Topiramate Tablets SMPC Taj Pharmaceuticals

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Topiramate Tablets USP 4.2 Posology and method of administration

Posology
15mg/100mg
It is recommended that therapy be initiated at a
1. Name of the medicinal low dose followed by titration to an effective
dose. Dose and titration rate should be guided by
product clinical response.
Topiramate Tablets USP 15mg Taj Pharma It is not necessary to monitor topiramate plasma
Topiramate Tablets USP 100mg Taj Pharma concentrations to optimize therapy with
Topiramate film-coated tablet. On rare
2. Qualitative and quantitative occasions, the addition of topiramate to
composition phenytoin may require an adjustment of the dose
of phenytoin to achieve optimal clinical
a) Each film-coated tablet contains: outcome. Addition or withdrawal of phenytoin
Topiramate USP 15mg and carbamazepine to adjunctive therapy with
Excipients q.s. Topiramate film-coated tablet may require
Colour: Yellow Oxide Of Iron & Titanium adjustment of the dose of Topiramate film-
Dioxide BP. coated tablet.
b) Each film-coated tablet contains: In patients with or without a history of seizures
Topiramate USP 100mg or epilepsy, antiepileptic drugs (AEDs)
Excipients q.s. including topiramate should be gradually
Colour: Yellow Oxide Of Iron & Titanium withdrawn to minimize the potential for seizures
Dioxide BP. or increased seizure frequency. In clinical trials,
daily dosages were decreased in weekly
For a full list of excipients, see section 6.1.
intervals by 50-100 mg in adults with epilepsy
and by 25-50 mg in adults receiving topiramate
3. Pharmaceutical form at doses up to 100 mg/day for migraine
Film-coated tablet. prophylaxis. In paediatric clinical trials,
topiramate was gradually withdrawn over a 2-8
4. Clinical particulars week period.
4.1 Therapeutic indications Monotherapy epilepsy

Monotherapy in adults, adolescents and children General
over 6 years of age with partial seizures with or
without secondary generalised seizures, and When concomitant AEDs are withdrawn to
primary generalised tonic-clonic seizures. achieve monotherapy with topiramate,
consideration should be given to the effects this
Adjunctive therapy in children aged 2 years and may have on seizure control. Unless safety
above, adolescents and adults with partial onset concerns require an abrupt withdrawal of the
seizures with or without secondary concomitant AED, a gradual discontinuation at
generalization or primary generalized tonic- the rate of approximately one-third of the
clonic seizures and for the treatment of seizures concomitant AED dose every 2 weeks is
associated with Lennox-Gastaut syndrome. recommended.
Topiramate is indicated in adults for the When enzyme inducing medicinal products are
prophylaxis of migraine headache after careful withdrawn, topiramate levels will increase. A
evaluation of possible alternative treatment decrease in Topiramate film-coated tablet
options. Topiramate is not intended for acute
treatment.
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(topiramate) dosage may be required if clinically Adults

indicated.
Therapy should begin at 25-50 mg nightly for
Adults one week. Use of lower initial doses has been
reported, but has not been studied
Dose and titration should be guided by clinical systematically. Subsequently, at weekly or bi-
response. Titration should begin at 25 mg weekly intervals, the dose should be increased
nightly for 1 week. The dosage should then be by 25-50 mg/day and taken in two divided
increased at 1- or 2-week intervals by doses. Some patients may achieve efficacy with
increments of 25 or 50 mg/day, administered in once-a-day dosing.
two divided doses. If the patient is unable to
tolerate the titration regimen, smaller increments In clinical trials as adjunctive therapy, 200 mg
or longer intervals between increments can be was the lowest effective dose. The usual daily
used. dose is 200-400 mg in two divided doses.
The recommended initial target dose for These dosing recommendations apply to all
topiramatemonotherapy in adults is 100 mg/day adults, including the elderly, in the absence of
to 200 mg/day in 2 divided doses. The underlying renal disease (see section 4.4).
maximum recommended daily dose is 500
mg/day in 2 divided doses. Some patients with Paediatric population (children aged 2 years and
above)
refractory forms of epilepsy have tolerated
topiramatemonotherapy at doses of 1,000 The recommended total daily dose of
mg/day. These dosing recommendations apply Topiramate film-coated tablet (topiramate) as
to all adults including the elderly in the absence adjunctive therapy is approximately 5 to 9
of underlying renal disease. mg/kg/day in two divided doses. Titration
Paediatric population (children over 6 years of should begin at 25 mg (or less, based on a range
age) of 1 to 3 mg/kg/day) nightly for the first week.
The dosage should then be increased at 1- or 2-
Dose and titration rate in children should be week intervals by increments of 1 to 3
guided by clinical outcome. Treatment of mg/kg/day (administered in two divided doses),
children over 6 years of age should begin at 0.5 to achieve optimal clinical response.
to 1 mg/kg nightly for the first week. The dosage
should then be increased at 1 or 2 week intervals Daily doses up to 30 mg/kg/day have been
studied and were generally well tolerated.
by increments of 0.5 to 1 mg/kg/day,
administered in two divided doses. If the child is Migraine
unable to tolerate the titration regimen, smaller
increments or longer intervals between dose Adults
increments can be used. The recommended total daily dose of topiramate
The recommended initial target dose range for for prophylaxis of migraine headache is 100
topiramatemonotherapy in children over 6 years mg/day administered in two divided doses.
of age is 100 mg/day depending on clinical Titration should begin at 25 mg nightly for 1
response, (this is about 2.0mg/kg/day in children week. The dosage should then be increased in
6-16 years). increments of 25 mg/day administered at 1-week
intervals. If the patient is unable to tolerate the
Adjunctive therapy epilepsy (partial onset titration regimen, longer intervals between dose
seizures with or without secondary adjustments can be used.
generalization, primary generalized tonic-clonic
seizures, or seizures associated with Lennox- Some patients may experience a benefit at a total
Gastaut syndrome) 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, Topiramate film-coated tablet is available in

caution is advised due to an increase incidence film-coated tablets formulation. It is
of side effects recommended that film-coated tablets not be
broken.
Paediatric population
Topiramate film-coated tablet can be taken
Topiramate film-coated tablet (topiramate) is not without regard to meals
recommended for treatment or prevention of
migraine in children due to insufficient data on 4.3 Contraindications
safety and efficacy. Hypersensitivity to the active substanceor to any
of the excipients listed in section 6.1.
General dosing recommendations for
Topiramate film-coated tablet in special patient Migraine prophylaxis in pregnancy and in
populations women of childbearing potential if not using a
highly effective method of contraception.
Renal impairment
4.4 Special warnings and precautions for use
In patients with impaired renal function In situations where rapid withdrawal of
(CLCR ≤70 mL/min) topiramate should be
topiramate is medically required, appropriate
administered with caution as the plasma and monitoring is recommended (see section 4.2).
renal clearance of topiramate are decreased.
Subjects with known renal impairment may As with other anti-epileptic drugs, some patients
require a longer time to reach steady-state at may experience an increase in seizure frequency
each dose. Half of the usual starting and or the onset of new types of seizures with
maintenance dose is recommended (see section topiramate. These phenomena may be the
5.2). consequence of an overdose, a decrease in
plasma concentrations of concomitantly used
In patients with end-stage renal failure, since anti-epileptics, progress of the disease, or a
topiramate is removed from plasma by paradoxical effect.
haemodialysis, a supplemental dose of
Topiramate film-coated tablet equal to Adequate hydration while using topiramate is
approximately one-half the daily dose should be very important. Hydration can reduce the risk of
administered on haemodialysis days. The nephrolithiasis (see below). Proper hydration
supplemental dose should be administered in prior to and during activities such as exercise or
divided doses at the beginning and completion exposure to warm temperatures may reduce the
of the haemodialysis procedure. The risk of heat-related adverse reactions (see
supplemental dose may differ based on the section 4.8).
characteristics of the dialysis equipment being
used (see section 5.2). Oligohydrosis
Hepatic impairment Oligohydrosis (decreased sweating) has been

reported in association with the use of
In patients with moderate to severe hepatic topiramate. Decreased sweating and rise in body
impairment topiramate should be administered temperature may occur especially in young
with caution as the clearance of topiramate is children exposed to high ambient temperature.
decreased.
Mood disturbances/depression
Elderly
An increased incidence of mood disturbances
No dose adjustment is required in the elderly and depression has been observed during
population providing renal function is intact. topiramate treatment.
Method of administration Suicide/suicide ideation
Suicidal ideation and behaviour have been In hepatically impaired patients, topiramate
reported in patients treated with anti-epileptic should be administered with caution as the
agents in several indications. A meta-analysis of clearance of topiramate may be decreased.
randomised placebo-controlled trials of anti-
epileptic drugs has shown a small increased risk Acute myopia and secondary angle-closure
glaucoma
of suicidal ideation and behaviour. The
mechanism of this risk is not known and the A syndrome consisting of acute myopia
available data do not exclude the possibility of associated with Secondary angleclosure
an increased risk for topiramate. glaucoma has been reported in patients receiving
In double blind clinical trials, suicide related topiramate. Symptoms include acute onset of
events (SREs) (suicidal ideation, suicide decreased visual acuity and/or ocular pain.
Ophthalmologic findings can include myopia,
attempts and suicide) occurred at a frequency of
0.5% in topiramate treated patients (46 out of anterior chamber shallowing, ocular hyperaemia
8,652 patients treated) and at a nearly 3 fold (redness) and increased intraocular pressure.
higher incidence than those treated with placebo Mydriasis may or may not be present. This
(0.2%; 8 out of 4,045 patients treated). syndrome may be associated with supraciliary
effusion resulting in anterior displacement of the
Patients therefore should be monitored for signs lens and iris, with secondary angle closure
of suicidal ideation and behaviour and glaucoma. Symptoms typically occur within 1
appropriate treatment should be considered. month of initiating topiramate therapy. In
Patients (and caregivers of patients) should be contrast to primary narrow angle glaucoma,
advised to seek medical advice should signs of which is rare under 40 years of age, secondary
suicidal ideation or behaviour emerge. angle closure glaucoma associated with
topiramate has been reported in paediatric
Nephrolithiasis
patients as well as adults. Treatment includes
Some patients, especially those with a discontinuation of topiramate, as rapidly as
predisposition to nephrolithiasis, may be at possible in the judgement of the treating
increased risk for renal stone formation and physician, and appropriate measures to reduce
associated signs and symptoms such as renal intraocular pressure. These measures generally
colic, renal pain or flank pain. result in a decrease in intraocular pressure.
Risk factors for nephrolithiasis include prior Elevated intraocular pressure of any aetiology, if
stone formation, a family history of left untreated, can lead to serious sequelae
nephrolithiasis and hypercalciuria. None of these including permanent vision loss.
risk factors can reliably predict stone formation A determination should be made whether
during topiramate treatment. In addition, patients patients with history of eye disorders should be
taking other medicinal products associated with treated with topiramate.
nephrolithiasis may be at increased risk.
Visual field defects
Decreased renal function
Visual field defects have been reported in
In patients with impaired renal function (CLCR patients receiving topiramate independent of
≤ 70 mL/min) topiramate should be elevated intraocular pressure. In clinical trials,
administered with caution as the plasma and most of these events were reversible after
renal clearance of topiramate are decreased. For topiramate discontinuation. If visual field
specific posology recommendations in patients
defects occur at any time during topiramate
with decreased renal function, see section 4.2.
treatment, consideration should be given to
Decreased hepatic function discontinuing the drug.
Metabolic acidosis topiramate therapy. If metabolic acidosis

develops and persists, consideration should be
Hyperchloraemic, non-anion gap, metabolic given to reducing the dose or discontinuing
acidosis (i.e. decreased serum bicarbonate below topiramate (using dose tapering).
the normal reference range in the absence of
respiratory alkalosis) is associated with Topiramate should be used with caution in
topiramate treatment. This decrease in serum patients with conditions or treatments that
bicarbonate is due to the inhibitory effect of represent a risk factor for the appearance of
topiramate on renal carbonic anhydrase. metabolic acidosis.
Generally, the decrease in bicarbonate occurs
Impairment of cognitive function
early in treatment although it can occur at any
time during treatment. These decrease are Cognitive impairment in epilepsy is
usually mild to moderate (average decrease of 4 multifactorial and may be due to the underlying
mmol/l at doses of 100 mg/day or above in aetiology, due to the epilepsy or due to the anti
adults and at approximately 6 mg/kg/day in epileptic treatment. There have been reports in
paediatric patients). Rarely, patients have the literature of impairment of cognitive
experienced decreases to values below 10 function in adults on topiramate therapy which
mmol/l. Conditions or therapies that predispose required reduction in dosage or discontinuation
to acidosis (such as renal disease, severe of treatment. However, studies regarding
respiratory disorders, status epilepticus, cognitive outcomes in children treated with
diarrhoea, surgery, ketogenic diet, or certain topiramate are insufficient and its effect in this
medicinal products) may be additive to the regard still needs to be elucidated.
bicarbonate-lowering effects of topiramate.
Hyperammonemia and encephalopathy
Chronic metabolic acidosis increases the risk of
renal stone formation and may potentially lead Hyperammonemia with or without
to osteopenia. encephalopathy has been reported with
topiramate treatment (see section 4.8). The risk
Chronic metabolic acidosis in paediatric patients for hyperammonemia with topiramate appears
can reduce growth rates. The effect of dose-related. Hyperammonemia has been
topiramate on bone-related sequelae has not reported more frequently when topiramate is
been systematically investigated in paediatric or used concomitantly with valproic acid (see
adult populations. section 4.5).
Depending on underlying conditions, In patients who develop unexplained lethargy or
appropriate evaluation including measurement changes in mental status associated with
of serum bicarbonate levels is recommended topiramatemonotherapy or adjunctive therapy, it
with topiramate therapy. If signs or symptoms is recommended to consider hyperammonemic
are present (e.g. Kussmaul's deep breathing, encephalopathy and measuring ammonia levels.
dyspnoea, anorexia, nausea, vomiting, excessive
tiredness, tachycardia or arrhythmia), indicative Nutritional supplementation
of metabolic acidosis, measurement of serum Some patients may experience weight loss
bicarbonate is recommended. If metabolic whilst on treatment with topiramate. It is
acidosis develops and persists, consideration recommended that patients on topiramate
should be given to reducing the dose or treatment should be monitored for weight loss.
discontinuing topiramate (using dose tapering). A dietary supplement or increased food intake
Depending on underlying conditions, may be considered if the patient is losing weight
appropriate evaluation including serum while on topiramate.
bicarbonate levels is recommended with Women of childbearing potential
Topiramate may cause fetal harm and fetal A pharmacokinetic interaction study of patients
growth restriction (small for gestational age and with epilepsy indicated the addition of
low birth weight) when administered to a topiramate to lamotrigine had no effect on
pregnant woman. The North American steady state plasma concentration of lamotrigine
Antiepileptic Drug pregnancy registry data for at topiramate doses of 100 to 400 mg/day. In
topiramatemonotherapy showed an approximate addition, there was no change in steady state
3-fold higher prevalence of major congenital plasma concentration of topiramate during or
malformations (4.3%), compared with a after removal of lamotrigine treatment (mean
reference group not taking AEDs (1.4%). In dose of 327 mg/day).
addition, data from other studies indicate that,
Topiramate inhibits the enzyme CYP 2C19 and
compared with monotherapy, there is an
may interfere with other substances metabolized
increased risk of teratogenic effects associated
with the use of AEDs in combination therapy. via this enzyme (e.g., diazepam, imipramin,
moclobemide, proguanil, omeprazol).
Before the initiation of treatment with
topiramate in a woman of childbearing potential, Effects of other antiepileptic medicinal product
on topiramate
pregnancy testing should be performed and a
highly effective contraceptive method advised Phenytoin and carbamazepine decrease the
(see section 4.5). The patient should be fully plasma concentration of topiramate. The
informed of the risks related to the use of addition or withdrawal of phenytoin or
topiramate during pregnancy (see sections 4.3 carbamazepine to topiramate therapy may
and 4.6). require an adjustment in dosage of the latter.
Lactose intolerance This should be done by titrating to clinical
effect. The addition or withdrawal of valproic
This medicinal product contains lactose. Patients acid does not produce clinically significant
with rare hereditary problems of galactose changes in plasma concentrations of topiramate
intolerance, Lapp lactase deficiency or glucose- and, therefore, does not warrant dosage
galactosemalabsorption should not take this adjustment of topiramate. The results of these
medicinal product. interactions are summarized below:
The container contains desiccant that must not AED AED Topiramate
be swallowed. Coadministered Concentration Concentration
4.5 Interaction with other medicinal products Phenytoin ↔** ↓
and other forms of interaction Carbamazepine ↔ ↓
Effects of topiramate on other antiepileptic (CBZ)
medicinal product
Valproic acid ↔ ↔
The addition of topiramate to other antiepileptic Lamotrigine ↔ ↔
drug (phenytoin, carbamazepine, valproic acid,
Phenobarbital ↔ NS
phenobarbital, primidone) has no effect on their
steady-state plasma concentrations, except in the Primidone ↔ NS
occasional patients, where the addition of ↔= No effect on plasma concentration (≤15%
topiramate to phenytoin may result in an change)
increase of plasma concentrations of phenytoin. ** = Plasma concentrations increase in
This is possibly due to inhibition of a specific individual patients
enzyme polymorphic isoform (CYP2C19). ↓= Plasma concentrations decrease
Consequently, any patient on phenytoin showing NS = Not studied
clinical signs or symptoms of toxicity should AED = antiepileptic drug
have phenytoin levels monitored.
Other medicinal product interactions dependent decrease in EE exposure for doses

between 200-800 mg/day (in epilepsy patients),
Digoxin there was no significant dose dependent change
In a single-dose study, serum digoxin area under in EE exposure for doses of 50-200 mg/day (in
plasma concentration curve (AUC) decreased healthy volunteers). The clinical significance of
12% due to concomitant administration of the changes observed is not known. The
Topiramate. The clinical relevance of this possibility of decreased contraceptive efficacy
observation has not been established. When and increased breakthrough bleeding should be
Topiramate is added or withdrawn in patients on considered in patients taking combination oral
digoxin therapy, careful attention should be contraceptive products with topiramate. Patients
given to the routine monitoring of serum taking estrogen containing contraceptives should
digoxin. be asked to report any change in their bleeding
patterns. Contraceptive efficacy can be
Central nervous system depressants decreased even in the absence of breakthrough
Concomitant administration of topiramate and bleeding.
alcohol or other central nervous system (CNS) Lithium
depressant medicinal products has not been
evaluated in clinical studies. It is recommended In healthy volunteers, there was an observed
that topiramate not be used concomitantly with reduction (18% for AUC) in systemic exposure
alcohol or other central nervous system for lithium during concomitant administration
depressant medicinal products. with topiramate 200 mg/day. In patients with
bipolar disorder, the pharmacokinetics of lithium
St John's Wort (Hypericumperforatum) were unaffected during treatment with
A risk of decreased plasma concentrations topiramate at doses of 200 mg/day; however,
resulting in a loss of efficacy could be observed there was an observed increase in systemic
with co-administration of topiramate and St exposure (26% for AUC) following topiramate
John's Wort. There have been no clinical studies doses of up to 600 mg/day. Lithium levels
evaluating this potential interaction. should be monitored when co-administered with
topiramate.
Oral contraceptives
Risperidone
In a pharmacokinetic interaction study in healthy
volunteers with a concomitantly administered Drug-drug interaction studies conducted under
combination oral contraceptive product single dose conditions in healthy volunteers and
containing 1 mg norethindrone (NET) plus 35 multiple dose conditions in patients with bipolar
µg ethinyl estradiol (EE), topiramate given in disorder, yielded similar results. When
the absence of other medications at doses of 50 administered concomitantly with topiramate at
to 200 mg/day was not associated with escalating doses of 100, 250 and 400 mg/day
statistically significant changes in mean there was a reduction in risperidone
exposure (AUC) to either component of the oral (administered at doses ranging from 1 to 6
contraceptive. In another study, exposure to EE mg/day) systemic exposure (16% and 33% for
was statistically significantly decreased at doses steady-state AUC at the 250 and 400 mg/day
of 200, 400, and 800 mg/day (18%, 21%, and doses, respectively). However, differences in
30%, respectively) when given as adjunctive AUC for the total active moiety between
therapy in epilepsy patients taking valproic acid. treatment with risperidone alone and
In both studies, topiramate (50-200 mg/day in combination treatment with topiramate were not
healthy volunteers and 200-800 mg/day in statistically significant. Minimal alterations in
epilepsy patients) did not significantly affect the pharmacokinetics of the total active moiety
exposure to NET. Although there was a dose (risperidone plus 9-hydroxyrisperidone) and no
alterations for 9-hydroxyrisperidone were tmax. The clinical significance of the effect of
observed. There were no significant changes in topiramate on metformin pharmacokinetics is
the systemic exposure of the risperidone total unclear. Oral plasma clearance of topiramate
active moiety or of topiramate. appears to be reduced when administered with
metformin. The extent of change in the
When topiramate was added to existing clearance is unknown. The clinical significance
risperidone (1-6 mg/day) treatment, adverse of the effect of metformin on topiramate
events were reported more frequently than prior pharmacokinetics is unclear.
to topiramate (250-400 mg/day) introduction
(90% and 54 % respectively). The most When topiramate is added or withdrawn in
frequently reported AE's when topiramate was patients on metformin therapy, careful attention
added to risperidone treatment were: should be given to the routine monitoring for
somnolence (27% and 12%), paraesthesia (22% adequate control of their diabetic disease state.
and 0%) and nausea (18% and 9% respectively).
Pioglitazone
Hydrochlorothiazide (HCTZ)
A drug-drug interaction study conducted in
A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state
healthy volunteers evaluated the steady-state pharmacokinetics of topiramate and pioglitazone
pharmacokinetics of HCTZ (25 mg every 24h) when administered alone and concomitantly. A
and topiramate (96 mg every 12h) when 15% decrease in the AUC ,ss of pioglitazone
administered alone and concomitantly. The with no alteration in Cmax,ss was observed.
results of this study indicate that This finding was not statistically significant. In
topiramateCmax increased by 27% and AUC addition, a 13% and 16% decrease in Cmax,ss
increased by 29% when HCTZ was added to and AUC ,ss respectively, of the active
topiramate. The clinical significance of this hydroxy-metabolite was noted as well as a 60%
change is unknown. The addition of HCTZ to decrease in Cmax,ss and AUC ,ss of the active
topiramate therapy may require an adjustment of keto-metabolite. The clinical significance of
the topiramate dose. The steady-state these findings is not known. When topiramate is
pharmacokinetics of HCTZ were not added to pioglitazone therapy or pioglitazone is
significantly influenced by the concomitant added to topiramate therapy, careful attention
administration of topiramate. Clinical laboratory should be given to the routine monitoring of
results indicated decreases in serum potassium patients for adequate control of their diabetic
after topiramate or HCTZ administration, which disease state.
were greater when HCTZ and topiramate were
administered in combination. Glyburide
Metformin A drug-drug interaction study conducted in

patients with type 2 diabetes evaluated the
A drug-drug interaction study conducted in steady-state pharmacokinetics of glyburide (5
healthy volunteers evaluated the steady-state mg/day) alone and concomitantly with
pharmacokinetics of metformin and topiramate topiramate (150 mg/day). There was a 25%
in plasma when metformin was given alone and reduction in glyburide AUC24 during topiramate
when metformin and topiramate were given administration. Systemic exposure of the active
simultaneously. The results of this study metabolites, 4-trans-hydroxy-glyburide (M1)
indicated that metformin mean Cmax and mean and 3-cis-hydroxyglyburide (M2), were also
AUC0-12h increased by 18% and 25%, reduced by 13% and 15%, respectively. The
respectively, while mean CL/F decreased 20% steady-state pharmacokinetics of topiramate
when metformin was co-administered with were unaffected by concomitant administration
topiramate. Topiramate did not affect metformin of glyburide. When topiramate is added to
glyburide therapy or glyburide is added to (topiramateconcentration) describes how the

topiramate therapy, careful attention should be coadministration of a drug listed in the first
given to the routine monitoring of patients for column modifies the concentration of
adequate control of their diabetic disease state. topiramate.
Other forms of interactions Summary of Results from Additional Clinical
Pharmacokinetic Drug Interaction Studies
Agents predisposing to nephrolithiasis
Topiramate, when used concomitantly with Concomitant Concomita TopiramateConcentr
other agents predisposing to nephrolithiasis, may Drug nt Drug ationa
increase the risk of nephrolithiasis. While using Concentrati
topiramate, agents like these should be avoided ona
since they may create a physiological Amitriptyline ↔20% NS
environment that increases the risk of renal stone increase in
formation. Cmax and
AUC of
Valproic acid nortriptylin
Concomitant administration of topiramate and e
valproic acid has been associated with metabolite
hyperammonemia with or without Dihydroergota ↔ ↔
encephalopathy in patients who have tolerated mine (Oral and
either medicinal product alone. In most cases, Subcutaneous)
symptoms and signs abated with discontinuation Haloperidol ↔31% NS
of either medicinal product (see section 4.4 and increase in
section 4.8). This adverse reaction is not due to a AUC of the
pharmacokinetic interaction. reduced
Hypothermia, defined as an unintentional drop metabolite
in body core temperature to <35°C, has been Propranolol ↔17% 9% and 16%
reported in association with concomitant use of increase in increase in Cmax,
topiramate and valproic acid (VPA) both in Cmax for 9% and17%
conjunction with hyperammonemia and in the 4-OH increase in AUC (40
absence of hyperammonemia. This adverse propranolol and 80 mg
event in patients using concomitant topiramate (TPM 50 propranolol q12h
and valproate can occur after starting topiramate mg q12h) respectively)
treatment or after increasing the daily dose of Sumatriptan ↔ NS
topiramate. (Oral and
Additional pharmacokinetic drug interaction Subcutaneous)
studies Pizotifen ↔ ↔
Clinical studies have been conducted to assess Diltiazem 25% 20% increase in
the potential pharmacokinetic drug interaction decrease in AUC
between topiramate and other agents. The AUC of
changes in Cmax or AUC as a result of the diltiazem
interactions are summarized below. The second and 18%
column (concomitant drug concentration) decrease in
describes what happens to the concentration of DEA, and
the concomitant drug listed in the first column ↔for
when topiramate is added. The third column DEM*
Venlafaxine ↔ ↔ Clinical data from pregnancy registries indicate

that infants exposed to topiramatemonotherapy
Flunarizine 16% ↔
have:
increase in
AUC • An increased risk of congenital malformations
(TPM 50 (particularly cleft lip/palate, hypospadias, and
mg q12h)b anomalies involving various body systems)
a
% values are the changes in treatment mean following exposure during the first trimester.
Cmax or AUC with respect to monotherapy The North American Antiepileptic Drug
↔= No effect on Cmax and AUC (≤15% change) pregnancy registry data for
of the parent compound topiramatemonotherapy showed an approximate
NS = Not studied 3-fold higher prevalence of major congenital
*DEA = des acetyl diltiazem, DEM = N- malformations (4.3%), compared with a
demethyldiltiazem reference group not taking AEDs(1.4%). In
b
Flunarizine AUC increased 14% in subjects addition, data from other studies indicate that,
taking flunarizine alone. Increase in exposure compared with monotherapy, there is an
may be attributed to accumulation during increased risk of teratogenic effects associated
achievement of steady state. with the use of AEDs in combination therapy.
4.6 Fertility, pregnancy and lactation The risk has been reported to be dose dependent;
Pregnancy effects were observed in all doses. In women
treated with topiramate who have had a child
Risk related to epilepsy and AEDs in general with a congenital malformation, there appears to
be an increased risk of malformations in
Specialist advice should be given to women who
subsequent pregnancies when exposed to
are of childbearing potential. The need for
topiramate.
treatment with AEDs should be reviewed when a
woman is planning to become pregnant. In • A higher prevalence of low birth weight
women being treated for epilepsy, sudden (<2500 grams) compared with a reference
discontinuation of AED therapy should be group.
avoided as this may lead to breakthrough
seizures that could have serious consequences • An increased prevalence of being small for
for the woman and the unborn child. gestational age (SGA; defined as birth weight
below the 10th percentile corrected for their
Monotherapy should be preferred whenever gestational age, stratified by sex). The long term
possible because therapy with multiple AEDs consequences of the SGA findings could not be
could be associated with a higher risk of determined.
congenital malformations than monotherapy,
depending on the associated antiepileptics. Indication epilepsy
Risk related to topiramate It is recommended to consider alternative

therapeutic options in women of child bearing
Topiramate was teratogenic in mice, rats and potential. If topiramate is used in women of
rabbits (see section 5.3). In rats, topiramate child bearing potential, it is recommended that
crosses the placental barrier. highly effective contraception be used (see
section 4.5), and that the woman is fully
In humans, topiramate crosses the placenta and
informed of the known risks of uncontrolled
similar concentrations have been reported in the
epilepsy to the pregnancy and the potential risks
umbilical cord and maternal blood.
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 The safety of topiramate was evaluated from a
options. In case of administration during the first clinical trial database consisting of 4,111
trimester, carful prenatal monitoring should be patients (3,182 on topiramate and 929 on
performed. placebo) who participated in 20 double-blind
trials and 2,847 patients who participated in 34
Indication migraine prophylaxis
open-label trials, respectively, for topiramate as
Topiramate is contraindicated in pregnancy, and adjunctive treatment of primary generalized
in women of child-bearing potential if a highly tonic-clonic seizures, partial onset seizures,
effective method of contraception is not used seizures associated with Lennox-
(see sections 4.3 and 4.5). Gastautsyndrome, monotherapy for newly or
recently diagnosed epilepsy or migraine
Breast-feeding prophylaxis. The majority of adverse reactions
Animal studies have shown excretion of were mild to moderate in severity. Adverse
topiramate in milk. The excretion of topiramate reactions identified in clinical trials, and during
in human milk has not been evaluated in post-marketing experience (as indicated by “*”)
controlled studies. Limited observations in are listed by their incidence in clinical trials in
patients suggest an extensive excretion of Table 1. Assigned frequencies are as follows:
topiramate into breast milk. Effects that have very common (≥ 1/10);
been observed in breastfed newborns/infants of common (≥ 1/100 to < 1/10);
treated mothers include diarrhea, drowsiness, uncommon (≥ 1/1,000 to < 1/100);
irritability and inadequate weight gain. rare (≥ 1/10,000 to < 1/1,000);
Therefore a decision must be made whether to not known (cannot be estimated from the available da
suspend breast-feeding or to discontinue/ abstain
The most common adverse reactions (those with
from topiramate therapy taking into account the
an incidence of >5% and greater than that
importance of the medicinal product to the
observed in placebo in at least 1 indication in
mother (see section 4.4).
double-blind controlled studies with topiramate)
Fertility include: anorexia, decreased appetite,
bradyphrenia, depression, expressive language
Animal studies did not reveal impairment of disorder, insomnia, coordination abnormal,
fertility by topiramate (see section 5.3). The disturbance in attention, dizziness, dysarthria,
effect of topiramate on human fertility has not dysgeusia, hypoesthesia, lethargy, memory
been established. impairment, nystagmus, paresthesia,
4.7 Effects on ability to drive and use somnolence, tremor, diplopia, vision blurred,
machines diarrhoea, nausea, fatigue, irritability, and
Topiramate has minor or moderate influence on weight decreased.
the ability to drive and use machines.
Table 1: Topiramate Adverse Drug Reactions
Topiramate acts on the central nervous system Syste Very Com Uncom Rare Not
and may produce drowsiness, dizziness or other m comm mon mon known
related symptoms. It may also cause visual Organ on
disturbances and/or blurred vision. These Class
adverse reactions could potentially be dangerous
in patients driving a vehicle or operating Infecti Nasop
machinery, particularly until such time as the ons haryng
individual patient's experience with the active and itis*
substance is established. infest
ations
4.8 Undesirable effects Blood Anae Leucop Neutro
and mia enia, penia* on, lack of

lymph thromb aggres spontan
atic ocytope sion, eous
syste nia mood speech,
m lympha altere sleep
disord denopat d, disorder
ers hy, agitati , affect
eosinop on, lability,
hilia mood libido
Immu Hyper Allergic swing decreas
ne sensiti oedema s, ed,
syste vity *, depres restless
m sed ness,
disord mood, crying,
ers anger, dysphe
abnor mia,
Metab Anore Metabol Acidosi mal euphori
olism xia, ic s behavi c mood,
and decreaacidosis hyperch our paranoi
nutriti sed , loraemi a,
on appetiHypoka c , perseve
disord te laemia, hypera ration,
ers increase mmone panic
d mia*, attack,
appetite hypera tearfuln
, mmone ess,
polydip mic reading
sia enceph disorder
alopath , initial
y* insomni
Psych Depres Brady Suicidal Mania, a, flat
iatric sion phreni ideation panic affect,
disord a, , suicide disorde thinking
ers insom attempt, r, abnorm
nia, hallucin feeling al, loss
expres ation, of of
sive psychot despair libido,
langua ic *, listless,
ge disorder hypoma middle
disord , nia insomni
er, hallucin a,
anxiet ation distracti
y, auditory bility,
confus , early
ional hallucin mornin
state, ation g
disori visual, awakeni
entati apathy, ng,
panic e quality
reaction disord sleep,
, er, burning
elevated dysart sensatio
mood hria, n,
Nervo Paraes Distur Depress Apraxia intenti sensory
us thesia, bance ed level , on loss,
syste somno in of circadia tremor parosmi
m lence attenti conscio n , a,
disord Dizzin on, usness, rhythm sedati cerebell
ers ess memo grand sleep on ar
ry mal disorde syndro
impair convuls r, me,
ment, ion, hyperae dysaest
amnes visual sthesia, hesia,
ia, field hyposm hypoge
cognit defect, ia, usia,
ive comple anosmi stupor,
disord x partial a, clumsin
er, seizures essentia ess,
menta , speech l aura,
l disorder tremor, ageusia,
impair , akinesi dysgrap
ment, psycho a, hia,
psych motor unrespo dysphas
omoto hyperac nsive to ia,
r tivity, stimuli neuropa
skills syncope thy
impair , peripher
ed, sensory al,
convu disturba presync
lsion, nce, ope,
coordi droolin dystoni
nation g, a,
abnor hyperso formica
mal, mnia, tion
tremor aphasia, Eye Vision Visual Blindne Angle
, repetitiv disord blurre acuity ss closure
lethar e ers d, reduced unilater glaucom
gy, speech, diplop , al, a*,
hypoa hypokin ia, scotoma blindne Maculo
esthes esia, visual , ss pathy*,
ia, dyskine distur myopia transien eye
nystag sia, bance *, t, moveme
mus, dizzines abnorm glauco nt
dysge s al ma, disorder
usia, postural sensatio accom *
balanc , poor n in modati conjunct
eye*, on ivaloede sion

dry eye, disorde ma* flushing
photoph r, , hot
obia, altered flush
blephar visual Respir Dyspn Dyspno
ospasm, depth atory, oea , eaexerti
lacrimat percepti thorac epista onal,
ion on, ic and xis, Paranas
increase scintilla media nasal al sinus
d, ting stinal conge hyperse
photops scotom disord stion, cretion,
ia, a, ers rhinor dyspho
mydrias eyelid rhea, nia
is, oedema cough
presbyo *, night *
pia blindne
ss, Gastr Nause Vomit Pancrea
amblyo ointes a, ing, titis,
pia tinal diarrh consti flatulen
disord oea pation ce,
Ear Vertig Deafnes ers , gastroo
and o, s, abdo esophag
labyri tinnitu deafnes minal eal
nth s, ear s pain reflux
disord pain unilater upper, disease,
ers al, dyspe abdomi
deafnes psia, nal pain
s abdo lower,
neurose minal hypoaes
nsory, pain, thesia
ear dry oral,
discomf mouth gingival
ort, , bleedin
hearing stoma g,
impaire ch abdomi
d disco nal
Cardi Bradyca mfort, distensi
ac rdia, paraes on,
disord sinus thesia epigastr
ers bradyca oral, ic
rdia, gastrit discomf
palpitati is, ort,
ons abdo abdomi
Vascu Hypote Raynau minal nal
lar nsion, d's disco tendern
disord orthosta phenom mfort ess,
ers tic enon salivary
hypoten hyperse
cretion, lar
oral weakn
pain, ess,
breath muscu
odour, loskel
glossod etal
ynia chest
Hepat Hepatiti pain
obiliar s, Renal Nephr Calculu Calculu
y Hepatic and olithia s s
disord failure urinar sis, urinary, ureteric
ers y pollak urinary , renal
Skin Alope Anhidro Stevens Toxic disord iuria, incontin tubular
and cia, sis, - epiderm ers dysuri ence, acidosis
subcut rash, hypoaes Johnso al a haemat *
aneou prurit thesia n necrolys uria,
s us facial, syndro is* incontin
tissue urticaria me* ence,
disord , erythe micturit
ers erythem ma ion
a, multifo urgency
pruritus rme*, , renal
generali skin colic,
sed, odour renal
rash abnorm pain
macular al, Repro Erectile
, skin periorbi ductiv dysfunc
discolo taloede e tion,
uration, ma*, syste sexual
dermatit urticari m and dysfunc
is alocalis breast tion
allergic, ed disord
swellin ers
g face Gener Fatigu Pyrexi Hyperth Face
Musc Arthra Joint Limb al e a, ermia, oedema
uloske lgia, swellin discomf disord asthen thirst, ,
letal muscl g*, ort* ers ia, influenz calcino
and e muscul and irritab a like sis
conne spasm oskeleta admin ility, illness*,
ctive s, l istrati gait sluggish
tissue myalg stiffness on site distur ness,
disord ia, , flank condit bance, peripher
ers muscl pain, ions feelin al
e muscle g coldnes
twitch fatigue abnor s,
ing, mal, feeling
muscu malais drunk,
e feeling • Initial insomnia

jittery • Suicidal ideation
Invest Weigh Weigh Crystal Blood
igatio t t urine bicarbo • Disturbance in attention
ns decrea increa present, nate • Lethargy
sed sed* tandem decreas
gait test ed • Circadian rhythm sleep disorder
abnorm • Poor quality sleep
al,
white • Lacrimation increased
blood
• Sinus bradycardia
cell
count • Feeling abnormal
decreas
ed, • Gait disturbance
Increase ADRs that were reported in children but not in
in liver adults in double-blind controlled studies include:
enzyme
s • Eosinophilia
Social Learnin • Psychomotor hyperactivity
circu g
mstan disabilit • Vertigo
ces y • Vomiting
* identified as an ADR from postmarketing • Hyperthermia
spontaneous reports. Its frequency was
calculated based on the incidence in clinical • Pyrexia
trials, or was calculated if the event did not
• Learning disability
occur in clinical trials..
Congenital malformations and fetal growth Reporting of suspected adverse reactions
restrictions (see section 4.4 and section 4.6).
Reporting suspected adverse reactions after
Paediatric population authorisation of the medicinal product is
important. It allows continued monitoring of the
ADRs reported more frequently (≥2-fold) in benefit/risk balance of the medicinal product.
children than in adults in double-blind controlled
studies include: 4.9 Overdose
Signs and symptoms
• Decreased appetite
Overdoses of topiramate have been reported.
• Increased appetite Signs and symptoms included convulsions,
• Hyperchloraemic acidosis drowsiness, speech disturbances, blurred vision,
diplopia, impaired mentation, lethargy, abnormal
• Hypokalaemia co-ordination, stupor, hypotension, abdominal
• Abnormal behaviour pain, agitation, dizziness and depression. The
clinical consequences were not severe in most
• Aggression cases, but deaths have been reported after
overdoses with multiple medicinal products
• Apathy
including topiramate.
Topiramate overdose can result in severe benzodiazepine-insensitive subtype of

metabolic acidosis (see section 4.4). GABAA receptor. Topiramate antagonized the
ability of kainate to activate the kainate/AMPA
Treatment
(α - amino-3-hydroxy-5-methylisoxazole-4-
In acute topiramate overdose, if the ingestion is propionic acid) subtype of excitatory amino acid
recent, the stomach should be emptied (glutamate) receptor, but had no apparent effect
immediately by lavage or by induction of on the activity of N-methyl-D-aspartate
emesis. Activated charcoal has been shown to (NMDA) at the NMDA receptor subtype. These
adsorb topiramate in vitro. Treatment should be effects of topiramate were concentration-
appropriately supportive and the patient should dependent over a range of 1 µM to 200 µM, with
be well hydrated. Haemodialysis has been minimum activity observed at 1 µM to 10 µM.
shown to be an effective means of removing
In addition, topiramate inhibits some
topiramate from the body.
isoenzymes of carbonic anhydrase. This
pharmacologic effect is much weaker than that
5. Pharmacological properties of acetazolamide, a known carbonic anhydrase
5.1 Pharmacodynamic properties inhibitor, and is not thought to be a major
Pharmacotherapeutic group: antiepileptics, other component of topiramate's antiepileptic activity.
antiepileptics, antimigrainepreparations. In animal studies, topiramate exhibits
Topiramate is classified as a sulphamate- anticonvulsant activity in rat and mouse
substituted monosaccharide. The precise maximal electroshock seizure (MES) tests and is
mechanism by which topiramate exerts its effective in rodent models of epilepsy, which
antiseizure and migraine prophylaxis effects are include tonic and absence-like seizures in the
unknown. Electrophysiological and biochemical spontaneous epileptic rat (SER) and tonic and
studies on cultured neurons have identified three clonic seizures induced in rats by kindling of the
properties that may contribute to the amygdala or by global ischemia. Topiramate is
antiepileptic efficacy of topiramate. only weakly effective in blocking clonic seizures
induced by the GABAA receptor antagonist,
Action potentials elicited repetitively by a pentylenetetrazole.
sustained depolarization of the neurons were
blocked by topiramate in a time-dependent Studies in mice receiving concomitant
manner, suggestive of a state-dependent sodium administration of topiramate and carbamazepine
channel blocking action. Topiramate increased or phenobarbital showed synergistic
the frequency at which γ- aminobutyrate anticonvulsant activity, while combination with
(GABA) activated GABAA receptors, and phenytoin showed additive anticonvulsant
enhanced the ability of GABA to induce a flux activity. In well-controlled add-on trials, no
of chloride ions into neurons, suggesting that correlation has been demonstrated between
topiramate potentiates the activity of this trough plasma concentrations of topiramate and
inhibitory neurotransmitter. its clinical efficacy. No evidence of tolerance
has been demonstrated in man.
This effect was not blocked by flumazenil, a
benzodiazepine antagonist, nor did topiramate Absence seizures
increase the duration of the channel open time, Two small one arm studies were carried out with
differentiating topiramate from barbiturates that children aged 4-11 years old (CAPSS-326 and
modulate GABAA receptors. TOPAMAT-ABS-001). One included 5 children
Because the antiepileptic profile of topiramate and the other included 12 children before it was
differs markedly from that of the terminated early due to lack of therapeutic
benzodiazepines, it may modulate a response. The doses used in these studies were
up to approximately 12mg/kg in study attributed to the higher percent body fat in

TOPAMAT-ABS-001 and a maximum of the female patients and is of no clinical
lesser of 9 mg/kg/day or 400 mg/day in study consequence.
CAPSS-326. These studies do not provide
Biotransformation
sufficient evidence to reach conclusion
regarding efficacy or safety in the paediatric Topiramate is not extensively metabolized
population. (~20%) in healthy volunteers. It is metabolized
up to 50% in patients receiving concomitant
5.2 Pharmacokinetic properties
The pharmacokinetic profile of topiramate antiepileptic therapy with known inducers of
compared to other AEDs shows a long plasma drug metabolizing enzymes. Six metabolites,
half-life, linear pharmacokinetics, predominantly formed through hydroxylation, hydrolysis and
glucuronidation, have been isolated,
renal clearance, absence of significant protein
binding, and lack of clinically relevant active characterized and identified from plasma, urine
metabolites. and faeces of humans. Each metabolite
represents less than 3% of the total radioactivity
Topiramate is not a potent inducer of drug excreted following administration of 14C-
metabolizing enzymes, can be administered topiramate. Two metabolites, which retained
without regard to meals, and routine monitoring most of the structure of topiramate, were tested
of plasma topiramate concentrations is not and found to have little or no anticonvulsant
necessary. In clinical studies, there was no activity.
consistent relationship between plasma
Elimination
concentrations and efficacy or adverse events.
Absorption In humans, the major route of elimination of
unchanged topiramate and its metabolites is via
Topiramate is rapidly and well absorbed. the kidney (at least 81% of the dose).
Following oral administration of 100 mg Approximately 66% of a dose of 14C-topiramate
topiramate to healthy subjects, a mean peak was excreted unchanged in the urine within four
plasma concentration (Cmax) of 1.5 µg/ml was days. Following twice a day dosing with 50 mg
achieved within 2 to 3 hours (Tmax). and 100 mg of topiramate the mean renal
clearance was approximately 18 ml/min and 17
Based on the recovery of radioactivity from the ml/min, respectively. There is evidence of renal
urine the mean extent of absorption of a 100 mg
tubular reabsorption of topiramate. This is
oral dose of 14C-topiramate was at least 81%. supported by studies in rats where topiramate
There was no clinically significant effect of food was co-administered with probenecid, and a
on the bioavailability of topiramate.
significant increase in renal clearance of
Distribution topiramate was observed. Overall, plasma
clearance is approximately 20 to 30 ml/min in
Generally, 13 to 17% of topiramate is bound to humans following oral administration.
plasma protein. A low capacity binding site for
topiramate in/on erythrocytes that is saturable Linearity/non-linearity
above plasma concentrations of 4 µg/ml has Topiramate exhibits low intersubject variability
been observed. The volume of distribution in plasma concentrations and, therefore, has
varied inversely with the dose. The mean predictable pharmacokinetics. The
apparent volume of distribution was 0.80 to 0.55 pharmacokinetics of topiramate are linear with
l/kg for a single dose range of 100 to 1200 mg.
plasma clearance remaining constant and area
An effect of gender on the volume of under the plasma concentration curve increasing
distribution was detected, with values for in a dose-proportional manner over a 100 to 400
females circa 50% of those for males. This was mg single oral dose range in healthy subjects.
Patients with normal renal function may take 4 hepatic impairment. Therefore, topiramate
to 8 days to reach steady-state plasma should be administered with caution in patients
concentrations. The mean Cmax following with hepatic impairment.
multiple, twice a day oral doses of 100 mg to
Elderly population
healthy subjects was 6.76 µg/ml. Following
administration of multiple doses of 50 mg and Plasma clearance of topiramate is unchanged in
100 mg of topiramate twice a day, the mean elderly subjects in the absence of underlying
plasma elimination half-life was approximately renal disease.
21 hours.
Paediatric population (pharmacokinetics, up to
Use with other AEDs 12 years of age)
Concomitant multiple-dose administration of The pharmacokinetics of topiramate in children,
topiramate, 100 to 400 mg twice a day, with as in adults receiving add-on therapy, are linear,
phenytoin or carbamazepine shows dose with clearance independent of dose and steady-
proportional increases in plasma concentrations state plasma concentrations increasing in
of topiramate. proportion to dose. Children, however, have a
Renal impairment higher clearance and a shorter elimination half-
life. Consequently, the plasma concentrations of
The plasma and renal clearance of topiramate topiramate for the same mg/kg dose may be
are decreased in patients with moderate and lower in children compared to adults. As in
severe impaired renal function (CLCR ≤ 70 adults, hepatic enzyme inducing AEDs decrease
ml/min). As a result, higher steady-state the steady-state plasma concentrations.
topiramate plasma concentrations are expected
for a given dose in renal-impaired patients as 5.3 Preclinical safety data
compared to those with normal renal function. In In nonclinical studies of fertility, despite
maternal and paternal toxicity as low as 8
addition, patients with renal impairment will
mg/kg/day, no effects on fertility were observed,
require a longer time to reach steady-state at
in male or female rats with doses up to 100
each dose. In patients with moderate and severe
mg/kg/day.
renal impairment, half of the usual starting and
maintenance dose is recommended. In preclinical studies, topiramate has been
Topiramate is effectively removed from plasma shown to have teratogenic effects in the species
by haemodialysis. A prolonged period of studied (mice, rats and rabbits). In mice, fetal
hemodialysis may cause topiramate weights and skeletal ossification were reduced at
concentration to fall below levels that are 500 mg/kg/day in conjunction with maternal
toxicity. Overall numbers of fetal malformations
required to maintain an anti-seizure effect. To
in mice were increased for all drug-treated
avoid rapid drops in topiramate plasma
concentration during hemodialysis, a groups (20, 100 and500 mg/kg/day).
supplemental dose of topiramate may be In rats, dosage-related maternal and
required. The actual adjustment should take into embryo/fetal toxicity (reduced fetal weights
account 1) the duration of dialysis period, 2) the and/or skeletal ossification) were observed down
clearance rate of the dialysis system being used, to 20 mg/kg/day with teratogenic effects (limb
and 3) the effective renal clearance of topiramate and digit defects) at 400 mg/kg/day and above.
in the patient being dialyzed. In rabbits, dosage-related maternal toxicity was
Hepatic impairment noted down to 10 mg/kg/day with embryo/fetal
toxicity (increased lethality) down to 35
Plasma clearance of topiramate decreased a mg/kg/day, and teratogenic effects (rib and
mean of 26% in patients with moderate to severe vertebral malformations) at 120 mg/kg/day.
The teratogenic effects seen in rats and rabbits Not all packs may be marketed.
were similar to those seen with carbonic
anhydrase inhibitors, which have not been 6.6 Special precautions for disposal and other
associated with malformations in humans. handling
No special requirements
Effects on growth were also indicated by lower
weights at birth and during lactation for pups 7. Manufactured In India By:
from female rats treated with 20 or 100 TAJ PHARMACEUTICALS LTD.
mg/kg/day during gestation and lactation. In Mumbai, India
rats, topiramate crosses the placental barrier.
Unit No. 214.Old Bake House,
In juvenile rats, daily oral administration of Maharashtra chambers of Commerce Lane,
topiramate at doses up to 300 mg/kg/day during Fort, Mumbai - 400001
the period of development corresponding to
at:Gujarat, INDIA.
infancy, childhood, and adolescence resulted in
toxicities similar to those in adult animals Customer Service and Product Inquiries:
(decreased food consumption with decreased 1-800-TRY-FIRST (1-800-222-434 & 1-800-
body weight gain, centrolobullar hepatocellular 222-825)
hypertrophy). There were no relevant effects on Monday through Saturday 9:00 a.m. to 7:00 p.m.
long bone (tibia) growth or bone (femur) mineral EST
density, preweaning and reproductive E-mail: tajgroup@tajpharma.com
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
Lactose monohydrate, Pregelatinised starch,
Microcrystalline cellulose, Croscarmellose
sodium, Magnesium stearate.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Do not store above 25°C. Keep the container
tightly closed in order to protect from moisture.
6.5 Nature and contents of container
Aluminium Blister Packs
Pack Size: 7, 14, 28, 30, 50, 90, 100 and 500
tablets.

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Topiramate 1 5mg, 1 00mg Ta blets TajPhar ma : U ses, Side E ffe cts, Intera ctions , Picture s, Warni ngs, Topiramate

Topiramate Tablets USP 4.2 Posology and method of administration

4.1 Therapeutic indications Monotherapy epilepsy

(topiramate) dosage may be required if clinically Adults

may be benefit in some patients, nevertheless, Topiramate film-coated tablet is available in

Hepatic impairment Oligohydrosis (decreased sweating) has been

Metabolic acidosis topiramate therapy. If metabolic acidosis

Other medicinal product interactions dependent decrease in EE exposure for doses

Metformin A drug-drug interaction study conducted in

glyburide therapy or glyburide is added to (topiramateconcentration) describes how the

Venlafaxine ↔ ↔ Clinical data from pregnancy registries indicate

Risk related to topiramate It is recommended to consider alternative

and mia enia, penia* on, lack of

eye*, on ivaloede sion

e feeling • Initial insomnia

Topiramate overdose can result in severe benzodiazepine-insensitive subtype of

up to approximately 12mg/kg in study attributed to the higher percent body fat in

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