TOPICLOMAX

Topiramate is a sulfamate-substituted monosaccharide.

Topiramate tablets are available as 25 mg, 50 mg, 100 mg, and 200 mg round tablets for oral administration.

Topiramate is a white crystalline powder with a bitter taste.

USP is most soluble in alkaline solutions containing sodium hydroxide or sodium phosphate and having a pH of to 10.

It is freely soluble in acetone, chloroform, dimethylsulfoxide, and ethanol.

The solubility in water is 9.8 mg/mL.

Its saturated solution has a pH of 6.3.

Topiramate has the molecular formula

C 12 H 21 NO 8 S and a molecular weight of 339.37.

Topiramate is designated chemically as 2,3:4,5-Di.

• O -isopropylidene-β-D-fructopyranose sulfamate and has the following structural formula: Topiramate tablets, USP contain the following inactive ingredients: anhydrous lactose, microcrystalline cellulose, pregelatinized maize starch, sodium starch glycolate type A potato, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol and talc.

In addition, individual tablets contain: 50 mg tablets: iron oxide yellow 100 mg tablets: iron oxide yellow, and D&C Yellow # 10 Aluminum Lake 200 mg tablets: iron oxide red, lecithin (soya), and iron oxide black chemical-structure.

In combination with other antiepileptics in children from 2 years of age, adolescents and adults in partial epilepsy with or without secondary generalisation or in generalised tonic-clonic seizures, as well as in the treatment of seizures associated with Lennox-Gastaut syndrome.

Topiramate is indicated in adults for prophylactic treatment of migraine after careful evaluation of possible therapeutic alternatives.

Topiramate is not indicated for the treatment of the crisis.

Hypersensitivity to the active substance or to any of the excipients mentioned in section 6.1.

As with other

AEMs, an increase in the frequency of seizures or the emergence of new types of seizures may occur in some patients with topiramate.

These phenomena may be due to an overdose, a decrease in plasma concentrations of associated AEMs, disease progression or a paradoxical effect.

Adequate hydration during topiramate therapy is very important.

Moisture may decrease the risk of nephrolithiasis.

Adequate hydration before and during activities such as physical exercise or exposure to high temperatures may decrease the risk of adverse effects related to heat.

Women in age of reproduction may be aggravated by a high degree of vitamin A and a low level of vitamin A and a low level of vitamin A may be harmful to the foetus.

The precise mechanisms by which topiramate exerts its anticonvulsant and preventive migraine effects are unknown; however, preclinical studies have revealed four properties that may contribute to topiramate's efficacy for epilepsy and the preventive treatment of migraine.

Electrophysiological and biochemical evidence suggests that topiramate, at pharmacologically relevant concentrations, blocks voltage-dependent sodium channels, augments the activity of the neurotransmitter gamma-aminobutyrate at some subtypes of the GABA-A receptor, antagonizes the AMPA/kainate subtype of the glutamate receptor, and inhibits the carbonic anhydrase enzyme, particularly isozymes II and IV. 12.2 Pharmacodynamics Topiramate has anticonvulsant activity in rat and mouse maximal electroshock seizure (MES) tests.

Topiramate is only weakly effective in blocking clonic seizures induced by the GABAA receptor antagonist, pentylenetetrazole.

Topiramate is also 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.

Changes (increases and decreases) from baseline in vital signs (systolic blood pressure-SBP, diastolic blood pressure-DBP, pulse) occurred more frequently in pediatric patients (6 to 17 years) treated with various daily doses of topiramate (50 mg, 100 mg, 200 mg, 2 to 3 mg/kg) than in patients treated with placebo in controlled trials for the preventive treatment of migraine.

The most notable changes were

SBP <90 mm Hg, DBP <50 mm Hg, SBP or DBP increases or decreases ≥20 mm Hg, and pulse increases or decreases ≥30 beats per minute.

These changes were often dose-related, and were most frequently associated with the greatest treatment difference at the 200 mg dose level.

Systematic collection of orthostatic vital signs has not been conducted.

The clinical significance of these various changes in vital signs has not been clearly established. 12.3 Pharmacokinetics Absorption of topiramate is rapid, with peak plasma concentrations occurring at approximately 2 hours following a 400 mg oral dose.

The relative bioavailability of topiramate from the tablet formulation is about 80% compared to a solution.

The bioavailability of topiramate is not affected by food.

The pharmacokinetics of topiramate are linear with dose proportional increases in plasma concentration over the dose range studied (200 to 800 mg/day).

The mean plasma elimination half-life is 21 hours after single or multiple doses.

Steady-state is thus reached in about 4 days in patients with normal renal function.

Topiramate is 15% to 41% bound to human plasma proteins over the blood concentration range of 0.5 to 250 mcg/mL.

The fraction bound decreased as blood concentration increased.

Carbamazepine and phenytoin do not alter the binding of topiramate.

Sodium valproate, at 500 mcg/mL (a concentration to 10 times higher than considered therapeutic for valproate) decreased the protein binding of topiramate from 23% to 13%.

Topiramate does not influence the binding of sodium valproate.

Topiramate is not extensively metabolized and is primarily eliminated unchanged in the urine (approximately 70% of an administered dose).

Six metabolites have been identified in humans, none of which constitutes more than 5% of an administered dose.

The metabolites are formed via hydroxylation, hydrolysis, and glucuronidation.

There is evidence of renal tubular reabsorption of topiramate.

In rats, given probenecid to inhibit tubular reabsorption, along with topiramate, a significant increase in renal clearance of topiramate was observed.

This interaction has not been evaluated in humans.

Overall, oral plasma clearance (CL/F) is approximately to 30 mL/min in adults following oral administration.

The clearance of topiramate was reduced by 42% in subjects with moderate renal impairment (creatinine clearance to 69 mL/min/1.73 m 2 ) and by 54% in subjects with severe renal impairment (creatinine clearance <30 mL/min/1.73 m 2 ) compared to subjects with normal renal function (creatinine clearance >70 mL/min/1.73 m 2 ) .

Topiramate is cleared by hemodialysis.

Using a high-efficiency, counterflow, single pass-dialysate hemodialysis procedure, topiramate dialysis clearance was 120 mL/min with blood flow through the dialyzer at 400 mL/min. This high clearance (compared to to 30 mL/min total oral clearance in healthy adults) will remove a clinically significant amount of topiramate from the patient over the hemodialysis treatment period.

Plasma clearance of topiramate decreased a mean of 26% in patients with moderate to severe hepatic impairment.

Age, Gender, and Race The pharmacokinetics of topiramate in elderly subjects (65 to 85 years of age, N=16) were evaluated in a controlled clinical study.

The elderly subject population had reduced renal function (creatinine clearance [-20%]) compared to young adults.

Following a single oral 100 mg dose, maximum plasma concentration for elderly and young adults was achieved at approximately to 2 hours.

Reflecting the primary renal elimination of topiramate, topiramate plasma and renal clearance were reduced 21% and 19%, respectively, in elderly subjects, compared to young adults.

Similarly, topiramate half-life was longer (13%) in the elderly.

Reduced topiramate clearance resulted in slightly higher maximum plasma concentration (23%) and AUC (25%) in elderly subjects than observed in young adults.

Topiramate clearance is decreased in the elderly only to the extent that renal function is reduced.

Clearance of topiramate in adults was not affected by gender or race.

Pharmacokinetics of topiramate were evaluated in patients age to <16 years.

Patients received either no or a combination of other antiepileptic drugs.

A population pharmacokinetic model was developed on the basis of pharmacokinetic data from relevant topiramate clinical studies.

This dataset contained data from 1217 subjects including 258 pediatric patients age to <16 years (95 pediatric patients <10 years of age).

Pediatric patients on adjunctive treatment exhibited a higher oral clearance (L/h) of topiramate compared to patients on monotherapy, presumably because of increased clearance from concomitant enzyme-inducing antiepileptic drugs.

In comparison, topiramate clearance per kg is greater in pediatric patients than in adults and in young pediatric patients (down to 2 years) than in older pediatric patients.

Consequently, the plasma drug concentration for the same mg/kg/day dose would be lower in pediatric patients compared to adults and also in younger pediatric patients compared to older pediatric patients.

Clearance was independent of dose.

As in adults, hepatic enzyme-inducing antiepileptic drugs decrease the steady state plasma concentrations of topiramate.

Pediatric Patients with Obesity A population

PK analysis of topiramate was conducted in 129 children <21 years of age with and without obesity to evaluate the potential impact of obesity on plasma topiramate exposures.

Obesity was defined as

BMI ≥ 95th percentile for age and sex based on CDC-recommended BMI for.

• age growth charts for males and females.

Using the currently recommended dosing regimens, children with obesity are likely to have median values of average concentration at steady-state and trough concentration at steady-state up to 20% lower and 19% lower, respectively, compared to children without obesity.

Dosage adjustment according to obesity status is not necessary.

In vitro studies indicate that topiramate does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, or CYP3A4/5 isozymes.

In vitro studies indicate that topiramate is a mild inhibitor of CYP2C19 and a mild inducer of CYP3A4.

Potential interactions between topiramate and standard AEDs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy.

The effects of these interactions on mean plasma AUCs are summarized in Table 11.

In Table 11, the second column (AED concentration) describes what happens to the concentration of the coadministered AED 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 when compared to topiramate given alone.

Table 11: Summary of AED Interactions with topiramate AED Coadministered AED Concentration Topiramate Concentration Phenytoin NC or 25% increase a 48% decrease Carbamazepine (CBZ) NC 40% decrease CBZ epoxide b NC NE Valproic acid 11% decrease 14% decrease Phenobarbital NC NE Primidone NC NE Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. b = Is not administered but is an active metabolite of carbamazepine.

NC = Less than 10% change in plasma concentration.

AED = Antiepileptic drug.

NE = Not Evaluated.

TPM = Topiramate Oral Contraceptives In a pharmacokinetic interaction study in healthy volunteers with a concomitantly administered combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 mcg ethinyl estradiol (EE), topiramate, given in the absence of other medications at doses of to 200 mg/day, was not associated with statistically significant changes in mean exposure (AUC) to either component of the oral contraceptive.

In another study, exposure to EE was statistically significantly decreased at doses of 200, 400, and 800 mg/day (18%, 21%, and 30%, respectively) when given as adjunctive therapy in patients taking valproic acid.

In both studies, topiramate (50 mg/day to 800 mg/day) did not significantly affect exposure to NET and there was no significant dose-dependent change in EE exposure for doses of to 200 mg/day. The clinical significance of the changes observed is not known.

In a single-dose study, serum digoxin AUC was decreased by 12% with concomitant topiramate administration.

The clinical relevance of this observation has not been established.

A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of hydrochlorothiazide (HCTZ) (25 mg every 24 hours) and topiramate (96 mg every 12 hours) 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 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.

A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of metformin (500 mg every 12 hours) and topiramate in plasma when metformin was given alone and when metformin and topiramate (100 mg every 12 hours) were given simultaneously.

The results of this study indicated that the mean metformin C max and AUC 0-12h increased by 18% and 25%, respectively, when topiramate was added.

Topiramate did not affect metformin t max.

The clinical significance of the effect of topiramate on metformin pharmacokinetics is not known.

Oral plasma clearance of topiramate appears to be reduced when administered with m.

The following are the following: a) a pharmacotherapeutic group: an antiepileptic group; b) a pharmacotherapeutic group; b) a pharmacotherapeutic group; b) a pharmacotherapeutic group; c) a pharmacotherapeutic group; c) a pharmacotherapeutic group; c) a pharmacotherapeutic group; c) a pharmacothetic group; c) a pharmacothetic group; c) a pharmacotherapeutic group; c) a pharmacothetic group; c) a pharmacothetic group; c) a pharmacothetic group; c) a pharmacothetic group; c) a pharmacothetic group; c) a pharmacothetic group; c) a pharmacothetic group; c) a pharmacothetic group; c) a pharmacothetic group; c) a pharmacothetic group; c) a metholic group; c) a meth pharmacotherapeutic group; c) a meth.

The safety of the topiramate is an infancy, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agility, agness, agness agness a.

Overdoses of topiramate have been reported.

Signs and symptoms included convulsions, drowsiness, speech disturbance, 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 involving topiramate.

Topiramate overdose has resulted in severe metabolic acidosis.

A patient who ingested a dose of topiramate between and 110 g was admitted to a hospital with a coma lasting to 24 hours followed by full recovery after to 4 days.

In the event of overdose, topiramate should be discontinued and general supportive treatment given until clinical toxicity has been diminished or resolved.

Hemodialysis is an effective means of removing topiramate from the body.

Topiramate initial dose, titration, and recommended maintenance dose varies by indication and.

Information for recommended dosage, and dosing considerations in patients with renal impairment, geriatric patients, and patients undergoing hemodialysis 2.1 Dosing in Monotherapy Epilepsy Adults and Pediatric Patients 10 Years of Age and Older The recommended dose for topiramate monotherapy in adults and pediatric patients 10 years of age and older is 400 mg/day in two divided doses.

The dose should be achieved by titration according to the following schedule (Table 1): Table 1: Monotherapy Titration Schedule for Adults and Pediatric Patients 10 years and older Morning Dose Evening Dose Week 1 25 mg 25 mg Week 2 50 mg 50 mg Week 3 75 mg 75 mg Week 4 100 mg 100 mg Week 5 150 mg 150 mg Week 6 200 mg 200 mg Pediatric Patients to 9 Years of Age Dosing in patients to 9 years of age is based on weight.

During the titration period, the initial dose of topiramate is 25 mg/day nightly for the first week.

Based upon tolerability, the dosage can be increased to 50 mg/day (25 mg twice daily) in the second week.

Dosage can be increased by to 50 mg/day each subsequent week as tolerated.

Titration to the minimum maintenance dose should be attempted over to 7 weeks of the total titration period.

Based upon tolerability and clinical response, additional titration to a higher dose (up to the maximum maintenance dose) can be attempted at to 50 mg/day weekly increments.

The total daily dose should not exceed the maximum maintenance dose for each range of body weight (Table 2).

Table 2: Monotherapy Target Total Daily Maintenance Dosing for Patients to 9 Years of Age Weight (kg) Total Daily Dose (mg/day) Minimum Maintenance Dose Total Daily Dose (mg/day) Maximum Maintenance Dose Up to 11 150 250 12 to 22 200 300 23 to 31 200 350 32 to 38 250 350 Greater than 38 250 400 * Administered in two equally divided doses 2.2 Dosing in Adjunctive Therapy Epilepsy Adults (17 Years of Age and Older) The recommended total daily dose of topiramate as adjunctive therapy in adults with partial onset seizures or Lennox-Gastaut Syndrome is to 400 mg/day in two divided doses, and 400 mg/day in two divided doses as adjunctive treatment in adults with primary generalized tonic-clonic seizures.

Topiramate should be initiated at to 50 mg/day, followed by titration to an effective dose in increments of to 50 mg/day every week.

Titrating in increments of 25 mg/day every week may delay the time to reach an effective dose.

Doses above 400 mg/day have not been shown to improve responses in adults with partial-onset seizures.

Patients to 16 Years of Age The recommended total daily dose of topiramate tablets as adjunctive therapy for pediatric patients to 16 years of age with partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome is approximately to 9 mg/kg/day in two divided doses.

Titration should begin at 25 mg/day (or less, based on a range of 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 to 3 mg/kg/day (administered in two divided doses), to achieve optimal clinical response.

Dose titration should be guided by clinical outcome.

The total daily dose should not exceed 400 mg/day. 2.3 Dosing for the Preventive Treatment of Migraine The recommended total daily dose of topiramate as treatment for patients 12 years of age and older for the preventive treatment of migraine is 100 mg/day administered in two divided doses (Table 3).

The recommended titration rate for topiramate for the preventive treatment of migraine is as follows: Table 3: Preventive Treatment of Migraine Titration Schedule for Patients 12 Years of Age and Older Morning Dose Evening Dose Week 1 None 25 mg Week 2 25 mg 25 mg Week 3 25 mg 50 mg Week 4 50 mg 50 mg Dose and titration rate should be guided by clinical outcome.

If required, longer intervals between dose adjustments can be used. 2.4 Administration Information Topiramate tablets can be taken without regard to meals.

Because of the bitter taste, tablets should not be broken. 2.5 Dosing in Patients with Renal Impairment In patients with renal impairment (creatinine clearance less than 70 mL/min/1.73 m 2 ), one-half of the usual adult dose of topiramate is recommended. 2.6 Dosing in Patients Undergoing Hemodialysis To avoid rapid drops in topiramate plasma concentration during hemodialysis, a supplemental dose of topiramate may be required.

The actual adjustment should take into account 1) the duration of dialysis period, 2) the clearance rate of the dialysis system being used, and 3) the effective renal clearance of topiramate in the patient being dialyzed.

Topiramate tablets, USP are available as debossed, film-coated, circular tablets in the following strengths and colors: 25 mg white (coded “S” on one side; “707” on the other) They are supplied as follows: 25 mg tablets Bottles of 30.……NDC 43063-998-30 Bottles of 60.….NDC 43063-998-60 16.2 Storage and Handling Store topiramate tablets at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) .

Protect from moisture.

Dispense in a tight container.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to topiramate during pregnancy.

Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant.

This registry is collecting information about the safety of antiepileptic drugs during pregnancy.

To enroll, patients can call the toll-free number 1-888-233-2334.

Information about the North American Drug Pregnancy Registry can be found at.

Topiramate can cause fetal harm when administered to a pregnant woman.

Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk of major congenital malformations, including but not limited to cleft lip and/or cleft palate (oral clefts), and of being small for gestational age (SGA) .

SGA has been observed at all doses and appears to be dose-dependent.

The prevalence of

SGA is greater in infants of women who received higher doses of topiramate during pregnancy.

In addition, the prevalence of SGA in infants of women who continued topiramate use until later in pregnancy is higher compared to the prevalence in infants of women who stopped topiramate use before the third trimester.

In multiple animal species, topiramate produced developmental toxicity, including increased incidences of fetal malformations, in the absence of maternal toxicity at clinically relevant doses.

All pregnancies have a background risk of birth defects, loss, or other adverse outcomes.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

In the

U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are to 4% and to 20%, respectively.

Fetal/Neonatal Adverse Reactions Consider the benefits and risks of topiramate when prescribing this drug to women of childbearing potential, particularly when topiramate is considered for a condition not usually associated with permanent injury or death.

Because of the risk of oral clefts to the fetus, which occur in the first trimester of pregnancy, all women of childbearing potential should be informed of the potential risk to the fetus from exposure to topiramate.

Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of topiramate use during pregnancy, and alternative therapeutic options should be considered for these patients.

Although the effect of topiramate on labor and delivery in humans has not been established, the development of topiramate-induced metabolic acidosis in the mother and/or in the fetus might affect the fetus’ ability to tolerate labor.

Topiramate treatment can cause metabolic acidosis.

The effect of topiramate-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus’ ability to tolerate labor.

Pregnant patients should be monitored for metabolic acidosis and treated as in the nonpregnant state.

Newborns of mothers treated with topiramate should be monitored for metabolic acidosis because of transfer of topiramate to the fetus and possible occurrence of transient metabolic acidosis following birth.

Based on limited information, topiramate has also been associated with pre-term labor and premature delivery.

Data from pregnancy registries indicate an increased risk of major congenital malformations, including but not limited to oral clefts in infants exposed to topiramate during the first trimester of pregnancy.

Other than oral clefts, no specific pattern of major congenital malformations or grouping of major congenital malformation types were observed.

NAAED pregnancy registry, when topiramate-exposed infants with only oral clefts were excluded, the prevalence of major congenital malformations (4.1%) was higher than that in infants exposed to a reference AED (1.8%) or in infants with mothers without epilepsy and without exposure to AEDs (1.1%).

The prevalence of oral clefts among topiramate-exposed infants (1.4%) was higher than the prevalence in infants exposed to a reference AED (0.3%) or the prevalence in infants with mothers without epilepsy and without exposure to AEDs(0.11%).

It was also higher than the background prevalence in United States (0.17%) as estimated by the Centers for Disease Control and Prevention (CDC).

The relative risk of oral clefts in topiramate-exposed pregnancies in the NAAED Pregnancy Registry was 12.5 (95% Confidence Interval [CI]5.9 to 26.37) as compared to the risk in a background population of untreated women.

Register reported a prevalence of oral clefts among infants exposed to topiramate monotherapy (3.2%) that was 16 times higher than the background rate in the UK (0.2%).

Data from the

NAAED pregnancy registry and a population-based birth registry cohort indicate that exposure to topiramate in utero is associated with an increased risk of SGA newborns (birth weight <10th percentile).

NAAED pregnancy registry, 19.7% of topiramate-exposed newborns were SGA compared to 7.9% of newborns exposed to a reference AED and 5.4% of newborns of mothers without epilepsy and without AED exposure.

In the Medical Birth Registry of

Norway (MBRN), a population-based pregnancy registry, 25% of newborns in the topiramate monotherapy exposure group were SGA compared to 9 % in the comparison group unexposed to AEDs.

The long-term consequences of the

SGA findings are not known.

When topiramate (0, 20, 100, or 500 mg/kg/day) was administered to pregnant mice during the period of organogenesis, incidences of fetal malformations (primarily craniofacial defects) were increased at all doses.

Fetal body weights and skeletal ossification were reduced at the highest dose tested in conjunction with decreased maternal body weight gain.

A no-effect dose for embryofetal developmental toxicity in mice was not identified.

The lowest dose tested, which was associated with increased malformations, is less than the maximum recommended human dose (MRHD) for epilepsy (400 mg/day) or migraine (100 mg/day) on a body surface area (mg/m 2 ) basis.

In pregnant rats administered topiramate (0, 20, 100, and 500 mg/kg/day or 0, 0.2, 2.5, 30, and 400 mg/kg/day) orally during the period of organogenesis, the frequency of limb malformations (ectrodactyly, micromelia, and amelia) was increased in fetuses at and 500 mg/kg/day. Embryotoxicity (reduced fetal body weights, increased incidences of structural variations) was observed at doses as low as 20 mg/kg/day. Clinical signs of maternal toxicity were seen at 400 mg/kg/day and above, and maternal body weight gain was reduced at doses of 100 mg/kg/day or greater.

The no-effect dose (2.5 mg/kg/day) for embryofetal developmental toxicity in rats is less than the MRHD for epilepsy or migraine on a mg/m 2 basis.

In pregnant rabbits administered topiramate (0, 20, 60, and 180 mg/kg/day or 0, 10, 35, and 120 mg/kg/day) orally during organogenesis, embryofetal mortality was increased at 35 mg/kg/day, and increased incidences of fetal malformations (primarily rib and vertebral malformations) were observed at 120 mg/kg/day. Evidence of maternal toxicity (decreased body weight gain, clinical signs, and/or mortality) was seen at 35 mg/kg/day and above.

The no-effect dose (20 mg/kg/day) for embryofetal developmental toxicity in rabbits is equivalent to the MRHD for epilepsy and approximately 4 times the MRHD for migraine on a mg/m 2 basis.

When topiramate (0, 0.2, 4, 20, and 100 mg/kg/day or 0, 2, 20, and 200 mg/kg/day) was administered orally to female rats during the latter part of gestation and throughout lactation, offspring exhibited decreased viability and delayed physical development at 200 mg/kg/day and reductions in pre.

• and/or postweaning body weight gain at 2 mg/kg/day and above.

Maternal toxicity (decreased body weight gain, clinical signs) was evident at 100 mg/kg/day or greater.

In a rat embryofetal development study which included postnatal assessment of offspring, oral administration of topiramate (0, 0.2, 2.5, 30, and 400 mg/kg) to pregnant animals during the period of organogenesis resulted in delayed physical development in offspring at 400 mg/kg/day and persistent reductions in body weight gain in offspring at 30 mg/kg/day and higher.

The no-effect dose (0.2 mg/kg/day) for pre.

• and postnatal developmental toxicity in rats is less than the MRHD for epilepsy or migraine on a mg/m 2 basis.

Patients 2 Years of Age and Older The safety and effectiveness of topiramate as adjunctive therapy for the treatment of partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome have been established in pediatric patients 2 years of age and older.

Pediatric Patients Below the

Age of 2 Years Safety and effectiveness in patients below the age of 2 years have not been established for the adjunctive therapy treatment of partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome.

In a single randomized, double-blind, placebo-controlled investigational trial, the efficacy, safety, and tolerability of topiramate oral liquid and sprinkle formulations as an adjunct to concurrent antiepileptic drug therapy in pediatric patients to 24 months of age with refractory partial-onset seizures were assessed.

After 20 days of double-blind treatment, topiramate (at fixed doses of 5, 15, and 25 mg/kg/day) did not demonstrate efficacy compared with placebo in controlling seizures.

In general, the adverse reaction profile for topiramate in this population was similar to that of older pediatric patients, although results from the above controlled study and an open-label, long-term extension study in these pediatric patients to 24 months old suggested some adverse reactions/toxicities (not previously observed in older pediatric patients and adults; i.e., growth/length retardation, certain clinical laboratory abnormalities, and other adverse reactions/toxicities that occurred with a greater frequency and/or greater severity than had been recognized previously from studies in older pediatric patients or adults for various indications).

These very young pediatric patients appeared to experience an increased risk for infections (any topiramate dose 12%, placebo 0%) and of respiratory disorders (any topiramate dose 40%, placebo 16%).

The following adverse reactions were observed in at least 3% of patients on topiramate and were 3% to 7% more frequent than in patients on placebo: viral infection, bronchitis, pharyngitis, rhinitis, otitis media, upper respiratory infection, cough, and bronchospasm.

A generally similar profile was observed in older pediatric patients.

Topiramate resulted in an increased incidence of patients with increased creatinine (any topiramate dose 5%, placebo 0%), BUN (any topiramate dose 3%, placebo 0%), and protein (any topiramate dose 34%, placebo 6%), and an increased incidence of decreased potassium (any topiramate dose 7%, placebo 0%).

This increased frequency of abnormal values was not dose-related.

Creatinine was the only analyte showing a noteworthy increased incidence (topiramate 25 mg/kg/day 5%, placebo 0%) of a markedly abnormal increase.

The significance of these findings is uncertain.

Topiramate treatment also produced a dose-related increase in the percentage of patients who had a shift from normal at baseline to high/increased (above the normal reference range) in total eosinophil count at the end of treatment.

The incidence of these abnormal shifts was 6 % for placebo, 10% for 5 mg/kg/day, 9% for 15 mg/kg/day, 14% for 25 mg/kg/day, and 11% for any topiramate dose.

There was a mean dose-related increase in alkaline phosphatase.

Topiramate produced a dose-related increased incidence of hyperammonemia.

Treatment with topiramate for up to 1 year was associated with reductions in Z SCORES for length, weight, and head circumference.

In open-label, uncontrolled experience, increasing impairment of adaptive behavior was documented in behavioral testing over time in this population.

There was a suggestion that this effect was dose-related.

However, because of the absence of an appropriate control group, it is not known if this decrement in function was treatment-related or reflects the patient’s underlying disease (e.g., patients who received higher doses may have more severe underlying disease) .

In this open-label, uncontrolled study, the mortality was 37 deaths/1000 patient years.

It is not possible to know whether this mortality rate is related to topiramate treatment, because the background mortality rate for a similar, significantly refractory, young pediatric population (1 to 24 months) with partial epilepsy is not known.

Patients 2 Years of Age and Older The safety and effectiveness of topiramate as monotherapy for the treatment of partial-onset seizures or primary generalized tonic-clonic seizures have been established in pediatric patients aged 2 years and older.

A one-year, active-controlled, open-label study with blinded assessments of bone mineral density (BMD) and growth in pediatric patients to 15 years of age, including 63 patients with recent or new onset of epilepsy, was conducted to assess effects of topiramate(N=28, 6 to 15 years of age) versus levetiracetam (N=35, 4 to 15 years of age) monotherapy on bone mineralization and on height and weight, which reflect growth.

Effects on bone mineralization were evaluated via dual-energy X-ray absorptiometry and blood markers.

Table 10 summarizes effects of topiramateat 12 months for key safety outcomes including BMD, height, height velocity, and weight.

Mean values for topiramateand the comparator were positive.

Therefore, the Least Square Mean treatment differences shown reflect a topiramate -induced attenuation of the key safety outcomes.

Statistically significant effects were observed for decreases in BMD (and bone mineral content) in lumbar spine and total body less head and in weight.

Subgroup analyses according to age demonstrated similar negative effects for all key safety outcomes (i.e., BMD, height, weight).

Table 10 Summary of Topiramate Treatment Difference Results at 12 Months for Key Safety Outcomes Safety Parameter Treatment Difference in Least Square Means (95 % Confidence Interval) Annual Change in BMD Lumbar Spine (g/cm 2 ) -0.036 (-0.058, -0.014) Annual Change in BMD TBLH (g/cm 2 ) -0.026 (-0.039, -0.012) Annual Change in Height (cm) (4 to 9 years, Primary Analysis Population for Height) -0.84 (-2.67, 0.99) Annual Change in Height (cm) (4 to 15 years) -0.75 (-2.21, 0.71) Annual Change in Height (cm) (10 to 15 years) -1.01 (-3.64, 1.61) Height Velocity (cm/year) (4 to 9 years) -1.00 (-2.76, 0.76) Height Velocity (cm/year) (4 to 15 years) -0.98 (-2.33, 0.37) Height Velocity (cm/Year) (10 to 15 years) -0.96 (-3.24, 1.32) Annual Change in Weight (kg) -2.05 (-3.66, -0.45) TBLH=total body less head ** Whereas no patients were randomized to to 5 year age subgroup for topiramate, 5 patients (4 to 5 years) were randomized to the active control group.

Metabolic acidosis (serum bicarbonate < 20 mEq/L) was observed in all topiramate-treated patients at some time in the study.

Over the whole study, 76% more topiramate-treated patients experienced persistent metabolic acidosis (i.e. 2 consecutive visits with or final serum bicarbonate < 20 mEq/L) compared to levetiracetam treated patients.

Over the whole study, 35% more topiramate-treated patients experienced a markedly abnormally low serum bicarbonate (i.e., absolute value < 17 mEq/L and ≥ 5 mEq/L decrease from pre-treatment), indicating the frequency of more severe metabolic acidosis, compared to levetiracetam-treated patients.

The decrease in

BMD at 12 months was correlated with decreased serum bicarbonate, suggesting that metabolic acidosis was at least a partial factor contributing to this adverse effect on BMD.

Topiramate-treated patients exhibited an increased risk for developing an increased serum creatinine and an increased serum glucose above the normal reference range compared to control patients.

Age of 2 Years Safety and effectiveness in patients below the age of 2 years have not been established for the monotherapy treatment of epilepsy.

Patients to 17 Years of Age Safety and effectiveness of topiramate for the preventive treatment of migraine was studied in 5 double-blind, randomized, placebo-controlled, parallel-group trials in a total of 219 pediatric patients, at doses of to 200 mg/day, or to 3 mg/kg/day. These comprised a fixed dose study in 103 pediatric patients to 17 years of age, a flexible dose (2 to 3 mg/kg/day), placebo-controlled study in 157 pediatric patients to 16 years of age (including 67 pediatric patients to 16 years of age), and a total of 49 pediatric patients to 17 years of age in 3 studies for the preventive treatment of migraine primarily in adults.

Open-label extension phases of 3 studies enabled evaluation of long-term safety for up to 6 months after the end of the double-blind phase.

Efficacy of topiramate for the preventive treatment of migraine in pediatric patients to 17 years of age is demonstrated for a 100 mg daily dose in Study 13.

Efficacy of topiramate (2 to 3 mg/kg/day) for the preventive treatment of migraine was not demonstrated in a placebo.

• controlled trial of 157 pediatric patients (6 to 16 years of age) that included treatment of 67 pediatric patients (12 to 16 years of age) for 20 weeks.

In the pediatric trials (12 to 17 years of age) in which patients were randomized to placebo or a fixed daily dose of topiramate, the most common adverse reactions with topiramate that were seen at an incidence higher (≥5%) than in the placebo group were: paresthesia, upper respiratory tract infection, anorexia, and abdominal pain.

The most common cognitive adverse reaction in pooled double-blind studies in pediatric patients to 17 years of age was difficulty with concentration/attention.

Markedly abnormally low serum bicarbonate values indicative of metabolic acidosis were reported in topiramate-treated pediatric migraine patients.

In topiramate-treated pediatric patients (12 to 17 years of age) compared to placebo-treated patients, abnormally increased results were more frequent for creatinine, BUN, uric acid, chloride, ammonia, total protein, and platelets.

Abnormally decreased results were observed with topiramate vs placebo treatment for phosphorus and bicarbonate.

Notable changes (increases and decreases) from baseline in systolic blood pressure, diastolic blood pressure, and pulse were observed occurred more commonly in pediatric patients treated with topiramate compared to pediatric patients treated with placebo.

Age of 12 Years Safety and effectiveness in pediatric patients below the age of 12 years have not been established for the preventive treatment of migraine.

In a double-blind study in 90 pediatric patients to 11 years of age (including 59 topiramate-treated and 31 placebo patients), the adverse reaction profile was generally similar to that seen in pooled double-blind studies of pediatric patients to 17 years of age.

The most common adverse reactions that occurred in topiramate-treated pediatric patients to 11 years of age, and at least twice as frequently than placebo, were gastroenteritis (12% topiramate, 6% placebo), sinusitis (10% topiramate, 3% placebo), weight loss (8% topiramate, 3% placebo) and paresthesia (7% topiramate, 0% placebo).

Difficulty with concentration/attention occurred in 3 topiramate-treated patients (5.

In clinical trials, 3% of patients were over age 60.

No age-related differences in effectiveness or adverse effects were evident.

However, clinical studies of topiramate did not include sufficient numbers of subjects age and over to determine whether they respond differently than younger subjects.

Dosage adjustment may be necessary for elderly with age-related renal impairment (creatinine clearance rate <70 mL/min/1.73 m 2 ) resulting in reduced clearance.