- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Excipients with known effectAlso includes lactose monohydrate:25 mg tablet contains 30.85 mg lactose monohydrate.For the full list of excipients, see section 6.1.
Description of the productWhite round tablets, 6 mm in diameter, TOP on one side, 25 on the other.
PosologyIt 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 Topamax. 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 Topamax may require adjustment of the dose of Topamax.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with or without a history of seizures or epilepsy, antiepileptic drugs (AEDs) including topiramate should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency.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 In paediatric clinical trials, topiramate was gradually withdrawn over a 2-8 week period.
GeneralWhen concomitant AEDs are withdrawn to achieve monotherapy with topiramate, consideration should be given to the effects this may have on seizure control.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 Topamax (topiramate) dosage may be required if clinically indicated.
AdultsDose 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 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 2.0mg/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)
AdultsTherapy 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 Topamax (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.
AdultsThe 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 populationTopamax (topiramate) is not recommended for treatment or prevention of migraine in children due to insufficient data on safety and efficacy.
General dosing recommendations for Topamax in special patient populations
Renal impairmentIn 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 is removed from plasma by haemodialysis, a supplemental dose of Topamax 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 impairmentIn patients with moderate to severe hepatic impairment topiramate should be administered with caution as the clearance of topiramate is decreased.
ElderlyNo dose adjustment is required in the elderly population providing renal function is intact.Method of administrationTopamax 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.Topamax can be taken without regard to meals.
OligohydrosisOligohydrosis (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/depressionAn increased incidence of mood disturbances and depression has been observed during topiramate treatment.
Suicide/suicide ideationSuicidal ideation and behaviour have been reported in patients treated with anti-epileptic 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.
NephrolithiasisSome 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. 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 functionIn 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 functionIn hepatically-impaired patients, topiramate should be administered with caution as the clearance of topiramate may be decreased.
Acute myopia and secondary angle closure glaucomaA 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 myopia, anterior chamber shallowing, ocular hyperaemia (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 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 defectsVisual 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 acidosisHyperchloremic, 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 metabolic acidosis increases the risk of renal stone formation and may potentially lead to osteopenia.Chronic metabolic acidosis in paediatric patients can reduce growth rates. The effect of topiramate on bone-related sequelae has not been systematically investigated in paediatric or adult populations.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 functionCognitive 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.
Nutritional supplementationSome 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 intoleranceTopamax tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medication.
Effects of other antiepileptic medicinal products on TopamaxPhenytoin and carbamazepine decrease the plasma concentration of topimarate. The addition or withdrawal of phenytoin or carbamazepine to Topamax 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 Topamax and, therefore, does not warrant dosage adjustment of Topamax. The results of these interactions are summarized below:
|AED Coadministered||AED Concentration||Topamax Concentration|
|↔ = 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
DigoxinIn a single-dose study, serum digoxin area under plasma concentration curve (AUC) decreased 12% due to concomitant administration of Topamax. The clinical relevance of this observation has not been established. When Topamax is added or withdrawn in patients on digoxin therapy, careful attention should be given to the routine monitoring of serum digoxin.
Central nervous system depressantsConcomitant administration of Topamax and alcohol or other central nervous system (CNS) depressant medicinal products has not been evaluated in clinical studies. It is recommended that Topamax 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.
Oral contraceptivesIn a pharmacokinetic interaction study in healthy volunteers with a concomitantly administered combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 µg ethinyl estradiol (EE), Topamax 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, Topamax (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 combination oral contraceptive products with Topamax. 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.
LithiumIn 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.
RisperidoneDrug-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.
MetforminA 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 Topamax 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.
PioglitazoneA 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 Topamax is added to pioglitazone therapy or pioglitazone is added to Topamax therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.
GlyburideA drug-drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state pharmacokinetics of glyburide (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 glyburide.When topiramate is added to glyburide therapy or glyburide is added to topiramate therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.
Other forms of interactions
Agents predisposing to nephrolithiasisTopamax, when used concomitantly with other agents predisposing to nephrolithiasis, may increase the risk of nephrolithiasis. While using Topamax, agents like these should be avoided since they may create a physiological environment that increases the risk of renal stone formation.
Valproic acidConcomitant 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. This adverse reaction is not due to a pharmacokinetic interaction. An association of hyperammonemia with topiramate monotherapy or concomitant treatment with other AEDs has not been established.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.
Additional pharmacokinetic drug interaction studiesClinical 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|
|Dihydroergotamine (Oral and Subcutaneous)||↔||↔|
|Haloperidol||↔ 31% increase in AUC of the reduced metabolite||NS|
|Propranolol||↔ 17% increase in Cmax 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|
|Diltiazem||25% decrease in AUC of diltiazem and 18% decrease in DEA, and ↔ for DEM*||20% increase in AUC|
|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.|
Risk related to epilepsy and AEDs in generalSpecialist advice should be given to women who are of childbearing potential. 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 unborn child. 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 topiramateTopiramate was teratogenic in mice, rats and rabbits (see section 5.3). In rats, topiramate crosses the placental barrier.Clinical data from pregnancy registries indicate that infants exposed to topiramate monotherapy have: • 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 incidence of major congenital malformations, compared with a reference group not taking AEDs. 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. • 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). The long term consequences of the SGA findings could not be determined.It is recommended that women of child bearing potential use highly effective contraception (see section 4.5) and consider alternative therapeutic options.
Indication epilepsyIt is recommended to consider alternative therapeutic options in women of child bearing potential. If topirmate is used in women of child bearing potential, it is recommended that highly effective contraception be used (see section 4.5), and that the woman is fully informed of the known risks of uncontrolled epilepsy to the pregnancy and the potential risks of the medicinal product to the foetus. If a woman plans a pregnancy, a preconceptional visit is recommended in order to reassess the treatment, and to consider other therapeutic options. In case of administration during the first trimester, careful prenatal monitoring should be performed.
Indication migraine prophylaxisTopiramate is contraindicated in pregnancy and in women of childbearing potential if a highly effective method of contraception is not used (see sections 4.3 and 4.5).
Brest-feedingAnimal 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 breast milk. Since many medicinal products are excreted into human milk, a decision must be made whether to suspend breast-feeding or to discontinue/ abstain from topiramate therapy taking into account the importance of the medicinal product to the mother (see section 4.4).
FertilityAnimal studies did not reveal impairment of fertility by topiramate (see section 5.3). The effect of topiramate on human fertility has not been established.
|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|
|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|
|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*|
|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||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, calcinosis|
|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 clinical trial data.|
Paediatric populationAdverse 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 reactionsReporting 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.
Signs and symptomsOverdoses 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).
TreatmentIn acute topiramate overdose, if the ingestion is recent, the stomach should be emptied immediately by lavage or by induction of emesis. Activated charcoal has been shown to adsorb topiramate in vitro. Treatment should be appropriately supportive and the patient should be well hydrated. Haemodialysis has been shown to be an effective means of removing topiramate from the body.
Absence seizuresTwo small one arm studies were carried out with children aged 4-11 years old (CAPSS-326 and TOPAMAT-ABS-001). One included 5 children and the other included 12 children before it was terminated early due to lack of therapeutic response. The doses used in these studies were up to approximately 12 mg/kg in study TOPAMAT-ABS-001 and a maximum of the lesser of 9 mg/kg/day or 400 mg/day in study CAPSS-326. These studies do not provide sufficient evidence to reach conclusion regarding efficacy or safety in the paediatric population.
AbsorptionTopiramate is rapidly and well absorbed. Following oral administration of 100 mg topiramate to healthy subjects, a mean peak plasma concentration (Cmax) of 1.5 µg/ml was achieved within 2 to 3 hours (Tmax).Based on the recovery of radioactivity from the urine the mean extent of absorption of a 100 mg oral dose of 14C-topiramate was at least 81%. There was no clinically significant effect of food on the bioavailability of topiramate.
DistributionGenerally, 13 to 17% of topiramate is bound to plasma protein. A low capacity binding site for topiramate in/on erythrocytes that is saturable above plasma concentrations of 4 µg/ml has been observed. The volume of distribution varied inversely with the dose. The mean apparent volume of distribution was 0.80 to 0.55 l/kg for a single dose range of 100 to 1200 mg. An effect of gender on the volume of distribution was detected, with values for females circa 50% of those for males. This was attributed to the higher percent body fat in female patients and is of no clinical consequence.
BiotransformationTopiramate is not extensively metabolized (~20%) in healthy volunteers. It is metabolized up to 50% in patients receiving concomitant antiepileptic therapy with known inducers of drug metabolizing enzymes. Six metabolites, formed through hydroxylation, hydrolysis and glucuronidation, have been isolated, characterized and identified from plasma, urine and faeces of humans. Each metabolite represents less than 3% of the total radioactivity excreted following administration of 14C-topiramate. Two metabolites, which retained most of the structure of topiramate, were tested and found to have little or no anticonvulsant activity.
EliminationIn humans, the major route of elimination of unchanged topiramate and its metabolites is via the kidney (at least 81% of the dose). Approximately 66% of a dose of 14C-topiramate was excreted unchanged in the urine within four days. Following twice a day dosing with 50 mg and 100 mg of topiramate the mean renal clearance was approximately 18 ml/min and 17 ml/min, respectively. There is evidence of renal tubular reabsorption of topiramate. This is supported by studies in rats where topiramate was co-administered with probenecid, and a significant increase in renal clearance of topiramate was observed. Overall, plasma clearance is approximately 20 to 30 ml/min in humans following oral administration.
Linearity/non-linearityTopiramate exhibits low intersubject variability in plasma concentrations and, therefore, has predictable pharmacokinetics. The pharmacokinetics of topiramate are linear with plasma clearance remaining constant and area under the plasma concentration curve increasing in a dose-proportional manner over a 100 to 400 mg single oral dose range in healthy subjects. Patients with normal renal function may take 4 to 8 days to reach steady-state plasma concentrations. The mean Cmax following multiple, twice a day oral doses of 100 mg to healthy subjects was 6.76 µg/ml. Following administration of multiple doses of 50 mg and 100 mg of topiramate twice a day, the mean plasma elimination half-life was approximately 21 hours.
Use with other AEDsConcomitant multiple-dose administration of topiramate, 100 to 400 mg twice a day, with phenytoin or carbamazepine shows dose proportional increases in plasma concentrations of topiramate.
Renal impairmentThe plasma and renal clearance of topiramate are decreased in patients with moderate and severe impaired renal function (CLCR ≤ 70 ml/min). As a result, higher steady-state topiramate plasma concentrations are expected for a given dose in renal-impaired patients as compared to those with normal renal function. In addition, patients with renal impairment will require a longer time to reach steady-state at each dose. In patients with moderate and severe renal impairment, half of the usual starting and maintenance dose is recommended.Topiramate is effectively removed from plasma by haemodialysis. A prolonged period of hemodialysis may cause topiramate concentration to fall below levels that are required to maintain an anti-seizure effect. To avoid rapid drops in topiramate plasma concentration during hemodialysis, a supplemental dose of topiramate may be required. The actual adjustment should take into account 1) the duration of dialysis period, 2) the clearance rate of the dialysis system being used, and 3) the effective renal clearance of topiramate in the patient being dialyzed.
Hepatic impairmentPlasma clearance of topiramate decreased a mean of 26% in patients with moderate to severe hepatic impairment. Therefore, topiramate should be administered with caution in patients with hepatic impairment.
Elderly populationPlasma clearance of topiramate is unchanged in elderly subjects in the absence of underlying renal disease.
Paediatric population (pharmacokinetics, up to 12 years of age)The pharmacokinetics of topiramate in children, as in adults receiving add-on therapy, are linear, with clearance independent of dose and steady-state plasma concentrations increasing in proportion to dose. Children, however, have a higher clearance and a shorter elimination half-life. Consequently, the plasma concentrations of topiramate for the same mg/kg dose may be lower in children compared to adults. As in adults, hepatic enzyme inducing AEDs decrease the steady-state plasma concentrations.
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