Topiramate 25 mg film-coated Tablets

Each tablet contains 25 mg of topiramate.

Excipients:

Each film-coated tablet contains 28.405 mg of lactose.

For a full list of excipients, see section 6.1.

Film-coated tablet.

Round, biconvex film-coated tablets with bevelled edges.

Topiramate 25 mg film-coated tablet

The white tablets are embossed TP on one side and 25 on the other side.

Adults, adolescents and children of 6-12 years of age: Adjunctive therapy of epileptic patients with partial onset and/or generalised tonic-clonic seizures.

Adults, adolescents and children of more than 12 years of age: Monotherapy of epileptic patients with partial onset and/or generalised tonic-clonic seizures.

Adults. Second-line treatment in prophylaxis of migraine.

The usefulness of Topiramate in the acute treatment of migraine has not been studied.

It is recommended to adjust the dose gradually up to the therapeutic level in order to avoid dose-dependent undesirable effects.

It is not necessary to assess the plasma levels for optimisation of treatment with topiramate.

When antiepileptic medicinal products are withdrawn in order to achieve single-drug treatment with topiramate, one must take into account the possible effects on control of seizures. If the patient's safety does not require rapid withdrawal of other concomitant epileptic treatment, gradual withdrawal of the concomitant epileptic treatment by one third every two weeks is recommended.

During withdrawal of active substances with enzyme-inducing activity, topiramate levels will increase. A reduction in the posology of topiramate may be required if clinically indicated.

For doses not realisable/practicable with this medicinal product other strengths of this medicinal product or other pharmaceutical forms and products are available.

Method of administration:

The tablets must not be divided / broken.

Topiramate may be administered with or without food with a sufficient quantity of fluid.

Epilepsy

Adjunctive treatment in epilepsy:

For adults and adolescents of more than 12 years of age:

The guideline for posology must begin with 25 mg to 50 mg of topiramate in the evening for one week. The total daily dose should be subsequently increased in 25 mg - 50 mg increments at weekly or fortnightly intervals and must be divided into two administrations. Adjustment of the dose must be controlled by clinical monitoring.

The minimum effective dose administered in the clinical studies as adjunctive treatment was 200 mg per day. Consequently, it was considered the minimum effective dose. The normal daily dose is 200 mg to 400 mg divided over two administrations. For some patients, good control of seizures is achieved with a single daily dose. Some patients may require a maximum daily dose of 800 mg.

Children aged 6 -12 years

The recommended total daily dose of topiramate as adjunctive therapy is approximately 5 to 9 mg/kg/day in two divided doses. Titration should begin at 25 mg nightly for the first week (or lower, e.g. 0.5-1 mg/kg/day). The dosage should then be increased at 1- or 2-week intervals by increments of about 1 mg/kg/day (administered in two divided doses), to achieve optimal clinical response. Dose titration should be guided by clinical outcome. Dose titration should be guided by clinical outcome.

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

Monotherapy

For adults and adolescents of more than 12 years of age:

The guideline for posology must begin with 25 mg in the evening for one week. The dose should be subsequently increased at intervals of 1 or 2 weeks in increments of 25 or 50 mg/day, divided into two administrations. If the patient is unable to tolerate the dose adjustment schedule, smaller increments or longer intervals may be used. Adjustment of the dose must be controlled by clinical monitoring.

The recommended initial target dose for single-drug treatment with topiramate in adults is 100 mg/day and the maximum recommended dose is 400 mg.

These recommendations for posology apply to all adults, including elderly subjects, in the absence of underlying renal disease (see section 4.4.).

Migraine prophylaxis in adults:

Titration should begin with 25 mg in the evening for one week. The dose should be subsequently increased in increments of 25 mg/day, administered at 1-week intervals. If the patient is unable to tolerate the titration regimen, longer intervals between the dose adjustments may be used.

The recommended total daily dose of topiramate as prophylactic treatment for migraine is 100 mg/day divided into two administrations. Higher doses did not result in any increased benefit. Some patients may experience a benefit at a total daily dose of 50 mg/day. The dose and its adjustment should be guided by clinical outcome.

Further information:

Patients with liver and/or renal impairment:

In patients with moderate (creatinine clearance of 30-69 ml/min) and severe renal impairment (creatinine clearance <30 ml/min), it is recommended to begin with half the usual daily dose and adjust the dose with smaller increments and at a slower rate than usual. As with all patients, the dose adjustment schedule must be controlled by clinical monitoring with the knowledge that more time may be required to achieve steady state following each change in dose in patients with renal impairment. In patients with moderate or severe renal failure, it may take 10 to 15 days in order to achieve the steady state concentration, in comparison to 4 to 8 days in patients with normal renal function.

Topiramate should be administered with caution in patients with liver impairment, since the latter may reduce its excretion.

Patients undergoing haemodialysis:

Since topiramate is excreted in plasma through haemodialysis, an additional dose of topiramate equal to approximately half the daily dose should be administered on the days of haemodialysis. The additional dose should be administered in divided doses at the beginning and end of the haemodialysis procedure. The additional dose may vary depending on the type of dialysis and equipment used. As with other patients, dose adjustment is performed depending on the clinical result (for example, control of seizures, avoidance of adverse events).

Withdrawal:

Antiepileptic medicinal products, including topiramate, must be withdrawn gradually in order to minimise the possibility of an increased frequency of seizures. In the clinical studies, the doses were reduced by 50 – 100 mg/day at weekly intervals.

Hypersensitivity to topiramate or to any of the excipients.

Prophylactic treatment of migraine: pregnancy and in women of childbearing potential if not an effective method of contraception is used (see section 4.6).

Renal impairment

The main route of elimination of topiramate and its metabolites is through the kidneys. Caution should be exercised in patients with moderate or severe renal impairment. Accumulation may occur owing to the reduced elimination and it may take more time than usual to achieve steady state. Dose adjustment should be performed at a more gradual rate than usual (see section 4.2).

Hydration

Adequate hydration is important during administration of topiramate. Hydration may reduce the risk of kidney stones (see below). Treatment with topiramate may reduce perspiration, mainly in paediatric patients. Activities such as exercise or exposure to high temperatures during use of topiramate may increase the risk of adverse reactions related to heat (see section 4.8).

Nephrolithiasis

There is an increased risk of formation of renal calculi and associated signs and symptoms such as renal colic and renal or lower back pain, particularly in patients who are predisposed to nephrolithiasis.

The risk factors for nephrolithiasis include previous formation of calculi, a familial history of nephrolithiasis and hypercalciuria. None of these factors can reliably predict formation of calculi during treatment with topiramate. Topiramate, when used concomitantly with other agents that predispose to nephrolithiasis (acetazolamide, triamteren and vitamin C> 2 g/day), may increase the risk of nephrolithiasis. During administration of topiramate, agents such as the latter and ketogenic dietary regimens should be avoided, since they may create a physiological environment that increases the risk of formation of renal calculi.

Impaired liver function

Topiramate should be administered with caution in patients with hepatic impairment, since it may reduce topiramate clearance.

Acute myopia and glaucoma secondary to closed angle

Glaucoma secondary to closed angle with acute myopia has been observed in patients receiving topiramate (see also section 4.8). Treatment includes discontinuation of topiramate as rapidly as possible according to medical opinion, in addition to appropriate measures in order to reduce intraocular pressure.

Metabolic acidosis

Hyperchloraemic metabolic acidosis (i.e. decrease in serum bicarbonate below the normal reference interval in the absence of respiratory alkalosis) is associated with treatment with topiramate. This reduction in serum bicarbonate is due to the inhibitory effect of topiramate on renal carbonic anhydrase. In general, reduction in bicarbonate occurs at the outset of treatment, although it may occur at any time during treatment. This type of reduction frequently occurs, but is normally slight to moderate (an average decrease of 4 mmol/l at a dose of 100 mg/day or more in adults and approximately 6 mg/kg/day in paediatric patients). On rare occasions, patients have experienced reductions to values of less than 10 mmol/l. Conditions or treatments that predispose to acidosis (such as renal disease, serious respiratory disorders, status epilepticus, diarrhoea, surgery, ketogenic diet or certain active substances) may be additive to the bicarbonate-reducing effects produced by topiramate.

Chronic metabolic acidosis increases the risk of formation of renal calculi.

Chronic metabolic acidosis in paediatric patients may result in osteomalacia (rickets) and may reduce growth rate. The effect of topiramate on growth and the sequelae related to bones have not been systematically investigated in paediatric populations or in adults.

It is recommended to measure the serum bicarbonate levels during treatment with topiramate, particularly in patients with conditions or treatment which predispose to metabolic acidosis. If metabolic acidosis develops and persists, a reduction in dose or withdrawal for topiramate should be considered (using a gradual reduction in dose).

Mood changes / depression

An increase in the incidence of mood changes and depression has been observed during treatment with topiramate (see section 4.8). Patients must be monitored in order to investigate signs of depression be referred for appropriate treatment if necessary.

Suicide/suicidal thoughts or clinical worsening

Suicidal ideation and behaviour have been reported ni patients treated with antiepileptic agents in several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for Topiramate.

Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

Migraine prophylaxis in adults

Patients under long-term treatment with topiramate for migraine prophylaxis must weigh themselves regularly and monitor themselves for weight loss. If clinically significant weight loss occurs, discontinuation of the medication should be considered.

Weight loss

Supplementary nutrition should be considered in patients with weight loss during treatment.

Lactose

This medicine contains lactose as an excipient. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

The container contains desiccant that must not be swallowed.

Effect of topiramate on other antiepileptic medicinal products

Combination of topiramate with carbamazepine, valoproic acid, phenobarbital, primidone or lamotrigine does not have any effect, or only a limited effect on its steady-state plasma concentrations. In isolated patients, treatment with topiramate and phenytoin may result in an increase in the plasma concentrations of phenytoin. Consequently, the plasma concentrations of phenytoin should be monitored in patients with symptoms of phenytoin toxicity.

Effects of other antiepileptic medicinal products on topiramate

During simultaneous treatment with phenytoin or carbamazepine, the topiramate plasma concentration decreases, probably due to metabolic induction. Addition to or removal from the treatment with topiramate of phenytoin or carbamazepine may require adjustment of the dose of the former. This must be performed by means of adjustment of the dose in order to determine the clinical effect.

Addition or removal of valproic acid or lamotrigine does not result in any clinically significant changes in the topiramate plasma concentration. There have been rare reports of encephalopathy with or without hyperamonaemia in patients treated with topiramate whilst they were also taking valproate or another antiepileptic medicinal product.

Other medicinal product interactions

Digoxin: the AUC (area under the curve) for a single dose of digoxin decreases by 12% owing to concomitant administration of topiramate. When patients are treated simultaneously with digoxin and topiramate, serum digoxin must be carefully monitored. Serum digoxin must also be carefully monitored after withdrawal of topiramate.

Contraceptives: in a pharmacokinetic interaction study in healthy volunteers, single-drug treatment with topiramate at a dose of 50 mg/day to 200 mg/day did not affect the exposure (AUC) of combined oral contraceptives (containing 1 mg of norethisterone plus 35 micrograms of ethynylestradiol). However, in another study, exposure to ethynylestradiol significantly decreased at a dose of topiramate of 200, 400 and 800 mg/day (18%, 21% and 30% respectively) when administered as adjunctive treatment in patients taking valproic acid, whereas the exposure to norethisterone was not affected. The clinical significance of these changes observed is unknown. One must consider the risk of reduction in efficacy of contraceptives even in the absence of breakthrough bleeding and the increase in intermenstrual haemorrhage in patients taking contraceptives containing oestrogens in conjunction with topiramate.

Patients taking oral contraceptives should be asked to report any change in their bleeding patterns. Patients taking oral contraceptives containing oestrogens should be advised to use some alternative non-hormonal method of contraception.

Hydrochlorothiazide (HCTZ):HCTZ increases exposure to topiramate by approximately 30%. The clinical importance of this change is unknown; however addition of HCTZ to treatment with topiramate may require an adjustment in the dose of topiramate. The pharmacokinetics of HCTZ are not significantly influenced by concomitant administration of topiramate. Clinical laboratory results showed a reduction in serum potassium following administration of topiramate or HCTZ, which was greater when HCTZ and topiramate were administered in combination.

Serum levels of lithium should be controlled if lithium is administered concomitant with topiramate, as, dependent on the dosage of topiramate, the serum levels of lithium may be reduced or enhanced.

Pharmacokinetic interaction studies in patients with diabetes mellitus type II showed 25 % reduction of the AUC of glibenclamide after introduction of topiramate (150 mg/day) to glibenclamide (5 mg/day). Systemic exposition of the active glibenclamide metabolites was also reduced. Steady state pharmacokinetics of topiramate were not altered. When topiramate is added to glibenclamide or glibenclamide is added to an existing topiramate medication, careful monitoring should take place in order to ensure adequate control of the diabetes mellitus.

Pharmacokinetic interaction studies have indicated, that topiramate influences the pharmacokinetics of flunaricine and diltiazem as well as the pharmacokinetic of the metabolites of diltiazem. Diltiazem increases the plasma level of topiramate.

Metformin: a study of pharmacological interactions performed in healthy volunteers assessed the steady-state plasma pharmacokinetics metformin, administered alone and with topiramate (metformin: 500 mg twice a day; topiramate: 100 mg twice a day). The result of this study indicated that the mean C_max and AUC _0-12h of metformin increased by 18% and 25% respectively, whereas mean CL/F decreased by 20% when metformin was administered concomitantly with topiramate. The clinical significance of the effect of topiramate on the pharmacokinetics of metformin is not clear. The oral plasma clearance of topiramate appears to be reduced when administered concomitantly with metformin. The degree of change in clearance is unknown. The clinical significance of the effect of metformin on the pharmacokinetics of topiramate is not clear. When topiramate is added or withdrawn in patients treated with metformin, scrupulous attention must be paid to the usual monitoring for adequate control of their diabetes.

Interactions with alcoholor CNS depressants: the effects on the central nervous system could increase with concomitant alcohol consumption. It is recommended not use topiramate in conjunction with alcohol or other CNS depressants.

Pioglitazone:the steady-state pharmacokinetics of topiramate did not appear significantly influenced by concomitant administration of pioglitazone. Topiramate results in a 15% reduction in exposure to pioglitazone and in a 16 and 60% reduction in exposure to the active (but less potent) hydroxy and keto metabolites of pioglitazone, respectively. The clinical significance of these findings is unknown. When topiramate is added to treatment with pioglitazone or pioglitazone is added to or withdrawn from treatment with topiramate, scrupulous attention must be paid to the usual monitoring for adequate control of their diabetes.

Additional pharmacokinetic studies of pharmacological interaction: topiramate does not modify exposure to amitryptiline. However, topiramate increases exposure to the active metabolite of amitryptiline, nortryptiline, by 20%. The clinical significance of this is unknown.

Topiramate does not modify exposure to haloperidol. However, it increases exposure to the reduced active metabolite of haloperidol by 31%. The clinical significance of this is unknown.

There are no pharmacokinetic interactions between topiramate and propranolol, dihydroergotamine or pizotifen.

Topiramate does not affect the pharmacokinetics of sumatriptan (oral or subcutaneous).

Possible interactions which have not been studied:

Topiramate inhibits the enzyme CYP 2C19 and may influence other active substances which are metabolised through this enzyme, such as diazepam, imipramine, moclobemide, proguanil and omeprazole. However, this has not been studied.

Simultaneous ingestion of carbonic anhydrase inhibitors (such as sulthiame, zonisamide) and topiramate has not been studied in clinical trials. Combination of these active substances may increase the adverse events due to carbonic anhydrase inhibition.

Pregnancy

An increase in the frequency of malformations (craniofacial malformations and malformation of the distal extremity and heart failure) has been observed following use of certain antiepileptic medicinal products during the first trimester of pregnancy.

Concomitant treatment appears to increase the risk of malformation; consequently it is important to administer single-drug treatment whenever possible.

It has been shown that topiramate has teratogenic effects in the species studied (mice, rats and rabbits). In rats, topiramate crosses the placental barrier.

Special counselling should be given to women who may become pregnant or who are of childbearing age. Women of childbearing age are recommended to use an adequate contraceptive method.

The need for antiepileptic treatment must be reviewed when a women is planning to become pregnant.

No sudden discontinuation of antiepileptic therapy should be undertaken as this may lead to breakthrough seizures which could have serious consequences for both mother and child.

Indication of epilepsy

No studies exist concerning administration of topiramate in pregnant women. However, topiramate should only be used in pregnancy if the possible benefit offsets the possible risk.

During post-marketing surveillance, cases of hypospadias have been reported in male neonates exposed in utero to topiramate, whether as single-drug treatment or as an adjunctive medicinal product for other antiepileptic medicinal product. It has not been established whether a causal relationship with topiramate exists.

However, if prophylaxis of seizures is affected or discontinued, this may incur a considerable risk for both the mother and foetus, which is probably more serious than the risk of malformation. Consequently, an antiepileptic medicinal product must only be prescribed during pregnancy taking account of what has been said above.

Indication of migraine prophylaxis

Treatment for migraine prophylaxis: During pregnancy, onset of seizures constitutes a considerable risk to the mother and infant. Prevention of seizures with topiramate, insofar as it is administered for the correct indication, therefore offsets the risk of malformations. Avoidance of migraine attacks however does not offset this risk. Consequently, topiramate for the indication of migraine prophylaxis is contraindicated during pregnancy and in women of childbearing potential if not an effective method of contraception is used (see section 4.3).

Lactation

Topiramate is excreted in the milk of human mothers. In isolated cases it has been observed that the ratio between plasma and milk is 1:1. Consequently, the importance of lactation must be considered, taking account of the importance of the medicinal product for the mother. Topiramate should not be used during breast feeding.

Topiramate has a major influence on the ability to drive and use machines.

Topiramate acts on the central nervous system and may cause somnolence, dizziness, visual disturbance and other related symptoms These adverse events could potentially be dangerous in patients driving a vehicle or operating machinery, particularly until such time as the individual patient's experience with the active substance is established.

The undesirable effect profile of topiramate is based on the data of clinical studies performed in 1800 patients.

Very common > 1/10;

Common (> 1/100 to < 1/10);

Uncommon (> 1/1000 to < 1/100);

Rare (> 1/10 000 to < 1/1000).

In patients treated with topiramate as concomitant treatment, approximately 1 case of thromboembolic events per 100 patients has been reported annually. Among the latter, the majority were treated for more than six months and had more than one risk factor. It was not possible to establish a relationship with topiramate.

Given that topiramate has been more frequently concomitantly administered with other antiepileptic agents, it is difficult to determine which agents, if any, are associated with undesirable effects.

Qualitatively, the type of undesirable events observed in the trials with single-drug treatment was generally similar to those observed during the trials with concomitant treatments. With the exception of paresthesia and fatigue, these undesirable effects were reported with a similar or lower incidence in the trials with single-drug treatment. In double-blind clinical trials, the clinically relevant undesirable effects which occurred with a incidence greater than or equal to 10% in adult patients treated with topiramate included: paresthesia, headache, fatigue, dizziness, somnolence, weight loss, nausea and anorexia.

Since its marketing, few cases of raised hepatic enzymes, metabolic acidosis and isolated cases of hepatitis and hepatic failure, in addition to seizures following withdrawal of topiramate (including in patients without a history of epilepsy) in patients treated with topiramate have been reported. The data from the clinical trials indicate that topiramate has been associated with an average reduction of 4 mmol/l in the serum bicarbonate level (see section 4.4). There have been rare reports of oligohydrosis with associated symptoms of fever and suffocation with use of topiramate. The majority of these cases occurred in children. Undesirable effects related to suicide have been uncommonly reported (see section 4.4).

Isolated cases of appearance of blisters on the skin and mucosal reactions have been reported (including erythema multiforme, pemphigus, Stevens-Johnson syndrome and toxic epidermal necrolysis). The majority of these cases occurred in patients taking other medicinal products also associated with occurrence of blisters on the skin and mucosal reactions.

Rarely, cases of acute myopia and glaucoma secondary to closed angle have been reported in patients treated with topiramate (see section 4.4). The symptoms include acute onset of reduction in visual acuity and/or eye pain, normally within one month after beginning treatment with topiramate. Both paediatric and adult patients have been affected.

Following marketing, very rare cases of transient blindness were reported. However, a causal relationship with treatment has not been established.

In double-blind clinical studies of migraine, the incidence of dose-related adverse events was, in general, lower than that observed in the epilepsy trials since lower doses were used in the migraine trials.

Children of 6 years of age or older:

In addition to the above mentioned undesirable effects, in clinical studies with children of 6 years of age or older the following undesirable effects were observed: hyperkinesia, abnormal behaviour, hypersalivation.

Signs and symptoms

Cases of overdose with topiramate have been reported. The signs and symptoms included headache, somnolence, impaired speech, blurred vision, diplopia, impaired mental activity, lethargy, abnormal coordination, drowsiness, hypotension, abdominal pain, agitation, dizziness, depression and convulsions. The clinical consequences were not serious in the majority of cases, but cases of death due to overdose with multiple active substances, including topiramate, have been reported.

Overdose with topiramate may result in serious metabolic acidosis (see section 4.4) and hypokalaemia.

A patient who ingested a dose calculated as between 96 and 110 g of topiramate was hospitalized with coma which lasted 20 - 24 hours, but complete recovery was obtained within 3 - 4 days.

Treatment

Treatment should be supportive. The unabsorbed active substance must be eliminated from the gastrointestinal tract by means of lavage or activated charcoal, if considered necessary from a clinical point of view. It has been demonstrated that haemodialysis is an effective means of eliminating topiramate from the body. The patient must be well hydrated.

Pharmacotherapeutic group: other antiepileptics, antimigraine preparations.

ATC code: N03AX11

Topiramate is classified as a sulfamate-substituted monosaccharide. Three pharmacological properties of topiramate have been identified which may contribute to its anticonvulsive activity.

Topiramate reduces the frequency at which the action potentials are generated when the neurones are exposed to sustained depolarisation indicating a status-dependent block of the voltage-sensitive sodium channels.

Topiramate increases the activity of GABA in some types of GABA receptors. Topiramate weakly antagonises the excitatory activity of the kainate/AMPA subtype of glutamate receptors, but does not have any apparent effect on the activity of N-methyl-D-aspartate (NMDA) subtype receptors.

Furthermore, topiramate inhibits some isoenzymes of carbonic anhydrase. It is not believed that this effect is a main component of the antiepileptic activity of topiramate.

The efficacy of topiramate in migraine prophylaxis was assessed in two multicenter, randomised, double-blind, placebo-controlled, parallel-group trials. The pooled results of the trials which assessed doses of topiramate of 50 (N = 233), 100 (N = 244) and 200 mg/day (N = 228) showed a mean percentage reduction in the primary efficacy endpoint, the mean rate of monthly periods of migraine, of 35%, 51% and 49% respectively, in comparison with 21% in the placebo group (N = 229). The doses of topiramate of 100 and 200 mg/day were statistically superior to placebo, whereas the dose of 50 mg/day was not statistically significant different from the placebo. Among the patients treated with 100 mg of topiramate/day, 27% achieved at least a 75% reduction in the frequency of migraine (placebo 11%), and 52% a reduction of at least 50%. (placebo 23%).

In a third multicenter, randomised, double-blind, parallel group study, it was demonstrated that the monthly frequency of migraine (primary endpoint) decreased by -0.8 periods/month when compared with the placebo baseline value. The reduction was -1.6 periods/month with 100 mg/day of topiramate and -1.1 periods/month with 200 mg of topiramate/day. These differences were not statistically significant.

In an additional supplementary study, based on analysis of primary efficacy, no statistically significant differences were observed between the target dose of 200 mg of topiramate and placebo (change in the monthly rate of periods of migraine versus the initial level).

Absorption

Topiramate is rapidly absorbed. Following oral ingestion of 400 mg, C_max is reached after approximately 2 hours. Topiramate has linear pharmacokinetics with a dose-dependent increase in plasma concentrations within the tested dose range of 200 - 800 mg/day.

No data concerning intravenous administration are available. Based on urinary recovery of radioactivity, the mean level of absorption of a dose of 100 mg of ¹⁴C-topiramate was at least 81%. Based on the urinary data, it may be estimated that the bioavailability is approximately 50%. Food does not have any clinically significant effect on topiramate. The variability in kinetics is 25 - 35%. The maximum plasma concentration (C_max) in healthy volunteers observed following a repeated dose of 100 mg twice a day was approximately 7 µg/ml.

Distribution

The mean apparent volume of distribution was 0.55 – 0.8 l/kg. There is a gender effect on volume of distribution, since the volume of distribution in women is approximately 50% of that of men. Topiramate binds to erythrocytes, but the bond is most probably saturated at 3 - 10 µg/ml. The rate of binding to plasma proteins is 13 - 17%. No data are available concerning distribution in CSF.

Metabolism

Topiramate is moderately metabolised (approximately 20%) in healthy volunteers. Following simultaneous administration of antiepileptics with a known enzyme inducing effect, metabolism may increase to 50%. Six metabolites have been isolated, characterised and identified from plasma, urine and faeces in humans.

Elimination

Renal clearance is approximately 18 ml/min. This is much less than expected, indicating tubular reabsorption of topiramate. In general, plasma clearance is approximately 20 to 30 ml/min following oral administration. The major route of elimination of topiramate and its metabolites is via the kidneys.

Following repeated administration of 50 mg and 100 mg of topiramate twice a day, the mean half-life is approximately 21 hours. Patients with normal renal function may take 4 - 8 days to achieve steady-state plasma concentrations, whereas patients with moderate to severe renal failure may require 10 - 15 days of treatment. Plasma and renal clearance of topiramate are decreased in patients with impaired renal function.

Special groups of patients

Renal failure:

In comparison with normal renal function (creatinine clearance> 70 ml/min), clearance of topiramate was 42% less in patients with moderate renal failure (creatinine clearance 30 - 69 ml/min) and 54% less in patients with severe kidney failure (creatinine clearance < 30 ml/min). In some patients with serious kidney failure, the reduction in clearance may be greater. In general, half the usual daily dose is recommended in patients with moderate or severe kidney failure.

Liver failure:

Plasma clearance of topiramate is reduced by 20 – 30% in patients with moderate or severe liver failure.

In general toxicity studies, toxicity induced by topiramate was identified, the target organs being the stomach, kidneys, urinary bladder and blood (anaemia). Toxicity was obvious in cases of systemic exposure of animals to levels inferior to those expected in patients receiving the recommended treatment. The clinical significance of these findings is unknown, but they cannot be ruled out.

The studies of reproductive toxicity showed that topiramate is teratogenic in the species studied (mice, rats and rabbits), at levels of systemic exposure lower than those expected in patients receiving the recommended treatment. The risk in humans is unknown, but cannot be ruled out.

Moderate inhibition of a rapid potassium channel has been demonstrated in vitro, suggesting a potential risk for QT prolongation at high doses in the presence of other arrhythmogenic factors.

Core:

• Lactose monohydrate

• Pregelatinised starch (i.e. potato starch)

• Microcrystalline cellulose

• Croscarmellose sodium

• Magnesium stearate

Coating:

• Hypromellose

• Titanium dioxide (E171)

• Macrogol 6000

Not applicable.

2 years.

Do not store above 25°C. Keep the container tightly closed.

Topiramate film-coated tablets are available in aluminium/aluminium blisters in packs sizes of 14, 20, 28, 50, 60, 100 and 200 film-coated tablets or in high density polyethylene (HDPE) bottles supplied in cardboard cartons in pack sizes of 14, 60, 200 film-coated tablets.

Not all pack sizes may be marketed.

The container contains desiccant capsules.

No special requirements.

Winthrop Pharmaceuticals UK Limited

One Onslow Street

Guildford

Surrey

GU1 4YS

UK

Trading as: Winthrop Pharmaceuticals, PO Box 611, Guildford, Surrey, GU1 4YS, UK.

PL 17780/0302

19/08/2008

21/11/2008