Special Warning : אזהרת שימוש

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 foetal 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 such an increased risk (see section 4.6).

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 (see sections 4.3 and 4.6). This includes the need for specialist consultation if the woman is planning a pregnancy to discuss switching to alternative treatments prior to discontinuation of contraception, and for prompt contact with a specialist if she becomes pregnant or thinks she may be pregnant.

Female children
Prescribers must ensure that parent(s)/caregiver(s) of female children using topiramate understand the need to contact a specialist once the 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.


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.


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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 Topamax 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 and sequelae). 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 TOPAMAX®. 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 TOPAMAX® therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with topiramate has been reported in paediatric patients as well as adults. Treatment includes discontinuation of TOPAMAX®, as rapidly as possible in the judgment of the treating physician, and appropriate measures to reduce intraocular pressure. These measures generally result in a decrease in intraocular pressure.

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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 antiepileptic 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.

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


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In patients who develop unexplained lethargy, or changes in mental status associated with topiramate monotherapy or adjunctive therapy, it is recommended to consider hyperammonaemic 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.

Lactose intolerance
Topamax tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Sodium
Each tablet contains less than 1 mmol sodium (23 mg), and is essentially ‘sodium free’.

Effects on Driving

4.7   Effects on ability to drive and use machines
Topamax 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 Topamax_spc_Sep2024_ref_EU SmPC Sep2024
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.