acute onset of decreased visual acuity and/or ocular pain. 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 Topamax therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with topiramate has been reported in paediatric patients as well as adults. Treatment includes discontinuation of Topamax as rapidly as possible in the 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 Topamax treatment. This decrease in serum bicarbonate is due to the inhibitory effect of Topamax 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 Topamax.
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 Topamax (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 Topamax 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 nephrolithiasis 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 Topamax 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 Topamax therapy. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing Topamax (using dose tapering).

Hyperammonemia and encephalopathy.

Hyperammonemia with or without encephalopathy has been reported with topiramate treatment (see Section 4.8 Adverse Effects (Undesirable Effects)). 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 Interactions with Other Medicines and Other Forms of Interactions).
Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy. In most cases, hyperammonemic encephalopathy abated with discontinuation of treatment. In patients who develop unexplained lethargy, or changes in mental status associated with topiramate monotherapy or adjunctive therapy, it is recommended to consider hyperammonemic encephalopathy and measuring ammonia levels.

Mood disturbances/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 Topamax on other antiepileptic drugs.

The addition of Topamax 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 Topamax to phenytoin may result in an increase of plasma concentrations of phenytoin. This is possibly due to inhibition of a specific enzyme polymorphic isoform (CYP2C19). Consequently, any patient on phenytoin showing clinical signs or symptoms of toxicity should have phenytoin levels monitored.

Effects of other antiepileptic drugs on Topamax.

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 Topamax therapy may require an adjustment in dosage of the latter. This should be done by titrating to clinical effect.
The addition or withdrawal of valproic acid does not produce clinically significant changes in plasma concentrations of topiramate and, therefore, does not warrant dosage adjustment of Topamax.
The results of these interactions are summarised in Table 3.
No data are available on the use of Topamax 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 Topamax. The clinical relevance of this observation has not been established. When Topamax is added or withdrawn in patients on digoxin therapy, careful attention should be given to the routine monitoring of serum digoxin.

CNS depressants.

Concomitant administration of Topamax and alcohol or other CNS depressant drugs has not been evaluated in clinical studies. It is recommended that Topamax 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 ethinyloestradiol (EO), Topamax given in the absence of other medications at doses of 50 to 200 mg/day was not associated with statistically significant changes in mean exposure (AUC) to either component of the oral contraceptive. In another study, exposure to 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, Topamax (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 Topamax. 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 Topamax (96 mg q12h) when administered alone and concomitantly. The results of this study indicate that Topamax Cmax increased by 27% and AUC increased by 29% when HCTZ was added to Topamax. The clinical significance of this change is unknown. The addition of HCTZ to Topamax therapy may require an adjustment of the Topamax dose. Clinical laboratory results indicated decreases in serum potassium after Topamax or HCTZ administration which were greater when HCTZ and Topamax were administered in combination.

Metformin.

A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of metformin and Topamax in plasma when metformin was given alone and when metformin and Topamax 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 Topamax. Topamax did not affect metformin tmax. The clinical significance of the effect of Topamax on metformin pharmacokinetics is unclear. Oral plasma clearance of Topamax 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 Topamax pharmacokinetics is unclear. When Topamax is added or withdrawn in patients on metformin therapy, careful attention should be given to the routine monitoring for adequate control of their diabetic disease state.

Pioglitazone.

A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of Topamax 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 Topamax is added to pioglitazone therapy or pioglitazone is added to Topamax therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.

Glibenclamide.

A drug-drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state pharmacokinetics of glibenclamide (5 mg/day) alone and concomitantly with topiramate (150 mg/day). There was a 25% reduction in glibenclamide 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.

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

Valproic acid.

Concomitant administration of topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. In most cases, symptoms and signs abated with discontinuation of either drug (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)). This adverse effect is not due to a pharmacokinetic interaction.
Hypothermia, defined as an unintentional drop in body core temperature to < 35°C, has been reported in association with concomitant use of topiramate and valproic acid (VPA) both in conjunction with hyperammonemia and in the absence of hyperammonemia. This adverse event in patients using concomitant topiramate and valproate can occur after starting topiramate treatment or after increasing the daily dose of topiramate.

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)
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 Topamax 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 Topamax in pregnant women.
Topamax 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 is 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 Topamax monotherapy showed a higher prevalence of low birth weight (< 2500 gram). 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 topiramate during pregnancy. In addition, the prevalence of SGA for women who continued topiramate use later in pregnancy is higher compared to women who stopped its use before the third trimester. The long term consequences of the SGA findings could not be determined. A causal relationship for low birth weight and SGA has not been established.
Topamax should be used during pregnancy only if potential benefit justifies the potential risk to the foetus. In treating and counselling 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. Diarrhea 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 bodyweight gain, centrolobullar hepatocellular hypertrophy and slight urothelial hyperplasia in the urinary bladder). There were no relevant effects on long bone (tibia) growth or bone (femur) mineral density, preweaning and reproductive development, neurological development (including assessments on memory and learning), mating and fertility or hysterotomy parameters. Exposure (plasma AUC) was up to 2-fold human exposure at the maximal recommended clinical dose.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial data.

The safety of Topamax was evaluated from a clinical trial database consisting of 4111 patients (3182 on Topamax and 929 on placebo) who participated in 20 double blind trials and 2847 patients who participated in 34 open label trials, respectively, for the treatment of primary generalized tonic clonic seizures, partial onset seizures, seizures associated with Lennox-Gastaut syndrome, newly or recently diagnosed epilepsy or migraine. The information presented in this section was derived from pooled data.
The majority of all adverse reactions were mild to moderate in severity.

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 data, adjunctive epilepsy trials - adult patients.

Adverse drug reactions (ADRs) reported in ≥ 1% of Topamax treated adult patients in double blind, placebo controlled adjunctive epilepsy trials are shown in Table 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 data, adjunctive epilepsy trials - paediatric patients.

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

Double blind, controlled data, monotherapy epilepsy trials - adult patients.

ADRs reported in ≥ 1% of Topamax treated adult patients in double blind, controlled monotherapy epilepsy trials are shown in Table 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 data, monotherapy epilepsy trials - paediatric patients.

ADRs reported in ≥ 2% of Topamax 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 data, migraine prophylaxis trials - adult patients.

ADRs reported in ≥ 1% of Topamax treated adult patients in double blind, placebo controlled migraine prophylaxis trials are shown in Table 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 Topamax treated adult patients are shown in Table 10.
ADRs reported, rate unspecified, in open label clinical trials of Topamax treated paediatric patients are shown in Table 11.

Postmarketing data.

Adverse events first identified as ADRs during postmarketing experience with Topamax, 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.

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

Dosage.

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 Topamax in adults and children for epilepsy are summarised in Table 1.

Epilepsy - monotherapy.

In newly diagnosed epileptic patients, Topamax monotherapy should be initiated at a low dose (see Table 1).
In patients who are being converted to Topamax 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 (see Drug withdrawal and dosage reduction; see Section 4.4 Special Warnings and Precautions for Use). When enzyme inducing drugs are withdrawn, topiramate levels will increase. A decrease in Topamax 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 1000 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.

Epilepsy - add-on therapy.

Adults.

Titration for add-on therapy should begin at 25 to 50 mg as a single (nightly) or divided dose for one week or longer. The dosage should then be increased by 25 to 100 mg/day at weekly or longer intervals to the target dose of 200 to 400 mg/day. The maximum recommended dose should not exceed 1000 mg/day. The daily dosage should be taken as two divided doses.

Children (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 optimise Topamax therapy. For patients receiving concomitant phenytoin and carbamazepine, dosage adjustment for Topamax 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 Topamax 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.

Method of administration.

Topamax tablets should be swallowed whole.
Topamax Sprinkle capsules can be swallowed whole. However, for patients who cannot swallow the capsules (e.g. young children and the elderly), the content of the capsules should be sprinkled on a small amount of soft food and swallowed immediately without chewing. This mixture should not be stored for future use.
Topamax can be taken without regard to meals.

Use in the elderly.

Caution is advised during titration in the elderly with renal disease and/or hepatic impairment (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

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). Patients with moderate and severe renal impairment may require a dose reduction. Half of the usual starting and maintenance dose is recommended (see Section 5.2 Pharmacokinetic Properties).

Use in patients undergoing haemodialysis.

Topiramate is cleared by haemodialysis. To avoid rapid reduction in topiramate plasma concentration during haemodialysis, a supplemental dose of Topamax equal to approximately one-half the daily dose should be administered on haemodialysis days. The supplemental dose should be administered in divided doses at the beginning and completion of the haemodialysis procedure. The supplemental dose may differ based on the characteristics of the dialysis equipment being used (see Section 5.2 Pharmacokinetic Properties). The actual adjustment should take into account 1) the duration of the 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.

Drug withdrawal and dosage reduction.

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

4.7 Effects on Ability to Drive and Use Machines

Topamax acts on the central nervous system and may produce drowsiness, dizziness or other related symptoms. It may also cause visual disturbances and/or blurred vision. These adverse events 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, Metabolic acidosis).
The highest topiramate overdose reported was calculated to be between 96 and 110 g and resulted in coma lasting 20 to 24 hours followed by full recovery after 3 to 4 days.

Treatment.

In the event of overdose, Topiramate should be discontinued and general supportive treatment given until clinical toxicity has been diminished or resolved. Haemodialysis has been shown to be an effective means of removing topiramate from the body. The patient should be well hydrated.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Topamax tablets contain and the inactive ingredients lactose monohydrate, pregelatinised maize starch, carnauba wax, microcrystalline cellulose, sodium starch glycollate, magnesium stearate, and the Opadry coating and colouring for each tablet comprising titanium dioxide, hypromellose, lauromacrogol 400 and polysorbate 80. Additionally, in the coating, the 50 mg and 100 mg tablets contain iron oxide yellow, and the 200 mg and 300 mg tablets contain iron oxide red.
Topamax Sprinkle capsules consist of sugar spheres enclosed in a gelatin capsule. The sugar spheres contain topiramate and the inactive ingredients: povidone, cellulose acetate and sucrose. The capsule shells contain gelatin and titanium dioxide, and are imprinted with black ink.

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

Topamax tablets and Sprinkle capsules should be stored in a dry place below 25°C. Protect Topamax tablets from light and store in the original package.
For Topamax Sprinkle capsules, do not store the drug/ food mixture.

6.5 Nature and Contents of Container

Tablets.

Opaque plastic bottle with tamper-evident closure containing 60 tablets. In each bottle, there is a desiccant canister which should not be swallowed.
Blister pack of an aluminium/aluminium foil in strips. Pack sizes of 20* or 60 tablets (* 25 mg tablets only).
Not all pack type or pack sizes may be marketed.

Sprinkle capsules.

Supplied in opaque bottles with tamper-evident closures. Each bottle contains 60 Sprinkle capsules.

6.6 Special Precautions for Disposal

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

Summary Table of Changes