Topiramatum

In situations where rapid withdrawal of topiramate is medically required, appropriate monitoring is recommended (see section 4.2). As with other antiepileptics, some patients may experience an increase in seizure frequency or the onset of new seizure types with topiramate. These phenomena may be a consequence of overdose, a decrease in plasma concentrations of concomitant antiepileptics, progression of the disease or a paradoxical effect. Adequate fluid intake is very important during treatment with topiramate. Hydration may reduce the risk of nephrolithiasis (see below). Adequate hydration before and during activities such as exercise or exposure to high temperatures may reduce the risk of heat-related adverse reactions (see section 4.8). Pregnancy Prevention Programme Topiramate, when administered to a pregnant woman, may cause serious congenital malformations and foetal growth restriction. Some data suggest an increased risk of neurodevelopmental disorders in children exposed to topiramate in utero, while other data do not suggest such an increased risk (see section 4.6). Women of childbearing potential A pregnancy test should be performed in women of childbearing potential before initiating treatment with topiramate. The patient must be fully informed of and must understand the risks associated with the use of topiramate during pregnancy (see sections 4.3 and 4.6). This includes the need to consult a specialist if the woman is planning to become pregnant, in order to discuss switching to alternative treatment before contraception is discontinued, and the need to contact a specialist promptly if the woman becomes pregnant or thinks she may be pregnant. Girls The prescriber must ensure that the parents/carers of girls taking topiramate understand the need to contact a specialist as soon as the girl reaches menarche. At this time, the patient and parents/carers should receive full information about the risks associated with in utero exposure to topiramate and the need to use highly effective contraception once relevant. The need to continue topiramate treatment should be reassessed and alternative treatment options should also be considered. Educational materials on these measures are available for healthcare professionals and for patients (or parents/carers). A patient guide must be provided to all women of childbearing potential taking topiramate and to the parents/carers of girls. A Patient Card is included with the Tolepso pack. Oligohidrosis Oligohidrosis has been reported in association with the use of topiramate. Oligohidrosis and hyperthermia may occur, particularly in children exposed to high ambient temperatures. Mood disturbances/depression An increased incidence of mood disturbances and depression has been observed during treatment with topiramate. Suicide/suicidal ideation Suicidal ideation and behaviour have been reported in patients treated with antiepileptics in several indications. A meta-analysis of randomised, placebo-controlled trials of antiepileptics 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 studies, suicide-related events (suicidal ideation, suicide attempts and suicide) occurred at a frequency of 0.5% (46 of 8,652 patients) in topiramate-treated patients, an incidence almost 3 times higher than in patients receiving placebo (0.2%; 8 of 4,045 patients). Patients should therefore be monitored for signs of suicidal ideation and behaviour and appropriate treatment should be considered. Patients (and their carers) should be advised to seek medical advice if 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 taking topiramate (see section 4.8). It is recommended that patients be informed of the signs of serious skin reactions. If SJS or TEN is suspected, treatment with Tolepso should be stopped. Nephrolithiasis Some patients, particularly those with a predisposition to nephrolithiasis, may be at increased risk of renal stone formation and the development of associated signs and symptoms such as renal colic, renal pain or flank pain. Risk factors for nephrolithiasis include a history of nephrolithiasis, a family history of nephrolithiasis and hypercalciuria (see below – Metabolic acidosis and sequelae). However, none of these reliably predicts stone formation during topiramate treatment. Patients at increased risk are in particular those who are also taking other medicinal products associated with nephrolithiasis. Impaired renal function Topiramate should be administered with caution in patients with impaired renal function (CrCl ≤70 mL/min), as both the plasma and renal clearance of topiramate are reduced. Dosing recommendations for patients with impaired renal function are given in section 4.2. Impaired hepatic function Topiramate should be administered with caution in patients with impaired hepatic function because of the potential for reduced topiramate clearance. Acute myopia and secondary angle-closure glaucoma A syndrome of acute myopia associated with secondary angle-closure glaucoma has been reported in patients treated with topiramate. Symptoms include sudden onset of decreased visual acuity and/or ocular pain. Ophthalmological findings may include myopia, mydriasis, shallowing of the anterior chamber, hyperaemia (ocular redness), choroidal detachment, retinal pigment epithelial detachment, macular striae and increased intraocular pressure. This syndrome appears to be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle-closure glaucoma. Symptoms usually occur within 1 month of starting topiramate. In contrast to primary angle-closure glaucoma, which is rare in people under 40 years of age, secondary angle-closure glaucoma associated with topiramate treatment has been reported in both paediatric and adult patients. Treatment consists of discontinuation of topiramate by the treating physician as rapidly as possible and appropriate measures to reduce intraocular pressure. These measures generally lead to a reduction in intraocular pressure. Raised intraocular pressure of any aetiology, if left untreated, may have serious sequelae, including permanent loss of vision. In patients with a history of visual disorder, a decision should be made as to whether topiramate treatment is appropriate. Visual field defects Visual field defects unrelated to increased intraocular pressure have been reported in patients taking topiramate. In clinical trials, most of these events were reversible after discontinuation of topiramate. If visual field defects occur at any time during topiramate treatment, discontinuation of this medicinal product should be considered. Metabolic acidosis and sequelae Hyperchloraemic, non-anion gap metabolic acidosis (i.e. a decrease in serum bicarbonate below the normal reference range in the absence of respiratory alkalosis) is associated with topiramate treatment. This reduction in serum bicarbonate is due to the inhibitory effect of topiramate on renal carbonic anhydrase. The reduction in bicarbonate generally occurs early in treatment, but may occur at any time during it. The reductions are usually mild to moderate (mean reduction of 4 mmol/L at a dose of 100 mg/day or higher in adults and at approximately 6 mg/kg/day in paediatric patients). Rarely, patients may experience reductions to values below 10 mmol/L. Conditions or therapies that predispose to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhoea, surgery, a ketogenic diet or certain medicinal products) may potentiate the bicarbonate-lowering effect of topiramate. Chronic, untreated metabolic acidosis increases the risk of nephrolithiasis and nephrocalcinosis and may potentially lead to osteopenia. Chronic metabolic acidosis may reduce growth rate in paediatric patients. The effect of topiramate on other bone defects has not been systematically studied in either the paediatric or adult population. A one-year open-label study was conducted in paediatric patients aged 6 to 15 years (see section 5.1). Depending on the underlying condition, appropriate evaluation, including serum bicarbonate levels, is recommended during topiramate treatment. If signs or symptoms suggestive of metabolic acidosis are present (e.g. Kussmaul deep breathing, dyspnoea, anorexia, nausea, vomiting, excessive fatigue, tachycardia or arrhythmia), measurement of serum bicarbonate levels is recommended. If metabolic acidosis develops and persists, a reduction in dose or discontinuation of topiramate (by tapering the dose) should be considered. Topiramate should be used with caution in patients with a tendency to metabolic acidosis or in patients treated with products that may induce metabolic acidosis. Impairment of cognitive function Cognitive impairment in epilepsy is multifactorial and may be due to the underlying aetiology, the epilepsy itself or antiepileptic treatment. Cases of cognitive impairment have been described in the literature in adults treated with topiramate that required a dose reduction or discontinuation of treatment. However, studies of the cognitive effects in children treated with topiramate are inadequate, and its influence in this area requires further clarification. Hyperammonaemia and encephalopathy Cases of hyperammonaemia, with or without manifestations of encephalopathy, have been reported during topiramate treatment (see section 4.8). The risk of hyperammonaemia with topiramate appears to be dose-dependent. Hyperammonaemia has been reported more frequently when topiramate was used concomitantly with valproic acid (see section 4.5). In patients who develop unexplained lethargy or a change in mental status associated with topiramate monotherapy or adjunctive therapy, it is recommended that hyperammonaemic encephalopathy be considered and serum ammonia levels measured. Nutritional supplementation Some patients may lose weight during topiramate treatment. It is recommended that weight loss be monitored in patients treated with topiramate. A dietary supplement or increased food intake may be given to patients losing weight while taking topiramate. Lactose intolerance Tolepso contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. Sodium This medicinal product contains less than 1 mmol (23 mg) sodium per film-coated tablet, that is to say essentially "sodium-free".