Topalex Tablets Range 25 mg; 50 mg; 100 mg Tablets

Epilepsy

TOPALEX is indicated as monotherapy in patients with newly diagnosed epilepsy or for conversion to monotherapy in patients with epilepsy. TOPALEX is indicated as adjunctive therapy for adults and children over 4 years old who are inadequately controlled on conventional first line anti-epileptic medicines for:

• partial onset seizures with or without secondarily generalized seizures.
• seizures associated with Lennox-Gastaut syndrome.
• primary generalized tonic clonic seizures.

For optimal control in both adults and children, it is recommended that therapy be initiated at a low dose, followed by titration to an effective dose. TOPALEX is available in tablets. It is recommended that tablets not be broken.

TOPALEX can be taken without regard to meals.

Posology

MONOTHERAPY

When concomitant AEMs are withdrawn to achieve monotherapy with topiramate, consideration should be given to the effects this may have on seizure control.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 AEM, a gradual discontinuation at the rate of approximately one-third of the concomitant AEM dose every 2 weeks is recommended. When enzyme inducing medicines are withdrawn, topiramate levels will increase. A decrease in TOPALEX dosage may be required if clinically indicated.

Adults: 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. Dose and titration rate should be guided by clinical outcome. The recommended initial target dose for topiramate monotherapy in adults is 100 mg/day and the maximum recommended daily dose is 500 mg. 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.

Children: Treatment of children aged 2 years and above 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. Dose and dose titration rate should be guided by clinical outcome. The recommended initial target dose range for topiramate monotherapy in children aged two years and above is 100 u2013 400 mg/day. Children with recently diagnosed partial onset seizures have received doses of up to 500 mg/day.

ADJUNCTIVE THERAPY

Adults: Therapy should begin at 25 - 50 mg nightly for one week. Subsequently, at weekly intervals, the dose should be increased by 25 - 50 mg/day and taken in two divided doses. Dose titration should be guided by clinical outcome. Some patients may achieve efficacy with once-a-day dosing. In clinical trials, 200 mg was effective and was the lowest dosage studied. This is therefore considered the minimal effective dose. The usual total daily dose is 200 mg to 400 mg in two divided doses. Some patients may require doses up to 800 mg per day, which is the maximum dose. It is recommended that therapy be initiated at a low dose, followed by titration to an effective dose. These dosing recommendations apply to all adults, including the elderly, in the absence of underlying renal disease. (see section 4.4 u2013 Renal impairment).

Children 4 years and over: The recommended total daily dose of TOPALEX 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. Dose titration should be guided by clinical outcome.

Hypersensitivity to any component of this product. The safety and efficacy of TOPALEX in children under 2 years has not yet been established. Pregnancy and lactation, as topiramate is teratogenic in animals, whilst there are no adequate data in humans. (see section 4.6)

Acute Myopia and Secondary Angle Closure Glaucoma

A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving TOPALEX. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, anterior chamber shallowing, ocular hyperemia (redness) and increased intraocular pressure. Mydriasis may or may not be present. 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 TOPALEX 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 TOPALEX, 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.

Oral contraceptives

Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding, see section 4.5.

Visual field defects

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

Metabolic Acidosis and sequelae

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 and consequent renal bicarbonate wasting. 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. However, 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 medicines) may be additive to the bicarbonate lowering effects of topiramate. Chronic, untreated metabolic acidosis may increase the risk of nephrolithiasis or nephrocalcinosis (see section 4.4 u2013 Nephrolithiasis).

Chronic metabolic acidosis in paediatric patients can reduce growth rates. A one year, open-label study in pediatric patients aged 6 to 15 years including 63 subjects with recent or new onset of epilepsy was conducted to assess the effects of topiramate (28 subjects) versus levetiracetam on growth, development, and bone mineralization. Continued growth was observed in both treatment groups but the topiramate group showed statistically significant reductions in mean annual change from baseline in body weight and bone mineral density compared to the levetiracetam group. A similar trend was also observed for height and height velocity but were not statistically significant. Growth-related changes were not clinically significant nor treatment limiting. Other confounding factors cannot be excluded. Chronic metabolic acidosis can lead to nephrolithiasis and increased risk for fractures. Evaluation of serum bicarbonate levels is recommended with topiramate therapy. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing topiramate (using dose tapering).

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). Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy. In most cases, hyperammonemic encephalopathy abated with discontinuation of treatment. 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.

Women of childbearing potential

TOPALEX may cause foetal harm when administered to a pregnant woman. There is an increased risk of pre-term labour and premature delivery associated with the use of Antiepileptic Medicines (AEMs) including topiramate.

Withdrawal of TOPALEX

In patients with or without a history of seizures or epilepsy, antiepileptic medicines, including TOPALEX, should be gradually withdrawn to minimise the potential for seizures or increased seizure frequency. In clinical trials, daily dosages were decreased in weekly intervals by 50 u2013 100 mg in adults with epilepsy. In clinical trials of children, TOPALEX was gradually withdrawn over a 2 u2013 8 week period. In situations where rapid withdrawal of TOPALEX is medically required, appropriate monitoring is recommended.

Renal impairment

Renal elimination is dependent on renal function and is independent of age. Patients with moderate or severe renal impairment may take 10 to 15 days to reach steady-state plasma concentrations as compared to 4 to 8 days in patients with normal renal function. As with all patients, the titration schedule should be guided by clinical outcome (i.e. seizure control, avoidance of side-effects) with the knowledge that subjects with known renal impairment may require a longer time to reach steady state at each dose.

Hydration

Oligohidrosis (decreased sweating) and anhidrosis have been reported in association with the use of TOPALEX. Decreased sweating and hyperthermia (rise in body temperature) may occur especially in young children exposed to high ambient temperatures. Adequate hydration while using TOPALEX 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 events (see section 4.8). Patients should be warned about this.

Mood Disturbances/Depression

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

Suicide / Suicidal Ideation

In double-blind clinical trials with TOPALEX suicide related events (suicidal ideation, suicide attempts and suicide) occurred at a frequency of 0.5 % in topiramate treated patients (46 out of 8 652 patients treated) compared to 0.2 % treated with placebo (8 out of 4 045 patients treated). One completed suicide was reported in a bipolar disorder double-blind trial in a patient on topiramate. Patients therefore should be monitored for signs of suicidal ideation and behaviour and appropriate treatment should be considered. Patients (and, when appropriate, caregivers of patients) should be advised to seek immediate 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 TOPALEX (see section 4.8). The majority of cases have occurred in patients concurrently taking other medications that are known to be associated with SJS and TEN. There have also been several cases in patients receiving monotherapy. It is recommended that patients be informed about the signs of serious skin reactions. If SJS or TEN are suspected, use of TOPALEX should be discontinued.

Nephrolithiasis

Some patients, especially those with a predisposition to nephrolithiasis, are 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 stone formation, a family history of nephrolithiasis and hypercalciuria (see section 4.4 u2013 Metabolic acidosis and sequelae). None of these risk factors can reliably predict stone formation during topiramate treatment. In addition, patients taking other medication associated with nephrolithiasis may be at increased risk. Concomitant use of TOPALEX with agents predisposing to nephrolithiasis (renal stone formation) should be avoided.

Hepatic impairment

In hepatically impaired patients, topiramate should be administered with caution as the clearance of topiramate may be decreased. Reports of hepatotoxicity and less commonly liver failure in patients taking TOPALEX with and without other medications have been received. Isolated reports have been received of hepatitis and hepatic failure occurring in patients taking multiple medications while being treated with TOPALEX.

Lactose intolerance and lactase deficiency

TOPALEX tablets contains lactose which may have an effect on the glycaemic control of patients with diabetes mellitus. TOPALEX tablets contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take TOPALEX tablets.

Effects of TOPALEX on Other Antiepileptic Medicines

The addition of TOPALEX to other antiepileptic medicines (phenytoin, carbamazepine, valproic acid, phenobarbital, primidone) has no effect on their steady-state plasma concentrations, except in the occasional patient, where the addition of TOPALEX 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 should have phenytoin levels monitored. A pharmacokinetic interaction study of patients with epilepsy indicated the addition of TOPALEX to lamotrigine had no effect on steady state plasma concentration of lamotrigine at TOPALEX doses of 100 to 400 mg/day. In addition, there was no change in steady state plasma concentration of TOPALEX during or after removal of lamotrigine treatment (mean dose of 327 mg/day). However the incidence of adverse effects was meaningfully increased on the combination.

Effects of Other Antiepileptic Medicines on TOPALEX

Phenytoin and carbamazepine decrease the plasma concentration of TOPALEX. The addition or withdrawal of phenytoin or carbamazepine to TOPALEX 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 TOPALEX and, therefore, does not warrant dosage adjustment of TOPALEX. The above interactions are summarised in the following table:

uf0ab = No effect on plasma concentration (u2264 15 % change) ** = Plasma concentrations increase in individual patients uf0af = Plasma concentrations decrease NS = Not studied AEM = Antiepileptic medicine

Other Medicine Interactions

Digoxin: Concomitant administration has shown a decrease in serum digoxin. When TOPALEX is added or withdrawn in patients on digoxin therapy, careful attention should be given to the routine monitoring of serum digoxin.

Oral Contraceptives: In a pharmacokinetic interaction study in healthy volunteers with a concomitantly administered combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 mcg ethinyl estradiol (EE), TOPALEX 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 patients taking valproic acid. In both studies, TOPALEX (50 mg/day to 800 mg/day) did not significantly affect exposure to NET. Although there was a dose dependent decrease in EE exposure for doses between 200 - 800 mg/day, there was no significant dose dependent change in EE exposure for doses of 50 - 200 mg/day. 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 combination oral contraceptive products with TOPALEX. Patients taking estrogen-containing contraceptives should be asked to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding.

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

Risperidone: Interaction studies conducted under single and multiple dose conditions in healthy volunteers and patients with bipolar disorder yielded similar results. When administered concomitantly with TOPALEX 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). 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 clinically significant changes in the systemic exposure of the risperidone total active moiety or of TOPALEX, therefore this interaction is not likely to be of clinical significance.

Hydrochlorothiazide (HCTZ): An interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of HCTZ (25 mg q24h) and TOPALEX (96 mg q12h) when administered alone and concomitantly. The results of this study indicate that TOPALEX C max increased by 27 % and AUC increased by 29 % when HCTZ was added to TOPALEX. The clinical significance of this change is unknown. The addition of HCTZ to TOPALEX therapy may require an adjustment of the TOPALEX dose. The steady-state pharmacokinetics of HCTZ were not significantly influenced by the concomitant administration of TOPALEX.

Clinical laboratory results indicated decreases in serum potassium after TOPALEX or HCTZ administration, which were greater when HCTZ and TOPALEX were administered in combination.

Metformin: An interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of metformin and TOPALEX in plasma when metformin was given alone and when metformin and TOPALEX were given simultaneously. The results of this study indicated that metformin mean C max and mean AUC 0 - 12h increased by 18 % and 25 %, respectively, while mean CL/F decreased 20 % when metformin was co-administered with TOPALEX. TOPALEX did not affect metformin t max. The clinical significance of the effect of TOPALEX on metformin pharmacokinetics is unclear. Oral plasma clearance of TOPALEX appears to be reduced when administered with metformin. The extent of change in the clearance is unknown. When TOPALEX 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: An interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of TOPALEX and pioglitazone when administered alone and concomitantly. A 15 % decrease in the AUC u03c4, ss of pioglitazone with no alteration in C max,ss was observed. This finding was not statistically significant. In addition, a 13 % and 16 % decrease in C max,ss and AUC u03c4,ss respectively, of the active hydroxy-metabolite was noted as well as a 60 % decrease in C max,ss and AUC u03c4,ss of the active keto-metabolite. The clinical significance of these findings is not known. When TOPALEX is added to pioglitazone therapy or pioglitazone is added to TOPALEX therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.

Glyburide: An interaction study conducted in patients with type 2 diabetes evaluated the steady-state pharmacokinetics of glyburide (5 mg/day) alone and concomitantly with TOPALEX (150 mg/day). There was a 25 % reduction in glyburide AUC 24 during TOPALEX 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 TOPALEX were unaffected by concomitant administration of glyburide. When TOPALEX is added to glyburide therapy or glyburide is added to TOPALEX therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.

CNS Depressants: Concomitant use of TOPALEX with alcohol or other central nervous system (CNS) depressant medicines should be avoided.

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

Pregnancy

Studies in animals and humans have shown reproductive toxicity. 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. There are no adequate and well-controlled studies using TOPALEX in pregnant women.

TOPALEX can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk of congenital malformations (e.g., craniofacial defects, such as cleft lip/palate, hypospadias, and anomalies involving various body systems). This has been reported with topiramate monotherapy and topiramate as part of a polytherapy regimen. In addition, data from other studies indicate that, compared with monotherapy, there is an increased risk of teratogenic effects associated with the use of AEMs (Anti-epileptic medications) in combination therapy. The risk has been observed in all doses and effects were reported to be dose-dependent. In women treated with topiramate who have had a child with congenital malformation, there appears to be an increased risk of malformations in subsequent pregnancies when exposed to topiramate. There is an increased risk of pre-term labour and premature delivery associated with the use of AEMs, including topiramate. Compared with a reference group not taking antiepileptic medicines, registry data for TOPALEX monotherapy showed a higher prevalence of low birth weight (< 2 500 grams). One pregnancy registry reported an increased frequency of infants who were small for gestational age (SGA; defined as birth weight below the 10th percentile corrected for their gestational age, stratified by sex) among those exposed to TOPALEX monotherapy in utero. SGA has been observed in all doses and is dose-dependent. The prevalence of SGA is greater in women who received higher doses of topiramate during pregnancy. In addition, the prevalence of SGA for women who continued topiramate use later in pregnancy is higher compared to women who stopped its use before the third trimester.

The long-term consequences of the SGA findings could not be determined. A causal relationship for low birth weight and SGA has not been established. TOPALEX should be used during pregnancy only if potential benefit justifies the potential risk to the foetus. In treating and counselling women of childbearing potential, the prescribing physician should weigh the benefits of therapy against the risks and consider alternative therapeutic options. If this medicine is used during pregnancy or if the patient becomes pregnant while taking this medicine, the patient should be apprised of the potential hazard to the foetus.

Breastfeeding

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 breast milk. Diarrhoea and somnolence have been reported in breastfed infants whose mothers receive topiramate treatment.

TOPALEX may produce central nervous system related events such as: drowsiness, dizziness or other related symptoms. It may also cause visual disturbances and/or blurred vision. These adverse events could potentially be dangerous in patients driving a vehicle or operating machinery, particularly until such time as the individual patientu2019s experience with the medicine is established. TOPALEX may be more sedating than other antiepileptic medicines.

Adverse events identified in clinical trials, are listed by their incidence in Table 1. Assigned frequencies are as follows: Very common u22651/10 Common u22651/100 to <1/10 Uncommon u22651/1 000 to <1/100 Rare u22651/10,000 to 5 % and greater than that observed in placebo in at least 1 indication in double-blind controlled studies with TOPALEX) 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.

Paediatric population

Adverse events reported more frequently (u2265 2-fold) in children than in adults in double-blind controlled studies include: decreased appetite, increased appetite, acidosis hyperchloraemic, 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, and gait disturbance. Adverse events that were reported in children but not in adults in double-blind controlled studies include: eosinophilia, psychomotor hyperactivity, vertigo, vomiting, hyperthermia, pyrexia, and learning disability.

System Organ Class Very Common Common Uncommon Rare Blood and lymphatic system disorders Anaemia Leucopenia, thrombocytopenia lymphadenopathy, eosinophilia Immune system disorders Hypersensitivity Metabolism and nutrition disorders Anorexia, decreased appetite Metabolic acidosis, hypokalaemia, increased appetite, polydipsia Acidosis hyperchloraemic 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, Mania, panic disorder, hypomania, 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 Nervous system disorders Paraesthesia, somnolence, dizziness Disturbance in attention, memory impairment, Depressed level of consciousness, grand mal convulsion, visual Apraxia, circadian rhythm sleep disorder, hyperaesthesia, hyposmia, amnesia, cognitive disorder, mental impairment, psychomotor skills impaired, convulsion, coordination abnormal, tremor, lethargy, hypoaesthesia, nystagmus, dysgeusia, balance disorder, dysarthria, intention tremor, sedation 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, anosmia, essential tremor, akinesia, unresponsive to stimuli neuropathy peripheral, presyncope, dystonia, formication Eye disorders Vision blurred, diplopia, visual disturbance Visual acuity reduced, scotoma, dry eye, photophobia, blepharospasm, lacrimation increased, photopsia, mydriasis, presbyopia Blindness unilateral, blindness transient, glaucoma, accommodation disorder, altered visual depth perception, scintillating scotoma, night blindness, amblyopia 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 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, gastro-oesophageal 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 Skin odour abnormal, urticaria localised Musculoskeletal and connective tissue disorders Arthralgia, muscle spasms, myalgia, muscle twitching, muscular weakness, musculoskeletal chest pain Musculoskeletal stiffness, flank pain, muscle fatigue Renal and urinary disorders Nephrolithiasis, pollakiuria, dysuria Calculus urinary, urinary incontinence, Calculus ureteric haematuria, incontinence, micturition urgency, renal colic, renal pain 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, sluggishness, peripheral coldness, feeling drunk, feeling jittery Face oedema, Investigations Weight decreased Crystal urine present, tandem gait test abnormal, white blood cell count decreased, increase in liver enzymes Blood bicarbonate decreased Social circumstances Learning disability

Signs and Symptoms

Overdosage of topiramate have been reported. Signs and symptoms included: convulsions, drowsiness, speech disturbances, blurred vision, diplopia, mentation impaired, 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 polydrug overdoses involving topiramate. Topiramate overdose can result in severe metabolic acidosis (see Section 4.4). The highest topiramate overdose reported was calculated to be between 96 and 110 g and resulted in coma lasting 20 to 24 hours followed by full recovery after 3 to 4 days.

Treatment

In the event of overdose, topiramate should be discontinued and general supportive treatment given until clinical toxicity has been diminished or resolved. Haemodialysis has been shown to be an effective means of removing topiramate from the body. The patient should be well hydrated. It is advisable to contact a poison control centre to obtain the latest recommendations for the management of an overdose.