ADVERSE REACTIONS, Post-Market Adverse Drug Reactions

Caution should be used when topiramate 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. (See

)

Metabolic Acidosis

Hyperchloremic, non-anion gap, metabolic acidosis (i.e. decreased serum bicarbonate below the normal reference range in the absence of respiratory alkalosis) is associated with topiramate treatment. This decrease in serum bicarbonate is due to the inhibitory effect of topiramate on renal carbonic anhydrase. Generally, the decrease in bicarbonate occurs early in treatment although it can occur at any time during treatment. These decreases are usually mild to moderate (average decrease of 4 mmol/L at doses of 100 mg/day or above in adults and at approximately 6 mg/kg/day in pediatric patients). Rarely, patients have experienced decreases to values below 10 mmol/L. Conditions or therapies that predispose to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, surgery, ketogenic diet, or certain 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 mmol/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 a markedly abnormally low serum bicarbonate (i.e., absolute value <17 mmol/L and >5 mmol/L decrease from pretreatment) in these trials was 3% for 400 mg/day, and 0% for placebo. 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 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 mmol/L and >5 mmol/L decrease from pretreatment) in these trials was 11% for topiramate 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. The incidence of persistent treatment-emergent decreases in serum bicarbonate in placebo-controlled trials for adults for prophylaxis of migraines 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 mmol/L and >5 mmol/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. Safety and effectiveness in patients below the age of 2 years have not been established. Topiramate is associated with metabolic acidosis. Chronic untreated metabolic acidosis in pediatric patients may cause osteomalacia (rickets) and may 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. Chronic metabolic acidosis in pediatric patients can reduce growth rates. The effect of topiramate on growth and bone-related sequelae has not been systematically investigated in pediatric or adult populations. 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.

Decreases in Serum Potassium with Concomitant Treatment with Hydrochlorothiazide (HCTZ)

In a drug interaction study. a greater decrease from baseline in serum potassium values was seen with concomitant treatment than for either drug alone. At the end of each treatment period, 27% (3/12) of

subjects on topiramate treatment alone and 25% (3/12) of subjects on HCTZ treatment alone showed a serum potassium value of <3.6 mEq/L, compared to 61% (14/23) of subjects on concomitant drug treatment. One of the subjects who had hypokalemia with concomitant treatment also had an abnormal ECG (nonspecific ST-T wave changes), which may have been related to the decrease in plasma potassium levels. Caution should be used when treating patients who are receiving topiramate and hydrochlorothiazide concomitantly. (See DRUG INTERACTIONS).

Nutritional Supplementation

A dietary supplement or increased food intake may be considered if the patient is losing weight while on this medication.

Hepatic/Biliary/pancreatic

Decreased Hepatic Function

In hepatically impaired patients, topiramate should be administered with caution as the clearance of topiramate was decreased compared with normal subjects.

Neurologic

Central Nervous System Effects

Adverse events most often associated with the use of topiramate were central nervous system-related and were observed in both epilepsy and migraine populations. In adults, the most significant of these can be classified into three general categories:

1. psychomotor slowing, difficulty with concentration and speech or language problems, in particular, word-finding difficulties,

2. somnolence or fatigue and

3. mood disturbances including irritability and depression.

In the controlled epilepsy adjunctive therapy trials, these events were generally mild to moderate, and generally occurred early in therapy. While the incidence of psychomotor slowing does not appear to be dose related, both language problems and difficulty with concentration or attention increased in frequency with increasing dosage in the six double-blind trials, suggesting that these events are dose related. (See ADVERSE REACTIONS, Post-Market Adverse Drug Reactions). Central nervous system and psychiatric-related events were also more frequently reported in topiramate-treated subjects in the migraine prophylaxis trials. These included: anorexia, dizziness, difficulty with memory, somnolence, language problems, and difficulty with concentration and attention. Most of the events were mild or moderate in severity, some of which led to withdrawal from treatment. (See ADVERSE REACTIONS, MIGRAINE).

In the double-blind phases of clinical trials with topiramate in approved and investigational indications, suicide attempts occurred at an incidence of 0.2% (13 reports/7,999 patients) on topiramate versus 0% (0 reports/3,150 patients) on placebo. One completed suicide was reported in a bipolar disorder trial in a patient on topiramate (see ADVERSE REACTIONS, Less Common Clinical Trial Adverse Drug Reactions (<2%) and Post-Market Adverse Drug Reactions). Additional nonspecific CNS effects occasionally observed with topiramate as add-on epilepsy therapy include dizziness or imbalance, confusion and memory problems. Although the duration of the epilepsy monotherapy studies was considerably longer than the epilepsy adjunctive therapy studies, these adverse events were reported at lower incidences in the monotherapy trials.

Paresthesia

Paresthesia, an effect associated with the use of other carbonic anhydrase inhibitors, appears to be a common effect of topiramate. Paresthesia was more frequently reported in the migraine prophylaxis and epilepsy monotherapy trials versus the adjunctive therapy trials in epilepsy. The higher incidence in the epilepsy monotherapy studies may have been related to the higher topiramate plasma concentrations achieved in the monotherapy studies. In the majority of instances, paresthesia did not lead to treatment discontinuation.

Ophthalmologic

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 a few days to 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 judgement of the treating physician. Other measures, in conjunction with discontinuation of topiramate, may be helpful (see ADVERSE REACTIONS, Post Market Adverse Drug Reactions). In all cases of acute visual blurring and/or painful/red eye(s), immediate consultation with an ophthalmologist/emergency room is recommended. levated intraocular pressure of any etiology, if left untreated, can lead to serious sequalae including permanent vision loss.

Renal

Kidney Stones

A total of 32/1,715 (1.5%) of patients exposed to topiramate during its epilepsy adjunctive therapy development reported the occurrence of kidney stones, an incidence about 10 times that expected in a similar, untreated population (M/F ratio: 27/1,092 male; 5/623 female). In double-blind epilepsy monotherapy studies, a total of 8/886 (0.9%) of adults reported the occurrence of kidney stones. In the general population, risk factors for kidney stone formation include gender (male), ages between 20-50 years, prior stone formation, family history of nephrolithiasis, and hypercalciuria. Based on logistic regression analysis of the clinical trial data, no correlation between mean topiramate dosage, duration of topiramate therapy, or age and the occurrence of kidney stones was established; of the risk factors evaluated, only gender (male) showed a correlation with the occurrence of kidney stones. In the pediatric patients studied, there were no kidney stones observed. Carbonic anhydrase inhibitors, e.g. acetazolamide, promote stone formation by reducing urinary citrate excretion and by increasing urinary pH. Concomitant use of topiramate, a weak carbonic anhydrase inhibitor, with other carbonic anhydrase inhibitors may create a physiological environment that increases the risk of kidney stone formation, and should therefore be avoided. Patients, especially those with a predisposition to nephrolithiasis, may have an increased risk of renal stone formation and associated signs and symptoms such as renal colic, renal pain or flank pain. Increased fluid intake increases the urinary output, lowering the concentration of substances involved in stone formation. Therefore, adequate hydration is recommended to reduce this risk. None of the risk factors for nephrolithiasis can reliably predict stone formation during topiramate treatment.

Adjustment of Dose in Renal Failure

CR

The major route of elimination of unchanged topiramate and its metabolites is via the kidney. Renal elimination is dependent on renal function and is independent of age. Patients with impaired renal function (CL < 70 mL/min/1.73m2) or with end-stage renal disease receiving hemodialysis treatments may take 10 to 15 days to reach steady-state plasma concentrations as compared to 4 to 8 days in patients with normal renal function. As with all patients, the titration schedule should be guided by clinical outcome (i.e. seizure control, avoidance of side effects) with the knowledge that patients with known renal impairment may require a longer time to reach steady-state at each dose (see DOSAGE AND ADMINISTRATION, Dosing Considerations).

Information for Patients

Pregnant Women

Patients should be reminded to inform their doctor if they are pregnant or intend to become pregnant while on topiramate therapy.

Adequate Hydration

Patients, especially those with predisposing factors, should be instructed to maintain an adequate fluid intake in order to minimize the risk of renal stone formation. Patients also should be instructed to increase and maintain fluid intake prior to and during activities such as exercise and exposure to warm temperatures to help prevent complications from decreased sweating.

Effects on Ability to Drive and Use Machines

Patients should be warned about the potential for somnolence, dizziness, confusion, and difficulty concentrating and advised not to drive or operate machinery until they have gained sufficient experience on topiramate to gauge whether it adversely affects their mental and/or motor performance.

Acute Myopia and Secondary Angle Closure Glaucoma

Patients taking topiramate should be told to immediately contact their doctor and/or go to the Emergency Room if they/ their child experience(s) sudden worsening of vision, blurred vision or painful/red eye(s).

Special Population

Pregnant Women

Like many other drugs, topiramate was teratogenic in mice, rats, and rabbits. In rats, topiramate crosses the placental barrier. There are no studies using topiramate in pregnant women. However, topiramate therapy should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus. In post-marketing experience, cases of hypospadias have been reported in male infants exposed in utero to topiramate, with or without other anticonvulsants; however, a causal relationship with topiramate has not been established. The effect of topiramate on labour and delivery in humans is unknown.

Nursing Women

Topiramate is excreted in the milk of lactating rats. The excretion of topiramate in human milk has not been evaluated in controlled studies. Limited observations in patients suggest an extensive excretion of topiramate into breast milk. Since the potential for serious adverse reactions in nursing infants exposed to topiramate exists, the prescriber should decide whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother and the risks to the infant.

Pediatrics (<2 years of age)

Safety and effectiveness in children under 2 years of age have not been established.

Weight loss in Pediatrics (>2 years of age)

Topiramate administration is associated with weight loss in some children that generally occurs early in therapy. Of those pediatric subjects treated in clinical trials for at least a year who experienced weight loss, 96% showed a resumption of weight gain within the period tested. In 2-4 year olds, the mean change in weight from baseline at 12 months (n=25) was +0.7 kg (range -1.1 to 3.2); at 24 months (n=14), the mean change was +2.2 (range -1.1 to 6.1). In 5-10 year olds, the mean change in weight from baseline at 12 months (n=88) was +0.7 kg (range -6.7 to 11.8); at 24 months (n=67), the mean change was +3.3 (range -8.6 to 20.0). Weight decreases, usually associated with anorexia or appetite changes, were reported as adverse events for 9% of patients treated with topiramate. The long-term effects of reduced weight gain in pediatric patients are not known.

Geriatrics (>65 years of age):

(See ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions.)

There is limited information in patients over 65 years of age. The possibility of age-associated renal function abnormalities should be considered when using topiramate.

Monitoring and Laboratory Tests

It has been observed in clinical trials that topiramate treated subjects experienced an average decrease in serum bicarbonate level of 4 mmol/L and an average increase in serum chloride level of 4 mmol/L (See WARNINGS AND PRECAUTIONS, Endocrine and Metabolism).

Hypokalemia Observed During Concomitant Treatment with Hydrochlorothiazide

In a drug interaction study with the diuretic hydrochlorothiazide (HCTZ), the percentage of patients with a serum potassium measurement of 3.6 mEq/L was greater at the end of concomitant treatment than at the end of treatment for either drug alone: 27% (3/11) of subjects on topiramate treatment alone and 25% (3/12) of subjects on HCTZ alone versus 61% (14/22) of subjects on concomitant drug treatment. (See WARNINGS AND PRECAUTIONS, Endocrine and Metabolism and DRUG INTERACTIONS.)

ADVERSE REACTIONS EPILEPSY

Adverse Drug Reaction Overview for Monotherapy

Adults

The most commonly observed adverse events associated with the use of topiramate at dosages of 100 to 400 mg per day in controlled trials in adults with newly diagnosed epilepsy were: paresthesia, fatigue, headache, somnolence, dizziness, upper respiratory tract infection, anorexia, weight decrease, depression, and nausea (see Table 1). Approximately 19% of the 886 adult patients who received topiramate as monotherapy in controlled clinical trials for patients with newly diagnosed epilepsy discontinued therapy due to adverse events. Adverse events associated with discontinuing therapy included paresthesia (2.6%), somnolence (2.5%), fatigue (2.3%), nausea (2.0%), and psychomotor slowing (1.6%).

Pediatrics

The most commonly observed adverse events associated with the use of topiramate at dosages of 100 to 400 mg per day in controlled trials in children with newly diagnosed epilepsy were: upper respiratory tract infection, headache, anorexia, difficulty with concentration/attention, weight decrease, somnolence, paresthesia, fever, and fatigue (see Table 2). Approximately 10% of the 245 pediatric patients who received topiramate as monotherapy in controlled clinical trials for patients with newly diagnosed epilepsy discontinued therapy due to adverse events. Adverse events associated with discontinuing therapy included difficulty with concentration/attention(2.0%). No pediatric patients withdrew due to psychomotor slowing.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction

information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Table 1: Incidence of Treatment-Emergent Adverse Events in Monotherapy Trials in Adults a where Rate was $ 2% in any Topiramate Group

Body System

50-100

Topiramate Dosage (mg/day) 200-400

Adverse Event (n=444) (n=329) (n=113)

Fatigue	18	18	19
Injury	9	8	4
Asthenia	4	5	4
Back Pain	3	2	5
Pain	3	2	5
Chest Pain	2	2	3
Fever	1	2	3
Syncope	2	1	1
Leg Pain	2	2	1
Peripheral Edema	1	<1	2

Body as a Whole-General Disorders

Paresthesia	23	39	38
Headache	23	16	19
Dizziness	16	13	13
Hypoesthesia	5	5	12
Language Problems	4	5	6
Ataxia	3	5	4
Speech Disorders/Related Speech Problems	2	3	3
Vertigo	2	3	4
Tremor	3	2	3
Hypertonia	1	2	2
Involuntary Muscle Contractions	1	2	4
Sensory Disturbances	1	1	4
Migraine	2	1	1
Abnormal Coordination	1	1	3
Convulsions Aggravated	1	0	2
Convulsions Grand Mal	<1	1	2
Gait Abnormal	<1	<1	3
Dyskinesia	0	0	2

Central & Peripheral Nervous System Disorders

Nausea	11	12	12
Diarrhea	6	8	12
Abdominal Pain	6	8	7
Dyspepsia	5	5	4
Vomiting	4	3	2
Constipation	2	3	1
Dry Mouth	1	2	6
Gastroenteritis	2	1	2
Gastritis	1	2	2
Tooth Ache	1	1	2
Gastrointestinal Disorder NOS	<1	<1	2
Hemorrhoids	<1	<1	2
Stomatitis Ulcerative	<1	0	2

Gastro-Intestinal System Disorders

Hearing and Vestibular Disorders

Tinnitus 1 2 2

Table 1 (cont'd): Incidence of Treatment-Emergent Adverse Events in Monotherapy Trials in Adults a where Rate was $ 2% in any Topiramate Group

Body System

50-100

Topiramate Dosage (mg/day) 200-400

Adverse Event (n=444) (n=329) (n=113)

Palpitation	1	1	4
Tachycardia	1	0	2

Heart Rate and Rhythm Disorders

Metabolic and Nutritional Disorders

Weight Decrease 9 14 18
Arthralgia	3	4	4
Myalgia	2	1	2
Muscle Weakness	1	1	2

Muscle-Skeletal System Disorders

Epistaxis	1	2	1
Hematoma	0	0	2

Platelet, Bleeding, & Clotting Disorders

Somnolence	11	15	19
Anorexia	8	14	11
Insomnia	9	8	9
Difficulty with Memory NOS	6	10	9
Depression	7	10	4
Difficulty with Concentration/Attention	6	9	8
Nervousness	6	7	8
Mood Problems	5	6	4
Anxiety	4	6	5
Confusion	4	5	7
Psychomotor Slowing	2	5	8
Cognitive Problems NOS	2	3	3
Agitation	2	2	3
Emotional Lability	1	3	2
Aggressive Reaction	2	1	2
Libido Decreased	1	2	1
Depression Aggravated	<1	2	3
Impotence	1	1	2

Psychiatric Disorders

Menstrual Disorder	3	1	8
Dysmenorrhea	2	2	0
Intermenstrual Bleeding	2	1	0
Menorrhagia	1	1	2
Pregnancy Unintended	1	1	2
Mastitis	0	0	2

Reproductive Disorders, Female

Reproductive Disorders, Male

Premature Ejaculation 0 0 2
Infection Viral	5	9	6
Otitis Media	2	1	2

Resistance Mechanism Disorders

Respiratory System Disorders

Upper Respiratory Tract Infection	15	13	10
Pharyngitis	5	5	2
Sinusitis	3	4	6
Rhinitis	3	3	5
Bronchitis	2	2	1
Coughing	2	2	2
Dyspnea	1	2	1
Pneumonia	1	<1	3

Respiratory System Disorders (cont'd)

50-100 (n=444)

Topiramate Dosage (mg/day) 200-400

(n=329)

500 (n=113)

Rash	3	4	3
Alopecia	3	3	1
Acne	1	3	2
Pruritus	1	3	1
Increased Sweating	1	<1	2
Maculopapular Rash	1	0	2
Special Senses Other, Disorders
Taste Perversion	3	5	6
Urinary System Disorders
Urinary Tract Infection	2	2	5
Micturition Frequency	1	2	4
Dysuria	<1	2	1
Cystitis	<1	2	1
Renal Calculus	<1	2	2
Vision Disorders
Vision Abnormal	3	4	4

Skin and Appendages Disorders

Diplopia 1 1 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 2: Incidence of Treatment-Emergent Adverse Events in Monotherapy Trials in Children Ages 6 up to 16Years a where Rate was $ 2% in any Topiramate Group

Topiramate Dosage (mg/day)

Body System

Adverse Event
Fatigue	7	10	14
Fever	2	11	7
Injury	4	2	14
Asthenia	0	3	7
Back Pain	2	2	0
Allergic Reaction	1	1	7
Allergy	0	1	7
Influenza-Like Symptoms	0	0	7

Body as a Whole-General Disorders

50-100 (n=125)

200-400 (n=106)

500 b

(n=14)

Central & Peripheral Nervous System Disorders

Headache	27	17	29
Dizziness	9	8	0
Paresthesia	4	11	7
Language Problems	0	3	7
Convulsions Grand Mal	2	0	7
Hypertonia	0	0	7
Hyperkinesia	2	0	21
Migraine	2	1	0
Muscle Contractions Involuntary	1	2	0
Tremor	2	0	0
Vertigo	0	3	0
Cramps Legs	2	0	0
Gait Abnormal	2	0	0

Table 2 (cont'd): Incidence of Treatment-Emergent Adverse Events in Monotherapy Trials in Children Ages 6 up to 16Years a where Rate was $ 2% in any Topiramate Group

Body System

50-100

Topiramate Dosage (mg/day) 200-400

500 b

Adverse Event (n=125) (n=106) (n=14)

Collagen Disorders

Auto-antibody Response 0 0 7
Diarrhea	9	7	7
Vomiting	8	6	14
Abdominal Pain	6	4	14
Nausea	4	5	14
Gastroenteritis	6	0	7
Constipation	1	0	7
Gastrointestinal Disorder NOS	0	0	7
Dyspepsia	2	1	0
Tooth Ache	1	1	7

Gastro-Intestinal System Disorders

Hearing and Vestibular Disorders

Earache 2 0 0
Weight Decrease	5	14	0
Acidosis	0	0	7

Metabolic and Nutritional Disorders

Muscle-Skeletal System Disorders

Arthralgia 1 2 7

Platelet, Bleeding, & Clotting Disorders

Epistaxis 2 4 14

Psychiatric Disorders

Anorexia	13	13	14
Somnolence	14	9	0
Difficulty with Concentration/Attention	6	13	7
Insomnia	5	4	14
Nervousness	5	6	0
Mood Problems	2	8	0
Difficulty with Memory NOS	4	2	14
Cognitive Problems NOS	1	6	0
Psychomotor Slowing	3	3	0
Aggressive Reaction	2	3	7
Depression	0	5	0
Sleep Disorder	2	2	0
Personality Disorder (Behaviour Problems)	2	2	0
Anxiety	2	1	0
Confusion	0	3	0
Emotional Lability	2	1	0
Red Blood Cell Disorders
Anemia	1	2	0
Reproductive Disorders, Female
Vaginitis	0	0	13
Dysmenorrhea	2	2	0
Intermenstrual Bleeding	0	2	0
Reproductive Disorders, Male
Testis Disorder	2	0	0
Resistance Mechanism Disorders
Infection Viral	4	7	7
Infection	2	6	0
Otitis Media	2	1	7

Table 2 (cont'd): Incidence of Treatment-Emergent Adverse Events in Monotherapy Trials in Children Ages 6 up to 16Years a where Rate was $ 2% in any Topiramate Group

Topiramate Dosage (mg/day)

Body System

50-100

200-400

500 b

Respiratory System Disorders
Upper Respiratory Tract Infection	26	25	21
Pharyngitis	9	5	21
Rhinitis	5	6	21
Sinusitis	3	6	14
Bronchitis	2	4	0
Asthma	2	1	0
Coughing	2	1	0
Skin and Appendages Disorders
Rash	3	4	21
Dermatitis	1	0	7
Alopecia	1	3	0
Acne	2	0	0
Nail Disorder	2	0	0
Pruritus	0	2	0
Rash Erythematous	2	0	0
Urinary System Disorders
Urinary Incontinence	2	2	7
Renal Calculus	0	0	7
Micturition Frequency	0	2	0
Urinary Tract Infection	2	0	0
Vascular Disorders

Adverse Event (n=125) (n=106) (n=14)

Flushing 1 4 7

Vision Disorders

Conjunctivitis 2 2 0

1. 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.

2. Due to n=14 in the 500 mg topiramate group, an incidence of 7% represents one patient.

Adverse Drug Reaction Overview for Adjunctive Therapy

Adults

The most commonly observed adverse events associated with the adjunctive use of topiramate at dosages of 200 to 400 mg per day in controlled trials in adults that were seen at greater frequency in patients treated with topiramate and did not appear to be dose related within this dosage range were: somnolence, dizziness, ataxia, speech disorders and related speech problems, psychomotor slowing, nystagmus, and paresthesia (see Table 3). The most common dose-related adverse events at dosages of 200 to 1,000 rng per day were: nervousness, difficulty with concentration or attention, confusion, depression, anorexia, language problems, and mood problems (see Table 4).

Pediatrics

Adverse events associated with the use of topiramate at dosages of 5 to 9 mg/kg/day in worldwide pediatric clinical trials that were seen at greater frequency in patients treated with topiramate were: fatigue, somnolence, anorexia, nervousness, difficulty with concentration/attention, difficulty with memory, aggressive reaction, and weight decrease. (See Table 5).

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Table 3: Incidence of Treatment-Emergent Adverse Events in Placebo-Controlled, Add-On Epilepsy Trials in ADULTSa..b (Events that occurred in $ 2% of Patients treated with topiramate and occurred more frequently in Patients treated with topiramate than placebo-treated patients)

Topiramate Dosage (mg/day)
Body System Adverse Event	Placebo (n=216)	200-400 (n=113)	600-1,000 (n=414)
Body as a Whole Asthenia	1.4	8.0	3.1
Back Pain	4.2	6.2	2.9
Chest Pain	2.8	4.4	2.4
Influenza-Like Symptoms	3.2	3.5	3.6
Leg Pain	2.3	3.5	3.6
Hot Flushes Nervous System Dizziness	1.9 15.3	2.7 28.3	0.7 32.1
Ataxia	6.9	21.2	14.5
Speech Disorders/Related Speech Problems	2.3	16.8	11.4
Nystagmus	9.3	15.0	11.1
Paresthesia	4.6	15.0	19.1
Tremor	6.0	10.6	8.9
Language Problems	0.5	6.2	10.4
Coordination Abnormal	1.9	5.3	3.6
Hypoaesthesia	0.9	2.7	1.2
Abnormal Gait Gastrointestinal System Nausea	1.4 7.4	1.8 11.5	2.2 12.1
Dyspepsia	6.5	8.0	6.3
Abdominal Pain	3.7	5.3	7.0
Constipation	2.3	5.3	3.4
Dry Mouth Metabolic and Nutritional Weight Decrease	0.9 2.8	2.7 7.1	3.9 12.8
Neuropsychiatric Somnolence	9.7	30.1	27.8
Psychomotor Slowing	2.3	16.8	20.8
Nervousness	7.4	15.9	19.3
Difficulty with Memory	3.2	12.4	14.5

Table 3 (cont'd): Incidence of Treatment-Emergent Adverse Events in Placebo-Controlled, Add-On Epilepsy Trials in ADULTSa..b (Events that occurred in $ 2% of Patients treated with topiramate and occurred more frequently in Patients treated with topiramate than placebo-treated patients)

Topiramate Dosage (mg/day)

Body System

Placebo

200-400

600-1,000

Adverse Event (n=216) (n=113) (n=414)

Confusion	4.2	9.7	13.8
Depression	5.6	8.0	13.0
Difficulty with Concentration/Attention	1.4	8.0	14.5
Anorexia	3.7	5.3	12.3
Agitation	1.4	4.4	3.4
Mood Problems	1.9	3.5	9.2
Aggressive Reaction	0.5	2.7	2.9
Apathy	0	1.8	3.1
Depersonalization	0.9	1.8	2.2
Emotional Lability	0.9	1.8	2.7
Reproductive, Female	(n=59)	(n=24)	(n=128)
Breast Pain, Female	1.7	8.3	0
Dysmenorrhea	6.8	8.3	3.1
Menstrual Disorder	0	4.2	0.8
Reproductive, Male	(n=157)	(n=89)	(n=286)
Prostatic Disorder	0.6	2.2	0
Respiratory System
Pharyngitis	2.3	7.1	3.1
Rhinitis	6.9	7.1	6.3
Sinusitis	4.2	4.4	5.6
Dyspnea	0.9	1.8	2.4

Neuropsychiatric (cont'd)

Skin and Appendages

Pruritus 1.4 1.8 3.1
Diplopia	5.6	14.2	10.4
Vision Abnormal	2.8	14.2	10.1
White Cell and RES Leukopenia	0.5	2.7	1.2

Vision

1. Patients in these add-on trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo.

2. 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 4: Incidence (%) of Dose-Related Adverse Events From Placebo-Controlled, Add-On Epilepsy Trials in ADULTS

		Topiramate Dosage (mg/day)
Placebo (n=216)	200 (n=45)	400 (n=68)	600 - 1,000 (n=414)
13.4	11.1	11.8	29.7
7.4	13.3	17.6	19.3
1.4	6.7	8.8	14.5
4.2	8.9	10.3	13.8
5.6	8.9	7.4	13
3.7	4.4	5.9	12.3
0.5	2.2	8.8	10.1
6	2.2	2.9	10.4

Adverse Event Fatigue

Nervousness

Difficulty with Concentration/Attention Confusion

Depression Anorexia Language problems Anxiety

Mood problems 1.9 0 5.9 9.2 In six double-blind clinical trials, 10.6% of subjects (n=l 13) assigned to a topiramate dosage of 200 to 400 mg/day in addition to their standard AED therapy discontinued due to adverse events, compared to 5.8% of subjects (n=69) receiving placebo. The percentage of subjects discontinuing due to adverse events appeared to increase at dosages above 400 mg/day. Overall, approximately 17% of all subjects (n=527) who received topiramate in the double-blind trials discontinued due to adverse events, compared to 4% of the subjects (n=216) receiving placebo. Table 5 lists treatment-emergent adverse events that occurred in at least 2% of children treated with 5 to 9 mg/kg/day topiramate in controlled trials that were numerically more common than in patients treated with placebo.

Table 5: Incidence (%) of Treatment-Emergent Adverse Events in Worldwide Pediatric Add-on Epilepsy Clinical Trials Experience (2-16 years of Age)a.b (Events that Occurred in $2% of Patients Treated with Topiramate and

Occurred More Frequently in Patients Treated with Topiramate Than Placebo-Treated Patients)

Body System/ Adverse Event

Body as a Whole - General Disorders

Placebo (N=101)

Topiramate (N=98)

Fatigue 5 16.3

Injury 12.9 14.3

Allergic Reaction 1 2
Gait Abnormal	5	8.2
Ataxia	2	6.1
Hyperkinesia	4	5.1
Dizziness	2	4.1
Speech Disorders/Related Speech Problems	2	4.1
Convulsions Aggravated	3	3.1
Hyporeflexia	0	2

Central & Peripheral Nervous System Disorders

Nausea	5	6.1
Saliva Increased	4	6.1
Constipation	4	5.1
Gastroenteritis	2	3.1

Gastrointestinal System Disorders

Weight Decrease	1	9.2
Thirst	1	2
Platelet, Bleeding & Clotting Disorders
Purpura	4	8.2
Epistaxis	1	4.1
Nervous Disorders
Somnolence	15.8	25.5
Anorexia	14.9	24.5
Nervousness	6.9	14.3
Personality Disorder (Behavior Problems)	8.9	11.2
Difficulty with Concentration/Attention	2	10.2
Aggressive Reaction	4	9.2
Insomnia	6.9	8.2
Mood Problems	6.9	7.1
Difficulty with Memory NOS c	0	5.1
Emotional Lability	5	5.1
Confusion	3	4.1
Psychomotor Slowing	2	3.1

Metabolic and Nutritional Disorders

Reproductive Disorders, Female

Leukorrhea 0 2.3

Resistance Mechanism Disorders

Infection Viral	3	7.1
Infection	3	3.1

Table 5 (cont'd): Incidence (%) of Treatment-Emergent Adverse Events in Worldwide Pediatric Add-on Epilepsy Clinical Trials Experience (2-16 years of Age)a.b (Events that Occurred in $2% of Patients Treated with Topiramate and Occurred More Frequently in Patients Treated with Topiramate Than Placebo-Treated Patients)

Body System/ Adverse Event

Upper Respiratory Tract Infection	36.6	36.7
Pneumonia	1	5.1
Skin and Appendages Disorders
Skin Disorder	2	3.1
Alopecia	1	2
Dermatitis	0	2
Hypertrichosis	1	2
Rash Erythematous Urinary System Disorders	0	2
Urinary Incontinence Vision Disorders	2	4.1
Eye Abnormality	1	2
Vision Abnormal	1	2

Respiratory System Disorders

Placebo (N=101)

Topiramate (N=98)

White Cell and RES Disorders

Leukopenia 0 2

1. Patients in these add-on trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate topiramate or placebo.

2. 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.

Not Otherwise Specified

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 events. In open extensions of the controlled clinical trials, approximately 9% of the 303 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%), language problems (1.3%), and difficulty with concentration/attention (1.3%). When the safety experience of patients receiving topiramate as adjunctive therapy in both double- blind and open-label trials (1,446 adults and 303 children) was analyzed, a similar pattern of adverse events emerged.

Less Common Clinical Trial Adverse Drug Reactions (<2%)

Adverse events that occurred less frequently but were considered potentially medically relevant included: taste perversion, cognitive problems (not otherwise specified) and psychosis/psychotic symptoms. In adult and pediatric patients, nephrolithiasis was reported rarely. Isolated cases of thromboembolic events have also been reported; a causal association with the drug has not been established. In clinical trials with topiramate, the occurrence rate for all potential cases of oligohidrosis (decreased sweating) was 0.25%. In clinical trials for topiramate in epilepsy, migraine prophylaxis and other investigational indications (obesity, bipolar disorder and diabetic peripheral neuropathy), suicide-related adverse events++ occurred at a rate of 0.8% (84 reports/10,846 patients) in topiramate versus 0.2% (5 reports/3,150 patients) in placebo groups. Although the average exposure time for patients on topiramate (approximately 10 months) was longer than for those on placebo (approximately 5 months), these adverse events were reported randomly over the exposure period. Suicide attempts occurred in 0.3% (33 reports/10,846 patients) of the topiramate-treated patients compared to 0% in placebo groups. Of these 33 attempts, one completed suicide was reported in a double-blind bipolar disorder trial and 3 in the open-label phase of the bipolar disorder trials (see WARNINGS AND PRECAUTIONS, Neurologic, Central Nervous System Effects).

++

Suicide-related adverse events include suicidal ideation, suicide attempt, suicide and any evidence of self-harm.

MIGRAINE

Adverse Drug Reaction Overview

Table 6 includes those adverse events reported for patients in four multicentre, randomized, double- blind, placebo-controlled, parallel-group migraine prophylaxis clinical trials where the incidence rate in any topiramate treatment group was at least 2% and was greater than that for placebo patients. Most of the adverse events were mild or moderate in severity and most occurred more frequently during the titration period than during the maintenance period.

Clinical Trial Adverse Drug Reactions

Table 6: Incidence % of Treatment-Emergent Adverse Events in Placebo-Controlled Migraine Trials Where Rate Was at Least 2% in Any Topiramate Group and Greater Than the Rate in Placebo-Treated Patients a

Body System/

Topiramate Dosage (mg/day)

Adverse Event

Fatigue	11	14	15	19
Injury	7	9	6	6
Asthenia	1	<1	2	2
Fever	1	1	1	2
Influenza-Like Symptoms Allergy	<1 <1	<1 2	<1 <1	2 <1

Body as a Whole - General Disorders

Placebo

(n=445)

(n=235)

(n=386)

(n=514)

Central & Peripheral Nervous System Disorders

Paresthesia	6	35	51	49
Dizziness	10	8	9	12
Hypoesthesia	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

Table 6 (cont'd): Incidence % of Treatment-Emergent Adverse Events in Placebo-Controlled Migraine Trials Where Rate Was at Least 2% in Any Topiramate Group and Greater Than the Rate in Placebo-Treated Patients a

Topiramate Dosage (mg/day)
Placebo	50	100	200
(n=445)	(n=235)	(n=386)	(n=514)

Body System/ Adverse Event

Nausea	8	9	13	14
Diarrhea	4	9	11	11
Abdominal Pain	5	6	6	7
Dyspesia	3	4	5	3
Dry Mouth	2	2	3	5
Vomiting	2	1	2	3
Gastroenteritis	1	3	3	2

Gastrointestinal System Disorders

Hearing and Vestibular Disorders

Tinnitus 1 <1 1 2
Weight Decrease	1	6	9	11
Thirst	<1	2	2	1

Metabolic and Nutritional Disorders

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

Table 6 (cont'd): Incidence % of Treatment-Emergent Adverse Events in Placebo-Controlled Migraine Trials Where Rate Was at Least 2% in Any Topiramate Group and Greater Than the Rate in Placebo-Treated Patients a

Topiramate Dosage (mg/day)
Placebo	50	100	200
(n=445)	(n=235)	(n=386)	(n=514)

Body System/ Adverse Event

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

Respiratory System Disorders

Skin and Appendages Disorders

Pruritus 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 Vision b	2	4	2	4
Conjunctivitis	1	1	2	1

1. 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.

2. 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 most common adverse events associated with discontinuing therapy in the topiramate-treated patients included paresthesia (6.7%), fatigue (4.3%), nausea (4.0%), difficulty with concentration/attention (2.9%), insomnia (2.7%), anorexia (2.1%), and dizziness (2.0%). In the 6-month migraine prophylaxis controlled trials, the proportion of patients who experienced one or more cognitive-related events was 19% for topiramate 50 mg/day, 22% for 100 mg/day, 28% for 200 mg/day and 10% for placebo. These dose-related adverse reactions typically began in the titration phase and often persisted into the maintenance phase but infrequently began in the maintenance phase. Table 7 shows adverse events that were dose-dependent.

Table 7: Incidence (%) of Dose-Related Adverse Events From Placebo-Controlled Migraine Trials a

Topiramate Dosage (mg/day)
Placebo (n=445)	50 (n=235)	100 (n=386)	200 (n=514)
6	35	51	49
11	14	15	19
8	9	13	14
6	9	15	14
10	8	9	12
1	6	9	11
2	7	7	11
4	9	11	11
2	3	6	10
5	8	7	10
2	6	7	8
3	4	5	6
4	3	4	6
2	3	6	5
2	2	3	5
2	2	3	4
1	2	2	4
<1	1	2	3
0	0	1	2

Body System/

Adverse Event

Paresthesia Fatigue Nausea Anorexia Dizziness

Weight decrease

Difficulty with Memory NOS Diarrhea

Difficulty with Concentration/Attention Somnolence

Hypoesthesia Anxiety Depression Mood Problems Dry Mouth Confusion

Involuntary Muscle Contractions Abnormal Vision

Renal Calculus

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

For the prophylactic treatment of migraine headache, topiramate has been administered to 1367 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 WHOART dictionary terminology. The following additional adverse events that were not described earlier were reported by greater than 1% of the 1367 topiramate-treated patients in the controlled clinical trials:

Body as a Whole:

pain, chest pain, allergic reaction

Central and 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: Reproductive Disorders, Female: Resistance Mechanism Disorders:

epistaxis

intermenstrual bleeding

infection, genital moniliasis

Respiratory System Disorders: Skin and Appendages Disorders: Vision Disorders:

pneumonia, asthma

rash, alopecia

abnormal accommodation, eye pain

Post-Market Adverse Drug Reactions

In addition to the adverse experiences reported during clinical trial testing of topiramate, the following adverse experiences have been reported in patients receiving marketed topiramate from worldwide use since approval. There are insufficient data to support an estimate of their incidence or to establish causation. The most frequently reported adverse events in spontaneous post-marketing reports on topiramate include:

Psychiatric:

somnolence or sedation, hallucination(s), depression, anorexia, aggressive reaction, psychosis, thinking abnormal, insomnia, emotional lability, delusion, amnesia, confusion, nervousness, agitation, concentration impaired, personality disorder, anxiety

Central and Peripheral Nervous System: Metabolic and Nutritional: Vision:

convulsions aggravated, paresthesia, speech disorder, ataxia, dizziness, convulsions, headache, hyperkinesia, convulsions grand mal, hypoaesthesia

weight decrease, metabolic acidosis, hypokalemia, hyperchloremia

vision abnormal (includes vision decreased, vision blurred, visual disturbance, visual impairment, amblyopia); rarely reported: diplopia, glaucoma, myopia, eye pain

Gastrointestinal:

nausea, diarrhea, abdominal pain, constipation, vomiting

Body as a Whole - General Disorders:

fatigue, fever, dehydration, flushing, hot flushes

Urinary System:

renal calculus

Skin and Appendages:

rash, alopecia, sweating decreased

White Cell and RES Disorders:

Leucopenia, thrombocytopenia

Oligohidrosis (decreased sweating) has been rarely reported with the use of topiramate. The majority of spontaneous post-marketing reports have been in children. Adverse events that may be related to potential cases of oligohidrosis include dehydration, hyperthermia, and heat intolerance. Adequate hydration prior to activities such as exercise or exposure to warm temperatures is recommended (see WARNINGS AND PRECAUTIONS, Endocrine and Metabolism). To date, there have been rare spontaneous, post-marketing reports of metabolic acidosis. In some cases, acidosis resolved after dosage reduction or upon discontinuation of topiramate (see WARNINGS AND PRECAUTIONS, Endocrine and Metabolism). Rare reports of encephalopathy with or without hyperammonemia have been received for patients treated with topiramate while also taking valproate or other antiepileptic medications (see DRUG INTERACTIONS). Reports of increases in liver function tests in patients taking topiramate with and without other medications have been received. Isolated reports have been received of hepatitis and hepatic failure occurring in patients taking multiple medications while being treated with topiramate. Very rare reports have also been received for bullous skin and mucosal reactions (including Stevens- Johnson syndrome, toxic epidermal necrolysis, erythema multiforme and pemphigus). The majority of these reports have occurred in patients taking other medications that can be associated with bullous skin and mucosal reactions.