6 ADVERSE REACTIONS

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]
Oligohydrosis and Hyperthermia [see Warnings and Precautions (5.3)]
Metabolic Acidosis [see Warnings and Precautions (5.4)]
Interaction With Alcohol [see Warnings and Precautions (5.5)]
Suicidal Behavior and Ideation [see Warnings and Precautions (5.6)]
Cognitive/Neuropsychiatric Adverse Reactions [see Warnings and Precautions (5.7)]
Fetal Toxicity [see Warnings and Precautions (5.8)]
Withdrawal of Antiepileptic Drugs [see Warnings and Precautions (5.9)]
Decrease of Bone Mineral Density [see Warnings and Precautions (5.10)]
Negative Effects on Growth (Height and Weight) [see Warnings and Precautions (5.11)]
Serious Skin Reactions [see Warnings and Precautions (5.12)]
Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid Use) [see Warnings and Precautions (5.13)]
Kidney Stones [see Warnings and Precautions (5.14)]
Hypothermia With Concomitant Valproic Acid Use [see Warnings and Precautions (5.15)]

The data described in the following sections were obtained using immediate-release topiramate tablets. TROKENDI XR ®has not been studied in a randomized, placebo-controlled Phase III clinical study; however, it is expected that TROKENDI XR ®would produce a similar adverse reaction profile as immediate-release topiramate.

6.1 Clinical Trials Experience

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

Monotherapy Epilepsy

Adults 16 Years of Age and Older

The most common adverse reactions in the controlled trial (Study 1) that occurred in adults in the 400 mg/day topiramate group and at an incidence higher (≥ 10%) than in the 50 mg per day group were: paresthesia, weight loss, and anorexia (see Table 3).

Approximately 21% of the 159 adult patients in the 400 mg/day group who received topiramate as monotherapy in Study 1 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 Years to 15 Years of Age

The most common adverse reactions in the controlled trial (Study 1) 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 (see Table 3).

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 in the 50 mg/day group) adverse reactions resulting in discontinuation in this trial were difficulty with concentration/attention, fever, flushing, and confusion.

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

Table 3: Adverse Reactions in the High Dose Group as Compared to the Low Dose Group, in Monotherapy Epilepsy Trial in Adult and Pediatric Patients
	Age Group
	Pediatric (6 to 15 Years)		Adult (Age ≥16 Years)
	Immediate-release 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 contraction	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 in 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 or 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	0	2
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 immediate-release 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 immediate-release topiramate or placebo.

The most common adverse reactions in the controlled clinical trial that occurred in adult patients in the 200-400 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 (see Table 4) [see Clinical Studies (14.3)] .

Table 4 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 to 1000 mg/day) compared to the incidence of these adverse reactions at the recommended dosing (200 to 400 mg/day) range.

Table 4: Most Common Adverse Reactions in Pooled Placebo- Controlled, Adjunctive Epilepsy Trials in Adults *,†
Body System/	Placebo	Topiramate Dosage (mg/day) 200-400
Adverse Reaction	(N=291) %	(N=183) %
* Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo † Values represent the percentage of patients reporting a given reaction. Patient may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category.
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
Confusion	5	11
Anorexia	4	10
Difficulty with concentration/attention	2	6
Mood problems	2	4
Agitation	2	3
Aggressive reaction	2	3
Emotional liability	1	3
Cognitive problems	1	3
Reproductive Disorders, Female
Breast pain	2	4
Respiratory System Disorders
Rhinitis	6	7
Pharyngitis	2	6
Sinusitis	4	5
Vision Disorders
Vision abnormal	2	13
Diplopia	5	10

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

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 immediate-release topiramate at dosages of 5 mg to 9 mg/kg/day (recommended dosage 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 immediate-release topiramate group with an incidence higher (≥10%) than in the placebo group were: fatigue and somnolence (see Table 5).

Table 5 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 dosage range) of immediate-release topiramate and was greater than placebo incidence.

Table 5: Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Epilepsy Trial in Pediatric Patients 2 to 15 Years of Age *,†
Body System/ Adverse Reaction	Placebo (N=101) %	Topiramate (N=98) %
* Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to topiramate or placebo † 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 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 mg/kg/day 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 clinical trials for the preventive treatment of migraine (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 immediate-release topiramate 100mg in the clinical trials for the preventive treatment of migraine 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 6).

Table 6 includes those adverse reactions that occurred in the placebo-controlled trials where the incidence in any immediate-release topiramate 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/day) compared to the incidence of these adverse reactions at the recommended dosing (100 mg/day).

Table 6: Adverse Reactions in Pooled, Placebo-Controlled, Migraine Trials in Adults *,†,‡
		Topiramate Dosage (mg/day)
Body System/ Adverse Reaction	Placebo (N=445) %	50 (N=235) %	100 (N=386) %
* Includes 35 adolescent patients age 12 to 15 years † Values represent the percentage of patients reporting a given reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category. ‡ Blurred vision was the most common term considered as vision abnormal. Blurred vision was an included term that accounted for more than 50% of reactions coded as vision abnormal, a preferred term
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
Hypoaesthesia	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 vision	2	4	2

Of the 1135 patients exposed to immediate-release topiramate in the adult placebo-controlled studies, 25% discontinued due to adverse reactions, compared to 10% of the 445 placebo patients. The adverse reactions associated with discontinuing therapy in the immediate-release topiramate-treated patients in these studies included paresthesia (7%), fatigue (4%), nausea (4%), difficulty with concentration/attention (3%), insomnia (3%), anorexia (2%), and dizziness (2%).

Patients treated in these studies 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, immediate-release topiramate 50 mg, 100 mg, and 200 mg groups, respectively.

Pediatric Patients 12 to 17 Years of Age

In five randomized, double-blind, placebo-controlled, parallel group clinical trials for the preventive treatment of migraine, most of the 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 clinical trials for the preventive treatment of migraine in pediatric patients 12 to 17 years of age, the most common adverse reactions with immediate-release 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 7). Table 7 shows adverse reactions from the pediatric trial (Study 13 [see Clinical Studies (14.4)] ) in which 103 pediatric patients were treated with placebo or 50 mg or 100 mg of immediate-release 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 immediate-release topiramate [see Clinical Studies (14.4)]. Table 7 also shows adverse reactions in pediatric patients in controlled migraine trials when the incidence in an immediate-release topiramate dose group was at least 5% or higher and greater than the incidence of placebo. Many adverse reactions shown in Table 7 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 immediate-release topiramate dosing (200 mg daily) compared to the incidence of these adverse reactions at the recommended dosing (100 mg daily).

Table 7: Adverse Reactions in Pooled Double-Blind Studies for the Preventive Treatment of Migraine in Pediatric Patients 12 to 17 Years of Age) *†
		Immediate-Release Topiramate Dosage
Body System/ Adverse Reaction	Placebo (N=45) %	50 mg/day (N=46) %	100 mg/day (N=48) %
* 35 adolescent patients aged 12 to <16 years were also included in adverse reaction assessment for adults † Incidence is based on the number of subjects experiencing at least 1 adverse event, not the number of events.
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
Somnolence	2	2	6
Insomnia	2	9	2
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 immediate-release topiramate-treated patients. Adverse reactions associated with discontinuing therapy that occurred in more than one immediate-release 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, immediate-release topiramate was associated with changes in several clinical laboratory analytes in randomized, double-blind, placebo-controlled studies [see Warnings and Precautions (5.4, 5.13)] . 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 (1-24 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 immediate-release 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 immediate-release topiramate (vs. placebo) [see Use in Specific Populations (8.4)] . TROKENDI XR ®is not indicated for partial-onset seizures in pediatric patients less than 6 years of age.

In pediatric patients (ranging from 6-17 years of age) receiving immediate-release topiramate for the preventive treatment of migraine, there was an increased incidence for an increased result (relative to normal analyte reference range) associated with immediate-release 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)]. TROKENDI XR ®is not indicated for the preventive treatment of migraine 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 immediate-release 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 (5.13)] , hypothermia with concomitant valproic acid [see Warnings and Precautions 5.15)] .

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) [see Warnings and Precautions (5.12)] , pemphigus

Urinary System Disorders: kidney stones, nephrocalcinosis [see Warnings and Precautions (5.14)]

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.