Topiramate (Page 4 of 11)

5.12 Hypothermia with Concomitant Valproic Acid Use

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

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)]
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)]
Serious Skin Reactions [see Warnings and Precautions ( 5.9)]
Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid [VPA] Use) [see Warnings and Precautions ( 5.10)]
Kidney Stones [see Warnings and Precautions ( 5.11)]
Hypothermia with Concomitant Valproic Acid (VPA) Use [see Warnings and Precautions ( 5.12)]

The data described in the following sections were obtained using topiramate tablets.

6.1 Clinical Trials Experience

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

Monotherapy Epilepsy
Adults 16 Years of Age and Older
The most common adverse reactions in the controlled clinical trial (Study 1) 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 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 to 15 Years of Age The most common adverse reactions in the controlled clinical 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 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 Trial (Study 1) in Adult and Pediatric Patients

Age Group

Pediatric (6 to 15 Years)

Adult (Age ≥16 Years)

Topiramate Daily Dosage Group (mg/day)

50

400

50

400

Body System Adverse Reaction

(N=74) %

(N=77) %

(N=160) %

(N=159) %

Body as a Whole — General Disorders

Asthenia

0

3

4

6

Fever

1

12

Leg pain

2

3

Central & Peripheral Nervous System Disorders

Paresthesia

3

12

21

40

Dizziness

13

14

Ataxia

3

4

Hypoesthesia

4

5

Hypertonia

0

3

Involuntary muscle contractions

0

3

Vertigo

0

3

Gastro-Intestinal System Disorders

Constipation

1

4

Diarrhea

8

9

Gastritis

0

3

Dry mouth

1

3

Liver and Biliary System Disorders

Increase Gamma-GT

1

3

Metabolic and Nutritional Disorders

Weight loss

7

17

6

17

Platelet, Bleeding & Clotting Disorders

Epistaxis

0

4

Psychiatric Disorders

Anorexia

4

14

Anxiety

4

6

Cognitive problems

1

6

1

4

Confusion

0

3

Depression

0

3

7

9

Difficulty with concentration 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

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, Adjunctive Epilepsy Trials in Adults *
*
Patients in these 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

Confusion

5

11

Anorexia

4

10

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

Reproductive Disorders

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.

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, Adjunctive Epilepsy Trials in Pediatric Patients 2 to 15 Years of Age *
*
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 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 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 topiramate 100 mg 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 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 Adults *
*
Includes 35 adolescent patients age 12 to 15 years.
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.
Blurred vision was the most common term considered as vision abnormal. Blurred vision was an included term that accounted for >50% of reactions coded as vision abnormal, a preferred term.
Body System / Adverse Reaction

Topiramate Dosage (mg/day)

Placebo (N=445) %
50 (N=235) %
100 (N=386) %

Body as a Whole-General Disorders

Fatigue

11

14

15

Injury

7

9

6

Central & Peripheral Nervous System Disorders

Paresthesia

6

35

51

Dizziness

10

8

9

Hypoesthesia

2

6

7

Language problems

2

7

6

Gastro-Intestinal System Disorders

Nausea

8

9

13

Diarrhea

4

9

11

Abdominal pain

5

6

6

Dyspepsia

3

4

5

Dry mouth

2

2

3

Gastroenteritis

1

3

3

Metabolic and Nutritional Disorders

Weight loss

1

6

9

Musculoskeletal System Disorders

Arthralgia

2

7

3

Psychiatric Disorders

Anorexia

6

9

15

Somnolence

5

8

7

Difficulty with memory

2

7

7

Insomnia

5

6

7

Difficulty with concentration/ attention

2

3

6

Mood problems

2

3

6

Anxiety

3

4

5

Depression

4

3

4

Nervousness

2

4

4

Confusion

2

2

3

Psychomotor slowing

1

3

2

Reproductive Disorders, Female

Menstrual disorder

2

3

2

Reproductive Disorders, Male

Ejaculation premature

0

3

0

Resistance Mechanism Disorders

Viral infection

3

4

4

Respiratory System Disorders

Upper respiratory tract infection

12

13

14

Sinusitis

6

10

6

Pharyngitis

4

5

6

Coughing

2

2

4

Bronchitis

2

3

3

Dyspnea

2

1

3

Skin and Appendages Disorders

Pruritis

2

4

2

Special Sense Other, Disorders

Taste perversion

1

15

8

Urinary System Disorders

Urinary tract infection

2

4

2

Vision Disorders

Blurred vision

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 clinical trials for the preventive treatment of migraine, 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 clinical trials for the preventive treatment of migraine 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 13 [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 Studies for the Preventive Treatment of Migraine in Pediatric Patients 12 to 17 Years of Age *
*
35 adolescent patients aged 12 to <16 years were also included in adverse reaction assessment for adults (Tables 10 and 11)
Incidence is based on the number of subjects experiencing at least 1 adverse event, not the number of events.
Included studies MIG-3006, MIGR-001, MIGR-002 and MIGR-003

Body System/

Adverse Reaction

Topiramate Dosage

Placebo

50 mg/day

100 mg/day

(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

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 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, 5.10)]. 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 of age) receiving topiramate for the preventive treatment of migraine, 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 the preventive treatment of migraine in pediatric patients less than 12 years of age.

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