ADVERSE REACTIONS
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.
The following adverse reactions are discussed in more detail in other sections of the labeling:
- Acute Myopia and Secondary Angle Closure [see Warnings and Precautions]
- Oligohidrosis and Hyperthermia [see Warnings and Precautions]
- Metabolic Acidosis [see Warnings and Precautions]
- Suicidal Behavior and Ideation [see Warnings and Precautions]
- Cognitive/Neuropsychiatric Adverse Reactions [see Warnings and Precautions]
- Fetal Toxicity [see Warnings and Precautions and Use in Specific Populations]
- Withdrawal of Antiepileptic Drugs (AEDs) [see Warnings and Precautions]
- Sudden Unexplained Death in Epilepsy (SUDEP) [see Warnings and Precautions]
- Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid [VPA] Use [see Warnings and Precautions]
- Kidney Stones [see Warnings and Precautions]
- Hypothermia with Concomitant Valproic Acid (VPA) Use [see Warnings and Precautions]
- Paresthesia [see Warnings and Precautions]
The data described in the following sections were obtained using TOPAMAX® (topiramate) Tablets.
Monotherapy Epilepsy
Adults ≥16 Years
The adverse reactions in the controlled trial that occurred most commonly in adults in the 400 mg/day TOPAMAX® group and at a rate higher (≥ 5 %) than in the 50 mg/day group were: paresthesia, weight decrease, anorexia, somnolence, and difficulty with memory (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 TOPAMAX® ) adverse reactions causing discontinuation in this trial were difficulty with memory, fatigue, asthenia, insomnia, somnolence, and paresthesia.
Pediatric Patients 6 to <16 Years of Age
The adverse reactions in the controlled trial that occurred most commonly in pediatric patients in the 400 mg/day TOPAMAX® group and at a rate higher (≥ 5%) than in the 50 mg/day group were fever, weight decrease, mood problems, cognitive problems, infection, flushing, and paresthesia (see Table 5).
Approximately 14% of the 77 pediatric patients in the 400 mg/day group who received TOPAMAX® 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 TOPAMAX® ) adverse reactions resulting in discontinuation in this trial were difficulty with concentration/attention, fever, flushing, and confusion.
Table 5: Incidence of Treatment-Emergent Adverse Reactions in Monotherapy Epilepsy Where the Rate Was at Least 2% in Any TOPAMAX® Group and the Rate in the 400 mg/day TOPAMAX® Group Was Greater Than the Rate in the 50 mg/day TOPAMAX® Group for Adults (≥16 Years) and Pediatric (6 to <16 Years) Patients in Study TOPMAX-EPMN-106
|
Age Group |
|
Pediatric
(6 to <16 Years) |
Adult
(Age ≥16 Years) |
|
TOPAMAX® Daily Dosage Group (mg/day) |
|
50 |
400 |
50 |
400 |
| Body System |
(N=74) |
(N=77) |
(N=160) |
(N=159) |
| Adverse Reaction |
%
|
%
|
%
|
%
|
|
Body as a Whole - General Disorders
|
| Asthenia |
0 |
3 |
4 |
6 |
| Chest pain |
|
| 1 |
2 |
| Fever |
1 |
12 |
|
|
| Leg pain |
|
| 2 |
3 |
|
Central & Peripheral Nervous System Disorders
|
| Ataxia |
|
| 3 |
4 |
| Dizziness |
|
| 13 |
14 |
| Hypertonia |
|
| 0 |
3 |
| Hypoesthesia |
|
| 4 |
5 |
| Muscle contractions involuntary |
0 |
3 |
|
|
| Paresthesia |
3 |
12 |
21 |
40 |
| Vertigo |
0 |
3 |
|
|
|
Gastro-Intestinal System Disorders
|
| Constipation |
|
| 1 |
4 |
| Diarrhea |
8 |
9 |
|
|
| Gastritis |
|
| 0 |
3 |
| Gastroesophageal reflux |
|
| 1 |
2 |
| Dry mouth |
|
| 1 |
3 |
|
Liver and Biliary System Disorders
|
| Gamma-GT increased |
|
| 1 |
3 |
|
Metabolic and Nutritional Disorders
|
| Weight decrease |
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 |
| Libido decreased |
|
| 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 |
| Infection viral |
3 |
6 |
6 |
8 |
|
Respiratory System Disorders
|
| Bronchitis |
1 |
5 |
3 |
4 |
| Dyspnea |
|
| 1 |
2 |
| Rhinitis |
5 |
6 |
2 |
4 |
| Sinusitis |
1 |
4 |
|
|
| Upper respiratory tract infection |
16 |
18 |
|
|
|
Skin and Appendages Disorders
|
| Acne |
|
| 2 |
3 |
| Alopecia |
1 |
4 |
3 |
4 |
| Pruritus |
|
| 1 |
4 |
| Rash |
3 |
4 |
1 |
4 |
|
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 |
|
|
| Urinary tract infection |
|
| 1 |
2 |
|
Vascular (Extracardiac) Disorders
|
| Flushing |
0 |
5 |
|
|
Adjunctive Therapy Epilepsy
The most commonly observed adverse reactions associated with the use of TOPAMAX® at dosages of 200 to 400 mg/day in controlled trials in adults with partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, that were seen at greater frequency in TOPAMAX®-treated patients and did not appear to be dose-related were somnolence, dizziness, ataxia, speech disorders and related speech problems, psychomotor slowing, abnormal vision, difficulty with memory, paresthesia and diplopia (see Table 6). The most common dose-related adverse reactions at dosages of 200 to 1,000 mg/day were fatigue, nervousness, difficulty with concentration or attention, confusion, depression, anorexia, language problems, anxiety, mood problems, and weight decrease (see Table 8).
Adverse reactions associated with the use of TOPAMAX® at dosages of 5 to 9 mg/kg/day in controlled trials in pediatric patients with partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, that were seen at greater frequency in TOPAMAX®- treated patients were fatigue, somnolence, anorexia, nervousness, difficulty with concentration/attention, difficulty with memory, aggressive reaction, and weight decrease (see Table 9).
In controlled clinical trials in adults, 11% of patients receiving TOPAMAX® 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 therapy included somnolence, dizziness, anxiety, difficulty with concentration or attention, fatigue, and paresthesia and increased at dosages above 400 mg/day. None of the pediatric patients who received TOPAMAX® adjunctive therapy at 5 to 9 mg/kg/day in controlled clinical trials discontinued due to adverse reactions.
Approximately 28% of the 1757 adults with epilepsy who received TOPAMAX® at dosages of 200 to 1,600 mg/day in clinical studies discontinued treatment because of adverse reactions; an individual patient could have reported more than one adverse reaction. These adverse reactions were psychomotor slowing (4.0%), difficulty with memory (3.2%), fatigue (3.2%), confusion (3.1%), somnolence (3.2%), difficulty with concentration/attention (2.9%), anorexia (2.7%), depression (2.6%), dizziness (2.5%), weight decrease (2.5%), nervousness (2.3%), ataxia (2.1%), and paresthesia (2.0%). Approximately 11% of the 310 pediatric patients who received TOPAMAX® at dosages up to 30 mg/kg/day discontinued due to adverse reactions. Adverse reactions associated with discontinuing therapy included aggravated convulsions (2.3%), difficulty with concentration/attention (1.6%), language problems (1.3%), personality disorder (1.3%), and somnolence (1.3%).
Incidence in Epilepsy Controlled Clinical Trials – Adjunctive Therapy – Partial Onset Seizures, Primary Generalized Tonic-Clonic Seizures, and Lennox-Gastaut Syndrome
Table 6 lists treatment-emergent adverse reactions that occurred in at least 1% of adults treated with 200 to 400 mg/day TOPAMAX® in controlled trials that were numerically more common at this dose than in the patients treated with placebo. In general, most patients who experienced adverse reactions during the first eight weeks of these trials no longer experienced them by their last visit. Table 9 lists treatment-emergent adverse reactions that occurred in at least 1% of pediatric patients treated with 5 to 9 mg/kg TOPAMAX® in controlled trials that were numerically more common than in patients treated with placebo.
The prescriber should be aware that these data were obtained when TOPAMAX® was added to concurrent antiepileptic drug therapy and cannot be used to predict the frequency of adverse reactions in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with data obtained from other clinical investigations involving different treatments, uses, or investigators. Inspection of these frequencies, however, does provide the prescribing physician with a basis to estimate the relative contribution of drug and non-drug factors to the adverse reaction incidences in the population studied.
Other Adverse Reactions Observed During Double-Blind Epilepsy Adjunctive Therapy Trials
Other adverse reactions that occurred in more than 1% of adults treated with 200 to 400 mg of TOPAMAX® in placebo-controlled epilepsy trials but with equal or greater frequency in the placebo group were headache, injury, anxiety, rash, pain, convulsions aggravated, coughing, fever, diarrhea, vomiting, muscle weakness, insomnia, personality disorder, dysmenorrhea, upper respiratory tract infection, and eye pain.
Table 6: Incidence of Treatment-Emergent Adverse Reactions in Placebo-Controlled, Add-On Epilepsy Trials in Adults
,
Where Incidence Was >1% in Any TOPAMAX® Group and Greater Than the Rate in Placebo-Treated Patients
|
|
TOPAMAX® Dosage (mg/day) |
| Body System/ |
Placebo |
200–400 |
600–1,000 |
| Adverse Reaction
|
(N=291) |
(N=183) |
(N=414) |
|
Body as a Whole-General Disorders
|
| Fatigue |
13 |
15 |
30 |
| Asthenia |
1 |
6 |
3 |
| Back pain |
4 |
5 |
3 |
| Chest pain |
3 |
4 |
2 |
| Influenza-like symptoms |
2 |
3 |
4 |
| Leg pain |
2 |
2 |
4 |
| Hot flushes |
1 |
2 |
1 |
| Allergy |
1 |
2 |
3 |
| Edema |
1 |
2 |
1 |
| Body odor |
0 |
1 |
0 |
| Rigors |
0 |
1 |
<1 |
|
Central & Peripheral Nervous System Disorders
|
| Dizziness |
15 |
25 |
32 |
| Ataxia |
7 |
16 |
14 |
| Speech disorders/Related speech problems |
2 |
13 |
11 |
| Paresthesia |
4 |
11 |
19 |
| Nystagmus |
7 |
10 |
11 |
| Tremor |
6 |
9 |
9 |
| Language problems |
1 |
6 |
10 |
| Coordination abnormal |
2 |
4 |
4 |
| Hypoesthesia |
1 |
2 |
1 |
| Gait abnormal |
1 |
3 |
2 |
| Muscle contractions involuntary |
1 |
2 |
2 |
| Stupor |
0 |
2 |
1 |
| Vertigo |
1 |
1 |
2 |
|
Gastro-Intestinal System Disorders
|
| Nausea |
8 |
10 |
12 |
| Dyspepsia |
6 |
7 |
6 |
| Abdominal pain |
4 |
6 |
7 |
| Constipation |
2 |
4 |
3 |
| Gastroenteritis |
1 |
2 |
1 |
| Dry mouth |
1 |
2 |
4 |
| Gingivitis |
<1 |
1 |
1 |
| GI disorder |
<1 |
1 |
0 |
|
Hearing and Vestibular Disorders
|
| Hearing decreased |
1 |
2 |
1 |
|
Metabolic and Nutritional Disorders
|
| Weight decrease |
3 |
9 |
13 |
|
Muscle-Skeletal System Disorders
|
| Myalgia |
1 |
2 |
2 |
| Skeletal pain |
0 |
1 |
0 |
|
Platelet, Bleeding, & Clotting Disorders
|
| Epistaxis |
1 |
2 |
1 |
|
Psychiatric Disorders
|
| Somnolence |
12 |
29 |
28 |
| Nervousness |
6 |
16 |
19 |
| Psychomotor slowing |
2 |
13 |
21 |
| Difficulty with memory |
3 |
12 |
14 |
| Anorexia |
4 |
10 |
12 |
| Confusion |
5 |
11 |
14 |
| Depression |
5 |
5 |
13 |
| Difficulty with concentration/attention |
2 |
6 |
14 |
| Mood problems |
2 |
4 |
9 |
| Agitation |
2 |
3 |
3 |
| Aggressive reaction |
2 |
3 |
3 |
| Emotional lability |
1 |
3 |
3 |
| Cognitive problems |
1 |
3 |
3 |
| Libido decreased |
1 |
2 |
<1 |
| Apathy |
1 |
1 |
3 |
| Depersonalization |
1 |
1 |
2 |
|
Reproductive Disorders, Female
|
| Breast pain |
2 |
4 |
0 |
| Amenorrhea |
1 |
2 |
2 |
| Menorrhagia |
0 |
2 |
1 |
| Menstrual disorder |
1 |
2 |
1 |
|
Reproductive Disorders, Male
|
| Prostatic disorder |
<1 |
2 |
0 |
|
Resistance Mechanism Disorders
|
| Infection |
1 |
2 |
1 |
| Infection viral |
1 |
2 |
<1 |
| Moniliasis |
<1 |
1 |
0 |
| Respiratory System Disorders
|
| Pharyngitis |
2 |
6 |
3 |
| Rhinitis |
6 |
7 |
6 |
| Sinusitis |
4 |
5 |
6 |
| Dyspnea |
1 |
1 |
2 |
|
Skin and Appendages Disorders
|
| Skin disorder |
<1 |
2 |
1 |
| Sweating increased |
<1 |
1 |
<1 |
| Rash erythematous |
<1 |
1 |
<1 |
|
Special Sense Other, Disorders
|
| Taste perversion |
0 |
2 |
4 |
|
Urinary System Disorders
|
| Hematuria |
1 |
2 |
<1 |
| Urinary tract infection |
1 |
2 |
3 |
| Micturition frequency |
1 |
1 |
2 |
| Urinary incontinence |
<1 |
2 |
1 |
| Urine abnormal |
0 |
1 |
<1 |
|
Vision Disorders
|
| Vision abnormal |
2 |
13 |
10 |
| Diplopia |
5 |
10 |
10 |
|
White Cell and RES Disorders
|
| Leukopenia |
1 |
2 |
1 |
Incidence in Study 119 – Add-On Therapy– Adults with Partial Onset Seizures
Study 119 was a randomized, double-blind, add-on/adjunctive, placebo-controlled, parallel group study with 3 treatment arms: 1) placebo; 2) TOPAMAX® 200 mg/day with a 25 mg/day starting dose, increased by 25 mg/day each week for 8 weeks until the 200 mg/day maintenance dose was reached; and 3) TOPAMAX® 200 mg/day with a 50 mg/day starting dose, increased by 50 mg/day each week for 4 weeks until the 200 mg/day maintenance dose was reached. All patients were maintained on concomitant carbamazepine with or without another concomitant antiepileptic drug.
The incidence of adverse reactions (Table 7) did not differ significantly between the 2 TOPAMAX® regimens. Because the frequencies of adverse reactions reported in this study were markedly lower than those reported in the previous epilepsy studies, they cannot be directly compared with data obtained in other studies.
Table 7: Incidence of Treatment-Emergent Adverse Reactions in Study 119
,
Where Incidence Was ≥ 2% in the TOPAMAX® Group and Greater Than the Rate in Placebo-Treated Patients
|
|
TOPAMAX®
Dosage (mg/day) |
| Body System/ |
Placebo |
200 |
| Adverse Reaction
|
(N=92) |
(N=171) |
|
Body as a Whole-General Disorders
|
| Fatigue |
4 |
9 |
| Chest pain |
1 |
2 |
|
Cardiovascular Disorders, General
|
| Hypertension |
0 |
2 |
|
Central & Peripheral Nervous System Disorders
|
| Paresthesia |
2 |
9 |
| Dizziness |
4 |
7 |
| Tremor |
2 |
3 |
| Hypoesthesia |
0 |
2 |
| Leg cramps |
0 |
2 |
| Language problems |
0 |
2 |
|
Gastro-Intestinal System Disorders
|
| Abdominal pain |
3 |
5 |
| Constipation |
0 |
4 |
| Diarrhea |
1 |
2 |
| Dyspepsia |
0 |
2 |
| Dry mouth |
0 |
2 |
|
Hearing and Vestibular Disorders
|
| Tinnitus |
0 |
2 |
|
Metabolic and Nutritional Disorders
|
| Weight decrease |
4 |
8 |
|
Psychiatric Disorders
|
| Somnolence |
9 |
15 |
| Anorexia |
7 |
9 |
| Nervousness |
2 |
9 |
| Difficulty with concentration/attention |
0 |
5 |
| Insomnia |
3 |
4 |
| Difficulty with memory |
1 |
2 |
| Aggressive reaction |
0 |
2 |
|
Respiratory System Disorders
|
| Rhinitis |
0 |
4 |
|
Urinary System Disorders
|
| Cystitis |
0 |
2 |
|
Vision Disorders
|
| Diplopia |
0 |
2 |
| Vision abnormal |
0 |
2 |
Table 8: Incidence (%) of Dose-Related Adverse Reactions From Placebo-Controlled, Add-On Trials in Adults With Partial Onset SeizuresDose-response studies were not conducted for other adult indications or for pediatric indications.
|
|
TOPAMAX® Dosage (mg/day) |
|
Placebo |
200 |
400 |
600 – 1,000 |
| Adverse Reaction |
(N = 216) |
(N = 45) |
(N = 68) |
(N = 414) |
| Fatigue |
13 |
11 |
12 |
30 |
| Nervousness |
7 |
13 |
18 |
19 |
| Difficulty with concentration/attention |
1 |
7 |
9 |
14 |
| Confusion |
4 |
9 |
10 |
14 |
| Depression |
6 |
9 |
7 |
13 |
| Anorexia |
4 |
4 |
6 |
12 |
| Language problems |
<1 |
2 |
9 |
10 |
| Anxiety |
6 |
2 |
3 |
10 |
| Mood problems |
2 |
0 |
6 |
9 |
| Weight decrease |
3 |
4 |
9 |
13 |
Table 9: Incidence (%) of Treatment-Emergent Adverse Reactions in Placebo-Controlled, Add-On Epilepsy Trials in Pediatric Patients (Ages 2 –16 Years)
,
(Reactions That Occurred in at Least 1% of TOPAMAX®-Treated Patients and Occurred More Frequently in TOPAMAX®-Treated Than Placebo-Treated Patients)
| Body System/ |
Placebo |
TOPAMAX®
|
| Adverse Reaction |
(N=101) |
(N=98) |
|
Body as a Whole - General Disorders
|
| Fatigue |
5 |
16 |
| Injury |
13 |
14 |
| Allergic reaction |
1 |
2 |
| Back pain |
0 |
1 |
| Pallor |
0 |
1 |
|
Cardiovascular Disorders, General
|
| Hypertension |
0 |
1 |
|
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 |
| Hyporeflexia |
0 |
2 |
| Convulsions grand mal |
0 |
1 |
| Fecal incontinence |
0 |
1 |
| Paresthesia |
0 |
1 |
|
Gastro-Intestinal System Disorders
|
| Nausea |
5 |
6 |
| Saliva increased |
4 |
6 |
| Constipation |
4 |
5 |
| Gastroenteritis |
2 |
3 |
| Dysphagia |
0 |
1 |
| Flatulence |
0 |
1 |
| Gastroesophageal reflux |
0 |
1 |
| Glossitis |
0 |
1 |
| Gum hyperplasia |
0 |
1 |
|
Heart Rate and Rhythm Disorders
|
| Bradycardia |
0 |
1 |
|
Metabolic and Nutritional Disorders
|
| Weight decrease |
1 |
9 |
| Thirst |
1 |
2 |
| Hypoglycemia |
0 |
1 |
| Weight increase |
0 |
1 |
|
Platelet, Bleeding, & Clotting Disorders
|
| Purpura |
4 |
8 |
| Epistaxis |
1 |
4 |
| Hematoma |
0 |
1 |
| Prothrombin increased |
0 |
1 |
| Thrombocytopenia |
0 |
1 |
|
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 |
| Appetite increased |
0 |
1 |
| Neurosis |
0 |
1 |
|
Reproductive Disorders, Female
|
| Leukorrhea |
0 |
2 |
|
Resistance Mechanism Disorders
|
| Infection viral |
3 |
7 |
|
Respiratory System Disorders
|
| Pneumonia |
1 |
5 |
| Respiratory disorder |
0 |
1 |
|
Skin and Appendages Disorders
|
| Skin disorder |
2 |
3 |
| Alopecia |
1 |
2 |
| Dermatitis |
0 |
2 |
| Hypertrichosis |
1 |
2 |
| Rash erythematous |
0 |
2 |
| Eczema |
0 |
1 |
| Seborrhea |
0 |
1 |
| Skin discoloration |
0 |
1 |
|
Urinary System Disorders
|
| Urinary incontinence |
2 |
4 |
| Nocturia |
0 |
1 |
|
Vision Disorders
|
| Eye abnormality |
1 |
2 |
| Vision abnormal |
1 |
2 |
| Diplopia |
0 |
1 |
| Lacrimation abnormal |
0 |
1 |
| Myopia |
0 |
1 |
|
White Cell and RES Disorders
|
| Leukopenia |
0 |
2 |
Other Adverse Reactions Observed During All Epilepsy Clinical Trials
TOPAMAX® has been administered to 2246 adults and 427 pediatric patients with epilepsy during all clinical studies, only some of which were placebo-controlled. During these studies, all adverse reactions were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse reactions, similar types of reactions were grouped into a smaller number of standardized categories using modified WHOART dictionary terminology. The frequencies presented represent the proportion of patients who experienced a reaction of the type cited on at least one occasion while receiving TOPAMAX®. Reported reactions are included except those already listed in the previous tables or text, those too general to be informative, and those not reasonably associated with the use of the drug.
Reactions are classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent occurring in at least 1/100 patients; infrequent occurring in 1/100 to 1/1000 patients; rare occurring in fewer than 1/1000 patients.
Autonomic Nervous System Disorders: Infrequent: vasodilation.
Body as a Whole: Frequent: syncope. Infrequent: abdomen enlarged. Rare: alcohol intolerance.
Cardiovascular Disorders, General: Infrequent: hypotension, postural hypotension, angina pectoris.
Central & Peripheral Nervous System Disorders: Infrequent: neuropathy, apraxia, hyperesthesia, dyskinesia, dysphonia, scotoma, ptosis, dystonia, visual field defect, encephalopathy, EEG abnormal. Rare: upper motor neuron lesion, cerebellar syndrome, tongue paralysis.
Gastrointestinal System Disorders: Infrequent: hemorrhoids, stomatitis, melena, gastritis, esophagitis. Rare: tongue edema.
Heart Rate and Rhythm Disorders: Infrequent: AV block.
Liver and Biliary System Disorders: Infrequent: SGPT increased, SGOT increased.
Metabolic and Nutritional Disorders: Infrequent: dehydration, hypocalcemia, hyperlipemia, hyperglycemia, xerophthalmia, diabetes mellitus. Rare: hypernatremia, hyponatremia, hypocholesterolemia, creatinine increased.
Musculoskeletal System Disorders: Frequent: arthralgia. Infrequent: arthrosis.
Neoplasms: Infrequent: thrombocythemia. Rare: polycythemia.
Platelet, Bleeding, and Clotting Disorders: Infrequent: gingival bleeding, pulmonary embolism.
Psychiatric Disorders: Frequent: impotence, hallucination, psychosis, suicide attempt. Infrequent: euphoria, paranoid reaction, delusion, paranoia, delirium, abnormal dreaming. Rare: libido increased, manic reaction.
Red Blood Cell Disorders: Frequent: anemia. Rare: marrow depression, pancytopenia.
Reproductive Disorders, Male: Infrequent: ejaculation disorder, breast discharge.
Skin and Appendages Disorders: Infrequent: urticaria, photosensitivity reaction, abnormal hair texture. Rare: chloasma.
Special Senses Other, Disorders: Infrequent: taste loss, parosmia.
Urinary System Disorders: Infrequent: urinary retention, face edema, renal pain, albuminuria, polyuria, oliguria.
Vascular (Extracardiac) Disorders: Infrequent: flushing, deep vein thrombosis, phlebitis. Rare: vasospasm.
Vision Disorders: Frequent: conjunctivitis. Infrequent: abnormal accommodation, photophobia, strabismus. Rare: mydriasis, iritis.
White Cell and Reticuloendothelial System Disorders: Infrequent: lymphadenopathy, eosinophilia, lymphopenia, granulocytopenia. Rare: lymphocytosis.
Migraine
In the four multicenter, randomized, double-blind, placebo-controlled, parallel group migraine prophylaxis clinical trials, most of the adverse reactions with TOPAMAX® were mild or moderate in severity. Most adverse reactions occurred more frequently during the titration period than during the maintenance period.
Table 10 includes those adverse reactions reported for patients in the placebo-controlled trials where the incidence in any TOPAMAX® treatment group was at least 2% and was greater than that for placebo patients.
Table 10: Incidence of Treatment-Emergent Adverse Reactions in Placebo-Controlled, Migraine Trials Where Incidence Was ≥2 % in Any TOPAMAX® Group and Greater Than the Rate in Placebo-Treated Patients
|
|
TOPAMAX® Dosage (mg/day) |
| Body System/ |
Placebo |
50 |
100 |
200 |
| Adverse Reaction |
(N=445) |
(N=235) |
(N=386) |
(N=514) |
|
Body as a Whole-General Disorders
|
| Fatigue |
11 |
14 |
15 |
19 |
| Injury |
7 |
9 |
6 |
6 |
| Asthenia |
1 |
<1 |
2 |
2 |
| Fever |
1 |
1 |
1 |
2 |
| Influenza-like symptoms |
<1 |
<1 |
<1 |
2 |
| Allergy |
<1 |
2 |
<1 |
<1 |
|
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 |
|
Gastro-Intestinal System Disorders
|
| Nausea |
8 |
9 |
13 |
14 |
| Diarrhea |
4 |
9 |
11 |
11 |
| Abdominal pain |
5 |
6 |
6 |
7 |
| Dyspepsia |
3 |
4 |
5 |
3 |
| Dry mouth |
2 |
2 |
3 |
5 |
| Vomiting |
2 |
1 |
2 |
3 |
| Gastroenteritis |
1 |
3 |
3 |
2 |
|
Hearing and Vestibular Disorders
|
| Tinnitus |
1 |
<1 |
1 |
2 |
|
Metabolic and Nutritional Disorders
|
| Weight decrease |
1 |
6 |
9 |
11 |
| Thirst |
<1 |
2 |
2 |
1 |
|
Musculoskeletal System Disorders
|
| Arthralgia |
2 |
7 |
3 |
1 |
|
Neoplasms
|
| Neoplasm |
<1 |
2 |
<1 |
<1 |
|
Psychiatric Disorders
|
| Anorexia |
6 |
9 |
15 |
14 |
| Somnolence |
5 |
8 |
7 |
10 |
| Difficulty with memory |
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 |
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 |
|
Respiratory System Disorders
|
| 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 |
|
Skin and Appendages Disorders
|
| Pruritis |
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
|
2 |
4 |
2 |
4 |
| Conjunctivitis |
1 |
1 |
2 |
1 |
Of the 1135 patients exposed to TOPAMAX® in the 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 TOPAMAX® -treated patients included paresthesia (7%), fatigue (4%), nausea (4%), difficulty with concentration/attention (3%), insomnia (3%), anorexia (2%), and dizziness (2%).
Patients treated with TOPAMAX® 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, TOPAMAX® 50, 100, and 200 mg groups, respectively.
Table 11 shows adverse reactions that were dose-dependent. Several central nervous system adverse reactions, including some that represented cognitive dysfunction, were dose-related. The most common dose-related adverse reactions were paresthesia, fatigue, nausea, anorexia, dizziness, difficulty with memory, diarrhea, weight decrease, difficulty with concentration/attention, and somnolence.
Table 11: Incidence (%) of Dose-Related Adverse Reactions From Placebo-Controlled, Migraine TrialsThe incidence of adverse reactions in the 200 mg/day group was ≥ 2% than the incidence in both the placebo group and the 50 mg/day group.
|
|
TOPAMAX® Dosage (mg/day) |
|
Placebo |
50 |
100 |
200 |
| Adverse Reaction |
(N=445) |
(N=235) |
(N=386) |
(N=514) |
| Paresthesia |
6 |
35 |
51 |
49 |
| Fatigue |
11 |
14 |
15 |
19 |
| Nausea |
8 |
9 |
13 |
14 |
| Anorexia |
6 |
9 |
15 |
14 |
| Dizziness |
10 |
8 |
9 |
12 |
| Weight decrease |
1 |
6 |
9 |
11 |
| Difficulty with memory |
2 |
7 |
7 |
11 |
| Diarrhea |
4 |
9 |
11 |
11 |
| Difficulty with concentration/attention |
2 |
3 |
6 |
10 |
| Somnolence |
5 |
8 |
7 |
10 |
| Hypoesthesia |
2 |
6 |
7 |
8 |
| Anxiety |
3 |
4 |
5 |
6 |
| Depression |
4 |
3 |
4 |
6 |
| Mood problems |
2 |
3 |
6 |
5 |
| Dry mouth |
2 |
2 |
3 |
5 |
| Confusion |
2 |
2 |
3 |
4 |
| Involuntary muscle contractions |
1 |
2 |
2 |
4 |
| Abnormal vision |
<1 |
1 |
2 |
3 |
| Renal calculus |
0 |
0 |
1 |
2 |
Other Adverse Reactions Observed During Migraine Clinical Trials
TOPAMAX®, for the treatment of prophylaxis of migraine headache, has been administered to 1367 patients in all clinical studies (includes double-blind and open-label extension). During these studies, all adverse reactions were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse reactions, similar types of reactions were grouped into a smaller number of standardized categories using modified WHOART dictionary terminology.
The following additional adverse reactions that were not described earlier were reported by greater than 1% of the 1367 TOPAMAX®-treated patients in the controlled clinical trials:
Body as a Whole: Pain, chest pain, allergic reaction.
Central & Peripheral Nervous System Disorders: Headache, vertigo, tremor, sensory disturbance, migraine aggravated.
Gastrointestinal System Disorders: Constipation, gastroesophageal reflux.
Musculoskeletal System Disorders: Myalgia.
Platelet, Bleeding, and Clotting Disorders: Epistaxis.
Reproductive Disorders, Female: Intermenstrual bleeding.
Resistance Mechanism Disorders: Infection, genital moniliasis.
Respiratory System Disorders: Pneumonia, asthma.
Skin and Appendages Disorders: Rash, alopecia.
Vision Disorders: Abnormal accommodation, eye pain.
Postmarketing and Other Experience
In addition to the adverse experiences reported during clinical testing of TOPAMAX®, the following adverse experiences have been reported worldwide in patients receiving TOPAMAX® post-approval.
These adverse experiences have not been listed above and data are insufficient to support an estimate of their incidence or to establish causation. The listing is alphabetized: bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), hepatic failure (including fatalities), hepatitis, maculopathy, pancreatitis, and pemphigus.
|
