4.1. Therapeutic indications

Monotherapy in adults, adolescents and children over 6 years of age with partial seizures with or without secondary generalised seizures, and primary generalised tonic-clonic seizures.

Adjunctive therapy in children aged 2 years and above, adolescents and adults with partial onset seizures with or without secondary generalization or primary generalized tonic-clonic seizures and for the treatment of seizures associated with Lennox-Gastaut syndrome.

Topiramate is indicated in adults for the prophylaxis of migraine headache after careful evaluation of possible alternative treatment options. Topiramate is not intended for acute treatment.

4.2. Posology and method of administration

Posology

It is recommended that therapy be initiated at a low dose followed by titration to an effective dose. Dose and titration rate should be guided by clinical response.

It is not necessary to monitor topiramate plasma concentrations to optimize therapy with topiramate. On rare occasions, the addition of topiramate to phenytoin may require an adjustment of the dose of phenytoin to achieve optimal clinical outcome. Addition or withdrawal of phenytoin and carbamazepine to adjunctive therapy with Topiramate Milpharm may require adjustment of the dose of Topiramate Milpharm.

In patients with or without a history of seizures or epilepsy, antiepileptic drugs (AEDs) including topiramate should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency. In clinical trials, daily dosages were decreased in weekly intervals by 50-100 mg in adults with epilepsy and by 25-50 mg in adults receiving topiramate at doses up to 100 mg/day for migraine prophylaxis. In paediatric clinical trials, topiramate was gradually withdrawn over a 2-8 week period.

Monotherapy epilepsy

General

When concomitant AEDs are withdrawn to achieve monotherapy with topiramate, consideration should be given to the effects this may have on seizure control.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

When enzyme inducing medicinal products are withdrawn, topiramate levels will increase.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

Adults

Dose and titration should be guided by clinical response. Titration should begin at 25 mg nightly for 1 week. The dosage should then be increased at 1- or 2-week intervals by increments of 25 or 50 mg/day, administered in two divided doses. If the patient is unable to tolerate the titration regimen, smaller increments or longer intervals between increments can be used.

The recommended initial target dose for Topiramate Milpharm monotherapy in adults is 100 mg/day to 200 mg/day in 2 divided doses. The maximum recommended daily dose is 500 mg/day in 2 divided doses. Some patients with refractory forms of epilepsy have tolerated topiramate monotherapy at doses of 1,000 mg/day. These dosing recommendations apply to all adults including the elderly in the absence of underlying renal disease.

Paediatric population (children over 6 years of age)

Dose and titration rate in children should be guided by clinical outcome. Treatment of children over 6 years of age should begin at 0.5 to 1 mg/kg nightly for the first week. The dosage should then be increased at 1 or 2 week intervals by increments of 0.5 to 1 mg/kg/day, administered in two divided doses. If the child is unable to tolerate the titration regimen, smaller increments or longer intervals between dose increments can be used.

The recommended initial target dose range for topiramate monotherapy in children over 6 years of age is 100 mg/day depending on clinical response, (this is about 2.0 mg/kg/day in children 6-16 years).

Adjunctive therapy epilepsy (partial onset seizures with or without secondary generalization, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome).

Adults

Therapy should begin at 25-50 mg nightly for one week. Use of lower initial doses has been reported, but has not been studied systematically. Subsequently, at weekly or bi-weekly intervals, the dose should be increased by 25-50 mg/day and taken in two divided doses. Some patients may achieve efficacy with once-a-day dosing.

In clinical trials as adjunctive therapy, 200 mg was the lowest effective dose. The usual daily dose is 200-400 mg in two divided doses.

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

Paediatric population (children aged 2 years and above)

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 (or less, based on a range of 1 to 3 mg/kg/day) nightly for the first week. The dosage should then be increased at 1- or 2-week intervals by increments of 1 to 3 mg/kg/day (administered in two divided doses), to achieve optimal clinical response.

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

Migraine

Adults

The recommended total daily dose of topiramate for prophylaxis of migraine headache is 100 mg/day administered in two divided doses. Titration should begin at 25 mg nightly for 1 week. The dosage should then be increased in increments of 25 mg/day administered at 1-week intervals. If the patient is unable to tolerate the titration regimen, longer intervals between dose adjustments can be used.

Some patients may experience a benefit at a total daily dose of 50 mg/day. Patients have received a total daily dose up to 200 mg/day. This dose may be benefit in some patients, nevertheless, caution is advised due to an increase incidence of side effects.

Paediatric population

Topiramate Milpharm is not recommended for treatment or prevention of migraine in children due to insufficient data on safety and efficacy.

General dosing recommendations for Topiramate Milpharm in special patient populations

Renal impairment

In patients with impaired renal function (CLCR ≤ 70 mL/min) topiramate should be administered with caution as the plasma and renal clearance of topiramate are decreased. Subjects with known renal impairment may require a longer time to reach steady-state at each dose. Half of the usual starting and maintenance dose is recommended (see section 5.2).

In patients with end-stage renal failure, since Topiramate Milpharm is removed from plasma by haemodialysis, a supplemental dose of topiramate equal to approximately one-half the daily dose should be administered on haemodialysis days. The supplemental dose should be administered in divided doses at the beginning and completion of the haemodialysis procedure. The supplemental dose may differ based on the characteristics of the dialysis equipment being used (see section 5.2).

Hepatic impairment

In patients with moderate to severe hepatic impairment topiramate should be administered with caution as the clearance of topiramate is decreased.

Elderly

No dose adjustment is required in the elderly population providing renal function is intact.

Method of administration

Topiramate is available in film coated tablets and a hard capsule formulation, for oral administration. It is recommended that film coated tablets not be broken. The hard capsule formulation is provided for those patients who cannot swallow tablets, e.g. paediatric and the elderly.

Topiramate can be taken without regard to meals.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Prophylaxis of migraine

• in pregnancy (see sections 4.4 and 4.6).

• in women of childbearing potential unless the conditions of the Pregnancy Prevention Programme are fulfilled (see sections 4.4, 4.5 and 4.6).

Epilepsy

• in pregnancy unless there is no suitable alternative (see sections 4.4 and 4.6).

• in women of childbearing potential unless the conditions of the Pregnancy Prevention Programme are fulfilled (see sections 4.4, 4.5 and 4.6).

4.4. Special warnings and precautions for use

In situations where rapid withdrawal of topiramate is medically required, appropriate monitoring is recommended (see section 4.2).

As with other AEDs, some patients may experience an increase in seizure frequency or the onset of new types of seizures with topiramate. These phenomena may be the consequence of an overdose, a decrease in plasma concentrations of concomitantly used AEDs, progress of the disease, or a paradoxical effect.

Adequate hydration while using topiramate is very important. Hydration can reduce the risk of nephrolithiasis (see below). Proper hydration prior to and during activities such as exercise or exposure to warm temperatures may reduce the risk of heat-related adverse reactions (see section 4.8).

Pregnancy prevention programme

Topiramate can cause major congenital malformations and fetal growth restriction when administered to a pregnant woman.

Some data suggest an increased risk of neurodevelopmental disorders in children exposed to topiramate in utero, while other data do not suggest an increased risk (see section 4.6).

Topiramate is contraindicated in women of childbearing potential unless the conditions of the Pregnancy Prevention Programme are fulfilled (see section 4.3 and 4.6))

The conditions of the Pregnancy Prevention Programme are that the prescriber must ensure that:

• Individual circumstances should be evaluated in each case. Involving the patient in the discussion to support her engagement, discuss therapeutic options and ensure her understanding of the risks and the measures needed to minimise the risks.

• The potential for pregnancy is assessed for all female patients.

• The patient has understood and acknowledged the risks of congenital malformations, neuro-developmental disorders and fetal growth restriction in children exposed to topiramate in utero.

• The patient understands the need to undergo pregnancy testing prior to initiation of topiramate and during treatment, as needed.

• The patient is counselled regarding contraception, and that the patient is capable of complying with the need to use effective contraception without interruption during the entire duration of treatment with topiramate and for at least 4 weeks after stopping treatment.

• The patient understands the need for regular (at least annual) review of treatment.

• The patient understands the need to consult her physician as soon as she is planning pregnancy to ensure timely discussion and switching to alternative treatment options prior to conception and before contraception is discontinued.

• The patient understands the need to urgently consult her physician in case of pregnancy.

• The patient has received the Patient Guide.

• The patient has acknowledged that she has understood the hazards and necessary precautions associated with topiramate use (Annual Risk Awareness Form).

These conditions also concern women who are not currently sexually active unless the prescriber considers that there are compelling reasons to indicate that there is no risk of pregnancy.

Women of childbearing potential

pregnancy testing should be performed before initiating treatment with topiramate in a woman of childbearing potential The patient must be fully informed and understand of the risks related to the use of topiramate during pregnancy (see sections 4.3 and 4.6). This includes the need to consult her doctor if the woman is planning a pregnancy to discuss switching to alternative treatments prior to discontinuation of contraception, and for prompt contact with a doctor if she becomes pregnant or thinks she may be pregnant.

This includes the need to consult her doctor as soon as she is planning for pregnancy, and for prompt contact with her doctor if she becomes pregnant or thinks she may be pregnant and is taking topiramate.

Female children

Prescribers must ensure that parent(s)/caregiver(s) of female children using topiramate understand the need to contact a specialist once the female child experiences menarche. At that time, the patient and parent(s)/caregiver(s) should be provided with comprehensive information about the risks due to topiramate exposure in utero, and the need for using highly effective contraception as soon as relevant. The need for continued topiramate therapy should be reassessed and alternative treatment options should also be considered.

Educational materials regarding these measures are available for healthcare professionals and patients (or parents/caregivers). The patient guide must be provided to all women of childbearing potential using topiramate and to parents/ caregivers of female children. A patient card is provided with the package of Topiramate film-coated tablets.

Oligohydrosis

Oligohydrosis (decreased sweating) has been reported in association with the use of topiramate. Decreased sweating and hyperthermia (rise in body temperature) may occur especially in young children exposed to high ambient temperature.

Mood disturbances/depression

An increased incidence of mood disturbances and depression has been observed during topiramate treatment.

Suicide/suicide ideation

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

In double blind clinical trials, suicide related events (SREs) (suicidal ideation, suicide attempts and suicide) occurred at a frequency of 0.5 % in topiramate treated patients (46 out of 8,652 patients treated) and at a nearly 3 fold higher incidence than those treated with placebo (0.2 %; 8 out of 4,045 patients treated).

Patients therefore should be monitored for signs of suicidal ideation and behaviour 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.

Serious skin reactions

Serious skin reactions (Stevens - Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)) have been reported in patients receiving topiramate (see section 4.8). It is recommended that patients be informed about the signs of serious skin reactions. If SJS or TEN are suspected, use of Topiramate should be discontinued.

Nephrolithiasis

Some patients, especially those with a predisposition to nephrolithiasis, may be at increased risk for renal stone formation 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 below – Metabolic acidosis). None of these risk factors can reliably predict stone formation during topiramate treatment. In addition, patients taking other medicinal products associated with nephrolithiasis may be at increased risk.

Decreased renal function

In patients with impaired renal function (CLCR ≤ 70 mL/min) topiramate should be administered with caution as the plasma and renal clearance of topiramate are decreased. For specific posology recommendations in patients with decreased renal function, see section 4.2.

Decreased hepatic function

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

Acute myopia and secondary angle closure glaucoma syndrome

A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving topiramate. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include some or all of the following: myopia, mydriasis, anterior chamber shallowing, ocular hyperaemia (redness), choroidal detachments, retinal pigment epithelial detachments, macular striae, and increased intraocular pressure. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating topiramate therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with topiramate has been reported in paediatric patients as well as adults. Treatment includes discontinuation of topiramate, as rapidly as possible in the judgment 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.

A determination should be made whether patients with history of eye disorders should be treated with topiramate.

Visual field defects

Visual field defects have been reported in patients receiving topiramate independent of elevated intraocular pressure. In clinical trials, most of these events were reversible after topiramate discontinuation. If visual field defects occur at any time during topiramate treatment, consideration should be given to discontinuing the drug.

Metabolic acidosis and sequelae

Hyperchloremic, non-anion gap, metabolic acidosis (i.e. decreased serum bicarbonate below the normal reference range in the absence of respiratory alkalosis) is associated with topiramate treatment.

This decrease in serum bicarbonate is due to the inhibitory effect of topiramate on renal carbonic anhydrase. Generally, the decrease in bicarbonate occurs early in treatment although it can occur at any time during treatment. These decreases are usually mild to moderate (average decrease of 4 mmol/l at doses of 100 mg/day or above in adults and at approximately 6 mg/kg/day in paediatric patients). Rarely, patients have experienced decreases 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 untreated metabolic acidosis increases the risk of nephrolithiasis and nephrocalcinosis and may potentially lead to osteopenia (see above - Nephrolithiasis).

Chronic metabolic acidosis in paediatric patients can reduce growth rates. The effect of topiramate on bone-related sequelae has not been systematically investigated in adult populations. For paediatric patients aged 6 to 15 years a one year, open-label study was conducted (see section 5.1).

Depending on underlying conditions, appropriate evaluation including serum bicarbonate levels is recommended with topiramate therapy. If signs or symptoms are present (e.g. Kussmaul's deep breathing, dyspnoea, anorexia, nausea, vomiting, excessive tiredness, tachycardia or arrhythmia), indicative of metabolic acidosis, measurement of serum bicarbonate is recommended. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing topiramate (using dose tapering).

Topiramate should be used with caution in patients with conditions or treatments that represent a risk factor for the appearance of metabolic acidosis.

Impairment of cognitive function

Cognitive impairment in epilepsy is multifactorial and may be due to the underlying aetiology, due to the epilepsy or due to the anti epileptic treatment. There have been reports in the literature of impairment of cognitive function in adults on topiramate therapy which required reduction in dosage or discontinuation of treatment. However, studies regarding cognitive outcomes in children treated with topiramate are insufficient and its effect in this regard still needs to be elucidated.

Hyperammonemia and encephalopathy

Hyperammonemia with or without encephalopathy has been reported with topiramate treatment (see section 4.8). The risk for hyperammonemia with topiramate appears dose-related. Hyperammonemia has been reported more frequently when topiramate is used concomitantly with valproic acid (see section 4.5).

In patients who develop unexplained lethargy, or changes in mental status associated with topiramate monotherapy or adjunctive therapy, it is recommended to consider hyperammonemic encephalopathy and measuring ammonia levels.

Nutritional supplementation

Some patients may experience weight loss whilst on treatment with topiramate. It is recommended that patients on topiramate treatment should be monitored for weight loss. A dietary supplement or increased food intake may be considered if the patient is losing weight while on topiramate.

Excipients:

Lactose:

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

Sodium:

This medicine contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Effects of topiramate on other antiepileptic medicinal products

The addition of topiramate to other AEDs (phenytoin, carbamazepine, valproic acid, phenobarbital, primidone) has no effect on their steady-state plasma concentrations, except in the occasional patient, where the addition of topiramate to phenytoin may result in an increase of plasma concentrations of phenytoin. This is possibly due to inhibition of a specific enzyme polymorphic isoform (CYP2C19). Consequently, any patient on phenytoin showing clinical signs or symptoms of toxicity should have phenytoin levels monitored.

A pharmacokinetic interaction study of patients with epilepsy indicated the addition of topiramate to lamotrigine had no effect on steady state plasma concentration of lamotrigine at topiramate doses of 100 to 400 mg/day. In addition, there was no change in steady state plasma concentration of topiramate during or after removal of lamotrigine treatment (mean dose of 327 mg/day).

Topiramate inhibits the enzyme CYP 2C19 and may interfere with other substances metabolized via this enzyme (e.g., diazepam, imipramine, moclobemide, proguanil, omeprazole).

Effects of other antiepileptic medicinal products 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 the latter. This should be done by titrating to clinical effect. The addition or withdrawal of valproic acid does not produce clinically significant changes in plasma concentrations of topiramate and, therefore, does not warrant dosage adjustment of topiramate. The results of these interactions are summarized below:

AED Coadministered

AED Concentration

Topiramate Concentration

Phenytoin

Carbamazepine (CBZ)

Valproic acid

Lamotrigine

Phenobarbital

Primidone

↔**

↔

↔

↔

↔

↔

↓

↓

↔

↔

NS

NS

↔ = No effect on plasma concentration (≤ 15% change)

** = Plasma concentrations increase in individual patients

↓ = Plasma concentrations decrease

NS = Not studied

AED = antiepileptic drug

Other medicinal product interactions

Digoxin

In a single-dose study, serum digoxin area under plasma concentration curve (AUC) decreased 12 %due to concomitant administration of topiramate. The clinical relevance of this observation has not been established. When topiramate is added or withdrawn in patients on digoxin therapy, careful attention should be given to the routine monitoring of serum digoxin.

Central nervous system depressants

Concomitant administration of topiramate and alcohol or other central nervous system (CNS) depressant medicinal products has not been evaluated in clinical studies. It is recommended that topiramate not be used concomitantly with alcohol or other CNS depressant medicinal products.

St John's Wort (Hypericum perforatum)

A risk of decreased plasma concentrations resulting in a loss of efficacy could be observed with co-administration of topiramate and St John's Wort. There have been no clinical studies evaluating this potential interaction.

Systemic hormonal contraceptivesIn a pharmacokinetic interaction study in healthy volunteers with a concomitantly administered combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 microg ethinyl estradiol (EE), topiramate given in the absence of other medications at doses of 50 to 200 mg/day was not associated with statistically significant changes in mean exposure (AUC) to either component of the oral contraceptive. In another study, exposure to EE was statistically significantly decreased at doses of 200, 400, and 800 mg/day (18 %, 21 %, and 30 %, respectively) when given as adjunctive therapy in epilepsy patients taking valproic acid. In both studies, topiramate (50-200 mg/day in healthy volunteers and 200-800 mg/day in epilepsy patients) did not significantly affect exposure to NET. Although there was a dose dependent decrease in EE exposure for doses between 200-800 mg/day (in epilepsy patients), there was no significant dose dependent change in EE exposure for doses of 50-200 mg/day (in healthy volunteers). 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 systemic contraceptive products with topiramate. Patients should be asked to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding. Women using systemic hormonal contraceptives should be advised to also use a barrier method.

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.

Risperidone

Drug-drug interaction studies conducted under single dose conditions in healthy volunteers and multiple dose conditions in 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). However, differences in AUC for the total active moiety between treatment with risperidone alone and combination treatment with topiramate were not statistically significant. Minimal alterations in the pharmacokinetics of the total active moiety (risperidone plus 9-hydroxyrisperidone) and no alterations for 9-hydroxyrisperidone were observed. There were no significant changes in the systemic exposure of the risperidone total active moiety or of topiramate.

When topiramate was added to existing risperidone (1-6 mg/day) treatment, adverse events were reported more frequently than prior to topiramate (250-400 mg/day) introduction (90 % and 54 % respectively). The most frequently reported AE's when topiramate was added to risperidone treatment were: somnolence (27 % and 12 %), paraesthesia (22 % and 0 %) and nausea (18 % and 9 % respectively).

Hydrochlorothiazide (HCTZ)

A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of HCTZ (25 mg every 24 h) and topiramate (96 mg every 12 h) when administered alone and concomitantly. The results of this study indicate that topiramate Cmax increased by 27 % and AUC increased by 29 % when HCTZ was added to topiramate. The clinical significance of this change is unknown. The addition of HCTZ to topiramate therapy may require an adjustment of the topiramate dose. The steady-state pharmacokinetics of HCTZ were not significantly influenced by the concomitant administration of topiramate. Clinical laboratory results indicated decreases in serum potassium after topiramate or HCTZ administration, which were greater when HCTZ and topiramate were administered in combination.

Metformin

A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of metformin and topiramate in plasma when metformin was given alone and when metformin and topiramate were given simultaneously. The results of this study indicated that metformin mean Cmax and mean AUC0-12h increased by 18 % and 25 %, respectively, while mean CL/F decreased 20 % when metformin was 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

A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of topiramate and pioglitazone when administered alone and concomitantly. A 15 % decrease in the AUC,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 AUC,ss respectively, of the active hydroxy-metabolite was noted as well as a 60 % decrease in Cmax,ss and AUC,ss of the active keto-metabolite. The clinical significance of these findings is not known. When topiramate is added to pioglitazone therapy or pioglitazone is added to topiramate therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.

Glibenclamide

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

Other forms of interactions

Agents predisposing to nephrolithiasis

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

Valproic acid

Concomitant administration of topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either medicinal product alone. In most cases, symptoms and signs abated with discontinuation of either medicinal product (see section 4.4 and section 4.8). This adverse reaction 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.

Warfarin

Decreased Prothrombin Time/International Normalized Ratio (PT/INR) has been reported in patients treated with topiramate in combination with warfarin. Therefore, INR should be carefully monitored in patients concomitantly treated with topiramate and warfarin.

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 summarized below. 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.

Summary of Results from Additional Clinical Pharmacokinetic Drug Interaction Studies

Concomitant Drug

Concomitant Drug Concentrationa

Topiramate Concentrationa

Amitriptyline

↔ 20 % increase in Cmax and AUC of nortriptyline metabolite

NS

Dihydro-ergotamine

(Oral and Subcutaneous)

↔

↔

Haloperidol

↔ 31 % increase in AUC of the

reduced metabolite

NS

Propranolol

↔ 17 % increase in C,max for 4-OH propranolol (TPM 50 mg q12h)

9 % and 16 % increase in Cmax, 9 % and17 % increase in AUC (40 and 80 mg propranolol q12h respectively)

Sumatriptan (Oral and Subcutaneous)

↔

NS

Pizotifen

↔

↔

Diltiazem

25 % decrease in AUC of diltiazem and 18 % decrease in DEA, and ↔ for DEM*

20 % increase in AUC

Venlafaxine

↔

↔

Flunarizine

16 % increase in AUC (TPM 50 mg q12h)b

↔

a = % values are the changes in treatment mean Cmax or AUC with respect to monotherapy

↔ = No effect on Cmax and AUC (≤ 15 % change) of the parent compound

NS = Not studied

*DEA = des acetyl diltiazem, DEM = N-demethyl diltiazem

b = Flunarizine AUC increased 14 % in subjects taking flunarizine alone. Increase in exposure may be attributed to accumulation during achievement of steady state.

4.6. Fertility, pregnancy and lactation

Pregnancy

Risk related to epilepsy and AEDs in general

Specialist advice regarding potential risks to a fetus caused by both seizures and antiepileptic treatment should be given to women of childbearing potential, and especially to women planning for pregnancy and women who are pregnant.. The need for treatment with AEDs should be reviewed when a woman is planning to become pregnant. In women being treated for epilepsy, sudden discontinuation of AED therapy should be avoided as this may lead to breakthrough seizures that could have serious consequences for the woman and the Fetus.

Monotherapy should be preferred whenever possible because therapy with multiple AEDs could be associated with a higher risk of congenital malformations than monotherapy, depending on the associated antiepileptics.

Risk related to topiramate

Topiramate was teratogenic in mice, rats and rabbits (see section 5.3). In rats, topiramate crosses the placental barrier.

In humans, topiramate crosses the placenta and similar concentrations have been reported in the umbilical cord and maternal blood.

Clinical data from pregnancy registries indicate that infants exposed to topiramate monotherapy have:

Major congenital malformation and fetal growth restriction

• An increased risk of congenital malformations (particularly cleft lip/palate, hypospadias, and anomalies involving various body systems) following exposure during the first trimester. The North American Antiepileptic Drug pregnancy registry data for topiramate monotherapy showed an approximate 3-fold higher prevalence of major congenital malformations (4.3%), compared with a reference group not taking AEDs (1.4%). Data from an observational population-based registry study from the Nordic countries showed a 2 to 3 fold higher prevalence of major congenital malformations (up to 9.5%) compared with a reference group not taking AEDs (3.0%). In addition, data from other studies indicate that, compared with monotherapy, there is an increased risk of teratogenic effects associated with the use of AEDs in combination therapy. The risk has been reported to be dose dependent; effects were observed in all doses. 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.

• A higher prevalence of low birth weight (<2500 grams) compared with a reference group.

• An increased prevalence of being small for gestational age (SGA; defined as birth weight below the 10th percentile corrected for their gestational age, stratified by sex). In the North American Antiepileptic Drug Pregnancy Registry, the risk of SGA in children of women receiving topiramate was 18 % compared with 5 % in children of women with epilepsy not receiving an AED. The long term consequences of the SGA findings could not be determined

Neurodevelopmental disorders

Data from two observational population- based pregnancy registry studies in largely the same dataset from the Nordic countries suggest there may be a 2 to 3-fold higher prevalence of autism spectrum disorders, intellectual disability or attention deficit hyperactivity disorder (ADHD) in almost 300 children of mothers with epilepsy exposed to topiramate in utero, compared with children of mothers with epilepsy not exposed to an AED. A third observational cohort study from the U.S.A. did not suggest an increased cumulative incidence of these outcomes by 8 years of age in approximately 1000 children of mothers with epilepsy exposed to topiramate in utero, compared with children of mothers with epilepsy not exposed to an AED.

Indication epilepsy

• Topiramate is contraindicated in pregnancy unless there is no suitable alternative treatment (see sections 4.3 and 4.4).

The woman must be fully informed of and understand risks of using topiramate during pregnancy This includes discussion about the risks of uncontrolled epilepsy to the pregnancy

• If a woman planning to become pregnant efforts should be made to switch to appropriate alternative treatment before contraception is discontinued,

• If a woman becomes pregnant while taking topiramate, she should promptly be referred to a specialist to reassess topiramate treatment and consider alternative treatment options.

• If topiramate is used during pregnancy, the patient should be referred to a specialist for evaluation and counselling regarding the exposed pregnancy. Careful prenatal monitoring should be performed.

Indication migraine prophylaxis

Topiramate is contraindicated in pregnancy and in women of childbearing potential (see sections 4.3 and 4.5).

Women of childbearing potential (all indications)

Topiramate is contraindicated in women of childbearing potential unless the conditions of the Pregnancy Prevention Programme are fulfilled (see sections 4.4, 4.5 and 4.6).

At least one highly effective method of contraception (such as intra-uterine device) or two complementary forms of contraception including a barrier method should be used (see sections 4.4 and 4.5) during treatment and for at least 4 weeks after stopping treatment with Topiramate Milpharm film-coated tablets .

Alternative therapeutic options should be considered in women of childbearing potential.

Pregnancy testing should be performed before initiating treatment with topiramate in a woman of childbearing potential.

The patient must be fully informed and understand the risks related to the use of topiramate during pregnancy. This includes the need to consult her doctor as soon as she is planning for pregnancy, and for prompt contact with her doctor if she becomes pregnant or thinks she may be pregnant and is taking topiramate.

For women with epilepsy, the risks of uncontrolled epilepsy to the pregnancy should also be taken into account (see sections 4.3 and 4.4).

For female children (see section 4.4)

Breast- feeding

Animal studies have shown excretion of topiramate in milk. The excretion of topiramate in human milk has not been evaluated in controlled studies. Limited observations in patients suggest an extensive excretion of topiramate into human milk. Effects that have been observed in breastfed newborns/infants of treated mothers include diarrhoea, drowsiness, irritability and inadequate weight gain. Therefore, a decision must be made whether to suspend breast-feeding or to discontinue/ abstain from topiramate therapy taking into account the benefit of breast-feeding for the child and the benefit of topiramate therapy for the women (see section 4.4).

Fertility

Animal studies did not reveal impairment of fertility by topiramate (see section 5.3). The effect of topiramate on human fertility has not been established.

4.7. Effects on ability to drive and use machines

Topiramate has minor or moderate influence on the ability to drive and use machines. Topiramate acts on the central nervous system and may produce drowsiness, dizziness or other related symptoms. It may also cause visual disturbances and/or blurred vision. These adverse reactions could potentially be dangerous in patients driving a vehicle or operating machinery, particularly until such time as the individual patient's experience with the medicinal products established.

4.8. Undesirable effects

The safety of topiramate was evaluated from a clinical trial database consisting of 4,111 patients (3,182 on topiramate and 929 on placebo) who participated in 20 double-blind trials and 2,847 patients who participated in 34 open-label trials, respectively, for topiramate as adjunctive treatment of primary generalized tonic-clonic seizures, partial onset seizures, seizures associated with Lennox-Gastaut syndrome, monotherapy for newly or recently diagnosed epilepsy or migraine prophylaxis. The majority of adverse reactions were mild to moderate in severity. Adverse reactions identified in clinical trials, and during post-marketing experience (as indicated by “*”) are listed by their incidence in clinical trials in Table 1. Assigned frequencies are as follows:

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

Not known

cannot be estimated from the available data

The most common adverse reactions (those with an incidence of >5 % and greater than that observed in placebo in at least 1 indication in double-blind controlled studies with topiramate) include: anorexia, decreased appetite, bradyphrenia, depression, expressive language disorder, insomnia, coordination abnormal, disturbance in attention, dizziness, dysarthria, dysgeusia, hypoesthesia, lethargy, memory impairment, nystagmus, paresthesia, somnolence, tremor, diplopia, vision blurred, diarrhoea, nausea, fatigue, irritability, and weight decreased.

Table 1: Topiramate Adverse Reactions

System Organ Class

Very common

Common

Uncommon

Rare

Not known

Infections and infestations

Nasopharyngitis*

Blood and lymphatic system disorders

Anaemia

Leucopenia, thrombocytopenia lymphadenopathy, eosinophilia

Neutropenia*

Immune system disorders

Hypersensitivity

Allergic oedema*

Metabolism and nutrition disorders

Anorexia, decreased appetite

Metabolic acidosis, Hypokalaemia, increased appetite, polydipsia

Acidosis hyperchloraemic ,hyperammonemia*, hyperammonemic, encephalopathy*

Psychiatric disorders

Depression

Bradyphrenia, insomnia, expressive language disorder, anxiety, confusional state, disorientation, aggression, mood altered, agitation, mood swings, depressed mood, anger, abnormal behaviour

Suicidal ideation, suicide attempt, hallucination, psychotic disorder, hallucination auditory, hallucination visual, apathy, lack of spontaneous speech, sleep disorder, affect lability, libido decreased, restlessness, crying, dysphemia, euphoric mood, paranoia, perseveration, panic attack, tearfulness, reading disorder, initial insomnia, flat affect, thinking abnormal, loss of libido, listless, middle insomnia, distractibility, early morning awakening, panic reaction, elevated mood

Mania, panic disorder, feeling of despair*, hypomania

Nervous system disorders

Paraesthesia, somnolence

Dizziness

Disturbance in attention, memory impairment, amnesia, cognitive disorder, mental impairment, psychomotor skills impaired, convulsion, coordination abnormal, tremor, lethargy, hypoaesthesia, nystagmus, dysgeusia, balance disorder, dysarthria, intention tremor, sedation

Depressed level of consciousness, grand mal convulsion, visual field defect, complex partial seizures, speech disorder, psychomotor hyperactivity, syncope, sensory disturbance, drooling, hypersomnia, aphasia, repetitive speech, hypokinesia, dyskinesia, dizziness postural, poor quality sleep, burning sensation, sensory loss, parosmia, cerebellar syndrome, dysaesthesia, hypogeusia, stupor, clumsiness, aura, ageusia, dysgraphia, dysphasia, neuropathy peripheral, presyncope, dystonia, formication

Apraxia, circadian rhythm sleep disorder, hyperaesthesia, hyposmia, anosmia, essential tremor, akinesia, unresponsive to stimuli

Eye disorders

Vision blurred, diplopia, visual disturbance

Visual acuity reduced, scotoma, myopia*, abnormal sensation in eye*, dry eye, photophobia, blepharospasm, lacrimation increased, photopsia, mydriasis, presbyopia

Blindness unilateral, blindness transient, glaucoma, accommodation disorder, altered visual depth perception, scintillating scotoma, eyelid oedema*, night blindness, amblyopia

Angle closure glaucoma*, Maculopathy*, eye movement disorder* , conjunctival oedema*, uvetis

Ear and labyrinth disorders

Vertigo, tinnitus, ear pain

Deafness, deafness unilateral, deafness neurosensory, ear discomfort, hearing impaired

Cardiac disorders

Bradycardia, sinus bradycardia, palpitations

Vascular disorders

Hypotension, orthostatic hypotension flushing, hot flush

Raynaud's phenomenon

Respiratory, thoracic and mediastinal disorders

Dyspnoea , epistaxis, nasal congestion, rhinorrhoea, cough*

Dyspnoea exertional, Paranasal sinus hypersecretion, dysphonia

Gastrointestinal disorders

Nausea, diarrhoea

Vomiting, constipation, abdominal pain upper, dyspepsia, abdominal pain, dry mouth, stomach discomfort, paraesthesia oral, gastritis, abdominal discomfort

Pancreatitis, flatulence, gastrooesophageal reflux disease, abdominal pain lower, hypoaesthesia oral, gingival bleeding, abdominal distension, epigastric discomfort, abdominal tenderness, salivary hypersecretion, oral pain, breath odour, glossodynia

Hepatobiliary disorders

Hepatitis, Hepatic failure

Skin and subcutaneous tissue disorders

Alopecia, rash, pruritus

Anhidrosis, hypoaesthesia facial, urticaria, erythema, pruritus generalised, rash macular, skin discolouration, dermatitis allergic, swelling face

Stevens-Johnson syndrome* erythema multiforme*, skin odour abnormal, periorbital oedema*, urticaria localised

Toxic epidermal necrolysis*

Musculoskeletal and connective tissue disorders

Arthralgia, muscle spasms, myalgia, muscle twitching, muscular weakness, musculoskeletal chest pain

Joint swelling*, musculoskeletal stiffness, flank pain, muscle fatigue

Limb discomfort*

Renal and urinary disorders

Nephrolithiasis, pollakiuria, dysuria, nephrocalcinosis*

Calculus urinary, urinary incontinence, haematuria, incontinence, micturition urgency, renal colic, renal pain

Calculus ureteric, renal tubular acidosis*

Reproductive system and breast disorders

Erectile dysfunction, sexual dysfunction

General disorders and administration site conditions

Fatigue

Pyrexia, asthenia, irritability, gait disturbance, feeling abnormal, malaise

Hyperthermia, thirst, influenza like illness*, sluggishness, peripheral coldness, feeling drunk, feeling jittery

Face oedema,

Investigations

Weight decreased

Weight increased*

Crystal urine present, tandem gait test abnormal, white blood cell count decreased, increase in liver enzymes

Blood bicarbonate decreased

Social circumstances

Learning disability

* identified as an adverse reaction from postmarketing spontaneous reports. Its frequency was calculated based on the incidence in clinical trials, or was calculated if the event did not occur in clinical trials.

Congenital malformations and fetal growth restrictions (see section 4.4 and section 4.6).

Paediatric population

Adverse reactions reported more frequently (≥2-fold) in children than in adults in double-blind controlled studies include:

• Decreased appetite

• Increased appetite

• Hyperchloraemic acidosis

• Hypokalaemia

• Abnormal behaviour

• Aggression

• Apathy

• Initial insomnia

• Suicidal ideation

• Disturbance in attention

• Lethargy

• Circadian rhythm sleep disorder

• Poor quality sleep

• Lacrimation increased

• Sinus bradycardia

• Feeling abnormal

• Gait disturbance

Adverse reactions that were reported in children but not in adults in double-blind controlled studies include:

• Eosinophilia

• Psychomotor hyperactivity

• Vertigo

• Vomiting

• Hyperthermia

• Pyrexia

• Learning disability.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Signs and symptoms

Overdoses of topiramate have been reported. Signs and symptoms included convulsions, drowsiness, speech disturbances, blurred vision, diplopia, impaired mentation, lethargy, abnormal coordination, stupor, hypotension, abdominal pain, agitation, dizziness and depression. The clinical consequences were not severe in most cases, but deaths have been reported after overdoses with multiple medicinal products including topiramate.

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

Treatment

In the event of overdose, topiramate should be discontinued and general supportive treatment given until clinical toxicity has been diminished or resolved. The patient should be well hydrated. Haemodialysis has been shown to be an effective means of removing topiramate from the body. Other measures may also be taken at the physician's discretion.