Topiramate is a sulfamate-substituted monosaccharide. TOPAMAX® (topiramate) Tablets are available as 25 mg, 50 mg, 100 mg, and 200 mg round tablets for oral administration. TOPAMAX® (topiramate capsules) Sprinkle Capsules are available as 15 mg and 25mg sprinkle capsules for oral administration as whole capsules or opened and sprinkled onto soft food.

Topiramate is a white crystalline powder with a bitter taste. Topiramate is most soluble in alkaline solutions containing sodium hydroxide or sodium phosphate and having a pH of 9 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 C₁₂H₂₁NO₈S 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:

TOPAMAX® (topiramate) Tablets contain the following inactive ingredients: lactose monohydrate, pregelatinized starch, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, purified water, carnauba wax, hypromellose, titanium dioxide, polyethylene glycol, synthetic iron oxide (50, 100, and 200 mg tablets) and polysorbate 80.

TOPAMAX® (topiramate capsules) Sprinkle Capsules contain topiramate coated beads in a hard gelatin capsule. The inactive ingredients are: sugar spheres (sucrose and starch), povidone, cellulose acetate, gelatin, silicone dioxide, sodium lauryl sulfate, titanium dioxide, and black pharmaceutical ink.

Monotherapy Epilepsy

TOPAMAX® (topiramate) Tablets and TOPAMAX® (topiramate capsules) Sprinkle Capsules are indicated as initial monotherapy in patients 10 years of age and older with partial onset or primary generalized tonic-clonic seizures.

Effectiveness was demonstrated in a controlled trial in patients with epilepsy who had no more than 2 seizures in the 3 months prior to enrollment. Safety and effectiveness in patients who were converted to monotherapy from a previous regimen of other anticonvulsant drugs have not been established in controlled trials.

Adjunctive Therapy Epilepsy

TOPAMAX® (topiramate) Tablets and TOPAMAX® (topiramate capsules) Sprinkle Capsules are indicated as adjunctive therapy for adults and pediatric patients ages 2-16 years with partial onset seizures, or primary generalized tonic-clonic seizures, and in patients 2 years of age and older with seizures associated with Lennox-Gastaut syndrome.

Migraine

TOPAMAX® (topiramate) Tablets and TOPAMAX® (topiramate capsules) Sprinkle Capsules are indicated for adults for the prophylaxis of migraine headache. The usefulness of TOPAMAX® in the acute treatment of migraine headache has not been studied.

Epilepsy

In the controlled add-on trials, no correlation has been demonstrated between trough plasma concentrations of topiramate and clinical efficacy. No evidence of tolerance has been demonstrated in humans. Doses above 400 mg/day (600, 800, or 1,000 mg/day) have not been shown to improve responses in dose-response studies in adults with partial onset seizures.

It is not necessary to monitor topiramate plasma concentrations to optimize TOPAMAX® therapy. On occasion, the addition of TOPAMAX® to phenytoin may require an adjustment of the dose of phenytoin to achieve optimal clinical outcome. Addition or withdrawal of phenytoin and/or carbamazepine during adjunctive therapy with TOPAMAX® may require adjustment of the dose of TOPAMAX® . Because of the bitter taste, tablets should not be broken.

TOPAMAX® can be taken without regard to meals.

Monotherapy Use

The recommended dose for topiramate monotherapy in adults and children 10 years of age and older is 400 mg/day in two divided doses. Approximately 58% of patients randomized to 400 mg/day achieved this maximal dose in the monotherapy controlled trial; the mean dose achieved in the trial was 275 mg/day. The dose should be achieved by titrating according to the following schedule:

	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

Adjunctive Therapy Use

Adults (17 Years of Age and Over) - Partial Seizures, Primary Generalized Tonic-Clonic Seizures, or Lennox-Gastaut Syndrome

The recommended total daily dose of TOPAMAX® as adjunctive therapy in adults with partial seizures is 200-400 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. It is recommended that therapy be initiated at 25 - 50 mg/day followed by titration to an effective dose in increments of 25 - 50 mg/week. Titrating in increments of 25 mg/week may delay the time to reach an effective dose. Daily doses above 1,600mg have not beenstudied.

In the study of primary generalized tonic-clonic seizures the initial titration rate was slower than in previous studies; the assigned dose was reached at the end of 8 weeks (see CLINICAL STUDIES, Adjunctive Therapy Controlled Trials in Patients With Primary Generalized Tonic-Clonic Seizures).

Pediatric Patients (Ages 2-16 Years) - Partial Seizures, Primary Generalized Tonic-Clonic Seizures, or Lennox-Gastaut Syndrome

The recommended total daily dose of TOPAMAX® (topiramate) as adjunctive therapy for patients with partial seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome is approximately 5 to 9 mg/kg/day in two divided doses. Titration should begin at 25 mg (or less, based on a range of 1 to 3 mg/kg/day) nightly for the first week. The dosage should then be increased at 1- or 2-week intervals by increments of 1 to 3 mg/kg/day (administered in two divided doses), to achieve optimal clinical response. Dose titration should be guided by clinical outcome.

In the study of primary generalized tonic-clonic seizures the initial titration rate was slower than in previous studies; the assigned dose of 6 mg/kg/day was reached at the end of 8 weeks (see CLINICAL STUDIES, Adjunctive Therapy Controlled Trials in Patients With Primary Generalized Tonic-Clonic Seizures).

Migraine

The recommended total daily dose of TOPAMAX® as treatment for prophylaxis of migraine headache is 100 mg/day administered in two divided doses. The recommended titration rate for topiramate for migraine prophylaxis to 100 mg/day is:

	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.

Administration of TOPAMAX® Sprinkle Capsules

TOPAMAX® (topiramate capsules) Sprinkle Capsules may be swallowed whole or may be administered by carefully opening the capsule and sprinkling the entire contents on a small amount (teaspoon) of soft food. This drug/food mixture should be swallowed immediately and not chewed. It should not be stored for future use.

Patients with Renal Impairment

In renally impaired subjects (creatinine clearance less than 70 mL/min/1.73m² ), one half of the usual adult dose is recommended. Such patients will require a longer time to reach steady-state at each dose.

Geriatric Patients (Ages 65 Years and Over)

Dosage adjustment may be indicated in the elderly patient when impaired renal function (creatinine clearance rate ≤70 mL/min/ 1.73 m² ) is evident (see DOSAGE AND ADMINISTRATION: Patients with Renal Impairment and CLINICAL PHARMACOLOGY: Special Populations: Age, Gender, and Race).

Patients Undergoing Hemodialysis

Topiramate is cleared by hemodialysis at a rate that is 4 to 6 times greater than a normal individual. Accordingly, a prolonged period of dialysis may cause topiramate concentration to fall below that required to maintain an anti-seizure effect. To avoid rapid drops in topiramate plasma concentration during hemodialysis, a supplemental dose of topiramate may be required. The actual adjustment should take into account 1) the duration of dialysis period, 2) the clearance rate of the dialysis system being used, and 3) the effective renal clearance of topiramate in the patient being dialyzed.

Patients with Hepatic Disease

In hepatically impaired patients topiramate plasma concentrations may be increased. The mechanism is not well understood.

TOPAMAX® (topiramate) Tablets are available as debossed, coated, round tablets in the following strengths and colors:

25 mg white (coded “TOP” on one side; “25” on the other)
50 mg light-yellow (coded “TOPAMAX” on one side; “50” on the other)
100 mg yellow (coded “TOPAMAX” on one side; “100” on the other)
200 mg salmon (coded “TOPAMAX” on one side; “200” on the other)

They are supplied as follows:

25 mg tablets - bottles of 60 count with desiccant (NDC 0045-0639-65)
50 mg tablets - bottles of 60 count with desiccant (NDC 0045-0640-65)
100 mg tablets - bottles of 60 count with desiccant (NDC 0045-0641-65)
200 mg tablets - bottles of 60 count with desiccant (NDC 0045-0642-65)

TOPAMAX® (topiramate capsules) Sprinkle Capsules contain small, white to off white spheres. The gelatin capsules are white and clear.

They are marked as follows:

15 mg capsule with “TOP” and “15 mg” on the side
25 mg capsule with “TOP” and “25 mg” on the side

The capsules are supplied as follows:

15 mg capsules - bottles of 60 (NDC 0045-0647-65)
25 mg capsules - bottles of 60 (NDC 0045-0645-65)

TOPAMAX® (topiramate) Tablets should be stored in tightly-closed containers at controlled room temperature (59 to 86°F, 15 to 30°C). Protect from moisture.

TOPAMAX® (topiramate capsules) Sprinkle Capsules should be stored in tightly-closed containers at or below 25°C (77°F). Protect from moisture.

TOPAMAX® (topiramate) and TOPAMAX® (topiramate capsules) are trademarks of Ortho-McNeil Neurologics, Inc.

ORTHO-McNEILNEUROLOGICS, INC.
Titusville, NJ 08560
10016700 © OMN 2005
Revised June 2005
FDA rev date: 10/19/2006

The data described in the following section were obtained using TOPAMAX® (topiramate) Tablets.

Monotherapy Epilepsy

The adverse events in the controlled trial that occurred most commonly in adults in the 400 mg/day group and at a rate higher than the 50 mg/day group were: paresthesia, weight decrease, somnolence, anorexia, dizziness, and difficulty with memory NOS [see Table 4].

The adverse events in the controlled trial that occurred most commonly in children (10 years up to 16 years of age) in the 400 mg/day group and at a rate higher than the 50 mg/day group were: weight decrease, upper respiratory tract infection, paresthesia, anorexia, diarrhea, and mood problems [see Table 5].

Approximately 21% of the 159 adult patients in the 400 mg/day group who received topiramate as monotherapy in the controlled clinical trial discontinued therapy due to adverse events. Adverse events associated with discontinuing therapy (≥2%) included depression, insomnia, difficulty with memory (NOS), somnolence, paresthesia, psychomotor slowing, dizziness, and nausea.

Approximately 12% of the 57 pediatric patients in the 400 mg/day group who received topiramate as monotherapy in the controlled clinical trial discontinued therapy due to adverse events. Adverse events associated with discontinuing therapy (≥5%) included difficulty with concentration/attention.

The prescriber should be aware that these data cannot be used to predict the frequency of adverse events in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during the clinical study. Similarly, the cited frequencies cannot be directly compared with data obtained from other clinical investigations involving different treatments, uses, or investigators. Inspection of these frequencies, however, does provide the prescribing physician with a basis to estimate the relative contribution of drug and non-drug factors to the adverse event incidences in the population studied.

Table 4: Incidence of Treatment-Emergent Adverse Events in the Monotherapy Epilepsy Trial in Adults^a Where Rate Was at Least 2% in the 400 mg/day Topiramate Group and Greater Than the Rate in the 50 mg/day Topiramate Group

	TOPAMAX® Dosage (mg/day)
Body System/ Adverse Event	50 (N=160)	400 (N=159)
Body as a Whole -General Disorders
Asthenia	4	6
Leg Pain	2	3
Chest Pain	1	2
Central & Peripheral Nervous System Disorders
Paresthesia	21	40
Dizziness	13	14
Hypoaesthesia	4	5
Ataxia	3	4
Hypertonia	0	3
Gastro-Intestinal System Disorders
Diarrhea	5	6
Constipation	1	4
Gastritis	0	3
Dry Mouth	1	3
Gastroesophageal Reflux	1	2
Liver and Biliary System Disorders
Gamma-GTIncreased	1	3
Metabolic and Nutritional Disorders
Weight Decrease	6	16
Psychiatric Disorders
Somnolence	9	15
Anorexia	4	14
Difficulty with Memory NOS	5	10
Insomnia	8	9
Depression	7	9
Difficulty with Concentration/Attention	7	8
Anxiety	4	6
Psychomotor Slowing	3	5
Mood Problems	2	5
Confusion	3	4
Cognitive Problem NOS	1	4
Libido Decreased	0	3
Reproductive Disorders, Female
Vaginal Hemorrhage	0	3
Red Blood Cell Disorders
Anemia	1	2
Resistance Mechanism Disorders
Infection Viral	6	8
Infection	2	3
Respiratory System Disorders
Bronchitis	3	4
Rhinitis	2	4
Dyspnea	1	2
Skin and Appendages Disorders
Rash	1	4
Pruritus	1	4
Acne	2	3
Special Senses Other, Disorders
Taste Perversion	3	5
Urinary System Disorders
Cystitis	1	3
Renal Calculus	0	3
Urinary Tract Infection	1	2
Dysuria	0	2
Micturition Frequency	0	2
a Values represent the percentage of patients reporting a given adverse event. Patients may have reported more than one adverse event during the study and can be included in more than one adverse event category.

Table 5: Incidence of Treatment-Emergent Adverse Events in the Monotherapy Epilepsy Trial in Children Ages 10 up to 16 Years^a Where Rate Was at Least 5% in the 400 mg/day Topiramate Group and Greater Than the Rate in the 50 mg/day Topiramate Group

	TOPAMAX® Dosage (mg/day)
Body System/ Adverse Event	50 (N=57)	400 (N=57)
Body as a Whole-General Disorders
Fever	0	9
Central & Peripheral Nervous System Disorders
Paresthesia	2	16
Gastro-Intestinal System Disorders
Diarrhea	5	11
Metabolic and Nutritional Disorders
Weight Decrease	7	21
Psychiatric Disorders
Anorexia	11	14
Mood Problems	2	11
Difficulty with Concentration/Attention	4	9
Cognitive Problems NOS	0	7
Nervousness	4	5
Resistance Mechanism Disorders
Infection Viral	4	9
Infection	2	7
Respiratory System Disorders
Upper Respiratory Tract Infection	16	18
Rhinitis	2	7
Bronchitis	2	7
Sinusitis	2	5
Skin and Appendages Disorders
Alopecia	2	5
a Values represent the percentage of patients reporting a given adverse event. Patients may have reported more than one adverse event during the study and can be included in more than one adverse event category.

Adjunctive Therapy Epilepsy

The most commonly observed adverse events associated with the use of topiramate at dosages of 200 to 400 mg/day in controlled trials in adults with partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, that were seen at greater frequency in topiramate-treated patients and did not appear to be dose-related were: somnolence, dizziness, ataxia, speech disorders and related speech problems, psychomotor slowing, abnormal vision, difficulty with memory, paresthesia and diplopia [see Table 6]. The most common dose-related adverse events at dosages of 200 to 1,000 mg/day were: fatigue, nervousness, difficulty with concentration or attention, confusion, depression, anorexia, language problems, anxiety, mood problems, and weight decrease [see Table8].

Adverse events associated with the use of topiramate at dosages of 5 to 9 mg/kg/day in controlled trials in pediatric patients with partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, that were seen at greater frequency in topiramate-treated patients were: fatigue, somnolence, anorexia, nervousness, difficulty with concentration/attention, difficulty with memory, aggressive reaction, and weight decrease [see Table 9].

In controlled clinical trials in adults, 11% of patients receiving topiramate 200 to 400 mg/day as adjunctive therapy discontinued due to adverse events. This rate appeared to increase at dosages above 400 mg/day. Adverse events associated with discontinuing therapy included somnolence, dizziness, anxiety, difficulty with concentration or attention, fatigue, and paresthesia and increased at dosages above 400 mg/day. None of the pediatric patients who received topiramate adjunctive therapy at 5 to 9mg/kg/day in controlled clinical trials discontinued due to adverse events.

Approximately 28% of the 1,757 adults with epilepsy who received topiramate at dosages of 200 to 1,600 mg/day in clinical studies discontinued treatment because of adverse events; an individual patient could have reported more than one adverse event. These adverse events were: psychomotor slowing (4.0%), difficulty with memory (3.2%), fatigue (3.2%), confusion (3.1%), somnolence (3.2%), difficulty with concentration/attention (2.9%), anorexia (2.7%), depression (2.6%), dizziness (2.5%), weight decrease (2.5%), nervousness (2.3%), ataxia (2.1%), and paresthesia (2.0%). Approximately 11% of the 310 pediatric patients who received topiramate at dosages up to 30 mg/kg/day discontinued due to adverse events. Adverse events associated with discontinuing therapy included aggravated convulsions (2.3%), difficulty with concentration/attention (1.6%), language problems (1.3%), personality disorder (1.3%), and somnolence (1.3%).

Incidence in Epilepsy Controlled Clinical Trials - Adjunctive Therapy - Partial Onset Seizures, Primary Generalized Tonic-Clonic Seizures, and Lennox-Gastaut Syndrome

Table 6 lists treatment-emergent adverse events that occurred in at least 1% of adults treated with 200 to 400 mg/day topiramate in controlled trials that were numerically more common at this dose than in the patients treated with placebo. In general, most patients who experienced adverse events during the first eight weeks of these trials no longer experienced them by their last visit. Table 9 lists treatment-emergent adverse events that occurred in at least 1% of pediatric patients treated with 5 to 9 mg/kg topiramate in controlled trials that were numerically more common than in patients treated with placebo.

The prescriber should be aware that these data were obtained when TOPAMAX® was added to concurrent antiepileptic drug therapy and cannot be used to predict the frequency of adverse events in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with data obtained from other clinical investigations involving different treatments, uses, or investigators. Inspection of these frequencies, however, does provide the prescribing physician with a basis to estimate the relative contribution of drug and non-drug factors to the adverse event incidences in the population studied.

Other Adverse Events Observed During Double-Blind Adjunctive Therapy Epilepsy Trials

Other events that occurred in more than 1% of adults treated with 200 to 400 mg of topiramate in placebo-controlled epilepsy trials but with equal or greater frequency in the placebo group were: headache, injury, anxiety, rash, pain, convulsions aggravated, coughing, fever, diarrhea, vomiting, muscle weakness, insomnia, personality disorder, dysmenorrhea, upper respiratory tract infection, and eye pain.

Table 6: Incidence of Treatment-Emergent Adverse Events in Placebo-Controlled, Add-On Epilepsy Trials in Adults^a,b Where Rate Was >1% in Any Topiramate Group and Greater Than the Rate in Placebo-Treated Patients

		TOPAMAX® Dosage (mg/day)
Body System/ Adverse Event c	Placebo (N=291)	200-400 (N=183)	600-1,000 (N=414)
Body as a Whole -General Disorders
Fatigue	13	15	30
Asthenia	1	6	3
Back Pain	4	5	3
Chest Pain	3	4	2
Influenza-Like Symptoms	2	3	4
Leg Pain	2	2	4
Hot Flushes	1	2	1
Allergy	1	2	3
Edema	1	2	1
Body Odor	0	1	0
Rigors	0	1	<1
Central & Peripheral Nervous System Disorders
Dizziness	15	25	32
Ataxia	7	16	14
Speech Disorders/ Related Speech Problems	2	13	11
Paresthesia	4	11	19
Nystagmus	7	10	11
Tremor	6	9	9
Language Problems	1	6	10
Coordination Abnormal	2	4	4
Hypoaesthesia	1	2	1
Gait Abnormal	1	3	2
Muscle Contractions Involuntary	1	2	2
Stupor	0	2	1
Vertigo	1	1	2
Gastro-Intestinal System Disorders
Nausea	8	10	12
Dyspepsia	6	7	6
Abdominal Pain	4	6	7
Constipation	2	4	3
Gastroenteritis	1	2	1
Dry Mouth	1	2	4
Gingivitis	<1	1	1
GI Disorder	<1	1	0
Hearing and Vestibular Disorders
Hearing Decreased	1	2	1
Metabolic and Nutritional Disorders
Weight Decrease	3	9	13
Muscle-Skeletal System Disorders
Myalgia	1	2	2
Skeletal Pain	0	1	0
Platelet, Bleeding, & Clotting Disorders
Epistaxis	1	2	1
Psychiatric Disorders
Somnolence	12	29	28
Nervousness	6	16	19
Psychomotor Slowing	2	13	21
Difficulty with Memory	3	12	14
Anorexia	4	10	12
Confusion	5	11	14
Depression	5	5	13
Difficulty with Concentration/Attention	2	6	14
Mood Problems	2	4	9
Agitation	2	3	3
Aggressive Reaction	2	3	3
Emotional Lability	1	3	3
Cognitive Problems	1	3	3
Libido Decreased	1	2	<1
Apathy	1	1	3
Depersonalization	1	1	2
Reproductive Disorders, Female
Breast Pain	2	4	0
Amenorrhea	1	2	2
Menorrhagia	0	2	1
Menstrual Disorder	1	2	1
Reproductive Disorders, Male
Prostatic Disorder	<1	2	0
Resistance Mechanism Disorders
Infection	1	2	1
Infection Viral	1	2	<1
Moniliasis	<1	1	0
Respiratory System Disorders
Pharyngitis	2	6	3
Rhinitis	6	7	6
Sinusitis	4	5	6
Dyspnea	1	1	2
Skin and Appendages Disorders
Skin Disorder	<1	2	1
Sweating Increased	<1	1	<1
Rash Erythematous	<1	1	<1
Special Sense Other, Disorders
Taste Perversion	0	2	4
Urinary System Disorders
Hematuria	1	2	<1
Urinary Tract Infection	1	2	3
Micturition Frequency	1	1	2
Urinary Incontinence	<1	2	1
Urine Abnormal	0	1	<1
Vision Disorders
Vision Abnormal	2	13	10
Diplopia	5	10	10
White Cell and RES Disorders
Leukopenia	1	2	1
a Patients in these add-on trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to TOPAMAX® or placebo. b Values represent the percentage of patients reporting a given adverse event. Patients may have reported more than one adverse event during the study and can be included in more than one adverse event category. c Adverse events reported by at least 1% of patients in the TOPAMAX® 200-400 mg/day group and more common than in the placebo group are listed in this table.

Incidence in Study 119 - Add-On Therapy- Adults with Partial Onset Seizures

Study 119 was a randomized, double-blind, placebo-controlled, parallel group study with 3 treatment arms: 1) placebo; 2) topiramate 200 mg/day with a 25 mg/day starting dose, increased by 25 mg/day each week for 8 weeks until the 200 mg/day maintenance dose was reached; and 3) topiramate 200 mg/day with a 50 mg/day starting dose, increased by 50 mg/day each week for 4 weeks until the 200 mg/day maintenance dose was reached. All patients were maintained on concomitant carbamazepine with or without another concomitant antiepileptic drug.

The incidence of adverse events (Table 7) did not differ significantly between the 2 topiramate regimens. Because the frequencies of adverse events reported in this study were markedly lower than those reported in the previous epilepsy studies, they cannot be directly compared with data obtained in other studies.

Table 7: Incidence of Treatment-Emergent Adverse Events in Study 119^a,b Where Rate Was ≥2% in the Topiramate Group and Greater Than the Rate in Placebo-Treated Patients

	TOPAMAX® Dosage (mg/day)
Body System/Adverse Event c	Placebo (N=92)	200 (N=171)
Body as a Whole - General Disorders
Fatigue	4	9
Chest Pain	1	2
Cardiovascular Disorders, General
Hypertension	0	2
Central & Peripheral Nervous System Disorders
Paresthesia	2	9
Dizziness	4	7
Tremor	2	3
Hypoasthesia	0	2
Leg Cramps	0	2
Language Problems	0	2
Gastro-Intestinal System Disorders
Abdominal Pain	3	5
Constipation	0	4
Diarrhea	1	2
Dyspepsia	0	2
Dry Mouth	0	2
Hearing and Vestibular Disorders
Tinnitus	0	2
Metabolic and Nutritional Disorders
Weight Decrease	4	8
Psychiatric Disorders
Somnolence	9	15
Anorexia	7	9
Nervousness	2	9
Difficulty with Concentration/Attention	0	5
Insomnia	3	4
Difficulty with Memory	1	2
Aggressive Reaction	0	2
Respiratory System Disorders
Rhinitis	0	4
Urinary System Disorders
Cystitis	0	2
Vision Disorders
Diplopia	0	2
Vision Abnormal	0	2

Table 8: Incidence (%) of Dose-Related Adverse Events From Placebo-Controlled, Add-On Trials in Adults with Partial Onset Seizures^a

		TOPAMAX® Dosage (mg/day)
Adverse Event	Placebo (N=216)	200 (N=45)	400 (N=68)	600-1,000 (N=414)
Fatigue	13	11	12	30
Nervousness	7	13	18	19
Difficulty with Concentration/Attention	1	7	9	14
Confusion	4	9	10	14
Depression	6	9	7	13
Anorexia	4	4	6	12
Language problems	<1	2	9	10
Anxiety	6	2	3	10
Mood problems	2	0	6	9
Weight decrease	3	4	9	13
a Dose-response studies were not conducted for other adult indications or for pediatric indications.

Table 9: Incidence (%) of Treatment-Emergent Adverse Events in Placebo-Controlled, Add-On Epilepsy Trials in Pediatric Patients Ages 2-16 Years^a,b (Events that Occurred in at Least 1% of Topiramate-Treated Patients and Occurred More Frequently in
Topiramate-Treated Than Placebo-Treated Patients)

Body System/ Adverse Event	Placebo (N=101)	Topiramate (N=98)
Body as a Whole - General Disorders
Fatigue	5	16
Injury	13	14
Allergic Reaction	1	2
Back Pain	0	1
Pallor	0	1
Cardiovascular Disorders, General
Hypertension	0	1
Central & Peripheral Nervous System Disorders
Gait Abnormal	5	8
Ataxia	2	6
Hyperkinesia	4	5
Dizziness	2	4
Speech Disorders/Related Speech Problems	2	4
Hyporeflexia	0	2
Convulsions Grand Mal	0	1
Fecal Incontinence	0	1
Paresthesia	0	1
Gastro-Intestinal System Disorders
Nausea	5	6
Saliva Increased	4	6
Constipation	4	5
Gastroenteritis	2	3
Dysphagia	0	1
Flatulence	0	1
Gastroesophageal Reflux	0	1
Glossitis	0	1
Gum Hyperplasia	0	1
Heart Rate and Rhythm Disorders
Bradycardia	0	1
Metabolic and Nutritional Disorders
Weight Decrease	1	9
Thirst	1	2
Hypoglycemia	0	1
Weight Increase	0	1
Platelet, Bleeding, & Clotting Disorders
Purpura	4	8
Epistaxis	1	4
Hematoma	0	1
Prothrombin Increased	0	1
Thrombocytopenia	0	1
Psychiatric Disorders
Somnolence	16	26
Anorexia	15	24
Nervousness	7	14
Personality Disorder (Behavior Problems)	9	11
Difficulty with Concentration/Attention	2	10
Aggressive Reaction	4	9
Insomnia	7	8
Difficulty with Memory NOS	0	5
Confusion	3	4
Psychomotor Slowing	2	3
Appetite Increased	0	1
Neurosis	0	1
Reproductive Disorders, Female
Leukorrhoea	0	2
Resistance Mechanism Disorders
Infection Viral	3	7
Respiratory System Disorders
Pneumonia	1	5
Respiratory Disorder	0	1
Skin and Appendages Disorders
Skin Disorder	2	3
Alopecia	1	2
Dermatitis	0	2
Hypertrichosis	1	2
Rash Erythematous	0	2
Eczema	0	1
Seborrhoea	0	1
Skin Discoloration	0	1
Urinary System Disorders
Urinary Incontinence	2	4
Nocturia	0	1
Vision Disorders
Eye Abnormality	1	2
Vision Abnormal	1	2
Diplopia	0	1
Lacrimation Abnormal	0	1
Myopia	0	1
White Cell and RES Disorders
Leukopenia	0	2
a Patients in these add-on trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to TOPAMAX® or placebo. b Values represent the percentage of patients reporting a given adverse event. Patients may have reported more than one adverse event during the study and can be included in more than one adverse event category.

Other Adverse Events Observed During All Epilepsy Clinical Trials

Topiramate has been administered to 2,246 adults and 427 pediatric patients with epilepsy during all clinical studies, only some of which were placebo controlled. During these studies, all adverse events were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse events, similar types of events were grouped into a smaller number of standardized categories using modified WHOART dictionary terminology. The frequencies presented represent the proportion of patients who experienced an event of the type cited on at least one occasion while receiving topiramate. Reported events are included except those already listed in the previous tables or text, those too general to be informative, and those not reasonably associated with the use of the drug.

Events are classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent occurring in at least 1/100 patients; infrequent occurring in 1/100 to 1/1000 patients; rare occurring in fewer than 1/1000 patients.

Autonomic Nervous System Disorders: Infrequent: vasodilation.

Body as a Whole: Frequent: syncope. Infrequent: abdomen enlarged. Rare: alcohol intolerance.

Cardiovascular Disorders, General: Infrequent: hypotension, postural hypotension, angina pectoris.

Central & Peripheral Nervous System Disorders: Infrequent: neuropathy, apraxia, hyperaesthesia, dyskinesia, dysphonia, scotoma, ptosis, dystonia, visual field defect, encephalopathy, EEG abnormal. Rare: upper motor neuron lesion, cerebellar syndrome, tongue paralysis.

Gastrointestinal System Disorders: Infrequent: hemorrhoids, stomatitis, melena, gastritis, esophagitis. Rare: tongue edema.

Heart Rate and Rhythm Disorders: Infrequent: AV block.

Liver and Biliary System Disorders: Infrequent: SGPTincreased, SGOTincreased.

Metabolic and Nutritional Disorders: Infrequent: dehydration,hypokalemia, alkaline phosphatase increased, hypocalcemia, hyperlipemia, hyperglycemia, xerophthalmia, diabetes mellitus. Rare: hyperchloremia, hypernatremia, hyponatremia, hypo-cholesterolemia, hypophosphatemia, creatinine increased.

Musculoskeletal System Disorders: Frequent: arthralgia. Infrequent: arthrosis.

Neoplasms: Infrequent: thrombocythemia. Rare: polycythemia.

Platelet, Bleeding, and Clotting Disorders: Infrequent: gingival bleeding, pulmonary embolism.

Psychiatric Disorders: Frequent: impotence, hallucination, psychosis, suicide attempt. Infrequent: euphoria, paranoid reaction, delusion, paranoia, delirium, abnormal dreaming. Rare: libido increased, manic reaction.

Red Blood Cell Disorders: Frequent: anemia. Rare: marrow depression, pancytopenia. Reproductive Disorders, Male: Infrequent: ejaculation disorder, breast discharge.

Skin and Appendages Disorders: Infrequent: urticaria, photosensitivity reaction, abnormal hair texture. Rare: chloasma.

Special Senses Other, Disorders: Infrequent: taste loss, parosmia.

Urinary System Disorders: Infrequent: urinary retention, face edema, renal pain, albuminuria, polyuria, oliguria.

Vascular (Extracardiac) Disorders: Infrequent: flushing, deep vein thrombosis, phlebitis. Rare: vasospasm.

Vision Disorders: Frequent: conjunctivitis. Infrequent: abnormal accommodation, photophobia, strabismus. Rare: mydriasis, iritis.

White Cell and Reticuloendothelial System Disorders: Infrequent: lymphadenopathy, eosinophilia, lymphopenia, granulocytopenia. Rare: lymphocytosis.

Migraine

In the four multicenter, randomized, double-blind, placebo-controlled, parallel group migraine prophylaxis clinical trials, most of the adverse events with topiramate were mild or moderate in severity. Most adverse events occurred more frequently during the titration period than during the maintenance period. Table 10 includes those adverse events reported for patients in the placebo-controlled trials where the incidence rate in any topiramate treatment group was at least 2 % and was greater than that for placebo patients.

Table 10: Incidence of Treatment-Emergent Adverse Events in Placebo-Controlled, Migraine Trials Where Rate Was ≥2 % in Any Topiramate Group and Greater than the Rate in Placebo-Treated Patients^a

		TOPAMAX® Dosage (mg/day)
Body System/ Adverse Event	Placebo (N=445)	50 (N=235)	100 (N=386	200 (N=514)
Body as a Whole -General Disorders
Fatigue	11	14	15	19
Injury	7	9	6	6
Asthenia	1	<1	2	2
Fever	1	1	1	2
Influenza-Like Symptoms	<1	<1	<1	2
Allergy	<1	2	<1	<1
Central & Peripheral Nervous System Disorders
Paresthesia	6	35	51	49
Dizziness	10	8	9	12
Hypoaesthesia	2	6	7	8
Language Problems	2	7	6	7
Involuntary Muscle Contractions	1	2	2	4
Ataxia	<1	1	2	1
Speech Disorders/Related
Speech Problems	<1	1	<1	2
Gastro-Intestinal System Disorders
Nausea	8	9	13	14
Diarrhea	4	9	11	11
Abdominal Pain	5	6	6	7
Dyspepsia	3	4	5	3
Dry Mouth	2	2	3	5
Vomiting	2	1	2	3
Gastroenteritis	1	3	3	2
Hearing and Vestibular Disorders
Tinnitus	1	<1	1	2
Metabolic and Nutritional Disorders
Weight Decrease	1	6	9	11
Thirst	<1	2	2	1
Musculoskeletal System Disorders
Arthralgia	2	7	3	1
Neoplasms
Neoplasm NOS	<1	2	<1	<1
Psychiatric Disorders
Anorexia	6	9	15	14
Somnolence	5	8	7	10
Difficulty with Memory NOS	2	7	7	11
Difficulty with Concentration/Attention	2	3	6	10
Insomnia	5	6	7	6
Anxiety	3	4	5	6
Mood Problems	2	3	6	5
Depression	4	3	4	6
Nervousness	2	4	4	4
Confusion	2	2	3	4
Psychomotor Slowing	1	3	2	4
Libido Decreased	1	1	1	2
Aggravated Depression	1	1	2	2
Agitation	1	2	2	1
Cognitive Problems NOS	1	<1	2	2
Reproductive Disorders, Female
Menstrual Disorder	2	3	2	2
Reproductive Disorders, Male
Ejaculation Premature	0	3	0	0
Resistance Mechanism Disorders
Viral Infection	3	4	4	3
Otitis Media	<1	2	1	1
Respiratory System Disorders
Upper Respiratory Tract Infection	12	13	14	12
Sinusitis	6	10	6	8
Pharyngitis	4	5	6	2
Coughing	2	2	4	3
Bronchitis	2	3	3	3
Dyspnea	2	1	3	2
Rhinitis	1	1	2	2
Skin and Appendages Disorders
Pruritis	2	4	2	2
Special Sense Other, Disorders
Taste Perversion	1	15	8	12
Taste Loss	<1	1	1	2
Urinary System Disorders
Urinary Tract Infection	2	4	2	4
Renal Calculus	0	0	1	2
Vision Disorders
Vision Abnormal	<1	1	2	3
Blurred Visionb	2	4	2	4
Conjunctivitis	1	1	2	1
a Values represent the percentage of patients reporting a given adverse event. Patients may have reported more than one adverse event during the study and can be included in more than one adverse event category. b Blurred vision was the most common term considered as vision abnormal. Blurred vision was an included term that accounted for > 50 % of events coded as vision abnormal, a preferred term.

Of the 1,135 patients exposed to topiramate in the placebo-controlled studies, 25% discontinued due to adverse events, compared to 10% of the 445 placebo patients. The adverse events associated with discontinuing therapy in the topiramate-treated patients included paresthesia (7%), fatigue (4%), nausea (4%), difficulty with concentration/attention (3%), insomnia (3%), anorexia (2%), and dizziness (2%).

Patients treated with topiramate experienced mean percent reductions in body weight that were dose-dependent. This change was not seen in the placebo group. Mean changes of 0%, -2%, - 3%, and - 4% were seen for the placebo group, topiramate 50, 100, and 200 mg groups, respectively.

Table 11 shows adverse events that were dose-dependent. Several central nervous system adverse events, including some that represented cognitive dysfunction, were dose-related. The most common dose-related adverse events were paresthesia, fatigue, nausea, anorexia, dizziness, difficulty with memory, diarrhea, weight decrease, difficulty with concentration/attention, and somnolence.

Table 11: Incidence (%) of Dose-Related Adverse Events
From Placebo-Controlled, Migraine Trials^a

		TOPAMAX® Dosage (mg/day)
Adverse Event	Placebo (N=445)	50 (N=235)	100 (N=386)	200 (N=514)
Paresthesia	6	35	51	49
Fatigue	11	14	15	19
Nausea	8	9	13	14
Anorexia	6	9	15	14
Dizziness	10	8	9	12
Weight decrease	1	6	9	11
Difficulty with Memory NOS	2	7	7	11
Diarrhea	4	9	11	11
Difficulty with Concentration/Attention	2	3	6	10
Somnolence	5	8	7	10
Hypoaesthesia	2	6	7	8
Anxiety	3	4	5	6
Depression	4	3	4	6
Mood Problems	2	3	6	5
Dry Mouth	2	2	3	5
Confusion	2	2	3	4
Involuntary Muscle Contractions	1	2	2	4
Abnormal Vision	<1	1	2	3
Renal Calculus	0	0	1	2
a The incidence rate of the adverse event in the 200 mg/day group was ≥2% than the rate in both the placebo group and the 50 mg/day group.

Other Adverse Events Observed During Migraine Clinical Trials

Topiramate, for the treatment of prophylaxis of migraine headache, has been administered to 1,367 patients in all clinical studies (includes double-blind and open-label extension). During these studies, all adverse events were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse events, similar types of events were grouped into a smaller number of standardized categories using modified WHOARTdictionary terminology.

The following additional adverse events that were not described earlier were reported by greater than 1% of the 1,367 topiramate-treated patients in the controlled clinical trials:

Body as a Whole: Pain, chest pain, allergic reaction.

Central & Peripheral Nervous System Disorders: Headache, vertigo, tremor, sensory disturbance, migraine aggravated.

Gastrointestinal System Disorders: Constipation, gastroesophageal reflux, tooth disorder.

Musculoskeletal System Disorders: Myalgia.

Platelet, Bleeding, and Clotting Disorders: Epistaxis.

Reproductive Disorders, Female: Intermenstrual bleeding.

Resistance Mechanism Disorders: Infection, genital moniliasis.

Respiratory System Disorders: Pneumonia, asthma.

Skin and Appendages Disorders: Rash, alopecia.

Vision Disorders: Abnormal accommodation, eye pain.

Postmarketing and Other Experience

In addition to the adverse experiences reported during clinical testing of TOPAMAX® , the following adverse experiences have been reported worldwide in patients receiving topiramate post-approval. These adverse experiences have not been listed above and data are insufficient to support an estimate of their incidence or to establish causation. The listing is alphabetized: bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), hepatic failure (including fatalities), hepatitis, pancreatitis, pemphigus, and renal tubular acidosis.

Drug Abuse And Dependence

The abuse and dependence potential of TOPAMAX® has not been evaluated in human studies.

In vitro studies indicate that topiramate does not inhibit enzyme activity for CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5 isozymes.

Antiepileptic Drugs

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 3.

In Table 3, the second column (AED concentration) describes what happens to the concentration of the 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 in experimental settings when TOPAMAX® was given alone.

Table 3: Summary of AED Interactions with TOPAMAX®

AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increasea	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxideb	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	15% increase
a = Plasma concentration increased 25% in some patients, generally those on a b.i.d. 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

In addition to the pharmacokinetic interaction described in the above table, concomitant administration of valproic acid and topiramate has been associated with hyperammonemia with and without encephalopathy (see PRECAUTIONS, Hyperammonemia and Encephalopathy Associated with Concomitant Valproic Acid Use).

Other Drug Interactions

Digoxin

In a single-dose study, serum digoxin AUC was decreased by 12% with concomitant TOPAMAX® administration. The clinical relevance of this observation has not been established.

CNS Depressants

Concomitant administration of TOPAMAX® and alcohol or other CNS depressant drugs has not been evaluated in clinical studies. Because of the potential of topiramate to cause CNS depression, as well as other cognitive and/or neuropsychiatric adverse events, topiramate should be used with extreme caution if used in combination with alcohol and other CNSdepressants.

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), TOPAMAX® given in the absence of other medications at doses of 50 to 200 mg/day was not associated with statistically significant changes in mean exposure (AUC) to either component of the oral contraceptive. In another study, exposure to EE was statistically significantly decreased at doses of 200, 400, and 800 mg/day (18%, 21%, and 30%, respectively) when given as adjunctive therapy in patients taking valproic acid. In both studies, TOPAMAX® (50 mg/day to 800 mg/day) did not significantly affect exposure to NET. Although there was a dose dependent decrease in EE exposure for doses between 200-800 mg/day, there was no significant dose dependent change in EE exposure for doses of 50-200 mg/day. The clinical significance of the changes observed is not known. The possibility of decreased contraceptive efficacy and increased breakthrough bleeding should be considered in patients taking combination oral contraceptive products with TOPAMAX® . Patients taking estrogen containing contraceptives should be asked to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding.

Hydrochlorothiazide (HCTZ)

A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of HCTZ (25 mg q24h) and topiramate (96 mg q12h) when administered alone and concomitantly. The results of this study indicate that topiramate Cmax increased by 27% and AUC increased by 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The addition of HCTZ to topiramate therapy may require an adjustment of the topiramate dose. The steady-state pharmacokinetics of HCTZ were not significantly influenced by the concomitant administration of topiramate. Clinical laboratory results indicated decreases in serum potassium after topiramate or HCTZ administration, which were greater when HCTZ and topiramate were administered in combination.

Metformin

A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of metformin and topiramate in plasma when metformin was given alone and when metformin and topiramate were given simultaneously. The results of this study indicated that metformin mean Cmax and mean AUC_0-12h increased by 18% and 25%, respectively, while mean CL/F decreased 20% when metformin was co-administered with topiramate. Topiramate did not affect metformin tmax. The clinical significance of the effect of topiramate on metformin pharmacokinetics is unclear. Oral plasma clearance of topiramate appears to be reduced when administered with metformin. The extent of change in the clearance is unknown. The clinical significance of the effect of metformin on topiramate pharmacokinetics is unclear. When TOPAMAX® is added or withdrawn in patients on metformin therapy, careful attention should be given to the routine monitoring for adequate control of their diabetic disease state.

Pioglitazone

A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of topiramate and pioglitazone when administered alone and concomitantly. A15% decrease in the AUC_τ,ss of pioglitazone with no alteration in Cmax,ss was observed. This finding was not statistically significant. In addition, a 13% and 16% decrease in Cmax,ss and AUC_τ,ss respectively, of the active hydroxy-metabolite was noted as well as a 60% decrease in Cmax,ss and AUC_τ,ss of the active keto-metabolite. The clinical significance of these findings is not known. When TOPAMAX® is added to pioglitazone therapy or pioglitazone is added to TOPAMAX® therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.

Lithium

Multiple dosing of topiramate 100 mg every 12 hrs decreased the AUC and Cmax of Lithium (300 mg every 8 hrs) by 20% (N=12, 6 M; 6 F).

Haloperidol

The pharmacokinetics of a single dose of haloperidol (5 mg) were not affected following multiple dosing of topiramate (100 mg every 12 hr) in 13 healthy adults (6 M, 7 F).

Amitriptyline

There was a 12% increase in AUC and Cmax for amitriptyline (25 mg per day) in 18 normal subjects (9 male; 9 female) receiving 200 mg/day of topiramate. Some subjects may experience a large increase in amitriptyline concentration in the presence of topiramate and any adjustments in amitriptyline dose should be made according to the patient's clinical response and not on the basis of plasma levels.

Sumatriptan

Multiple dosing of topiramate (100 mg every 12 hrs) in 24 healthy volunteers (14 M, 10 F) did not affect the pharmacokinetics of single dose sumatriptan either orally (100 mg) or subcutaneously (6 mg).

Risperidone

There was a 25% decrease in exposure to risperidone (2 mg single dose) in 12 healthy volunteers (6 M, 6 F) receiving 200 mg/day of topiramate. Therefore, patients receiving risperidone in combination with topiramate should be closely monitored for clinical response.

Propranolol

Multiple dosing of topiramate (200 mg/day) in 34 healthy volunteers (17 M, 17 F) did not affect the pharmacokinetics of propranolol following daily 160 mg doses. Propranolol doses of 160 mg/day in 39 volunteers (27M, 12F) had no effect on the exposure to topiramate at a dose of 200 mg/day of topiramate.

Dihydroergotamine

Multiple dosing of topiramate (200 mg/day) in 24 healthy volunteers (12 M, 12 F) did not affect the pharmacokinetics of a 1 mg subcutaneous dose of dihydroergotamine. Similarly, a 1 mg subcutaneous dose of dihydroergotamine did not effect the pharmacokinetics of a 200 mg/day dose of topiramate in the same study.

Others

Concomitant use of TOPAMAX® , a carbonic anhydrase inhibitor, with other carbonic anhydrase inhibitors, e.g., aceta-zolamide or dichlorphenamide, may create a physiological environment that increases the risk of renal stone formation, and should therefore be avoided.

Drug/Laboratory Tests Interactions

There are no known interactions of topiramate with commonly used laboratory tests.

Metabolic Acidosis

Hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis) is associated with topiramate treatment. This metabolic acidosis is caused by renal bicarbonate loss due to the inhibitory effect of topiramate on carbonic anhydrase. Such electrolyte imbalance has been observed with the use of topiramate in placebo-controlled clinical trials and in the post-marketing period. Generally, topiramate-induced metabolic acidosis occurs early in treatment although cases can occur at any time during treatment. Bicarbonate decrements are usually mild-moderate (average decrease of 4 mEq/Lat daily doses of 400 mg in adults and at approximately 6 mg/kg/day in pediatric patients); rarely, patients can experience severe decrements to values below 10 mEq/L. Conditions or therapies that predispose to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, surgery, ketogenic diet, or drugs) may be additive to the bicarbonate lowering effects of topiramate.

In adults, the incidence of persistent treatment-emergent decreases in serum bicarbonate (levels of <20 mEq/L at two consecutive visits or at the final visit) in controlled clinical trials for adjunctive treatment of epilepsy was 32% for 400 mg/day, and 1% for placebo. Metabolic acidosis has been observed at doses as low as 50 mg/day. The incidence of persistent treatment-emergent decreases in serum bicarbonate in adults in the epilepsy controlled clinical trial for monotherapy was 15% for 50 mg/day and 25% for 400 mg/day. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value <17 mEq/L and >5 mEq/L decrease from pretreatment) in the adjunctive therapy trials was 3% for 400 mg/day, and 0% for placebo and in the monotherapy trial was 1% for 50 mg/day and 7% for 400 mg/day. Serum bicarbonate levels have not been systematically evaluated at daily doses greater than 400 mg/day.

In pediatric patients (<16 years of age), the incidence of persistent treatment-emergent decreases in serum bicarbonate in placebo-controlled trials for adjunctive treatment of Lennox-Gastaut syndrome or refractory partial onset seizures was 67% for TOPAMAX® (at approximately 6 mg/kg/day), and 10% for placebo. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value <17 mEq/L and >5 mEq/L decrease from pretreatment) in these trials was 11% for TOPAMAX® and 0% for placebo. Cases of moderately severe metabolic acidosis have been reported in patients as young as 5 months old, especially at daily doses above 5 mg/kg/day.

In pediatric patients (10 years up to 16 years of age), the incidence of persistent treatment-emergent decreases in serum bicarbonate in the epilepsy controlled clinical trial for monotherapy was 7% for 50 mg/day and 20% for 400 mg/day. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value <17 mEq/L and >5 mEq/L decrease from pretreatment) in this trial was 4% for 50 mg/day and 4% for 400 mg/day.

The incidence of persistent treatment-emergent decreases in serum bicarbonate in placebo-controlled trials for adults for prophylaxis of migraine was 44% for 200 mg/day, 39% for 100 mg/day, 23% for 50 mg/day, and 7% for placebo. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value <17 mEq/L and >5 mEq/L decrease from pretreatment) in these trials was 11% for 200 mg/day, 9% for 100 mg/day, 2% for 50 mg/day, and <1% for placebo.

Some manifestations of acute or chronic metabolic acidosis may include hyperventilation, nonspecific symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or stupor. Chronic, untreated metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis, and may also result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with an increased risk for fractures. Chronic metabolic acidosis in pediatric patients may also reduce growth rates. A reduction in growth rate may eventually decrease the maximal height achieved. The effect of topiramate on growth and bone-related sequelae has not been systematically investigated.

Measurement of baseline and periodic serum bicarbonate during topiramate treatment is recommended. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing topiramate (using dose tapering). If the decision is made to continue patients on topiramate in the face of persistent acidosis, alkali treatment should be considered.

Acute Myopia and Secondary Angle Closure Glaucoma

A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving TOPAMAX® . Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, anterior chamber shallowing, ocular hyperemia (redness) and increased intraocular pressure. Mydriasis may or may not be present. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating TOPAMAX® therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with topiramate has been reported in pediatric patients as well as adults. The primary treatment to reverse symptoms is discontinuation of TOPAMAX® as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation of TOPAMAX® , may be helpful.

Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss.

Oligohidrosis and Hyperthermia

Oligohidrosis (decreased sweating), infrequently resulting in hospitalization, has been reported in association with TOPAMAX® use. Decreased sweating and an elevation in body temperature above normal characterized these cases. Some of the cases were reported after exposure to elevated environmental temperatures.

The majority of the reports have been in children. Patients, especially pediatric patients, treated with TOPAMAX® should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. Caution should be used when TOPAMAX® is prescribed with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, other carbonic anhydrase inhibitors and drugs with anticholinergic activity.

Withdrawal of AEDs

Antiepileptic drugs, including TOPAMAX® , should be withdrawn gradually to minimize the potential of increased seizure frequency.

Cognitive/Neuropsychiatric Adverse Events

Adults

Adverse events most often associated with the use of TOPAMAX® were related to the central nervous system and were observed in both the epilepsy and migraine populations. In adults, the most frequent of these can be classified into three general categories: 1) Cognitive-related dysfunction (e.g., confusion, psychomotor slowing, difficulty with concentration/attention, difficulty with memory, speech or language problems, particularly word-finding difficulties); 2) Psychiatric/behavioral disturbances (e.g., depression or mood problems); and 3) Somnolence or fatigue.

Cognitive-Related Dysfunction

The majority of cognitive-related adverse events were mild to moderate in severity, and they frequently occurred in isolation. Rapid titration rate and higher initial dose were associated with higher incidences of these events. Many of these events contributed to withdrawal from treatment (see ADVERSE REACTIONS, Table 4, Table 6, and Table 10 ).

In the original add-on epilepsy controlled trials (using rapid titration such as 100-200 mg/day weekly increments), the proportion of patients who experienced one or more cognitive-related adverse events was 42% for 200 mg/day, 41% for 400 mg/day, 52% for 600 mg/day, 56% for 800 and 1000 mg/day, and 14% for placebo. These dose-related adverse reactions began with a similar frequency in the titration or in the maintenance phase, although in some patients the events began during titration and persisted into the maintenance phase. Some patients who experienced one or more cognitive-related adverse events in the titration phase had a dose-related recurrence of these events in the maintenance phase. In the monotherapy epilepsy controlled trial, the proportion of patients who experienced one or more cognitive-related adverse events was 19% for TOPAMAX® 50 mg/day and 26% for 400 mg/day.

In the 6-month migraine prophylaxis controlled trials using a slower titration regimen (25 mg/day weekly increments), the proportion of patients who experienced one or more cognitive-related adverse events was 19% for TOPAMAX® 50 mg/day, 22% for 100 mg/day, 28% for 200 mg/day, and 10% for