Topiramate Capsules

Name: Topiramate Capsules

Contraindications

None.

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)]
  •   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.

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)


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
Dysuria
 0
 2
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

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
Neoplasms
Neoplasm
 <1
 2
 <1
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 Ageabc

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.

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

Non-clinical toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

An increase in urinary bladder tumors was observed in mice given topiramate (20, 75, and 300 mg/kg) in the diet for 21 months. The elevated bladder tumor incidence, which was statistically significant in males and females receiving 300 mg/kg, was primarily due to the increased occurrence of a smooth muscle tumor considered histomorphologically unique to mice. Plasma exposures in mice receiving 300 mg/kg were approximately 0.5 to 1 times steady-state exposures measured in patients receiving topiramate monotherapy at the recommended human dose (RHD) of 400 mg, and 1.5 to 2 times steady-state topiramate exposures in patients receiving 400 mg of topiramate plus phenytoin. The relevance of this finding to human carcinogenic risk is uncertain. No evidence of carcinogenicity was seen in rats following oral administration of topiramate for 2 years at doses up to 120 mg/kg (approximately 3 times the RHD on a mg/m2basis).

Mutagenesis

Topiramate did not demonstrate genotoxic potential when tested in a battery of in vitro and in vivo assays. Topiramate was not mutagenic in the Ames test or the in vitro mouse lymphoma assay; it did not increase unscheduled DNA synthesis in rat hepatocytes in vitro; and it did not increase chromosomal aberrations in human lymphocytes in vitro or in rat bone marrow in vivo.

Impairment of Fertility

No adverse effects on male or female fertility were observed in rats at doses up to 100 mg/kg (2.5 times the RHD on a mg/m2basis).

Clinical Studies

The studies described in the following sections were conducted using topiramate tablets.

Monotherapy Epilepsy

Patients with Partial Onset or Primary Generalized Tonic-Clonic Seizures

Adults and Pediatric Patients 10 Years of Age and Older

The effectiveness of topiramate as initial monotherapy in adults and pediatric patients 10 years of age and older with partial onset or primary generalized tonic-clonic seizures was established in a multicenter, randomized, double-blind, parallel-group trial.  

The trial was conducted in 487 patients diagnosed with epilepsy (6 to 83 years of age) who had 1 or 2 well-documented seizures during the 3-month retrospective baseline phase who then entered the study and received topiramate 25 mg/day for 7 days in an open-label fashion. Forty-nine percent of patients had no prior AED treatment and 17% had a diagnosis of epilepsy for greater than 24 months. Any AED therapy used for temporary or emergency purposes was discontinued prior to randomization. In the double-blind phase, 470 patients were randomized to titrate up to 50 mg/day or 400 mg/day. If the target dose could not be achieved, patients were maintained on the maximum tolerated dose. Fifty-eight percent of patients achieved the maximal dose of 400 mg/day for > 2 weeks, and patients who did not tolerate 150 mg/day were discontinued. The primary efficacy assessment was a between-group comparison of time to first seizure during the double-blind phase. Comparison of the Kaplan-Meier survival curves of time to first seizure favored the topiramate 400 mg/day group over the topiramate 50 mg/day group (Figure 1). The treatment effects with respect to time to first seizure were consistent across various patient subgroups defined by age, sex, geographic region, baseline body weight, baseline seizure type, time since diagnosis, and baseline AED use.

Figure 1: Kaplan-Meier Estimates of Cumulative Rates for Time to First Seizure

            Pediatric Patients 2 to 9 Years of Age

The conclusion that topiramate is effective as initial monotherapy in pediatric patients 2 to 9 years of age with partial onset or primary generalized tonic-clonic seizures was based on a pharmacometric bridging approach using data from the controlled epilepsy trials described in labeling. This approach consisted of first showing a similar exposure response relationship between pediatric patients down to 2 years of age and adults when topiramate was given as adjunctive therapy. Similarity of exposure-response was also demonstrated in pediatric patients 6 to less than 16 years of age and adults when topiramate was given as initial monotherapy. Specific dosing in pediatric patients 2 to 9 years of age was derived from simulations utilizing plasma exposure ranges observed in pediatric and adult patients treated with topiramate initial monotherapy [see Dosage and Administration (2.1)].

Adjunctive Therapy Epilepsy

Adult Patients With Partial Onset Seizures

The effectiveness of topiramate as an adjunctive treatment for adults with partial onset seizures was established in six multicenter, randomized, double-blind, placebo-controlled trials, two comparing several dosages of topiramate and placebo and four comparing a single dosage with placebo, in patients with a history of partial onset seizures, with or without secondarily generalized seizures.

Patients in these studies were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate tablets or placebo. In each study, patients were stabilized on optimum dosages of their concomitant AEDs during baseline phase lasting between 4 and 12 weeks. Patients who experienced a pre-specified minimum number of partial onset seizures, with or without secondary generalization, during the baseline phase (12 seizures for 12-week baseline, 8 for 8-week baseline or 3 for 4-week baseline) were randomly assigned to placebo or a specified dose of topiramate tablets  in addition to their other AEDs.

Following randomization, patients began the double-blind phase of treatment. In five of the six studies, patients received active drug beginning at 100 mg per day; the dose was then increased by 100 mg or 200 mg/day increments weekly or every other week until the assigned dose was reached, unless intolerance prevented increases. In the sixth study (Study 6), the 25 or 50 mg/day initial doses of topiramate were followed by respective weekly increments of 25 or 50 mg/day until the target dose of 200 mg/day was reached. After titration, patients entered a 4, 8 or 12-week stabilization period. The numbers of patients randomized to each dose and the actual mean and median doses in the stabilization period are shown in Table 11.

Pediatric Patients 2 to 16 Years of Age with Partial Onset Seizures

The effectiveness of topiramate as an adjunctive treatment for pediatric patients 2 to 16 years of age with partial onset seizures was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 7), comparing topiramate and placebo in patients with a history of partial onset seizures, with or without secondarily generalized seizures (see Table 12).

Patients in this study were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate tablets or placebo. In this study, patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least six partial onset seizures, with or without secondarily generalized seizures, during the baseline phase were randomly assigned to placebo or topiramate tablets in addition to their other AEDs.

Following randomization, patients began the doubleblind phase of treatment. Patients received active drug beginning at 25 or 50 mg/day; the dose was then increased by 25 mg to 150 mg/day increments every other week until the assigned dosage of 125, 175, 225, or 400 mg/day based on patients' weight to approximate a dosage of 6 mg/kg/day was reached, unless intolerance prevented increases. After titration, patients entered an 8 week stabilization period.

Patients With Primary Generalized Tonic-Clonic Seizures

The effectiveness of topiramate as an adjunctive treatment for primary generalized tonic-clonic seizures in patients 2 years of age and older was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 8),  comparing a single dosage of topiramate and placebo (see Table 12).

Patients in this study were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate or placebo. Patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least three primary generalized tonic-clonic seizures during the baseline phase were randomly assigned to placebo or topiramate in addition to their other AEDs.

Following randomization, patients began the double-blind phase of treatment. Patients received active drug beginning at 50 mg/day for four weeks; the dose was then increased by 50 mg to 150 mg/day increments every other week until the assigned dose of 175, 225, or 400 mg/day based on patients' body weight to approximate a dosage of 6 mg/kg/day was reached, unless intolerance prevented increases. After titration, patients entered a 12-week stabilization period.

Patients With Lennox-Gastaut Syndrome

The effectiveness of topiramate as an adjunctive treatment for seizures associated with Lennox-Gastaut syndrome was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 9) comparing a single dosage of topiramate with placebo in patients 2 years of age and older (see Table 12).

Patients in this study were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate tablets or placebo. Patients who were experiencing at least 60 seizures per month before study entry were stabilized on optimum dosages of their concomitant AEDs during a 4-week baseline phase. Following baseline, patients were randomly assigned to placebo or topiramate in addition to their other AEDs. Active drug was titrated beginning at 1 mg/kg/day for a week; the dose was then increased to 3 mg/kg/day for one week then to 6 mg/kg/day. After titration, patients entered an 8-week stabilization period. The primary measures of effectiveness were the percent reduction in drop attacks and a parental global rating of seizure severity.

Table 11 Topiramate Dose Summary During the Stabilization Periods of Each of Six Double-blind, Placebo-Controlled, Add-On Trials in Adults with Partial Onset Seizuresa

a  Dose-response studies were not conducted for other indications or pediatric partial onset seizures.

b  Placebo dosages are given as the number of tablets. Placebo target dosages were as follows: Protocol 3,   4 tablets/day; Protocols 1 and 4, 6 tablets/day; Protocols Y5 and 6, 8 tablets/day; Protocol 2, 10 tablets/day.
Protocol

 Stabilization Dose
 Target Topiramate Dosage (mg/day)






Placebob
 200
 400
 600
 800
 1,000
1
 N
 42
 42
 40
 41
 -
 -
Mean Dose
 5.9
 200
 390
 556
 -
 -
Median Dose
 6
 200
 400
 600
 -
 -
2
 N
 44
 -
 -
 40
 45
 40
Mean Dose
 9.7
 -
 -
 544
 739
 796
Median Dose
 10
 -
 -
 600
 800
 1,000
3
 N
 23
 -
 19
 -
 -
 -
Mean Dose
 3.8
 -
 395
 -
 -
 -
Median Dose
 4
 -
 400
 -
 -
 -
4
 N
 30
 -
 -
 28
 -
 -
Mean Dose
 5.7
 -
 -
 522
 -
 -
Median Dose
 6
 -
 -
 600
 -
 -
5
 N
 28
 -
 -
 -
 25
 -
Mean Dose
 7.9
 -
 -
 -
 568
 -
Median Dose
 8
 -
 -
 -
 600
 -
6
 N
 90
 157
 -
 -
 -
 -
Mean Dose
 8
 200
 -
 -
 -
 -
Median Dose
 8
 200
 -
 -
 -
 -

In all add-on trials, the reduction in seizure rate from baseline during the entire doubleblind phase was measured. The median percent reductions in seizure rates and the responder rates (fraction of patients with at least a 50% reduction) by treatment group for each study are shown below in Table 12. As described above, a global improvement in seizure severity was also assessed in the Lennox-Gastaut trial.

Table 12 Efficacy Results in Double-Blind, Placebo-Controlled, Add-On Epilepsy Trials

Comparisons with placebo: ap = 0.080; bp ≤ 0.010; cp ≤ 0.001; dp ≤ 0.050;e p = 0.065; fp ≤ 0.005; gp = 0.071;

h Median % reduction and % responders are reported for PGTC Seizures;

i Median % reduction and % responders for drop attacks, i.e., tonic or atonic seizures;

j Percent of patients who were minimally, much, or very much improved from baseline

* For Protocols 7 and 8, protocol-specified target dosages (< 9.3 mg/kg/day) were assigned based on subject's weight to approximate a dosage of 6 mg/kg per day; these dosages corresponded to mg/day dosages of 125, 175, 225, and 400 mg/day.
Protocol Efficacy Results
Target Topiramate Dosage (mg/day)







Placebo
 200
 400
 600
 800
 1,000
 ≈ 6 mg/kg/day*
Partial Onset Seizures
Studies in Adults














1
 N
 45
 45
 45
 46
 -
 -
 -
Median % Reduction
 12
 27a
 48b
 45c
 -
 -
 -
% Responders
 18
 24
 44d
 46d
 -
 -
 -
2
 N
 47
 -
 -
 48
 48
 47
 -
Median % Reduction
 2
 -
 -
 41c
 41c
 36c
 -
% Responders
 9
 -
 -
 40c
 41c
 36d
 -
3
 N
 24
 -
 23
 -
 -
 -
 -
Median % Reduction
 1
 -
 41e
 -
 -
 -
 -
% Responders
 8
 -
 35d
 -
 -
 -
 -
4
 N
 30
 -
 -
 30
 -
 -
 -
Median % Reduction
 -12
 -
 -
 46f
 -
 -
 -
% Responders
 10
 -
 -
 47c
 -
 -
 -
5
 N
 28
 -
 -
 -
 28
 -
 -
Median % Reduction
 -21
 -
 -
 -
 24c
 -
 -
% Responders
 0
 -
 -
 -
 43c
 -
 -
6
 N
 91
 168
 -
 -
 -
 -
 -
Median % Reduction
 20
 44c
 -
 -
 -
 -
 -
% Responders
 24
 45c
 -
 -
 -
 -
 -
Studies in Pediatric Patients
7
 N
 45
 -
 -
 -
 -
 -
 41
Median % Reduction
 11
 -
 -
 -
 -
 -
 33d
% Responders
 20
 -
 -
 -
 -
 -
 39
Primary Generalized Tonic-Clonich
8
 N
 40
 -
 -
 -
 -
 -
 39
Median % Reduction
 9
 -
 -
 -
 -
 -
 57d
% Responders
 20
 -
 -
 -
 -
 -
 56c
Lennox-Gastaut Syndromei
9
 N
 49
 -
 -
 -
 -
 -
 46
Median % Reduction
 -5
 -
 -
 -
 -
 -
 15d
% Responders
 14
 -
 -
 -
 -
 -
 28g
Improvement in Seizure Severityj
 28
 -
 -
 -
 -
 52d

Subset analyses of the antiepileptic efficacy of topiramate tablets in these studies showed no differences as a function of gender, race, age, baseline seizure rate, or concomitant AED. In clinical trials for epilepsy, daily dosages were decreased in weekly intervals by 50 to 100 mg/day in adults and over a 2 to 8 week period in pediatric patients; transition was permitted to a new antiepileptic regimen when clinically indicated.

Migraine Prophylaxis

Adult Patients

The results of 2 multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trials established the effectiveness of topiramate in the prophylactic treatment of migraine headache. The design of both trials (Study 10 was conducted in the U.S. and Study 11 was conducted in the U.S. and Canada) was identical, enrolling patients with a history of migraine, with or without aura, for at least 6 months, according to the International Headache Society (IHS) diagnostic criteria. Patients with a history of cluster headaches or basilar, ophthalmoplegic, hemiplegic, or transformed migraine headaches were excluded from the trials. Patients were required to have completed up to a 2-week washout of any prior migraine preventive medications before starting the baseline phase.

Patients who experienced 3 to 12 migraine headaches over the 4 weeks in the baseline phase were randomized to either topiramate 50 mg/day, 100 mg/day, 200 mg/day, or placebo and treated for a total of 26 weeks (8-week titration period and 18-week maintenance period). Treatment was initiated at 25 mg/day for one week, and then the daily dosage was increased by 25 mg increments each week until reaching the assigned target dose or maximum tolerated dose (administered twice daily).

Effectiveness of treatment was assessed by the reduction in migraine headache frequency, as measured by the change in 4-week migraine rate (according to migraines classified by IHS criteria) from the baseline phase to double-blind treatment period in each topiramate treatment group compared to placebo in the Intent-To-Treat (ITT) population.

In Study 10, a total of 469 patients (416 females, 53 males), ranging in age from 13 to 70 years, were randomized and provided efficacy data. Two hundred sixty-five patients completed the entire 26-week double-blind phase. The median average daily dosages were 48 mg/day, 88 mg/day, and 132 mg/day in the target dose groups of topiramate 50, 100, and 200 mg/day, respectively.

The mean migraine headache frequency rate at baseline was approximately 5.5 migraine headaches/28 days and was similar across treatment groups. The change in the mean 4-week migraine headache frequency from baseline to the double-blind phase was -1.3, -2.1, and -2.2 in the topiramate 50, 100, and 200 mg/day groups, respectively, versus -0.8 in the placebo group (see Figure 2). The treatment differences between the topiramate 100 and 200 mg/day groups versus placebo were similar and statistically significant (p<0.001 for both comparisons).

In Study11, a total of 468 patients (406 females, 62 males), ranging in age from 12 to 65 years, were randomized and provided efficacy data. Two hundred fifty-five patients completed the entire 26-week double-blind phase. The median average daily dosages were 47 mg/day, 86 mg/day, and 150 mg/day in the target dose groups of topiramate 50, 100, and 200 mg/day, respectively.

The mean migraine headache frequency rate at baseline was approximately 5.5 migraine headaches/28 days and was similar across treatment groups. The change in the mean 4- week migraine headache period frequency from baseline to the double-blind phase was - 1.4, -2.1, and -2.4 in the topiramate 50, 100, and 200 mg/day groups, respectively, versus -1.1 in the placebo group (see Figure 2). The differences between the topiramate 100 and 200 mg/day groups versus placebo were similar and statistically significant (p=0.008 and p <0.001, respectively).

In both studies, there were no apparent differences in treatment effect within age or gender subgroups. Because most patients were Caucasian, there were insufficient numbers of patients from different races to make a meaningful comparison of race.

For patients withdrawing from topiramate, daily dosages were decreased in weekly intervals by 25 to 50 mg/day.

Figure 2

Reduction in 4-Week Migraine Headache Frequency

(Studies 10 and 11 for adults and adolescents)

Pediatric Patients 12 to 17 Years of Age

The effectiveness of topiramate as prophylaxis for migraine headache in pediatric patients 12 to 17 years of age was established in a multicenter, randomized, double-blind, parallel-group trial. The study enrolled 103 patients (40 male, 63 female) 12 to 17 years of age with episodic migraine headaches with or without aura. Patient selection was based on IHS criteria for migraines (using proposed revisions to the 1988 IHS pediatric migraine criteria [IHS-R criteria]).

Patients who experienced 3 to 12 migraine attacks (according to migraines classified by patient reported diaries) and ≤14 headache days (migraine and non-migraine) during the 4-week prospective baseline period were randomized to either topiramate 50 mg/day, 100 mg/day, or placebo and treated for a total of 16 weeks (4-week titration period followed by a 12-week maintenance period). Treatment was initiated at 25 mg/day for one week, and then the daily dosage was increased by 25 mg increments each week until reaching the assigned target dose or maximum tolerated dose (administered twice daily). Approximately 80% or more patients in each treatment group completed the study. The median average daily dosages were 45 and 79 mg/day in the target dose groups of topiramate 50 and 100 mg/day, respectively.

Effectiveness of treatment was assessed by comparing each topiramate treatment group to placebo (ITT population) for the percent reduction from baseline to the last 12 weeks of the double-blind phase in the monthly migraine attack rate (primary endpoint). The percent reduction from baseline to the last 12 weeks of the double-blind phase in average monthly migraine attack rate is shown in Table 13. The 100 mg topiramate dose produced a statistically significant treatment difference relative to placebo of 28% reduction from baseline in the monthly migraine attack rate.

The mean reduction from baseline to the last 12 weeks of the double-blind phase in average monthly attack rate, a key secondary efficacy endpoint in Study 12 (and the primary efficacy endpoint in Studies 10 and 11, of adults) was 3.0 for 100 mg topiramate dose and 1.7 for placebo. This 1.3 treatment difference in mean reduction from baseline of monthly migraine rate was statistically significant (p = 0.0087).

Table 13 Percent Reduction from Baseline to the Last 12 Weeks of Double-Blind Phase in Average Monthly Attack Rate: Study 12 (Intent-to-Treat Analysis Set)

a P-values (two-sided) for comparisons relative to placebo are generated by applying an ANCOVA model on ranks that includes subject's stratified age at baseline, treatment group, and analysis center as factors and monthly migraine attack rate during baseline period as a covariate.

b P-values for the dose groups are the adjusted p-value according to the Hochberg multiple comparison procedure.

c Indicates p-value is <0.05 (two-sided).

Placebo
 Topiramate
 Topiramate


50 mg/day
 100 mg/day
Category
 (N=33)
 (N=35)
 (N=35)
Baseline


Median
 3.6
 4
 4
Last 12 Weeks of Double-Blind Phase


Median
 2.3
 2.3
 1
Percent Reduction (%)


Median
 44.4
 44.6
 72.2
P-value versus
 0.7975
 0.0164c
Placeboa,b


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