5.1 Acute Myopia and Secondary Angle Closure Glaucoma

A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving topiramate. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, anterior chamber shallowing, ocular 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 topiramate therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with topiramate has been reported in pediatric patients as well as adults. The primary treatment to reverse symptoms is discontinuation of topiramate as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation of topiramate, may be helpful.

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

5.2 Visual Field Defects

Visual field defects (independent of elevated intraocular pressure) have been reported in clinical trials and in postmarketing experience in patients receiving topiramate. In clinical trials, most of these events were reversible after topiramate discontinuation. If visual problems occur at any time during topiramate treatment, consideration should be given to discontinuing the drug.

5.3 Oligohidrosis and Hyperthermia

Oligohidrosis (decreased sweating), infrequently resulting in hospitalization, has been reported in association with topiramate 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 pediatric patients. Patients (especially pediatric patients) treated with topiramate should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. Caution should be used when topiramate is given 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.

5.4 Metabolic Acidosis

Topiramate can cause hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis). This metabolic acidosis is caused by renal bicarbonate loss due to carbonic anhydrase inhibition by topiramate. Topiramate-induced metabolic acidosis can occur at any time during treatment. Bicarbonate decrements are usually mild-moderate (average decrease of 4 mEq/L at 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 patients to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, ketogenic diet, or specific drugs) may be additive to the bicarbonate lowering effects of topiramate.

Metabolic acidosis was commonly observed in adult and pediatric patients treated with topiramate in clinical trials. The incidence of decreased serum bicarbonate in pediatric trials, for adjunctive treatment of Lennox-Gastaut syndrome or refractory partial onset seizures was as high as 67% for topiramate (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 up to 11%, compared to < 2% for placebo.

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, which may decrease the maximal height achieved. The effect of topiramate on growth and bone-related sequelae has not been systematically investigated in long-term, placebo-controlled trials. Long-term, open-label treatment of pediatric patients 1 to 24 months old with intractable partial epilepsy, for up to 1 year, showed reductions from baseline in length, weight, and head circumference compared to age and sex-matched normative data, although these patients with epilepsy are likely to have different growth rates than normal 1 to 24 month old pediatrics. Reductions in length and weight were correlated to the degree of acidosis [see Use in Specific Populations (8.4)]. Topiramate treatment that causes metabolic acidosis during pregnancy can possibly produce adverse effects on the fetus and might also cause metabolic acidosis in the neonate from possible transfer of topiramate to the fetus [see Warnings and Precautions (5.7), Use in Specific Populations (8.1)].

Measurement of Serum Bicarbonate in Epilepsy and Migraine Patients

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.

5.5 Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including topiramate, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo- treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.

Table 4 shows absolute and relative risk by indication for all evaluated AEDs.

Table 4 Risk by Indication for Antiepileptic Drugs in the Pooled Analysis

** Indication**	** Placebo Patients** ** with Events per** ** 1000 Patients**	** Drug Patients with** ** Events per 1000** ** Patients**	** Relative Risk:** ** Incidence of Events** ** in Drug** ** Patients/Incidence** ** in Placebo Patients**	** Risk Difference:** ** Additional Drug** ** Patients with** ** Events per 1000** ** Patients**
Epilepsy	1	3.4	3.5	2.4
Psychiatric	5.7	8.5	1.5	2.9
Other	1	1.8	1.9	0.9
Total	2.4	4.3	1.8	1.9

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing topiramate or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

5.6 Cognitive/Neuropsychiatric Adverse Reactions

Topiramate can cause cognitive/neuropsychiatric adverse reactions. 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.

Adult Patients

Cognitive-Related Dysfunction

Rapid titration rate and higher initial dose were associated with higher incidences of cognitive-related dysfunction.

In adult epilepsy add-on controlled trials, which used rapid titration (100 mg/day to 200 mg/day weekly increments), and target topiramate doses of 200 mg to 1000 mg/day, 56% of patients in the 800 mg/day and 1000 mg/day dose groups experienced cognitive-related dysfunction compared to approximately 42% of patients in the 200 mg/day to 400 mg/day groups and 14% for placebo. In this rapid titration regimen, these dose-related adverse reactions began in the titration or in the maintenance phase, and in some patients these events began during titration and persisted into the maintenance phase.

In the monotherapy epilepsy controlled trial, the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50 mg/day and 26% for 400 mg/day.

In the 6-month migraine prophylaxis controlled trials, which used a slower titration regimen (25 mg/day weekly increments), the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50 mg/day, 22% for 100 mg/day (the recommended dose), 28% for 200 mg/day, and 10% for placebo. Cognitive adverse reactions most commonly developed during titration and sometimes persisted after completion of titration.

Psychiatric/Behavioral Disturbances

Psychiatric/behavioral disturbances (e.g., depression, mood) were dose-related for both the adjunctive epilepsy and migraine populations [see Warnings and Precautions (5.5)].

Somnolence/Fatigue

Somnolence and fatigue were the adverse reactions most frequently reported during clinical trials of topiramate for adjunctive epilepsy. For the adjunctive epilepsy population, the incidence of fatigue, appeared dose related. For the monotherapy epilepsy population, the incidence of somnolence was dose-related. For the migraine population, the incidences of both fatigue and somnolence were dose-related and more common in the titration phase.

Pediatric Patients

In pediatric epilepsy trials (adjunctive and monotherapy), the incidence of cognitive/neuropsychiatric adverse reactions was generally lower than that observed in adults. These reactions included psychomotor slowing, difficulty with concentration/attention, speech disorders/related speech problems, and language problems. The most frequently reported cognitive/neuropsychiatric reactions in pediatric epilepsy patients during adjunctive therapy double- blind studies were somnolence and fatigue. The most frequently reported cognitive/neuropsychiatric reactions in pediatric epilepsy patients in the 50 mg/day and 400 mg/day groups during the monotherapy double-blind study were headache, dizziness, anorexia, and somnolence.

In pediatric migraine patients, the incidence of cognitive/neuropsychiatric adverse reactions was increased in topiramate-treated patients compared to placebo.

The risk for cognitive/neuropsychiatric adverse reactions was dose-dependent, and was greatest at the highest dose (200 mg). This risk for cognitive/neuropsychiatric adverse reactions was also greater in younger patients (6 to 11 years of age) than in older patients (12 to 17 years of age). The most common cognitive/neuropsychiatric adverse reaction in these trials was difficulty with concentration/attention. Cognitive adverse reactions most commonly developed during titration and sometimes persisted for various durations after completion of titration.

The Cambridge Neuropsychological Test Automated Battery (CANTAB) was administered to adolescents (12 to 17 years) to assess the effects of topiramate on cognitive function at baseline and at the end of the Study 12 [see Clinical Studies (14.3)].

Mean change from baseline in certain CANTAB tests suggests that topiramate treatment may result in psychomotor slowing and decreased verbal fluency.

5.7 Fetal Toxicity

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 for cleft lip and/or cleft palate (oral clefts) and for being small for gestational age. When multiple species of pregnant animals received topiramate at clinically relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring [see Use in Specific Populations (8.1)].

Consider the benefits and the risks of topiramate when administering this drug in women of childbearing potential, particularly when topiramate is considered for a condition not usually associated with permanent injury or death [see Use in Specific Populations (8.8) Patient Counseling Information (17) ]. Topiramate should be used during pregnancy only if the potential benefit outweighs the potential risk. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1, 8.8)]

5.8 Withdrawal of Antiepileptic Drugs

In patients with or without a history of seizures or epilepsy, antiepileptic drugs, including topiramate, should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency [see Clinical Studies (14)]. In situations where rapid withdrawal of topiramate is medically required, appropriate monitoring is recommended.

5.9 Hyperammonemia and Encephalopathy (Without and With Concomitant

Valproic Acid Use)

Topiramate treatment can cause hyperammonemia with or without encephalopathy [see Adverse Reactions (6.2)]. The risk for hyperammonemia with topiramate appears dose-related. Hyperammonemia has been reported more frequently when topiramate is used concomitantly with valproic acid. Postmarketing cases of hyperammonemia with or without encephalopathy have been reported with topiramate and valproic acid in patients who previously tolerated either drug alone [see Drug Interactions (7.1)].

Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy and/or vomiting. In most cases, hyperammonemic encephalopathy abated with discontinuation of treatment.

The incidence of hyperammonemia in pediatric patients 12 to 17 years of age in migraine prophylaxis trials was 26% in patients taking topiramate monotherapy at 100 mg/day, and 14% in patients taking topiramate at 50 mg/day, compared to 9% in patients taking placebo. There was also an increased incidence of markedly increased hyperammonemia at the 100 mg dose.

Dose-related hyperammonemia was also seen in pediatric patients 1 to 24 months of age treated with topiramate and concomitant valproic acid for partial onset epilepsy and this was not due to a pharmacokinetic interaction.

In some patients, hyperammonemia can be asymptomatic.

Monitoring for Hyperammonemia

Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, topiramate treatment or an interaction of concomitant topiramate and valproic acid treatment may exacerbate existing defects or unmask deficiencies in susceptible persons.

In patients who develop unexplained lethargy, vomiting, or changes in mental status associated with any topiramate treatment, hyperammonemic encephalopathy should be considered and an ammonia level should be measured.

5.10 Kidney Stones

Topiramate increases the risk of kidney stones. During adjunctive epilepsy trials, the risk for kidney stones in topiramate-treated adults was 1.5%, an incidence about 2 to 4 times greater than expected in a similar, untreated population. As in the general population, the incidence of stone formation among topiramate-treated patients was higher in men. Kidney stones have also been reported in pediatric patients taking topiramate for epilepsy or migraine. During long-term (up to 1 year) topiramate treatment in an open- label extension study of 284 pediatric patients 1 month to 24 months old with epilepsy, 7% developed kidney or bladder stones. Topiramate is not approved for treatment of epilepsy in pediatric patients less than 2 years old [see Use in Specific Populations (8.4)].

Topiramate is a carbonic anhydrase inhibitor. Carbonic anhydrase inhibitors can promote stone formation by reducing urinary citrate excretion and by increasing urinary pH [see Warnings and Precautions (5.4)]. The concomitant use of topiramate with any other drug producing metabolic acidosis, or potentially in patients on a ketogenic diet, may create a physiological environment that increases the risk of kidney stone formation, and should therefore be avoided.

Increased fluid intake increases the urinary output, lowering the concentration of substances involved in stone formation. Hydration is recommended to reduce new stone formation.

5.11 Hypothermia with Concomitant Valproic Acid Use

Hypothermia, defined as a drop in body core temperature to < 35°C (95°F), has been reported in association with topiramate use with concomitant valproic acid both in conjunction with hyperammonemia and in the absence of hyperammonemia. This adverse reaction in patients using concomitant topiramate and valproate can occur after starting topiramate treatment or after increasing the daily dose of topiramate [see Drug Interactions (7.1)]. Consideration should be given to stopping topiramate or valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels.

The following serious adverse reactions are discussed in more detail in other sections of the labeling:

• Acute Myopia and Secondary Angle Closure Glaucoma [see Warnings and Precautions (5.1)]
• Visual Field Defects [see Warnings and Precautions (5.2)]
• Oligohidrosis and Hyperthermia [see Warnings and Precautions (5.3)]
• Metabolic Acidosis [see Warnings and Precautions (5.4)]
• Suicidal Behavior and Ideation [see Warnings and Precautions (5.5)]
• Cognitive/Neuropsychiatric Adverse Reactions [see Warnings and Precautions (5.6)]
• Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid [VPA] Use) [see Warnings and Precautions (5.9)]
• Kidney Stones [see Warnings and Precautions (5.10)]
• Hypothermia with Concomitant Valproic Acid (VPA) Use [see Warnings and Precautions (5.11)]

The data described in the following sections were obtained using Topiramate Tablets.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the incidence of adverse reactions observed in the clinical trials of a drug cannot be directly compared to the incidence of adverse reactions in the clinical trials of another drug, and may not reflect the incidence of adverse reactions observed in practice.

Monotherapy Epilepsy

Adults 16 Years of Age and Older

The most common adverse reactions in the controlled clinical trial that occurred in adults in the 400 mg/day topiramate group and at an incidence higher (≥ 10 %) than in the 50 mg/day group were: paresthesia, weight loss and anorexia (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 reactions. The most common (≥ 2% more frequent than low-dose 50 mg/day topiramate) adverse reactions causing discontinuation were difficulty with memory, fatigue, asthenia, insomnia, somnolence, and paresthesia.

Pediatric Patients 6 to 15 Years of Age

The most common adverse reactions in the controlled clinical trial that occurred in pediatric patients in the 400 mg/day topiramate group and at an incidence higher (≥ 10%) than in the 50 mg/day group were fever and weight loss (Table 5).

Approximately 14% of the 77 pediatric patients in the 400 mg/day group who received topiramate as monotherapy in the controlled clinical trial discontinued therapy due to adverse reactions. The most common (≥ 2% more frequent than low-dose 50 mg/day topiramate) adverse reactions resulting in discontinuation were difficulty with concentration/attention, fever, flushing, and confusion.

Table 5 presents the incidence of adverse reactions occurring in at least 3% of adult and pediatric patients treated with 400 mg/day topiramate and occurring with greater incidence than 50 mg/day topiramate.

Table 5 Adverse Reactions in the High Dose Group As Compared to the Low Dose Group, in Monotherapy Epilepsy Trials in Adult and Pediatric Patients

	** Age Group**
** Pediatric (6 to 15 Years)**	** Adult** ** (Age** ≥** 16 Years )**
** Topiramate Daily Dosage Group (mg/day)**
** 50**	** 400**	** 50**	** 400**
** Body System** Adverse Reaction	** (N=74) %**	** (N=77) %**	** (N=160)** ** %**	** (N=159)** ** %**
** Body as a Whole - General Disorders**
Asthenia	0	3	4	6
Fever	1	12
Leg pain			2	3
** Central & Peripheral Nervous System Disorders**
Paresthesia	3	12	21	40
Dizziness			13	14
Ataxia			3	4
Hypoesthesia			4	5
Hypertonia			0	3
Involuntary muscle contractions	0	3
Vertigo	0	3
** Gastro-Intestinal System Disorders**
Constipation			1	4
Diarrhea	8	9
Gastritis			0	3
Dry mouth			1	3
** Liver and Biliary System Disorders**
Increase Gamma-GT			1	3
** Metabolic and Nutritional Disorders**
Weight loss	7	17	6	17
** Platelet, Bleeding & Clotting Disorders**
Epistaxis	0	4
** Psychiatric Disorders**
Anorexia			4	14
Anxiety			4	6
Cognitive problems	1	6	1	4
Confusion	0	3
Depression	0	3	7	9
Difficulty with concentration/attention	7	10	7	8
Difficulty with memory	1	3	6	11
Insomnia			8	9
Decrease in libido			0	3
Mood problems	1	8	2	5
Personality disorder (behavior problems)	0	3
Psychomotor slowing			3	5
Somnolence			10	15
** Red Blood Cell Disorders**
Anemia	1	3
** Reproductive Disorders, Female**
Intermenstrual Bleeding	0	3
Vaginal Hemorrhage			0	3
** Resistance Mechanism Disorders**
Infection	3	8	2	3
Viral Infection	3	6	6	8
** Respiratory System Disorders**
Bronchitis	1	5	3	4
Upper respiratory tract infection	16	18
Rhinitis	5	6	2	4
Sinusitis	1	4
** Skin and Appendages Disorders**
Alopecia	1	4	3	4
Pruritus			1	4
Rash	3	4	1	4
Acne			2	3
** Special Senses Other, Disorders**
Taste perversion			3	5
** Urinary System Disorders**
Cystitis			1	3
Micturition frequency	0	3
Renal calculus			0	3
Urinary incontinence	1	3
** Vascular (Extracardiac) Disorders**
Flushing	0	5

Adjunctive Therapy Epilepsy

Adults 16 Years of Age and Older

In pooled controlled clinical trials in adults with partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, 183 patients received adjunctive therapy with

Topiramate at dosages of 200 to 400 mg/day (recommended dosage range) and 291 patients received placebo. Patients in these trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo.

The most common adverse reactions in the controlled clinical trial that occurred in adult patients in the 200 mg/day to 400 mg/day topiramate group with an incidence higher (≥ 10 %) than in the placebo group were: dizziness, speech disorders/related speech problems, somnolence, nervousness, psychomotor slowing, and vision abnormal (Table 6).

Table 6 presents the incidence of adverse reactions occurring in at least 3% of adult patients treated with 200 to 400 mg/day topiramate and was greater than placebo incidence. The incidence of some adverse reactions (e.g., fatigue, dizziness, paresthesia, language problems, psychomotor slowing, depression, difficulty with concentration/attention, mood problems) was dose- related and much greater at higher than recommended topiramate dosing (i.e., 600 mg to 1000 mg daily) compared to the incidence of these adverse reactions at the recommended dosing (200 mg to 400 mg daily) range.

Table 6 Most Common Adverse Reactions in Pooled Placebo-Controlled, Add-On Epilepsy Trials in Adultsa

aPatients in these add-on/adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo.
** Body System** Adverse Reaction	Placebo	Topiramate Dosage (mg/day) 200 to 400
	(N=291)	(N=183)
** Body as a Whole-General Disorders**
Fatigue	13	15
Asthenia	1	6
Back pain	4	5
Chest pain	3	4
Influenza-like symptoms	2	3
** Central & Peripheral Nervous System Disorders**
Dizziness	15	25
Ataxia	7	16
Speech disorders/Related speech problems	2	13
Paresthesia	4	11
Nystagmus	7	10
Tremor	6	9
Language problems	1	6
Coordination abnormal	2	4
Gait abnormal	1	3
** Gastro-Intestinal System Disorders**
Nausea	8	10
Dyspepsia	6	7
Abdominal pain	4	6
Constipation	2	4
** Metabolic and Nutritional Disorders**
Weight loss	3	9
** Psychiatric Disorders**
Somnolence	12	29
Nervousness	6	16
Psychomotor slowing	2	13
Difficulty with memory	3	12
Anorexia	4	10
Confusion	5	11
Difficulty with concentration/attention	2	6
Mood problems	2	4
Agitation	2	3
Aggressive reaction	2	3
Emotional lability	1	3
Cognitive problems	1	3
Breast pain	2	4
** Respiratory System Disorders**
Pharyngitis	2	6
Rhinitis	6	7
Sinusitis	4	5
** Vision Disorders**
Vision abnormal	2	13
Diplopia	5	10

In controlled clinical trials in adults, 11% of patients receiving topiramate 200 to 400 mg/day as adjunctive therapy discontinued due to adverse reactions. This rate appeared to increase at dosages above 400 mg/day. Adverse reactions associated with discontinuing topiramate included somnolence, dizziness, anxiety, difficulty with concentration or attention, fatigue, and paresthesia and increased at dosages above 400 mg/day.

Pediatric Patients 2 to 15 Years of Age

In pooled, controlled clinical trials in pediatric patients (2 to 15 years of age) with partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, 98 patients received adjunctive therapy with topiramate at dosages of 5 to 9 mg/kg/day (recommended dose range) and 101 patients received placebo.

The most common adverse reactions in the controlled clinical trial that occurred in pediatric patients in the 5 mg to 9 mg/kg/day topiramate group with an incidence higher (≥ 10 %) than in the placebo group were: fatigue and somnolence (Table 7).

Table 7 presents the incidence of adverse reactions that occurred in at least 3% of pediatric patients 2 to 15 years of age receiving 5 mg to 9 mg/kg/day (recommended dose range) of topiramate and was greater than placebo incidence.

Table 7 Adverse Reactions in Pooled Placebo-Controlled, Add-On Epilepsy Trials in Pediatric Patients 2 to 15 Years of Agea,b

a Patients in these add-on/adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo.
b Values represent the percentage of patients reporting a given adverse reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category.
** Body System/** Adverse Reaction	** Placebo**	** Topiramate**
	** (N=101)**	** (N=98)**
	** %**	** %**
** Body as a Whole - General Disorders**
Fatigue	5	16
Injury	13	14
** 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
** Gastro-Intestinal System Disorders**
Nausea	5	6
Saliva increased	4	6
Constipation	4	5
Gastroenteritis	2	3
** Metabolic and Nutritional Disorders**
Weight loss	1	9
** Platelet, Bleeding, & Clotting Disorders**
Purpura	4	8
Epistaxis	1	4
** 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	0	5
Confusion	3	4
Psychomotor slowing	2	3
** Resistance Mechanism Disorders**
Infection viral	3	7
** Respiratory System Disorders**
Pneumonia	1	5
** Skin and Appendages Disorders**
Skin disorder	2	3
** Urinary System Disorders**
Urinary incontinence	2	4

None of the pediatric patients who received topiramate adjunctive therapy at 5 to 9 mg/kg/day in controlled clinical trials discontinued due to adverse reactions.

Migraine

Adults

In the four multicenter, randomized, double-blind, placebo-controlled, parallel group migraine prophylaxis clinical trials (which included 35 pediatric patients 12 to 15 years of age), most adverse reactions occurred more frequently during the titration period than during the maintenance period.

The most common adverse reactions with topiramate 100 mg in migraine prophylaxis clinical trials of predominantly adults that were seen at an incidence higher (≥5 %) than in the placebo group were: paresthesia, anorexia, weight loss, taste perversion, diarrhea, difficulty with memory, hypoesthesia, and nausea (see Table 8).

Table 8 includes those adverse reactions that occurred in the placebo- controlled trials where the incidence in any topiramate treatment group was at least 3% and was greater than that for placebo patients. The incidence of some adverse reactions (e.g., fatigue, dizziness, somnolence, difficulty with memory, difficulty with concentration/attention) was dose-related and greater at higher than recommended topiramate dosing (200 mg daily) compared to the incidence of these adverse reactions at the recommended dosing (100 mg daily).

Table 8 Adverse Reactions in Pooled, Placebo-Controlled, Migraine Trials in Adultsab

a Includes 35 adolescent patients age 12 to 15 years.
b Values represent the percentage of patients reporting a given adverse reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category.
c Blurred vision was the most common term considered as vision abnormal. Blurred vision was an included term that accounted for >50% of reactions coded as vision abnormal, a preferred term.
** Body System** / Adverse Reaction		Topiramate Dosage (mg/day)
Placebo (N=445) %	50 (N=235) %	100 (N=386) %
** Body as a Whole-General Disorders**
Fatigue	11	14	15
Injury	7	9	6
** Central & Peripheral Nervous System Disorders**
Paresthesia	6	35	51
Dizziness	10	8	9
Hypoesthesia	2	6	7
Language problems	2	7	6
** Gastro-Intestinal System Disorders**
Nausea	8	9	13
Diarrhea	4	9	11
Abdominal pain	5	6	6
Dyspepsia	3	4	5
Dry mouth	2	2	3
Gastroenteritis	1	3	3
** Metabolic and Nutritional Disorders**
Weight loss	1	6	9
** Musculoskeletal System Disorders**
Arthralgia	2	7	3
** Psychiatric Disorders**
Anorexia	6	9	15
Somnolence	5	8	7
Difficulty with memory	2	7	7
Insomnia	5	6	7
Difficulty with concentration/ attention	2	3	6
Mood problems	2	3	6
Anxiety	3	4	5
Depression	4	3	4
Nervousness	2	4	4
Confusion	2	2	3
Psychomotor slowing	1	3	2
** Reproductive Disorders, Female**
Menstrual disorder	2	3	2
** Reproductive Disorders, Male**
Ejaculation premature	0	3	0
** Resistance Mechanism Disorders**
Viral infection	3	4	4
** Respiratory System Disorders**
Upper respiratory tract infection	12	13	14
Sinusitis	6	10	6
Pharyngitis	4	5	6
Coughing	2	2	4
Bronchitis	2	3	3
Dyspnea	2	1	3
** Skin and Appendages Disorders**
Pruritis	2	4	2
** Special Sense Other, Disorders**
Taste perversion	1	15	8
** Urinary System Disorders**
Urinary tract infection	2	4	2
** Vision Disorders**
Blurred visionc	2	4	2

Of the 1,135 patients exposed to topiramate in the adult placebo-controlled studies, 25% of topiramate-treated patients discontinued due to adverse reactions, compared to 10% of the 445 placebo-treated patients. The adverse reactions 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.

Pediatric Patients 12 to 17 Years of Age

In five, randomized, double-blind, placebo-controlled, parallel group migraine prophylaxis clinical trials, most adverse reactions occurred more frequently during the

titration period than during the maintenance period. Among adverse reactions with onset during titration, approximately half persisted into the maintenance period.

In four, fixed-dose, double-blind migraine prophylaxis clinical trials in topiramate-treated pediatric patients 12 to 17 years of age, the most common adverse reactions with topiramate 100 mg that were seen at an incidence higher (≥5%) than in the placebo group were: paresthesia, upper respiratory tract infection, anorexia, and abdominal pain (see Table 9). Table 9 shows adverse reactions from the pediatric trial (Study 12 [see Clinical Studies (14.3)]) in which 103 pediatric patients were treated with placebo or 50 mg or 100 mg of topiramate, and three predominantly adult trials in which 49 pediatric patients (12 to 17 years of age) were treated with placebo or 50 mg, 100 mg or 200 mg of topiramate. Table 9 also shows adverse reactions in pediatric patients in the controlled migraine trials when the incidence in a topiramate dose group was at least 5 % or higher and greater than the incidence of placebo. Many adverse reactions shown in Table 9 indicate a dose-dependent relationship. The incidence of some adverse reactions (e.g., allergy, fatigue, headache, anorexia, insomnia, somnolence, and viral infection) was dose- related and greater at higher than recommended topiramate dosing (200 mg daily) compared to the incidence of these adverse reactions at the recommended dosing (100 mg daily).

Table 9 Adverse Reactions in Pooled Double-Blind Migraine Prophylaxis Studies in Pediatric Patients 12 to 17 Years of Agea,b,c

a 35 adolescent patients aged 12 to <16 years were also included in adverse reaction assessment for adults (Tables 10 and 11)
b Incidence is based on the number of subjects experiencing at least 1 adverse event, not the number of events.
c Included studies MIG-3006, MIGR-001, MIGR-002 and MIGR-003
		** Topiramate Dosage**
** Body System/**	** Placebo**	** 50 mg/day**	** 100 mg/day**
Adverse Reaction	** (N=45)**	** (N=46)**	** (N=48)**
	** %**	** %**	** %**
** Body as a Whole – General Disorders**
Fatigue	7	7	8
Fever	2	4	6
** Central & Peripheral Nervous System Disorders**
Paresthesia	7	20	19
Dizziness	4	4	6
** Gastrointestinal System Disorders**
Abdominal pain	9	7	15
Nausea	4	4	8
** Metabolic and Nutritional Disorders**
Weight loss	2	7	4
** Psychiatric Disorders**
Anorexia	4	9	10
Insomnia	2	9	2
Somnolence	2	2	6
** Resistance Mechanism Disorders**
Infection viral	4	4	8
** Respiratory System Disorders**
Upper respiratory tract infection	11	26	23
Rhinitis	2	7	6
Sinusitis	2	9	4
Coughing	0	7	2
** Special Senses Other, Disorders**
Taste perversion	2	2	6
** Vision Disorders**
Conjunctivitis	4	7	4

In the double-blind placebo-controlled studies, adverse reactions led to discontinuation of treatment in 8% of placebo patients compared with 6% of topiramate-treated patients. Adverse reactions associated with discontinuing therapy that occurred in more than one topiramate-treated patient were fatigue (1%), headache (1%), and somnolence (1%).

Increased Risk for Bleeding

Topiramate is associated with an increased risk for bleeding. In a pooled analysis of placebo-controlled studies of approved and unapproved indications, bleeding was more frequently reported as an adverse reaction for topiramate than for placebo (4.5% versus 3.0% in adult patients, and 4.4% versus 2.3% in pediatric patients). In this analysis, the incidence of serious bleeding events for topiramate and placebo was 0.3% versus 0.2% for adult patients, and 0.4% versus 0% for pediatric patients.

Adverse bleeding reactions reported with topiramate ranged from mild epistaxis, ecchymosis, and increased menstrual bleeding to life-threatening hemorrhages. In patients with serious bleeding events, conditions that increased the risk for bleeding were often present, or patients were often taking drugs that cause thrombocytopenia (other antiepileptic drugs) or affect platelet function or coagulation (e.g., aspirin, nonsteroidal anti- inflammatory drugs, selective serotonin reuptake inhibitors, or warfarin or other anticoagulants).

Other Adverse Reactions Observed During Clinical Trials

Other adverse reactions seen during clinical trials were: abnormal coordination, eosinophilia, gingival bleeding, hematuria, hypotension, myalgia, myopia, postural hypotension, scotoma, suicide attempt, syncope, and visual field defect.

Laboratory Test Abnormalities

Adult Patients

In addition to changes in serum bicarbonate (i.e., metabolic acidosis), sodium chloride and ammonia, topiramate was associated with changes in several clinical laboratory analytes in randomized, double-blind, placebo-controlled studies [see Warnings and Precautions (5.4, 5.9)]. Controlled trials of adjunctive topiramate treatment of adults for partial onset seizures showed an increased incidence of markedly decreased serum phosphorus (6% topiramate versus 2% placebo), markedly increased serum alkaline phosphatase (3% topiramate versus 1% placebo), and decreased serum potassium (0.4 % topiramate versus 0.1 % placebo).

Pediatric Patients

In pediatric patients (1 month to 24 months) receiving adjunctive topiramate for partial onset seizures, there was an increased incidence for an increased result (relative to normal analyte reference range) associated with topiramate (vs. placebo) for the following clinical laboratory analytes: creatinine, BUN, alkaline phosphatase, and total protein, The incidence was also increased for a decreased result for bicarbonate (i.e., metabolic acidosis), and potassium with topiramate (vs. placebo) [see Use in Specific Populations (8.4)]. Topiramate is not indicated for partial onset seizures in pediatric patients less than 2 years of age.

In pediatric patients (ranging from 6 years to 17 years old) receiving topiramate for migraine prophylaxis, there was an increased incidence for an increased result (relative to normal analyte reference range) associated with topiramate (vs. placebo) for the following clinical laboratory analytes: creatinine, BUN, uric acid, chloride, ammonia, alkaline phosphatase, total protein, platelets, and eosinophils, The incidence was also increased for a decreased result for phosphorus, bicarbonate, total white blood count, and neutrophils [see Use in Specific Populations (8.4)]. Topiramate is not indicated for prophylaxis of migraine headache in pediatric patients less than 12 years of age.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of topiramate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

**Body as a Whole-General Disorders:**oligohydrosis and hyperthermia [see Warnings and Precautions (5.3)], hyperammonemia, hyperammonemic encephalopathy [see Warnings and Precautions (5.9)], hypothermia with concomitant valproic acid [see Warnings and Precautions (5.11)]

**Gastrointestinal System Disorders:**hepatic failure (including fatalities), hepatitis, pancreatitis

**Skin and Appendage Disorders:**bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), pemphigus

**Urinary System Disorders:**kidney stones [see Warnings and Precautions (5.10)]

**Vision Disorders:**acute myopia, secondary angle closure glaucoma [see Warnings and Precautions (5.1)], maculopathy

Hematological Disorders: decrease of the International Normalized Ratio (INR) or prothrombin time when given concomitantly with vitamin K antagonist anticoagulant medications such as warfarin.

7 DRUG INTERACTIONS

7.1 Antiepileptic Drugs

Concomitant administration of phenytoin or carbamazepine with topiramate resulted in a clinically significant decrease in plasma concentrations of topiramate when compared to topiramate given alone. A dosage adjustment may be needed [see Dosage and Administration (2.1), Clinical Pharmacology (12.3).]

Concomitant administration of valproic acid and topiramate has been associated with hypothermia and hyperammonemia with and without encephalopathy. Examine blood ammonia levels in patients in whom the onset of hypothermia has been reported [see Warnings and Precautions (5.9, 5.11) and Clinical Pharmacology (12.3)].

7.2 CNS Depressants

Concomitant administration of topiramate 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 reactions, topiramate should be used with extreme caution if used in combination with alcohol and other CNS depressants.

7.3 Oral Contraceptives

The possibility of decreased contraceptive efficacy and increased breakthrough bleeding may occur in patients taking combination oral contraceptive products with topiramate. 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 [see Clinical Pharmacology (12.3)].

7.4 Lithium

An increase in systemic exposure of lithium following topiramate doses of up to 600 mg/day can occur. Lithium levels should be monitored when co- administered with high-dose topiramate [see Clinical Pharmacology (12.3)].

7.5 Other Carbonic Anhydrase Inhibitors

Concomitant use of topiramate, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., zonisamide or acetazolamide) may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Therefore, patients given topiramate concomitantly with another carbonic anhydrase inhibitor should be monitored particularly closely for the appearance or worsening of metabolic acidosis [see Clinical Pharmacology (12.3)].

7.6 Hydrochlorothiazide (HCTZ)

Topiramate Cmax and AUC increased when HCTZ was added to topiramate. The clinical significance of this change is unknown. The addition of HCTZ to topiramate may require a decrease in the topiramate dose [see Clinical Pharmacology (12.3)].

7.7 Pioglitazone

A decrease in the exposure of pioglitazone and its active metabolites were noted with the concurrent use of pioglitazone and topiramate in a clinical trial. The clinical relevance of these observations is unknown; however, when topiramate is added to pioglitazone therapy or pioglitazone is added to topiramate therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state [see Clinical Pharmacology (12.3)].

7.8 Amitriptyline

Some patients 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 [see Clinical Pharmacology (12.3)].

8.1 Pregnancy

Pregnancy Category D.[see Warnings and Precautions (5.7)]

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 for cleft lip and/or cleft palate (oral clefts) and for being small for gestational age. When multiple species of pregnant animals received topiramate at clinically relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring. Topiramate should be used during pregnancy only if the potential benefit outweighs the potential risk. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.8)].

Pregnancy Registry

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

http://www.aedpregnancyregistry.org/.

Human Data

Data from pregnancy registries indicate an increased risk of oral clefts in infants exposed to topiramate during the first trimester of pregnancy. In the NAAED pregnancy registry, the prevalence of oral clefts among topiramate- exposed infants (1.1%) was higher than the prevalence of infants exposed to a reference AED (0.36%) or the prevalence of infants in mothers without epilepsy and without exposure to AEDs (0.12%). 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 9.6 (95% Confidence Interval [CI] 4 to 23) as compared to the risk in a background population of untreated women. The UK Epilepsy and Pregnancy 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 small for gestational age (SGA) newborns (birth weight <10th percentile). In the 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.

Topiramate treatment can cause metabolic acidosis [see Warnings and Precautions (5.4)]. 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 [see Warnings and Precautions (5.4)]. 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.

Animal Data

Topiramate has demonstrated selective developmental toxicity, including teratogenicity, in multiple animal species at clinically relevant doses. When oral doses of 20, 100 or 500 mg/kg were administered to pregnant mice during the period of organogenesis, the incidence of fetal malformations (primarily craniofacial defects) was increased at all doses. The low dose is approximately 0.2 times the recommended human dose (RHD) 400 mg/day on a mg/m2basis. Fetal body weights and skeletal ossification were reduced at 500 mg/kg in conjunction with decreased maternal body weight gain.

In rat studies (oral doses of 20, 100, and 500 mg/kg or 0.2, 2.5, 30, and 400 mg/kg), the frequency of limb malformations (ectrodactyly, micromelia, and amelia) was increased among the offspring of dams treated with 400 mg/kg (10 times the RHD on a mg/m2basis) or greater during the organogenesis period of pregnancy. Embryotoxicity (reduced fetal body weights, increased incidence of structural variations) was observed at doses as low as 20 mg/kg (0.5 times the RHD on a mg/m2basis). Clinical signs of maternal toxicity were seen at 400 mg/kg and above, and maternal body weight gain was reduced during treatment with 100 mg/kg or greater.

In rabbit studies (20, 60, and 180 mg/kg or 10, 35, and 120 mg/kg orally during organogenesis), embryo/fetal mortality was increased at 35 mg/kg (2 times the RHD on a mg/m2basis) or greater, and teratogenic effects (primarily rib and vertebral malformations) were observed at 120 mg/kg (6 times the RHD on a mg/m2basis). Evidence of maternal toxicity (decreased body weight gain, clinical signs, and/or mortality) was seen at 35 mg/kg and above.

When female rats were treated during the latter part of gestation and throughout lactation (0.2, 4, 20, and 100 mg/kg or 2, 20, and 200 mg/kg), offspring exhibited decreased viability and delayed physical development at 200 mg/kg (5 times the RHD on a mg/m2basis) and reductions in pre-and/or postweaning body weight gain at 2 mg/kg (0.05 times the RHD on a mg/m2 basis) and above. Maternal toxicity (decreased body weight gain, clinical signs) was evident at 100 mg/kg or greater.

In a rat embryo/fetal development study with a postnatal component (0.2, 2.5, 30, or 400 mg/kg during organogenesis; noted above), pups exhibited delayed physical development at 400 mg/kg (10 times the RHD on a mg/m2basis) and persistent reductions in body weight gain at 30 mg/kg (1 times the RHD on a mg/m2basis) and higher.

8.2 Labor and Delivery

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 [see Use in Specific Populations (8.1)].

8.3 Nursing Mothers

Limited data on 5 breastfeeding infants exposed to topiramate showed infant plasma topiramate levels equal to 10 to 20% of the maternal plasma level. The effects of this exposure on infants are unknown. Caution should be exercised when administered to a nursing woman.

8.4 Pediatric Use

Adjunctive Treatment for Partial Onset Epilepsy in Pediatric Patients 1 to 24 months

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 1 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 1 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 [see Adverse Reactions (6)].

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. The significance of these findings is uncertain.

Topiramate produced a dose-related increased incidence of hyperammonemia [see Warnings and Precautions (5.9)].

Treatment with topiramate for up to 1 year was associated with reductions in Z SCORES for length, weight, and head circumference. [see Warnings and Precautions (5.4), Adverse Reactions (6)].

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) [see Warnings and Precautions (5.6)].

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.

Monotherapy Treatment in Partial Onset Epilepsy in Patients < 2 Years Old

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

Migraine Prophylaxis in Pediatric Patients 12 to 17 Years of Age

Safety and effectiveness of topiramate in the prophylaxis of migraine was studied in 5 double-blind, randomized, placebo-controlled, parallel-group trials in a total of 219 pediatric patients, at doses of 50 to 200 mg/day, or 2 to 3 mg/kg/day. These comprised a fixed dose study in 103 pediatric patients 12 to 17 years of age [see Clinical Studies (14.3)], a flexible dose (2 to 3 mg/kg/day), placebo-controlled study in 157 pediatric patients 6 to 16 years of age (including 67 pediatric patients 12 to 16 years of age), and a total of 49 pediatric patients 12 to 17 years of age in 3 studies of migraine prophylaxis 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 migraine prophylaxis in pediatric patients 12 to 17 years of age is demonstrated for a 100 mg daily dose in Study 12 [see Clinical Studies (14.3)]. Efficacy of topiramate (2 to 3 mg/kg/day) for migraine prophylaxis 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 [see Adverse Reactions (6)].

The most common cognitive adverse reaction in pooled double-blind studies in pediatric patients 12 to 17 years of age was difficulty with concentration/attention [see Warnings and Precautions (5.6)].

Markedly abnormally low serum bicarbonate values indicative of metabolic acidosis were reported in topiramate-treated pediatric migraine patients [see Warnings and Precautions (5.4)].

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 [see Warnings and Precautions (5.12)].

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 [see Clinical Pharmacology (12.2)].

Migraine Prophylaxis in Pediatric Patients 6 to 11 Years of Age

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

In a double-blind study in 90 pediatric patients 6 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 12 to 17 years of age. The most common adverse reactions that occurred in topiramate-treated pediatric patients 6 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%) and 0 placebo-treated patients.

The risk for cognitive adverse reaction was greater in younger patients (6 to 11 years of age) than in older patients (12 to 17 years of age) [see Warnings and Precautions (5.6)].

Juvenile Animal Studies

When topiramate (30, 90, or 300 mg/kg/day) was administered orally to rats during the juvenile period of development (postnatal days 12 to 50), bone growth plate thickness was reduced in males at the highest dose, which is approximately 5 to 8 times the maximum recommended pediatric dose (9 mg/kg/day) on a body surface area (mg/m2) basis.

8.5 Geriatric Use

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 65 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 m2) resulting in reduced clearance [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)].

8.6 Renal Impairment

The clearance of topiramate is reduced in patients with moderate (creatinine clearance 30 to 69 mL/min/1.73 m2) and severe (creatinine clearance <30 mL/min/1.73 m2) renal impairment. A dosage adjustment is recommended in patients with moderate or severe renal impairment [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)].

8.7 Patients Undergoing Hemodialysis

Topiramate is cleared by hemodialysis at a rate that is 4 to 6 times greater than in a normal individual. A dosage adjustment may be required [see Dosage and Administration (2.6), Clinical Pharmacology (12.3)].

8.8 Women of Childbearing Potential

Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk for cleft lip and/or cleft palate (oral clefts) [see Warnings and Precautions (5.7) and Use in Specific Populations (8.1)]. Consider the benefits and the 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 before many women know they are pregnant, all women of childbearing potential should be apprised of the potential hazard to the fetus from exposure to topiramate. If the decision is made to use topiramate, women who are not planning a pregnancy should use effective contraception [see Drug Interactions (7.3)]. 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.

MEDICATION GUIDE

Topiramate (toe-PIR-a-mate) Tablets, USP

Topiramate (toe-PIR-a-mate) Capsules, USP

What is the most important information I should know about Topiramate?

**Topiramate may cause eye problems.**Serious eye problems include:

• any sudden decrease in vision with or without eye pain and redness.
• a blockage of fluid in the eye causing increased pressure in the eye (secondary angle closure glaucoma).
• These eye problems can lead to permanent loss of vision if not treated.
• You should call your healthcare provider right away if you have any new eye symptoms, including any new problems with your vision.

**Topiramate****may cause decreased sweating and increased body temperature (fever).**People, especially children, should be watched for signs of decreased sweating and fever, especially in hot temperatures. Some people may need to be hospitalized for this condition. If a high fever, a fever that does not go away, or decreased sweating develops, call your healthcare provider right away.

Topiramate******can increase the level of acid in your blood (metabolic acidosis).**If left untreated, metabolic acidosis can cause brittle or soft bones (osteoporosis, osteomalacia, osteopenia), kidney stones, can slow the rate of growth in children, and may possibly harm your baby if you are pregnant. Metabolic acidosis can happen with or without symptoms. Sometimes people with metabolic acidosis will:

• feel tired
• not feel hungry (loss of appetite)
• feel changes in heartbeat
• have trouble thinking clearly

Your healthcare provider should do a blood test to measure the level of acid in your blood before and during your treatment with topiramate. If you are pregnant, you should talk to your healthcare provider about whether you have metabolic acidosis.

*Like other antiepileptic drugs, topiramate may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.

Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:

• thoughts about suicide or dying
• attempts to commit suicide
• new or worse depression
• new or worse anxiety
• feeling agitated or restless
• panic attacks
• trouble sleeping (insomnia)
• new or worse irritability
• acting aggressive, being angry, or violent
• acting on dangerous impulses
• an extreme increase in activity and talking (mania)
• other unusual changes in behavior or mood

Do not stop topiramate without first talking to a healthcare provider.

• Stopping topiramate suddenly can cause serious problems.
• Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.

How can I watch for early symptoms of suicidal thoughts and actions?

• Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
• Keep all follow-up visits with your healthcare provider as scheduled.
• Call your healthcare provider between visits as needed, especially if you are worried about symptoms.

Topiramate can harm your unborn baby.

• If you take topiramate during pregnancy, your baby has a higher risk for birth defects called cleft lip and cleft palate. These defects can begin early in pregnancy, even before you know you are pregnant.
• Cleft lip and cleft palate may happen even in children born to women who are not taking any medicines and do not have other risk factors.
• There may be other medicines to treat your condition that have a lower chance of birth defects.
• All women of childbearing age should talk to their healthcare providers about using other possible treatments instead of topiramate. If the decision is made to use topiramate, you should use effective birth control (contraception) unless you are planning to become pregnant. You should talk to your doctor about the best kind of birth control to use while you are taking topiramate.
• Tell your healthcare provider right away if you become pregnant while taking topiramate. You and your healthcare provider should decide if you will continue to take topiramate while you are pregnant.
• If you take topiramate during pregnancy, your baby may be smaller than expected at birth. The long-term effects of this are not known.Talk to your healthcare provider if you have questions about this risk during pregnancy.
• Metabolic acidosis may have harmful effects on your baby. Talk to your healthcare provider if topiramate has caused metabolic acidosis during your pregnancy.
• Pregnancy Registry: If you become pregnant while taking topiramate, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of topiramate and other antiepileptic drugs during pregnancy.

What is topiramate?

Topiramate is a prescription medicine used:

• to treat certain types of seizures (partial onset seizures and primary generalized tonic-clonic seizures) in adults and children 2 years and older,
• with other medicines to treat certain types of seizures (partial onset seizures, primary generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome) in adults and children 2 years and older.
• to prevent migraine headaches in adults and adolescents 12 years and older.

Before taking topiramate, tell your healthcare provider about all of your medical conditions, including if you:

• have or have had depression, mood problems, or suicidal thoughts or behavior.
• have kidney problems, have kidney stones, or are getting kidney dialysis.
• have a history of metabolic acidosis (too much acid in the blood).
• have liver problems.
• have weak, brittle, or soft bones (osteomalacia, osteoporosis, osteopenia, or decreased bone density).
• have lung or breathing problems.
• have eye problems, especially glaucoma.
• have diarrhea.
• have a growth problem.
• are on a diet high in fat and low in carbohydrates, which is called a ketogenic diet.
• are having surgery.
• are pregnant or plan to become pregnant.
• are breastfeeding or plan to breastfeed. Topiramate passes into breast milk. It is not known if the topiramate that passes into breast milk can harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take topiramate.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Topiramate and other medicines may affect each other causing side effects.

Especially tell your healthcare provider if you take:

• Valproic acid (such as DEPAKENE®or DEPAKOTE®).
• any medicines that impair or decrease your thinking, concentration, or muscle coordination.
• birth control pills. Topiramate may make your birth control pills less effective. Tell your healthcare provider if your menstrual bleeding changes while you are taking birth control pills and topiramate.

Ask your healthcare provider if you are not sure if your medicine is listed above.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist each time you get a new medicine. Do not start a new medicine without talking with your healthcare provider.

How should I take topiramate?

• Take topiramate exactly as prescribed.
• Your healthcare provider may change your dose.Do not change your dose without talking to your healthcare provider.
• Take topiramate tablets whole.Do not chew the tablets. They may leave a bitter taste.
• Topiramate capsules may be swallowed whole or may be opened and sprinkled on a teaspoon of soft food. Drink fluids right after eating the food and medicine mixture to make sure it is all swallowed.Do not chew the food and medicine mixture. *Do not store any medicine and food mixture for later use.
• Topiramate can be taken before, during, or after a meal. Drink plenty of fluids during the day. This may help prevent kidney stones while taking topiramate.
• If you take too much topiramate, call your healthcare provider right away or go to the nearest emergency room.
• If you miss a single dose of topiramate, take it as soon as you can. However, if you are within 6 hours of taking your next scheduled dose, wait until then to take your usual dose of topiramate, and skip the missed dose.Do not double your dose. If you have missed more than one dose, you should call your healthcare provider for advice. *Do not stop taking topiramate without talking to your healthcare provider. Stopping topiramate suddenly may cause serious problems. If you have epilepsy and you stop taking topiramate suddenly, you may have seizures that do not stop. Your healthcare provider will tell you how to stop taking topiramate slowly.
• Your healthcare provider may do blood tests while you take topiramate.

What should I avoid while taking topiramate?

• You should not drink alcohol while taking topiramate. Topiramate and alcohol can affect each other causing side effects such as sleepiness and dizziness.
• Do not drive a car or operate machinery until you know how topiramate affects you. Topiramate can slow your thinking and motor skills, and may affect vision.

What are the possible side effects of topiramate?

Topiramate may cause serious side effects including:

See "What is the most important information I should know about topiramate?"

*High blood ammonia levels. High ammonia in the blood can affect your mental activities, slow your alertness, make you feel tired, or cause vomiting. This has happened when topiramate is taken with a medicine called valproic acid (DEPAKENE®and DEPAKOTE®). *Effects on thinking and alertness. Topiramate may affect how you think and cause confusion, problems with concentration, attention, memory, or speech. Topiramate may cause depression or mood problems, tiredness, and sleepiness. *Dizziness or loss of muscle coordination. *Kidney stones. Drink plenty of fluids when taking topiramate to decrease your chances of getting kidney stones. *Low body temperature. Taking topiramate when you are also taking valproic acid can cause a drop in body temperature to less than 95○F, feeling tired, confusion, or coma.

Call your healthcare provider right away if you have any of the symptoms above.

The most common side effects of topiramate include:

• tingling of the arms and legs (paresthesia)
• not feeling hungry
• nausea
• a change in the way foods taste
• diarrhea
• weight loss
• nervousness
• upper respiratory tract infection
• speech problems
• tiredness
• dizziness
• sleepiness/drowsiness
• slow reactions
• difficulty with memory
• pain in the abdomen
• fever
• abnormal vision
• decreased feeling or sensitivity, especially in the skin

Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all the possible side effects of topiramate.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store topiramate?

• Store topiramate at 20o to 25o C (68o to 77o F) [See USP Controlled Room Temperature].
• Keep topiramate in a tightly closed container.
• Keep topiramate dry and away from moisture. Keep**topiramate*** and all medicines out of the reach of children.**

General information about the safe and effective use topiramate.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use topiramate for a condition for which it was not prescribed. Do not give topiramate to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about topiramate that is written for health professionals.

Please address medical inquiries to, MedicalAffairs@zydususa.com or Tel.: 1-877-993-8779.

What are the ingredients in topiramate?

Topiramate Tablets, USP

Active ingredient: topiramate, USP

Inactive ingredients: colloidal silicon dioxide, hypromellose, lactose anhydrous, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, talc and titanium dioxide.

Topiramate Capsules, USP

Active ingredient: topiramate, USP

Inactive ingredients: cellulose acetate, gelatin, hypromellose, povidone, sodium lauryl sulfate, sugar spheres, talc and titanium dioxide.

DEPAKENE® and DEPAKOTE® are registered trademarks of Abbott Laboratories.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

This product's label may have been updated. For current full prescribing information, please visit www.zydususa.com.