TOPICLOMAX

Topiramate is a anti-epileptic drug used to manage seizures and prevent migraines.

It was initially approved by the

FDA in 1996.

In 2004, topiramate was approved for the prevention of migraine in adults. 6, 19, 23 Since 2012, the extended-release formulation has been approved in combination with phentermine for chronic weight management therapy in adults.

Characteristics that distinguish topiramate from other antiepileptic drugs are a monosaccharide chemical structure containing a sulfamate, and 40% of its mass accounted for by oxygen.

Interestingly, topiramate was discovered by chance when attempts were made to formulate a novel antidiabetic drug.

Topiramate is indicated for the following conditions: 1)Monotherapy for partial onset or primary generalized tonic-clonic seizures for patients 2 years of age and above 2)Adjunctive therapy for partial onset seizures or primary generalized tonic-clonic seizures for both adult and pediatric patients above 2 years old 3)Adjunctive therapy for seizures associated with Lennox-Gastaut syndrome in patients above 2 years of age 4)Prophylaxis of migraine in children 12 years of age and older and adults.

Topiramate is also used off-label as an adjunct therapy for weight management and for mood disorders.

Topiramate prevents the occurrence of seizures and prevents migraine symptoms by reducing neural pathway excitability. 8, 19 It is important to note that this drug may cause metabolic acidosis, mood changes, suicidal thoughts and attempts, as well as kidney stones.

When topiramate is combined with valproic acid, it is known to cause hypothermia.

Gamma-aminobutyric acid receptor subunit alpha-1 Agonist Voltage-gated sodium channel alpha subunit Inhibitor Kainate receptors Antagonist + 3 more targets.

After a 400 mg dose in one clinical trial, topiramate reached maximal concentrations within 1.8-4.3 hours and ranged from 1.73-28.7 ug/mL.

Food did not significantly affect the extent of absorption, despite delaying time to peak concentration.

In patients with normal creatinine clearance, steady state concentrations are reached within 4 days.

The bioavailability of topiramate in tablet form is about 80% compared to a topiramate solution.

The mean apparent volume of distribution of topiramate ranges from 0.6-0.8 L/kg when doses of 100 mg to 1200 mg are given.

Topiramate readily crosses the blood-brain barrier.

The metabolites of topiramate are not known to be active.

The metabolism of topiramate is characterized by reactions of glucuronidation, hydroxylation and hydrolysis that lead to the production of six minor metabolites.

Some of topiramate's metabolites include 2,3-desisopropylidene topiramate, 4,5-desisopropylidene topiramate, 9-hydroxy topiramate, and 10-hydroxy topiramate.

Hover over products below to view reaction partners Topiramate 2,3-Desisopropylidene Topiramate 10-hydroxy topiramate 9-hydroxy topiramate 4,5-Desisopropylidene topiramate.

Topiramate is mainly eliminated through the kidneys.

About 70-80% of the eliminated dose is found unchanged in the urine. 3, 19.

The elimination half-life is reported to be in the range of 19-23 hours.

If topiramate is given with enzyme-inducers, the half-life can be reduced to 12-15 hours because of increased metabolism.

The mean oral plasma clearance of topiramate ranges from 22-36 mL/min while the renal clearance is 17-18 mL/min, according to one pharmacokinetic study.

FDA label for topiramate indicates a similar oral plasma clearance of approximately 20-30 mL/min in adults.

Improve decision support & research outcomes With structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates.

View sample adverse effects data in our new Data Library! See the data Improve decision support & research outcomes with our structured adverse effects data.

LD50 of intraperitoneal topiramate in the rat is above 1500 mg/kg.

Overdose information

In a study of 4 healthy adult women taking topiramate, the severity of clinical effects following an overdose ranged from asymptomatic to severe, with no deaths reported.

According to the

FDA prescribing information for topiramate, an overdose may cause hypotension, severe metabolic acidosis, coma, abdominal pain, visual disturbances, convulsions, drowsiness, speech abnormalities, impaired mentation and coordination, stupor, agitation, dizziness, as well as depression.

In the case of a recent ingestion of topiramate, the stomach contents should be emptied through the induction of emesis or gastric lavage.

Offer supportive treatment, including activated charcoal and hemodialysis.

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.