SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Topiramat Orion 25 mg film-coated tablets Topiramat Orion 50 mg film-coated tablets Topiramat Orion 100 mg film-coated tablets Topiramat Orion 200 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Topiramat Orion 25 mg film-coated tablets: Each film-coated tablet contains 25 mg topiramate. Excipient: 20.09 mg lactose/film-coated tablet

Topiramat Orion 50 mg film-coated tablets: Each film-coated tablet contains 50 mg topiramate. Excipient:. 40.19 mg lactose/film-coated tablet

Topiramat Orion 100 mg film-coated tablets: Each film-coated tablet contains 100 mg topiramate. Excipient: 80.37 mg lactose/film-coated tablet

Topiramat Orion 200 mg film-coated tablets: Each film-coated tablet contains 200 mg topiramate. Excipient: 58.62 mg lactose/film-coated tablet

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet.

Topiramat Orion 25 mg film-coated tablets: White, circular, biconvex film-coated tablets debossed with ‘E’ on one side and ‘22’ on the other side.

Topiramat Orion 50 mg film-coated tablets: Light yellow colored, circular, biconvex film-coated tablets debossed with ‘E’ on one side and ‘33’ on the other side.

Topiramat Orion 100 mg film-coated tablets: Dark yellow colored, circular, biconvex beveled edged film-coated tablets debossed with ‘E’ on one side and ‘23’ on the other side.

Topiramat Orion 200 mg film-coated tablets: Pink colored, circular, biconvex, beveled edged film-coated tablets debossed with ‘E’ on one side and ‘24’ on the other side.

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4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Epilepsy - as monotherapy in adults, adolescents and children with 2 years and above who have generalised tonic- clonic seizures and/or partial onset seizures (with or without secondarily generalised seizures) - as adjunctive therapy in adults, adolescents and children with 2 years and above who have partial seizures (with or without secondarily generalised seizures) and/or primary generalised tonic-clonic seizures and/or seizures associated with Lennox Gastaut Syndrome.

Migraine In adults: The prophylaxis of migraine headache in patients intolerant of or unresponsive to other migraine treatments. Topiramate is not intended to treat an acute migraine attack.

4.2 Posology and method of administration

General: For optimal seizure control and to avoid dose-dependent undesirable effects it is recommended that therapy be initiated at a low dose followed by titration to a clinically effective dose.

Estimation of plasma levels is not necessary for optimisation of topiramate therapy.

Topiramat Orion should not be divided or broken.

Topiramat Orion can be taken without regard to meals and should be swallowed unchewed with a sufficient quantity of liquid.

When concomitant antiepilepsy drugs (AED) are withdrawn to achieve monotherapy with topiramate, consideration should be given to the effects this may have on seizure control. Unless safety concerns require an abrupt withdrawal of the concomitant AED, a gradual discontinuation at the rate of approximately one- third of the concomitant AED dose every 2 weeks is recommended.

When enzyme inducing medicinal products are withdrawn topiramate levels will increase. A decrease in topiramate dosage may be required if clinically indicated.

Topiramate should be withdrawn gradually to minimise the potential of increased seizure frequency. In clinical trials, dosages were decreased by 50–100 mg/day at weekly intervals. In some patients, dose decrease was accelerated without complications.

The following dosing recommendations apply to children, adolescents and all adults, including the elderly, in the absence of underlying renal disease (see section 4.4).

For doses not realisable/practicable with this medicinal product other strengths of this medicinal product are available.

Monotherapy in Adults and Adolescents aged 12 years and over: Titration should begin at 25 mg in the evening for 7 days. The dosage should then be increased at 7 day or 14 day intervals by increments of 25–50 mg/day, administered in two divided doses. If the patient is unable to tolerate the titration regimen, smaller dose increments or longer intervals between dose increments may be used. Dose titration should be guided by clinical outcome.

The recommended initial target dose for topiramate monotherapy in adults is 100 mg/day. The recommended maximum daily dose is 400 mg.

Children of 2 years and above

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Treatment should begin at 0.5–1 mg/kg in the evening for the first week. The dosage should then be increased at 7 day or 14 day intervals by increments of 0.5–1 mg/kg/day, administered in two divided doses. If the child is unable to tolerate the titration regimen, smaller increments or longer intervals between dose increments can be used. Dose and dose titration rate should be guided by clinical outcome.

The recommended initial target dose range for topiramate monotherapy in children is 3–6 mg/kg/day.

Children less than 2 years

The use of the medicinal product in children less than 2 years of age is not recommended as no data are available.

Adjunctive Therapy in Adults and Adolescents aged 12 years and over: Titration should begin at 25–50 mg in the evening for 7 days. The dosage should then be increased at 7 day or 14 day intervals by increments of 25–50 mg/day, administered in two divided doses. If the patient is unable to tolerate the titration regimen, smaller dose increments or longer intervals between dose increments may be used. Dose titration should be guided by clinical outcome.

The minimal effective dose given in clinical studies as adjunctive therapy was 200 mg per day. The usual total daily dose is 200 mg to 400 mg administered in two divided doses. Some patients may achieve efficacy with a once-a-day dosing. Some patients may require higher doses. Some patients may require the maximum daily dose of 800 mg.

Children of 2 years and above

The recommended total daily dose of topiramate is approximately 5–9 mg/kg/day in two divided doses. Titration should begin at 25 mg/day in the evening for the first week (or lower, e.g. 0.5–1 mg/kg/day). The dosage should then be increased at 7 day or 14 day 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.

In individual children daily doses up to 30 mg/kg/day have been studied and were generally well tolerated.

Prophylaxis of Migraine in Adults: Titration should begin at 25 mg in the evening for 7 days. The dosage should then be increased at 7 day intervals by increments of 25 mg/day. If the patient is unable to tolerate the regimen, longer intervals between dose adjustments may be used.

The recommended total daily dose of topiramate for prophylaxis of migraine in adults is 100 mg/day administered in two divided doses. Higher doses do not result in increased benefit. Some patients may experience a benefit at a total daily dose of 50 mg/day. Dose and titration should be guided by clinical outcome.

Impaired RenalFunction: For patients with moderate (creatinine clearance 30-69 ml/min) and severe (creatinine clearance <30 ml/min) renal dysfunction, it is recommended to start with half of the daily dose than usual and to titrate with smaller steps and at slower pace as is usual. As with all patients, the titrations schedule should be guided by clinical outcome with the knowledge that it may require longer to reach steady-state after each dose change in renally impaired patients. In patients with moderate or severe renal impairment, it may take 10 to 15 days to reach steady concentrations as compared to 4 to 8 days in patients with normal renal function.

Impaired HepaticFunction: In hepatically impaired patients, topiramate should be administered with caution as the clearance of topiramate may be decreased (see section 4.4 and 5.2).

3 Patients Undergoing Haemodialysis: Topiramate is removed from plasma by haemodialysis. Therefore a supplemental dose of topiramate equal to approximately one-half the daily dose should be administered on haemodialysis days. The supplemental dose should be administered in divided doses at the beginning and completion of the haemodialysis procedure. The supplemental dose may differ based on the characteristics of the dialysis equipment being used. As for all patients, the dose titration should be guided by clinical outcome (e.g. seizure control, avoidance of side effects).

4.3 Contraindications

Hypersensitivity to topiramate or to any of the excipients in the medicinal product.

Treatment for prophylaxis of migraine during pregnancy, and in women of child bearing potential if not using an effective method of contraception (see section 4.6).

4.4 Special warnings and precautions for use

General:

Hydration: Adequate hydration while using topiramate is important. Hydration can reduce the risk of nephrolithiasis (see below). Treatment with topiramate may decrease sweating, primarily in paediatric patients. Activities such as exercise or exposure to warm temperatures while using topiramate may increase the risk of heat-related adverse events (see section 4.8).

Weight loss: Patients on long-term topiramate treatment should be regularly monitored for weight loss. A dietary supplement or increased food intake may be considered if the patient is losing weight or has inadequate weight gain while on this medication. If clinically significant weight loss occurs, discontinuation of the medication should be considered.

Topiramate should only be used for the prophylaxis of migraine and is not intended for acute treatment.

Renal Impairment: Caution should be exercised when treating patients with moderate to severe renal impairment (see section 4.2) as subjects with known renal impairment may require longer to reach a steady state at each dose.

Nephrolithiasis: Based on the inhibitory effect of topiramate on carbonic anhydrase, there is an increased risk of renal stone formation and associated signs and symptoms such as renal colic, renal pain or flank pain, especially in patients with a predisposition to nephrolithiasis.

Risk factors for nephrolithiasis include prior stone formation, a family history of nephrolithiasis and hypercalciuria. However, none of these risk factors reliably predict stone formation during topiramate treatment. In addition, patients taking other medication associated with nephrolithiasis (Triamteren, Azetazolamide, Vitamin C ≥ 2g/day) may be at increased risk. Such medication should be avoided.

Ketogenic diets should be avoided whilst on topiramate therapy since they may create a physiological environment that increases the risk of renal stone formation.

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

Acute Myopia and Secondary Angle Closure Formation: Acute myopia associated with secondary angle closure glaucoma has been reported in both adults and children receiving topiramate. Symptoms typically occur within 1 month of the start of treatment and include

4 decreased visual acuity and/or ocular pain. Ophthalmological findings include bilateral myopia, anterior chamber shallowing, hyperaemia and increased intra-ocular pressure with or without mydriasis. There may be supraciliary effusion resulting in anterior displacement of the lens and iris. Treatment includes discontinuation of topiramate as rapidly as is clinically feasible and appropriate measures to reduce intraocular pressure. If increased intra-ocular pressure is suspected, immediate specialist advice should be sought. Reports of transient blindness have also been received post-marketing.

Metabolic Acidosis: Hyperchloraemic, non-anion gap, metabolic acidosis (i.e. decreased serum bicarbonate below the normal reference range in the absence of respiratory alkalosis) is associated with topiramate treatment. This decrease in serum bicarbonate is due to the inhibitory effect of topiramate on renal carbonic anhydrase. Generally, the decrease in bicarbonate occurs early in treatment although it can occur at any time during treatment. These decreases are frequent but 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 medicinal products) may be additive to the bicarbonate lowering effects of topiramate.

Chronic metabolic acidosis in paediatric patients can reduce growth rates and may cause osteomalacia (rickets). The effect of topiramate on growth and bone-related sequelae has not been systematically investigated in paediatric or adult populations.

Measurement of serum bicarbonate levels is recommended with topiramate therapy, especially in patients with conditions or therapies that predispose to metabolic acidosis. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing topiramate (using dose tapering).

Chronic metabolic acidosis enhances the risk of stone formation.

Mood disturbances/Depression: Mood disturbances and depression are common during topiramate treatment (see section 4.8). Patients should be monoitored for signs of depression and referred for appropriate treatment if necessary.

Suicide attempt: In double-blind clinical trials, suicide related events (SREs) (suicidal ideation, suicide attempts and suicide) occurred at a frequency of 0.5% in topiramate treated patients (43 out of 7,999 treated patients) and at a 3 fold higher incidence than in those treated with placebo (0.15%; 5 out of 3,150 patients treated).

Patients (and care-givers of patients) should be advised to seek medical advice immediately should suicidal thoughts emerge.

In accordance with good clinical practice, patients with a history of depression and/or suicidal behaviour, adolescents and young adults may be at a greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment.

Lactose This medicinal product contains lactose monohydrate. Patients with rare heredity problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption, should not take this medicine.

Notice! The tablet container contains desiccant. Do not swallow.

4.5 Interaction with other medicinal products and other forms of interaction In an in-vitro study, topiramate was a weak inducer of CYP3A4 enzyme formation in a concentration- dependent manner. This may explain why ethinyl-estradiol (a CYP3A4 substrate) exposure was increased after high doses of topiramate, but not after low doses of topiramate. No other clinical relevant interactions where topiramate acts as a CYP3A4 inducer are reported.

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

Effect of other antiepileptic drugs on topiramate: Phenytoin and carbamazepine decrease the plasma concentration of topiramate. The addition or withdrawal of phenytoin or carbamazepine to topiramate therapy may require an adjustment in dosage of topiramate. This should be done by titrating to clinical effect.

The addition or withdrawal of valproic acid or lamotrigine does not produce clinically significant changes in plasma concentrations of topiramate and, therefore, does not warrant dosage adjustment of topiramate. Concomitant administration of topiramate and valproic acid or other antiepileptic medication 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. This adverse event is not due to a pharmacokinetic interaction.

Effects of topiramate on other antiepileptic drugs: The addition of topiramate to other antiepileptic drugs (carbamazepine, valproic acid, phenobarbital, primidone or lamotrigine) has no clinically significant effect on their steady-state plasma concentrations. In some patients, treatment with topiramate and phenytoin may result in an increase of plasma concentrations of phenytoin. Consequently, it is advised that any patient on phenytoin should have phenytoin levels monitored.

Other drug interactions: Cardiovascular drugs: Digoxin: In a single-dose study, serum digoxin area under plasma concentration curve (AUC) decreased by 12% due to concomitant administration of topiramate. Serum digoxin should be carefully monitored during the first weeks after starting topiramate treatment, when markedly changing the topiramate dose or when discontinuing topiramate treatment.

Diltiazem: Topiramate at a dose of 150 mg/day reduced the exposure to diltiazem and the metabolite des acetyl diltiazem by 25% and 18% respectively, but does not change the exposure to the metabolite N-demethyl diltiazem. The effect of topiramate may be more pronounced at higher doses. Treatment with diltiazem increased the exposure of topiramate by 20%. The effect of diltiazem may be higher when topiramate is used in combination with other AEDs.

Hydrochlorothiazide (HCTZ): HCTZ increases the topiramate exposure by approximately 30%. The clinical relevance of this change is unknown, but the addition of HCTZ to topiramate therapy may require an adjustment of the topiramate dose. The pharmacokinetics of HCTZ is not significantly influenced by the concomitant administration of topiramate. Clinical laboratory results indicate a decrease in serum potassium after topiramate or HCTZ administration, which was greater when HCTZ and topiramate were administered in combination.

Propranolol: 17% increase in Cmax for 4-OH propranolol and 16% increase in Cmax and 17% in AUC for topiramate has been reported during the concomitant treatment of both drugs.

Oral contraceptives: In a pharmacokinetic interaction study with a combined oral contraceptive (1 mg norethisterone plus 35 µg ethinyl estradiol) in healthy volunteers, topiramate monotherapy at doses of 50 to 200 mg/day did not affect exposure (AUC) of the oral contraceptive. However, in another study, exposure to ethinyl estradiol was significantly decreased at topiramate doses of 200, 400 and 800 mg/day when given as an adjunctive therapy in patients taking valproic acid. The levels of norethisterone exposure were not affected. The clinical significance of the changes observed is not known. The risk of decreased contraceptive efficacy and increased breakthrough bleeding should be considered in patients taking estrogen containing contraceptive

6 products in combination with topiramate. Patients who are taking oral contraceptives containing estrogen should be advised to report any change in their menstrual bleeding pattern.

Antidiabetic drugs: Metformin: A drug-drug interaction study conducted in healthy volunteers evaluated in the steady-state pharmacokinetics of metformin 500 mg twice daily and topiramate 100 mg twice daily in plasma when metformin was given alone and when metformin and topiramate were given simultaneously. The results of this study indicated that metformin mean Cmax and mean AUC0-12h increased by 18% and 25%, respectively, while mean CL/F decreased 20% when metformin was co-administered with topiramate. Topiramate did not affect metformin tmax. The clinical significance of the effect of topiramate on metformin pharmacokinetics is unclear. Oral plasma clearance of topiramate appears to be reduced when administered with metformin. The extent of change in the clearance is unknown. The clinical significance of the effect of metformin on topiramate pharmacokinetics is unclear. When topiramate is added or withdrawn in patients on metformin therapy, careful attention should be given to the routine monitoring for adequate control of their diabetic disease state.

Pioglitazone: The steady-state pharmacokinetics of topiramate were not significantly influenced by the concomitant administration of pioglitazone. Topiramate causes a 15% decline in pioglitazone exposure and in the exposure of the active (but less potent) hydroxy- and keto-metabolites of pioglitazone by 16% and 60%, respectively. The clinical significance of these findings is not known. When topiramate is added or withdrawn in patients on pioglitazone therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.

Glibenclamide (Glyburide): Concomitant treatment with topiramate when slowly titrated over 5 weeks and maintained at 150 mg/day for 1 week resulted in a 25% reduction in glyburide AUC24 and a modest reduction in the systemic exposure of the active metabolites, 4-trans-hydroxy-glyburide (M1) and 3-cis-hydroxyglyburide (M2). It may not be excluded that the effect of topiramate is more pronounced at higher doses. The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide. When topiramate is added to glyburide therapy or glyburide is added to topiramate therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.

Psychoactive drugs: Risperidone: When administered concomitantly with topiramate at escalating doses of 100 to 400 mg/day for one week plus the dose titration period, there was a reduction in risperidone 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 (respiidone plus 9-hydroxyrisperidone) and no alterations for 9- hydroxyrespiridone were observed. The effect may be slightly more marked during longer co-treatment and at higher topiramate doses.

Lithium: In healthy volunteers, there was an observed reduction (18% for AUC) in systemic exposure for lithium during concomitant administration with topiramate 200 mg/day. In patients with bipolar disorder, the pharmacokinetics of lithium were unaffected during treatment with topiramate at doses of 200 mg/day; however, there was an observed increase in systemic exposure (26% for AUC) following topiramate doses of up to 600 mg/day. Lithium levels should be monitored when co-administered with topiramate

Amitriptyline: Topiramate does not change the exposure to amitriptyline. However, topiramate increases the exposure to the active amitriptyline metabolite, nortriptyline, by 20%. The clinical relevance of this is not known.

Haloperidole: Topiramate does not change the exposure to haloperidole. However, topiramate increases the exposure to the active reduced haloperidole metabolite by 31%. The clinical relevance of this is not known.

7 Venlafaxine: Venlafaxine does not affect the pharmacokinetics of topiramate. Topiramate 150 mg daily did not affect the pharmacokinetics of venlafaxine or its active metabolite. However, the effect of higher topiramate doses is unknown.

Interactions with alcohol: Central nervous effects might increase in concomitant use with alcohol. It is recommended not to use topiramate in combination with alcohol or other CNS depressants.

Anti-migraine drugs: There are no pharmacokinetic interactions between topiramate and dihydroergotamine or pizotifen.

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

Others: Topiramate, when used concomitantly with other agents predisposing to nephrolithiasis (e.g. acetazolamide, triamteren, zonisamide and Vitamin C > 2g), may increase the risk of nephrolithiasis. While using topiramate, agents like these should be avoided since they may create a physiological environment that increases the risk of renal stone formation.

Concomitant intake of carbonic anhydrase inhibitors (e.g. sultiame, zonisamide) and topiramate has not been examined in clinical studies. Combination of these drugs may increase the side effects due to inhibition of the carbonic anhydrase.

Pharmacokinetic interaction studies have indicated that topiramate influences the pharmacokinetics of flunarizine.

4.6 Pregnancy and lactation Pregnancy: Risks associated with epilepsy and antiepileptics in general Specialist advice should be given to women who are likely to become pregnant or who are of childbearing potential. It is recommended that women of childbearing potential use adequate contraception. The need for antiepileptic treatment should be reviewed when a woman is planning to become pregnant. The risk of birth defect is increased by factor 2 to 3 in the offspring of mothers treated with an antiepileptic. Most frequently reported are cleft lip, cardiovascular malformations and neural tube defects. Multiple antiepileptic drug therapy may be associated with a higher risk of congenital malformations than monotherapy and therefore it is important that monotherapy is practised whenever possible. 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.

Topiramate has been shown to have teratogenic effects in the species studied (mice, rats and rabbits). In rats, topiramate has been shown to cross the placental barrier.

Risks associated with topiramate There are no studies of topiramate in pregnant women. Therefore topiramate should only be used during pregnancy if the potential benefits for the mother outweigh the potential risks to the foetus. In any case, the risk of foetal exposure to topiramate and the risk of sudden discontinuation of therapy need to be considered.

In post marketing experience, hypospadias in male infants exposed in utero to topiramate, with or without other anticonvulsants, have been reported. However, a causal relationship with topiramate has not been established.

Risks of migraine prophylaxis with topiramate Treatment for prophylaxis of migraine with topiramate is contraindicated in pregnancy and in women of childbearing potential if an effective method of contraception is not used (see section 4.3).

8 Lactation: Topiramate is excreted into human breast milk. Limited observation suggests a plasma milk ratio of 1:1. As a potential risk to the child cannot be excluded, topiramate should not be used during breast feeding. If topiramate therapy during breast feeding is required, the mother needs to ablactate.

4.7 Effects on ability to drive and use machines

Topiramate may have a major influence on the ability to drive and use machines. Topiramate acts on the central nervous system and may produce drowsiness, dizziness and other related symptoms that may affect the ability to concentrate when sharpened attention is required. Patients should be advised to exercise caution when driving or using machines until the individual patients experience with the drug is established.

4.8 Undesirable effects

The safety profile for topiramate is based on data from subjects and patients in adjunctive therapy trials.

9 Frequency of Adverse Events Organ System Very Common Common Uncommon Rare Disorder (≥1/10) (≥1/100 and <1/10) (≥1/1000and <1/100) (≥1/10000 and <1/1000) General disorders Dizziness, fatigue, Skeletal pain, allergic and somnolence, reaction, insomnia administration nervousness, site conditions headache, nausea Metabolism and Weight loss Metabolic acidosis nutrition disorders Blood and Anaemia, epistaxis, Neutropenia lymphatic system purpura, leucopenia, disorders thrombocytopenia Psychiatric Difficulty with Apathy, asthenia, Hallucinations, disorders memory, anorexia, euphoria, emotional personality disorders, confusion and lability, agitation, suicidal ideation, suicidal psychomotor cognitive problems, attempts slowing, decreased libido, depression, aggressive reactions, concentration psychosis or psychotic disturbances, symptoms anxiety Respiratory, Dyspnoea thoracic and mediastinal disorders Gastrointestinal Constipation, abdominal Diarrhoea, vomiting and disorders pain dry mouth Skin and Alopecia Folliculitis and pruritus subcutaneous disorders Renal and Urinary incontinence, urinary nephrolithiasis disorders Nervous system Ataxia, Tremor, abnormal co- Hypokinesia, stupor disorders paraesthesia, ordination, abnormal speech disorders, gait, nystagmus, taste aphasia perversion Hepatobiliary Increase in liver disorders enzymes Eye disorders Diplopia, Acute myopia abnormal vision and secondary angle closure glaucoma, eye pain Reproductive Menstrual disturbances, system and impotence breast disorders

10 In patients treated with topiramate as adjunctive therapy, approximately 1 case of thrombo-embolic events per 100 patient years has been reported. Of these, the majority were treated for more than half a year and had more than one risk factor. No relation to topiramate could be established.

Since topiramate has most frequently been co-administered with other antiepileptic agents, it is difficult to determine which agents, if any, are associated with adverse events.

Qualitatively, the types of adverse events observed in monotherapy trials were generally similar to those observed during adjunctive therapy trials. With the exception of paraesthesia and fatigue, these adverse events were reported at similar or lower incidence rates in monotherapy trials. In double-blind clinical trials clinically relevant adverse events occurring at an incidence greater than or equal to 10% in the topiramate- treated adult patients included: paraesthesia, headache, fatigue, dizziness, somnolence, weight decrease, nausea and anorexia.

From marketing use, rare reports of increases in liver enzymes, metabolic acidosis and isolated reports of hepatitis and hepatic failure as well as also convulsions after withdrawal of topiramate have been received in patients treated with topiramate. Clinical trial data indicates that topiramate has been associated with an average decrease of 4 mmol/l in the serum bicarbonate level (see also section 4.4). Oligohidrosis sometimes with accompanying symptoms of fever and flushing have been reported rarely with the use of topiramate. The majority of these reports have been in children. Suicide related events have been reported uncommonly (see section 4.4)

Isolated reports have also been received for bullous skin and mucosal reactions (including erythema multiforme, pemphigus, Stevens-Johnson syndrome and toxic epidermal necrolysis). The majority of these reports have occurred in patients taking other medications also associated with bullous skin and mucosal reactions.

There have been rare reports of acute myopia and secondary angle closure glaucoma in patients treated with topiramate (see also section 4.4). Symptoms include acute onset of decreased visual acuity and/or ocular pain, typically within 1 month of initiating topiramate therapy. Paediatric patients as well as adults have been affected.

From post-marketing use, very rare reports of transient blindness have been received. However a causal relationship with the treatment has not been established. In addition pyrexia, feeling abnormal, hyperammonemia and rash has been reported with the use of topiramate.

Children ≥ 2 years:

In addition to the above mentioned undesirable effects, in clinical studies with children ≥ 2 years the following undesirable effects were observed: hyperkinesia, abnormal behaviour, hypersalivation. In double-blind clinical trials for migraine, the incidence of dose related side effects were in general lower than in epilepsy trials, because lower doses were used in the migraine trials.

4.9 Overdose

Signs and Symptoms: Signs and symptoms reported include: drowsiness, speech disturbances, blurred vision, diplopia, impaired mentation, lethargy, abnormal coordination, stupor, hypotension, abdominal pain, agitation, dizziness, depression and seizures.

Topiramate overdose can result in severe metabolic acidosis (see section 4.4) and hypokalemia.

A patient who ingested a dose of topiramate calculated to be 96–110 g was admitted to hospital with coma lasting 20–24 hours but made a full recovery after 3 to 4 days.

The clinical consequences were not severe in most cases, but deaths have been reported after polydrug overdoses involving topiramate.

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Treatment: General supportive measures are indicated. In acute topiramate overdose were the ingestion is recent, the gastro-intestinal tract should be emptied by gastric lavage or by induction of emesis or activated charcoal should be given to prevent the absorption of topiramate. Haemodialysis has been shown to be an effective means of removing topiramate from the body. The patient should be well hydrated.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties Pharmacotherapeutic group: Other antiepileptics; Antimigraine preparations ATC code: N03 AX11

Topiramate is a novel antiepileptic agent classified as a sulphamate-substituted monosaccharide. Three pharmacological properties of topiramate have been identified that may contribute to its anticonvulsant activity.

Topiramate reduces the frequency at which action potentials are generated when neurones are subjected to a sustained depolarisation indicative of a state-dependent blockade of voltage-sensitive sodium channels.

Topiramate enhances the activity of GABA at some types of GABA receptors. Topiramate weakly antagonises the excitatory activity of kainite/AMPA subtype of glutamate receptor but has no apparent effect on the activity of N-methyl-D-aspartate (NMDA) at the NMDA receptor subtype.

In addition, topiramate inhibits some isoenzymes of carbonic anhydrase. This effect is not thought to be a major component of topiramate antiepileptic activity.

The efficacy of topiramate in prophylaxis of migraine was evaluated in two multicenter randomized, double- blind, placebo-controlled parallel group trials. The pooled results of the trials evaluating topiramate doses of 50 mg/day (N=233), 100 mg/day (N=244) and 200 mg/day (N=228) found a median percent reduction in the primary efficacy endpoint, average monthly migraine period rate, of 35%, 51% and 49% respectively, compared to 21% for the placebo group (N=229). The 100 and 200 mg/day doses of topiramate were statistically superior to placebo, while differences for the 50 mg/day dose compared to placebo were not statistically significant. 27% of patients administered topiramate 100 mg/day achieved at least a 75% reduction in migraine frequency (placebo 11%), whilst 52% achieved at least a 50% reduction (placebo 23%).

In a third multicenter randomized, double-blind, placebo-controlled parallel group study the monthly frequency of migraine periods (the primary endpoint) decreased by –0.8 periods/month from base period for placebo. The reduction under topiramate 100 mg/day was –1.6 periods/month, and under topiramate 200 mg/day it was 1.1 periods/month. Differences were not statistically significant.

In a supplemental study, no statistically significant differences were found between the topiramate 200 mg target dose and placebo in change in the monthly migraine episode rate from baseline.

5.2 Pharmacokinetic properties Absorption: Topiramate is rapidly absorbed. After oral intake of 400 mg, C max is reached after approximately 2 hours. Topiramate has linear pharmacokinetics with a dose-proportional increase of the plasma concentration in the tested dose range of 200-800 mg/day.

There are no data from intravenous administration.

12 Recovery of radioactivity from urine indicates that the mean extent of absorption of a 100 mg dose of 14C topiramate was at least 81%. There is no clinically significant effect of food on topiramate.

The variability in the kinetics is 25-35%. The maximal plasma concentration (Cmax) in healthy volunteers seen after repeated dosage of 100 mg twice daily is apprioximately 7 microg/ml.

Distribution: The mean apparent volume of distribution has been measured as 0.55–0.8 l/kg for single doses up to 1200 mg. There is an effect of gender on the volume of distribution with the distribution volume in females being approximately 50% of that in males. Topiramate is known to bind to erythrocytes but the binding is likely to be saturated at 3–10 μg/ml. Generally, 13–17% of topiramate is bound to plasma proteins.

Based on data from urine, the bioavailability may be estimated to approximately 50%. The variability in the kinetics is 25–35%. There is no information concerning distribution to CSF.

Metabolism: Topiramate is moderately metabolized (approximately 20%) in healthy volunteers. Topiramate metabolism may increase by up to 50% in patients receiving concomitant antiepileptic therapy with known inducers of drug metabolising enzymes. Six metabolites have been isolated, characterised and identified from plasma, urine and human faeces.

Elimination: In humans the major route of elimination of topiramate and its metabolites is via the kidney. Renal clearance is approximately 18 ml/min. This is less than expected and indicates a tubular reabsorption of topiramate. Overall, following oral administration in humans, plasma clearance is approximately 20 to 30 ml/min.

Special Patient Populations: Renal Impairment: Topiramate has linear pharmacokinetics with a dose-proportional increase of the plasma concentration in the tested dose range of 100–800 mg/day. Patients with normal renal function may take 4 to 8 days to reach steady-state plasma concentrations whilst patients with moderate to severe renal impairment may take 10–15 days. The mean maximal plasma concentration (Cmax) in healthy volunteers following multiple, twice daily oral doses of 100 mg was approximately 7 μg/ml. Following administration of multiple doses of 50 mg and 100 mg topiramate twice daily, the mean plasma half-life was approximately 21 hours.

The plasma and renal clearance of topiramate are decreased in patients with impaired renal function. Compared to normal renal function (creatinine clearance >70 mg/min/1.73 m3), topiramate clearance was 42% lower in patients with moderate renal impairment (creatinine clearance <30–69 ml/min) and 54% lower in patients with severe renal impairment (creatinine clearance <30 ml/min). In some patients with severe renal impairment, the reduction in clearance can be larger. In general, half of the usual daily dose is recommended in patients with moderate or severe renal impairment.

Hepatic Impairment: Plasma clearance of topiramate is decreased by 20–30% in patients with moderate to severe hepatic impairment.

13 Elderly Patients: Plasma clearance of topiramate in elderly patients, in the absence of underlying renal disease, is unchanged.

Paediatric Patients: The pharmacokinetics of topiramate in children, as in adults receiving adjunctive therapy, are linear, with clearance independent of dose and steady-state plasma concentrations increasing in proportion to dose. Children, however, have a higher clearance and shorter elimination half-life. Consequently, the plasma concentrations of topiramate for the same mg/kg dose may be lower in children compared to adults. As in adults, hepatic enzyme inducing antiepileptic drugs decrease steady-state plasma concentrations.

5.3 Preclinical safety data In general toxicity studies, topiramate-induced toxicity was identified, with target organs being the stomach, kidney, urinary bladder, and blood (anaemia). Toxicity was evident at systemic exposures of animals, which were below that expected in patients given recommended therapy. The clinical relevance of these findings is unknown, but cannot be excluded.

There is no evidence on genotoxic potential of topiramate. In a carcinogenicity study in the mouse, bladder tumors of smooth muscle origin were observed but were considered to be species specific and thus not relevant to humans. No evidence of carcinogenic potential has been seen in the rat.

Reproductive toxicity studies, showed that topiramate was teratogenic and embryotoxic in the species studied (mice, rats and rabbits), at systemic exposure levels below that expected in patients given recommended therapy. The human risk is unknown, but cannot be excluded.

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.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core: Cellulose, microcrystalline Lactose monohydrate Maize starch, pregelatinised Sodium starch glycolate (type A) Magnesium stearate

Film-coating: Hypromellose Titanium dioxide (E171) Macrogol 400 Polysorbate 80 Iron oxide yellow (E172) (only in 50mg and 100mg) Iron oxide red (E172) (only in 200 mg).

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

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Store below 300C.

6.5 Nature and contents of container

White opaque HDPE bottle with polypropylene cap and silica gel desiccant sachet in pack size of 60 and 100 film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. MARKETING AUTHORISATION HOLDER

To be completed nationally.

8. MARKETING AUTHORISATION NUMBER(S)

To be completed nationally.

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

To be completed nationally.

10. DATE OF REVISION OF THE TEXT

July 2008.

To be completed nationally.

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