TOPIRAMATE 25MG FILM-COATED TABLET

Active substance: TOPIRAMATE

View full screen / Print PDF » Download PDF ⇩

Transcript
SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Topiramate 25 mg Film-coated tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 25 mg of topiramate.
Excipient(s) with known effect:
Each 25 mg tablet contains 28.93 mg of lactose.
For full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Film-coated tablet.
25 mg tablets are white, round and convex.

4.

CLINICAL PARTICULARS

4.1.

Therapeutic indications
Monotherapy in adults, adolescents and children over 6 years of age with partial
seizures with or without secondary generalised seizures, and primary generalised
tonic-clonic seizures.
Adjunctive therapy in children aged 2 years and above, adolescents and adults with
partial onset seizures with or without secondary generalization or primary generalized
tonic-clonic seizures and for the treatment of seizures associated with Lennox-Gastaut
syndrome.
Topiramate is indicated in adults for the prophylaxis of migraine headache after
careful evaluation of possible alternative treatment options. Topiramate is not
intended for acute treatment.

4.2

Posology and method of administration

General
It is recommended that therapy be initiated at a low dose followed by titration to an effective
dose. Dose and titration rate should be guided by clinical response.
Topiramate is available in film-coated tablets formulation. It is recommended that film-coated
tablets not be broken.
It is not necessary to monitor topiramate plasma concentrations to optimize therapy with
Topiramate. On rare occasions, the addition of topiramate to phenytoin may require an
adjustment of the dose of phenytoin to achieve optimal clinical outcome. Addition or
withdrawal of phenytoin and carbamazepine to adjunctive therapy with Topiramate may
require adjustment of the dose of Topiramate.
Topiramate can be taken without regard to meals.
In patients with or without a history of seizures or epilepsy, antiepileptic drugs including
topiramate should be gradually withdrawn to minimize the potential for seizures or increased
seizure frequency. In clinical trials, daily dosages were decreased in weekly intervals by
50-100 mg in adults with epilepsy and by 25-50 mg in adults receiving topiramate at doses up
to 100 mg/day for migraine prophylaxis. In paediatric clinical trials, topiramate was gradually
withdrawn over a 2-8 week period.
Monotherapy epilepsy
General
When concomitant antiepileptic drugs (AEDs) are withdrawn to achieve monotherapy with
topiramate, consideration should be given to the effects this may have on seizure control.
Unless safety concerns require an abrupt withdrawal of the concomitant AED, a gradual
discontinuation at the rate of approximately one-third of the concomitant AED dose every 2
weeks is recommended.
When enzyme inducing medicinal products are withdrawn, topiramate levels will increase. A
decrease in Topiramate (topiramate) dosage may be required if clinically indicated.
Adults
Dose and titration should be guided by clinical response. Titration should begin at 25 mg
nightly for 1 week. The dosage should then be increased at 1- or 2-week intervals by
increments of 25 or 50 mg/day, administered in two divided doses. If the patient is unable to
tolerate the titration regimen, smaller increments or longer intervals between increments can
be used.
The recommended initial target dose for topiramate 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)
Adults
Therapy should begin at 25-50 mg nightly for one week. Use of lower initial doses has been
reported, but has not been studied systematically. Subsequently, at weekly or bi-weekly
intervals, the dose should be increased by 25-50 mg/day and taken in two divided doses.
Some patients may achieve efficacy with once-a-day dosing.
In clinical trials as adjunctive therapy, 200 mg was the lowest effective dose. The usual daily
dose is 200-400 mg in two divided doses.
These dosing recommendations apply to all adults, including the elderly, in the absence of
underlying renal disease (see section 4.4).
Paediatric population (children aged 2 years and above)
The recommended total daily dose of Topiramate (topiramate) as adjunctive therapy is
approximately 5 to 9 mg/kg/day in two divided doses. Titration should begin at 25 mg (or
less, based on a range of 1 to 3 mg/kg/day) nightly for the first week. The dosage should then
be increased at 1- or 2-week intervals by increments of 1 to 3 mg/kg/day (administered in two
divided doses), to achieve optimal clinical response.
Daily doses up to 30 mg/kg/day have been studied and were generally well tolerated.
Migraine
Adults
The recommended total daily dose of topiramate for prophylaxis of migraine headache is
100 mg/day administered in two divided doses. Titration should begin at 25 mg nightly for 1
week. The dosage should then be increased in increments of 25 mg/day administered at 1week intervals. If the patient is unable to tolerate the titration regimen, longer intervals
between dose adjustments can be used.
Some patients may experience a benefit at a total daily dose of 50 mg/day. Patients have
received a total daily dose up to 200 mg/day. This dose may be benefit in some patients,
nevertheless, caution is advised due to an increase incidence of side effects
Paediatric population
Topiramate (topiramate) is not recommended for treatment or prevention of migraine in
children due to insufficient data on safety and efficacy.

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



In patients with end-stage renal failure, since topiramate is removed from plasma by
haemodialysis, a supplemental dose of Topiramate equal to approximately one-half the daily
dose should be administered on haemodialysis days. The supplemental dose should be
administered in divided doses at the beginning and completion of the haemodialysis
procedure. The supplemental dose may differ based on the characteristics of the dialysis
equipment being used (see section 5.2).
Hepatic impairment
In patients with moderate to severe hepatic impairment topiramate should be administered
with caution as the clearance of topiramate is decreased.
Elderly
No dose adjustment is required in the elderly population providing renal function is intact.

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section
6.1.
Migraine prophylaxis in pregnancy and in women of childbearing potential if not
using effective methods of contraception
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 for further details).
As with other anti-epileptic drugs, 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 antiepileptics, 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).
Oligohydrosis
Oligohydrosis (decreased sweating) has been reported in association with the use of
topiramate. Decreased sweating and hyperthermia (rise in body temperature) may occur
especially in young children exposed to high ambient temperature.

Mood disturbances/depression
An increased incidence of mood disturbances and depression has been observed during
topiramate treatment.
Suicide/suicide ideation
Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic
agents in several indications. A meta-analysis of randomised placebo-controlled trials of antiepileptic drugs 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.
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. 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,
Renal impairment.



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
A syndrome consisting of acute myopia associated with secondary angle closure glaucoma
has been reported in patients receiving topiramate. Symptoms include acute onset of
decreased visual acuity and/or ocular pain. Ophthalmologic findings can include 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.
Metabolic acidosis
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 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 function
Cognitive impairment in epilepsy is multifactorial and may be due to the underlying
aetiology, due to the epilepsy or due to the anti epileptic treatment. There have been reports in
the literature of impairment of cognitive function in adults on topiramate therapy which
required reduction in dosage or discontinuation of treatment. However, studies regarding
cognitive outcomes in children treated with topiramate are insufficient and its effect in this
regard still needs to be elucidated.
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
Topiramate contains lactose. Patients with rare hereditary problems of galactose intolerance,
Lapp lactase deficiency or glucose-galactose malabsorption should not take this medication.

4.5

Interaction with other medicinal products and other forms of interaction

Effects of Topiramate on other antiepileptic medicinal products
The addition of topiramate to other antiepileptic drugs (phenytoin, carbamazepine, valproic
acid, phenobarbital, primidone) has no effect on their steady-state plasma concentrations,
except in the occasional patient, where the addition of topiramate to phenytoin may result in
an increase of plasma concentrations of phenytoin. This is possibly due to inhibition of a
specific enzyme polymorphic isoform (CYP2C19). Consequently, any patient on phenytoin
showing clinical signs or symptoms of toxicity should have phenytoin levels monitored.
A pharmacokinetic interaction study of patients with epilepsy indicated the addition of
topiramate to lamotrigine had no effect on steady state plasma concentration of lamotrigine at
topiramate doses of 100 to 400 mg/day. In addition, there was no change in steady state
plasma concentration of topiramate during or after removal of lamotrigine treatment (mean
dose of 327 mg/day).
Topiramate inhibits the enzyme CYP 2C19 and may interfere with other substances
metabolized via this enzyme (e.g., diazepam, imipramine, moclobemide, proguanil,
omeprazole).
Effects of other antiepileptic medicinal products on topiramate
Phenytoin and carbamazepine decrease the plasma concentration of topiramate. The addition
or withdrawal of phenytoin or carbamazepine to topiramate therapy may require an
adjustment in dosage of the latter. This should be done by titrating to clinical effect. The
addition or withdrawal of valproic acid does not produce clinically significant changes in
plasma concentrations of topiramate and, therefore, does not warrant dosage adjustment of
topiramate. The results of these interactions are summarized below:

AED Concentration
**








Phenytoin

Topiramate
Concentration






AED Coadministered

Carbamazepine (CBZ)
Valproic acid
Lamotrigine
Phenobarbital
NS
NS
Primidone
= No effect on plasma concentration ( 15% change)
** = Plasma concentrations increase in individual patients
= Plasma concentrations decrease
NS = Not studied
AED = antiepileptic drug






Other medicinal product interactions
Digoxin
In a single-dose study, serum digoxin area under plasma concentration curve (AUC)
decreased 12% due to concomitant administration of topiramate. The clinical relevance of this
observation has not been established. When topiramate is added or withdrawn in patients on
digoxin therapy, careful attention should be given to the routine monitoring of serum digoxin.
CNS depressants
Concomitant administration of topiramate and alcohol or other CNS depressant medicinal
products has not been evaluated in clinical studies. It is recommended that topiramate not be
used concomitantly with alcohol or other CNS depressant medicinal products.
St John’s Wort (Hypericum perforatum)
A risk of decreased plasma concentrations resulting in a loss of efficacy could be observed
with co-administration of topiramate and St John’s Wort. There have been no clinical studies
evaluating this potential interaction.
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 µg ethinyl estradiol (EE), topiramate given in the absence of other medications at
doses of 50 to 200 mg/day was not associated with statistically significant changes in mean
exposure (AUC) to either component of the oral contraceptive. In another study, exposure to
EE was statistically significantly decreased at doses of 200, 400, and 800 mg/day (18%, 21%,
and 30%, respectively) when given as adjunctive therapy in epilepsy patients taking valproic
acid. In both studies, topiramate (50-200 mg/day in healthy volunteers and 200-800 mg/day in
epilepsy patients) did not significantly affect exposure to NET. Although there was a dose
dependent decrease in EE exposure for doses between 200-800 mg/day (in epilepsy patients),
there was no significant dose dependent change in EE exposure for doses of 50-200 mg/day
(in healthy volunteers). The clinical significance of the changes observed is not known. The
possibility of decreased contraceptive efficacy and increased breakthrough bleeding should be
considered in patients taking combination oral contraceptive products with topiramate.
Patients taking oestrogen 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 healthy volunteers, there was an observed reduction (18% for AUC) in systemic exposure
for lithium during concomitant administration with topiramate 200 mg/day. In patients with
bipolar disorder, the pharmacokinetics of lithium were unaffected during treatment with
topiramate at doses of 200 mg/day; however, there was an observed increase in systemic
exposure (26% for AUC) following topiramate doses of up to 600 mg/day. Lithium levels
should be monitored when co-administered with topiramate.
Risperidone
Drug-drug interaction studies conducted under single dose conditions in healthy volunteers
and multiple dose conditions in patients with bipolar disorder, yielded similar results. When
administered concomitantly with topiramate at escalating doses of 100, 250 and 400 mg/day
there was a reduction in risperidone (administered at doses ranging from 1 to 6 mg/day)
systemic exposure (16% and 33% for steady-state AUC at the 250 and 400 mg/day doses,
respectively). However, differences in AUC for the total active moiety between treatment
with risperidone alone and combination treatment with topiramate were not statistically
significant. Minimal alterations in the pharmacokinetics of the total active moiety (risperidone
plus 9-hydroxyrisperidone) and no alterations for 9-hydroxyrisperidone were observed. There
were no significant changes in the systemic exposure of the risperidone total active moiety or
of topiramate. When topiramate was added to existing risperidone (1-6 mg/day) treatment,
adverse events were reported more frequently than prior to topiramate (250-400 mg/day)
introduction (90% and 54 % respectively). The most frequently reported AE’s when
topiramate was added to risperidone treatment were: somnolence (27% and 12%),
paraesthesia (22% and 0%) and nausea (18% and 9% respectively).
Hydrochlorothiazide (HCTZ)
A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state
pharmacokinetics of HCTZ (25 mg q24h) and topiramate (96 mg q12h) when administered
alone and concomitantly. The results of this study indicate that topiramate Cmax increased by
27% and AUC increased by 29% when HCTZ was added to topiramate. The clinical
significance of this change is unknown. The addition of HCTZ to topiramate therapy may
require an adjustment of the topiramate dose. The steady-state pharmacokinetics of HCTZ
were not significantly influenced by the concomitant administration of topiramate. Clinical
laboratory results indicated decreases in serum potassium after topiramate or HCTZ
administration, which were greater when HCTZ and topiramate were administered in
combination.
Metformin
A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state
pharmacokinetics of metformin and topiramate in plasma when metformin was given alone
and when metformin and topiramate were given simultaneously. The results of this study
indicated that metformin mean Cmax and mean AUC0-12h increased by 18% and 25%,
respectively, while mean CL/F decreased 20% when metformin was co-administered with
topiramate. Topiramate did not affect metformin tmax. The clinical significance of the effect of
topiramate on metformin pharmacokinetics is unclear. Oral plasma clearance of topiramate
appears to be reduced when administered with metformin. The extent of change in the
clearance is unknown. The clinical significance of the effect of metformin on topiramate
pharmacokinetics is unclear.

When topiramate is added or withdrawn in patients on metformin therapy, careful attention
should be given to the routine monitoring for adequate control of their diabetic disease state.
Pioglitazone
A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state
pharmacokinetics of topiramate and pioglitazone when administered alone and concomitantly.
A 15% decrease in the AUCτ,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
AUCτ,ss respectively, of the active hydroxy-metabolite was noted as well as a 60% decrease in
Cmax,ss and AUCτ,ss of the active keto-metabolite. The clinical significance of these findings is
not known. When topiramate is added to pioglitazone therapy or pioglitazone is added to
topiramate therapy, careful attention should be given to the routine monitoring of patients for
adequate control of their diabetic disease state.
Glyburide
A drug-drug interaction study conducted in patients with type 2 diabetes evaluated the steadystate 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 nephrolithiasis
Topiramate, when used concomitantly with other agents predisposing to nephrolithiasis, may
increase the risk of nephrolithiasis. While using topiramate, agents like these should be
avoided since they may create a physiological environment that increases the risk of renal
stone formation.
Valproic acid
Concomitant administration of topiramate and valproic acid has been associated with
hyperammonaemia 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 hyperammonaemia with topiramate monotherapy or concomitant treatment
with other anti-epileptics 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 studies

Clinical studies have been conducted to assess the potential pharmacokinetic drug interaction
between topiramate and other agents. The changes in Cmax or AUC as a result of the
interactions are summarized below. The second column (concomitant drug concentration)
describes what happens to the concentration of the concomitant drug listed in the first column
when topiramate is added. The third column (topiramate concentration) describes how the
coadministration of a drug listed in the first column modifies the concentration of topiramate.
Summary of Results from Additional Clinical Pharmacokinetic Drug Interaction
Studies
Topiramate
Concomitant Drug
Concomitant Drug
Concentrationa
Concentrationa
Amitriptyline
20% increase in Cmax and
NS



AUC of nortriptyline metabolite


31% increase in AUC of the
reduced metabolite

NS




Propranolol



Dihydroergotamine
(Oral and Subcutaneous)
Haloperidol

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)
NS

Sumatriptan (Oral and
Subcutaneous)
Pizotifen
Diltiazem
25% decrease in AUC of
20% increase in AUC
diltiazem and 18% decrease in
DEA, and for DEM*
Venlafaxine
Flunarizine
16% increase in AUC
b
(TPM 50 mg q12h)
a
% values are the changes in treatment mean Cmax or AUC with respect to monotherapy
= No effect on Cmax and AUC ( 15% change) of the parent compound
NS = Not studied
*DEA = des acetyl diltiazem, DEM = N-demethyl diltiazem
b
Flunarizine AUC increased 14% in subjects taking flunarizine alone. Increase in exposure
may be attributed to accumulation during achievement of steady state.

















4.6

Fertility, pregnancy and lactation

Topiramate was teratogenic in mice, rats and rabbits. In rats, topiramate crosses the placental
barrier.
Data from the U.K. pregnancy register and the North American Antiepileptic Drug (NAAED)
pregnancy registry indicate that infants exposed to topiramate monotherapy in the first
trimester have an increased risk of congenital malformations (e.g., craniofacial defects, such
as cleft lip/palate, hypospadias, and anomalies involving various body systems). The NAAED

pregnancy registry data for topiramate monotherapy showed an approximate 3-fold higher
incidence of major congenital malformations, compared with a reference group not taking
antiepileptic drugs. Furthermore, there was a higher prevalence of low birth weight (< 2500
grams) following topiramate treatment than in the reference group.
In addition, data from these registries and other studies indicate that, compared with
monotherapy, there is an increased risk of teratogenic effects associated with the use of antiepileptic drugs in combination therapy.
It is recommended that women of child bearing potential use adequate contraception and
consider alternative therapeutic options.
Animal studies have shown excretion of topiramate in milk. The excretion of topiramate in
human milk has not been evaluated in controlled studies. Limited observations in patients
suggest an extensive excretion of topiramate into 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 (section 4.4).
Indication Epilepsy
During pregnancy, topiramate should be prescribed after fully informing the woman of the
known risks of uncontrolled epilepsy to the pregnancy and the potential risks of the medicinal
product to the foetus.
Indication Migraine Prophylaxis
Topiramate is contraindicated in pregnancy, and in women of childbearing potential if an
effective method of contraception is not used (see sections 4.3 and 4.5).

4.7

Effects on ability to drive and use machines

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

4.8

Undesirable effects

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

1/10
1/100 to <1/10
1/1,000 to <1/100
1/10,000 to <1/1,000






Very common
Common
Uncommon
Rare

Not known
cannot be estimated from the available data
The most common ADRs (those with an incidence of >5% and greater than that observed in
placebo in at least 1 indication in double-blind controlled studies with topiramate) include:
anorexia, decreased appetite, bradyphraenia, depression, expressive language disorder,
insomnia, coordination abnormal, disturbance in attention, dizziness, dysarthria, dysgeusia,
hypoesthesia, lethargy, memory impairment, nystagmus, paraesthesia, somnolence, tremor,
diplopia, vision blurred, diarrhoea, nausea, fatigue, irritability, and weight decreased.
Paediatric population
ADRs 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
ADRs that were reported in children but not in adults in double-blind controlled studies
include:
• Eosinophilia,
• Psychomotor hyperactivity,
• Vertigo,
• Vomiting,
• Hyperthermia,
• Pyrexia,
• Learning disability.

System Organ
Class
Infections and
infestations

Table 1: Topiramate Adverse Drug Reactions
Common
Uncommon
Rare

Very common

Nasopharyngitis
*
Neutropenia*
Leukopenia,
thrombocytopenia
lymphadenopathy,
eosinophilia

Blood and
lymphatic system
disorders

Anaemia

Immune system
disorders

Hypersensitivity

Metabolism and
nutrition
disorders

Anorexia,
decreased
appetite

Acidosis
Metabolic
hyperchloraemic
acidosis,
Hypokalaemia,
increased appetite,
polydipsia

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,
dysphaemia,
euphoric mood,
paranoia,
perseveration,
panic attack,
tearfulness,
reading disorder,
initial insomnia,
flat affect,
thinking
abnormal, loss of
libido, listless,
middle insomnia,
distractibility,
early morning

Psychiatric
disorders

Not known

Depression

Allergic
oedema*,
conjunctival
oedema*

Mania, panic
disorder, feeling
of despair*,
hypomania

awakening, panic
reaction, elevated
mood

nervous system
disorders

Eye disorders

Ear and labyrinth

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

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

Vertigo, tinnitus, Deafness,

Angle closure
glaucoma*,
Maculopathy*,
eye movement
disorder*

disorders

ear pain

deafness
unilateral,
deafness
neurosensory, ear
discomfort,
hearing impaired

Cardiac disorders

Bradycardia, sinus
bradycardia,
palpitations

Vascular
disorders

Hypotension,
Raynaud's
orthostatic
phenomenon
hypotension
flushing, hot flush,

Respiratory,
thoracic and
mediastinal
disorders

Gastrointestinal
disorders

Dyspnoea,
epistaxis, nasal
congestion,
rhinorrhoea

Nausea,
diarrhoea

Dyspnoea
exertional,
Paranasal sinus
hypersecretion,
dysphonia

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

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

Hepatobiliary
disorders
Skin and
subcutaneous
tissue disorders

Cough

Hepatitis,
Hepatic failure
Alopecia, rash,
pruritus

Anhidrosis,
hypoaesthesia
facial, urticaria,
erythema,
pruritus
generalised, rash
macular, skin
discolouration,

StevensJohnson
syndrome*
erythema
multiforme*,
skin odour
abnormal,
periorbital

Toxic
epidermal
necrolysis*

dermatitis
allergic,
swelling face

oedema*,
urticaria
localised

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

Limb
discomfort*

Musculoskeleta
l and
connective
tissue disorders

Arthralgia,
muscle spasms,
myalgia,
muscle
twitching,
muscular
weakness,
musculoskeleta
l chest pain

Renal and
urinary
disorders

Nephrolithiasis, Calculus
pollakiuria,
urinary, urinary
dysuria
incontinence,
haematuria,
incontinence,
micturition
urgency, renal
colic, renal pain

Reproductive
system and
breast disorders

General
disorders and
administration
site conditions

Calculus
ureteric, renal
tubular
acidosis*

Erectile
dysfunction,
sexual
dysfunction
Fatigue

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

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

Face oedema,
calcinosis

Blood
Crystal urine
present, tandem bicarbonate
gait test abnormal, decreased
white blood cell
count decreased,
Increase in liver
enzymes
Social
Learning
circumstances
disability
* identified as an ADR from postmarketing spontaneous reports. Its frequency was calculated based on
clinical trial data.
Investigations

Weight
decreased

Weight
increased*

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Healthcare professionals are asked to report any suspected adverse reactions via the yellow
card scheme.

4.9.

Overdose
Signs and symptoms
Overdoses of topiramate have been reported. Signs and symptoms included
convulsions, drowsiness, speech disturbances, blurred vision, diplopia,
impaired mentation, lethargy, abnormal coordination, stupor, hypotension,
abdominal pain, agitation, dizziness and depression. The clinical consequences
were not severe in most cases, but deaths have been reported after overdoses
with multiple medicinal products including topiramate.
Topiramate overdose can result in severe metabolic acidosis (see section 4.4).
Treatment
In 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.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: other antiepileptics, antimigraine preparations, ATC code:
N03AX11
Topiramate is classified as a sulfamate-substituted monosaccharide. The precise mechanism
by which topiramate exerts its antiseizure and migraine prophylaxis effects are unknown.
Electrophysiological and biochemical studies on cultured neurons have identified three
properties that may contribute to the antiepileptic efficacy of topiramate.
Action potentials elicited repetitively by a sustained depolarization of the neurons were
blocked by topiramate in a time-dependent manner, suggestive of a state-dependent sodium
channel blocking action. Topiramate increased the frequency at which -aminobutyrate
(GABA) activated GABAA receptors, and enhanced the ability of GABA to induce a flux of
chloride ions into neurons, suggesting that topiramate potentiates the activity of this inhibitory
neurotransmitter.

γ

This effect was not blocked by flumazenil, a benzodiazepine antagonist, nor did topiramate
increase the duration of the channel open time, differentiating topiramate from barbiturates
that modulate GABAA receptors.

Because the antiepileptic profile of topiramate differs markedly from that of the
benzodiazepines, it may modulate a benzodiazepine-insensitive subtype of GABAA receptor.
Topiramate antagonized the ability of kainate to activate the kainate/AMPA ( -amino-3hydroxy-5-methylisoxazole-4-propionic acid) subtype of excitatory amino acid (glutamate)
receptor, but had no apparent effect on the activity of N-methyl-D-aspartate (NMDA) at the
NMDA receptor subtype. These effects of topiramate were concentration-dependent over a
range of 1 µM to 200 µM, with minimum activity observed at 1 µM to 10 µM.

α

In addition, topiramate inhibits some isoenzymes of carbonic anhydrase. This pharmacologic
effect is much weaker than that of acetazolamide, a known carbonic anhydrase inhibitor, and
is not thought to be a major component of topiramate's antiepileptic activity.
In animal studies, topiramate exhibits anticonvulsant activity in rat and mouse maximal
electroshock seizure (MES) tests and is effective in rodent models of epilepsy, which include
tonic and absence-like seizures in the spontaneous epileptic rat (SER) and tonic and clonic
seizures induced in rats by kindling of the amygdala or by global ischemia. Topiramate is
only weakly effective in blocking clonic seizures induced by the GABAA receptor antagonist,
pentylenetetrazole.
Studies in mice receiving concomitant administration of topiramate and carbamazepine or
phenobarbital showed synergistic anticonvulsant activity, while combination with phenytoin
showed additive anticonvulsant activity. In well-controlled add-on trials, no correlation has
been demonstrated between trough plasma concentrations of topiramate and its clinical
efficacy. No evidence of tolerance has been demonstrated in man.
Absence seizures
Two 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.

5.2

Pharmacokinetic properties

The pharmacokinetic profile of topiramate compared to other antiepileptic drugs shows a long
plasma half-life, linear pharmacokinetics, predominantly renal clearance, absence of
significant protein binding, and lack of clinically relevant active metabolites.
Topiramate is not a potent inducer of drug metabolizing enzymes, can be administered
without regard to meals, and routine monitoring of plasma topiramate concentrations is not
necessary. In clinical studies, there was no consistent relationship between plasma
concentrations and efficacy or adverse events.
Absorption
Topiramate 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.
Distribution
Generally, 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.
Metabolism
Topiramate 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.
Elimination
In 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.
Topiramate 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.
Concomitant 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.
The plasma and renal clearance of topiramate are decreased in patients with impaired renal
function (CLCR 60 ml/min), and the plasma clearance is decreased in patients with endstage renal disease. 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. Topiramate is effectively removed from plasma by haemodialysis.



Plasma clearance of topiramate is decreased in patients with moderate to severe hepatic
impairment.

Plasma 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 anti-epileptic
drugs decrease the steady-state plasma concentrations.

5.3

Preclinical safety data

In nonclinical studies of fertility, despite maternal and paternal toxicity as low as
8 mg/kg/day, no effects on fertility were observed, in male or female rats with doses up to
100 mg/kg/day.
In preclinical studies, topiramate has been shown to have teratogenic effects in the species
studied (mice, rats and rabbits). In mice, foetal weights and skeletal ossification were reduced
at 500 mg/kg/day in conjunction with maternal toxicity. Overall numbers of foetal
malformations in mice were increased for all drug-treated groups (20, 100 and 500
mg/kg/day).
In rats, dosage-related maternal and embryo/foetal toxicity (reduced foetal weights and/or
skeletal ossification) were observed down to 20 mg/kg/day with teratogenic effects (limb and
digit defects) at 400 mg/kg/day and above. In rabbits, dosage-related maternal toxicity was
noted down to 10 mg/kg/day with embryo/foetal toxicity (increased lethality) down to 35
mg/kg/day, and teratogenic effects (rib and vertebral malformations) at 120 mg/kg/day.
The teratogenic effects seen in rats and rabbits were similar to those seen with carbonic
anhydrase inhibitors, which have not been associated with malformations in humans. Effects
on growth were also indicated by lower weights at birth and during lactation for pups from
female rats treated with 20 or 100 mg/kg/day during gestation and lactation. In rats,
topiramate crosses the placental barrier.
In juvenile rats, daily oral administration of topiramate at doses up to 300 mg/kg/day during
the period of development corresponding to infancy, childhood, and adolescence resulted in
toxicities similar to those in adult animals (decreased food consumption with decreased body
weight gain, centrolobular hepatocellular hypertrophy). There were no relevant effects on
long bone (tibia) growth or bone (femur) mineral density, preweaning and reproductive
development, neurological development (including assessments on memory and learning),
mating and fertility or hysterotomy parameters.
In a battery of in vitro and in vivo mutagenicity assays, topiramate did not show genotoxic
potential.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Tablet nucleus
Lactose monohydrate
Pregelatinized maize starch
Sodium starch glycolate Type A
Microcrystalline cellulose
Magnesium stearate

Tablet coating
Basic butylated methacrylate copolymer
Sodium laurilsulfate
Stearic acid
Magnesium stearate
Talc
Titanium dioxide (E171)

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
3 years.

6.4

Special precautions for storage
This medicinal product does not require any special storage conditions.

6.5

Nature and contents of container

Tablets are packed in PVC/PCTFE/PVC and Aluminium blister.
Tablets are available in blisters with 10 and 60 tablets. Not all pack sizes may be
marketed.

6.6

Special precautions for disposal
No special requirements.
Any unused product or waste material should be disposed of in accordance with local
requirements.

7

MARKETING AUTHORISATION HOLDER
MORNINGSIDE HEALTHCARE LIMITED
115 NARBOROUGH ROAD
LEICESTER
LE3 0PA
UK

8

MARKETING AUTHORISATION NUMBER(S)
PL 20117/0164

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
26/12/2012

10

DATE OF REVISION OF THE TEXT
26/12/2012

Expand view ⇕

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

Hide
(web3)