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Topamax

"The U.S. Food and Drug Administration today approved Aptiom (eslicarbazepine acetate) as an add-on medication to treat seizures associated with epilepsy.

Epilepsy is a brain disorder caused by abnormal or excessive activity in the brain"...

Topamax

Side Effects
Interactions

SIDE EFFECTS

The following adverse reactions are discussed in more detail in other sections of the labeling:

The data described in the following sections were obtained using TOPAMAX® (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

The adverse reactions in the controlled trial that occurred most commonly in adults in the 400 mg/day TOPAMAX® group and at an incidence 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 an incidence higher ( > 5%) than in the 50 mg/day group were fever, weight decrease, mood problems, cognitive problems, infection, flushing, and paresthesia (see Table 5). Table 5 also presents the incidence of adverse reactions occurring in at least 2% of adult and pediatric patients treated with 400 mg/day TOPAMAX® and occurring with greater incidence than 50 mg/day TOPAMAX®.

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 Incidence Was at Least 2% in Any TOPAMAX® Group and the Incidence in the 400 mg/day TOPAMAX® Group Was Greater Than the Incidence in the 50 mg/day TOPAMAX® Group for Adults ( ≥ 16 Years) and Pediatric (6 to < 16 Years) Patients in Study TOPMAX-EPMN-106

Body System Adverse Reaction Age Group
Pediatric (6 to < 16 Years) Adult (Age ≥ 16 Years)
TOPAMAX® Daily Dosage Group (mg/day)
50
(N=74)%*
400
(N=77)%*
50
(N=160)%*
400
(N=159)%*
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, Femalef
  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    
*Percentages calculated with the number of subjects in each group as denominator
† N with Female Reproductive Disorders – Incidence calculated relative to the number of females; Pediatric TPM 50 mg n=40; Pediatric TPM 400 mg n=33; Adult TPM 50 mg n=84; TPM 400 mg n=80

Adjunctive Therapy Epilepsy

The most commonly observed adverse reactions associated with the use of TOPAMAX® at dosages of 200 to 400 mg/day (recommended dose range) in controlled trials in adults with partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, that were seen at an incidence higher ( ≥ 5%) than in the placebo group were : somnolence, weight decrease, anorexia, dizziness, ataxia, speech disorders and related speech problems, language problems, psychomotor slowing, confusion, abnormal vision, difficulty with memory, paresthesia, diplopia, nervousness, and asthenia (see Table 6). Dose-related adverse reactions at dosages of 200 to 1,000 mg/day are shown in Table 8.

The most commonly observed 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 an incidence higher ( ≥ 5%) than in the placebo group were : fatigue, somnolence, anorexia, nervousness, difficulty with concentration/attention, difficulty with memory, aggressive reaction, and weight decrease (see Table 9). Table 9 also presents the incidence of adverse reactions occurring in at least 1% of pediatric patients treated with TOPAMAX®and occurring with greater incidence than placebo.

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 the incidence of adverse reactions that occurred in at least 1% of adults treated with 200 to 400 mg/day TOPAMAX® (and also higher daily dosing of 600 mg to 1000 mg) in controlled trials and that was numerically greater with TOPAMAX®than 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 the incidence of treatment-emergent adverse reactions that occurred in at least 1% of pediatric patients treated with 5 to 9 mg/kg TOPAMAX® in controlled trials and that was numerically greater than the incidence 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 Adultsa,b Where Incidence Was ≥ 1% in Any TOPAMAX® Group and Greater Than the Incidence in Placebo-Treated Patients

Body System/ Adverse Reactionc TOPAMAX® Dosage (mg/day)
Placebo
(N=291)
200-400
(N=183)
600-1,000
(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
a Patients in these add-on/ adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to TOPAMAX® or placebo.
bValues 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 Adverse reactions reported by at least 1% of patients in the TOPAMAX® 200-400 mg/day group and more common than in the placebo group are listed in this table.

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 most commonly observed adverse reactions associated with the use of TOPAMAX® that were seen at an incidence higher ( ≥ 5%) than in the placebo group were : paresthesia, nervousness, somnolence, difficulty with concentration/attention, and fatigue (see Table 7). Because these TOPAMAX® treatment difference incidence (TOPAMAX® % - Placebo %) of many 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 119a,b Where Incidence Was ≥ 2% in the TOPAMAX® Group and Greater Than the Rate in Placebo-Treated Patients

Body System/ Adverse Reactionc Placebo
(N=92)
TOPAMAX® Dosage (mg/day)
200
(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
aPatients in these add-on/adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to TOPAMAX® or placebo.
bValues 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 Adverse reactions reported by at least 2% of patients in the TOPAMAX® 200 mg/day group and more common than in the placebo group are listed in this table.

Table 8: Incidence (%) of Dose-Related Adverse Reactions From Placebo-Controlled, Add-On Trials in Adults With Partial Onset Seizuresa

Adverse Reaction Placebo
(N = 216)%
TOPAMAX® Dosage (mg/day)
2005
(N=45) %
400
(N = 68) %
600 - 1,000
(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
aDose-response studies were not conducted for other adult indications or for pediatric indications.

Table 9: Incidence (%) of Treatment-Emergent Adverse Reactions in Placebo-Controlled, Add-On Epilepsy Trials in Pediatric Patients (Ages 2 -16 Years)a,b (Reactions That Occurred in at Least 1% of TOPAMAX®-Treated Patients and Occurred More Frequently in TOPAMAX®-Treated Than Placebo-Treated Patients)

Body System/ Adverse Reaction Placebo
(N=101) %
TOPAMAX®
(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
aPatients in these add-on/adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to TOPAMAX® or placebo.
bValues 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.

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

Adults

In the four multicenter, randomized, double-blind, placebo-controlled, parallel group migraine prophylaxis clinical trials (which included 35 adolescent patients age 12 to 15 years), 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.

The most commonly observed adverse reactions associated with the use of the 100 mg TOPAMAX® dose in controlled trials in migraine prophylaxis trials of predominantly adults that were seen at an incidence higher ( ≥ 5 %) than in the placebo group were : paresthesia, anorexia, weight decrease, taste perversion, diarrhea, difficulty with memory, hypoesthesia, and nausea (see Table 10). 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 Patientsab

Body System/ Adverse Reaction Placebo
(N=445) %
TOPAMAX® Dosage (mg/day)
50
(N=235) %
100
(N=386) %
200
(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 visionc 2 4 2 4
  Conjunctivitis 1 1 2 1
a Includes 35 adolescent patients age 12 to 15 years.
bValues 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.
cBlurred 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.

Of the 1135 patients exposed to TOPAMAX® in the adult placebo-controlled studies, 25% discontinued due to adverse reactions, compared to 10% of the 445 placebo patients. The adverse reactions associated with discontinuing therapy in the 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 (treatment difference ≥ 5% for the 100 mg dose) were : paresthesia, nausea, anorexia, difficulty with memory, diarrhea, weight decrease, and hypoesthesia.

Table 11: Incidence (%) of Dose-Related Adverse Reactions From Placebo-Controlled, Migraine Trialsab

Adverse Reaction Placebo
(N=445) %
TOPAMAX® Dosage (mg/day)
50
(N=235) %
100
(N=386) %
200
(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
aIncludes 35 adolescent patients age 12 to < 16 years
bThe 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.

Adolescents 12 to 17 Years of Age

In five, 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. 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 TOPAMAX®-treated adolescent patients, the most commonly observed adverse reactions associated with the use of 100 mg of TOPAMAX® 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 12). Table 12 shows adverse reactions from the adolescent pivotal trial (Study 3 demonstrating the efficacy of TOPAMAX®; [see Clinical Studies]) in which there were 103 adolescent patients who were treated with placebo or 50 mg or 100 mg of TOPAMAX® and three predominantly adult trials in which there were 49 adolescent patients (12 to 17 years) who were treated with placebo or 50 mg, 100 mg or 200 mg of TOPAMAX®. Table 12 also shows adverse reactions in adolescents in the controlled migraine trials when the incidence in a TOPAMAX® dose group was at least 5 % or higher than the incidence of placebo. Many adverse reactions shown in Table 12 indicated a dose-dependent relationship.

Table 12: Incidence (%) of Treatment-Emergent Adverse Reactions in at Least 5% or Greater than the Placebo Incidence of Adolescents (12-17 Years) in Any TOPAMAX® Group in Pooled Double-Blind Migraine Prophylaxis Studiesabc

Body System/ Adverse Reaction Placebo
(N=45) %
TOPAMAX® Dosage
50 mg/day
(N=46) %
100 mg/day
(N=48) %
200 mg/day
(N=13) %
Body as a Whole - General Disorders
  Allergy 0 0 4 8
  Fatigue 7 7 8 15
  Fever 2 4 6 0
  Leg pain 0 2 2 8
Central & Peripheral Nervous System Disorders
  Dizziness 4 4 6 0
  Headache 2 2 4 8
  Language problems 2 0 0 15
  Muscle contractions involuntary 0 0 0 8
  Paresthesia 7 20 19 38
Endocrine Disorders
  Hyperthyroidism 0 0 0 8
Gastrointestinal System Disorders
  Abdominal pain 9 7 15 15
  Diarrhea 0 2 2 8
  Nausea 4 4 8 0
Metabolic and Nutritional Disorders
  Oedema pharynx 0 0 0 8
  Weight decrease 2 7 4 31
Platelet, Bleeding & Clotting Disorders
  Epistaxis 0 2 2 8
Psychiatric Disorders
  Anorexia 4 9 10 15
  Anxiety 0 0 0 8
  Difficulty with concentration/attention 0 0 2 15
  Difficulty with memory 2 0 0 8
  Insomnia 2 9 2 0
  Mood problems 4 2 2 8
  Psychomotor slowing 0 2 0 8
  Somnolence 2 2 6 15
Resistance Mechanism Disorders
  Infection viral 4 4 8 15
  Otitis media 0 0 0 8
Respiratory System Disorders
  Coughing 0 7 2 0
  Laryngitis 0 0 0 8
  Rhinitis 2 7 6 8
  Sinusitis 2 9 4 15
  Upper respiratory tract infection 11 26 23 23
Skin and Appendages Disorders
  Rash erythematous 0 0 0 8
Special Senses Other, Disorders
  Taste perversion 2 2 6 8
Vision Disorders
  Conjunctivitis 4 7 4 0
a35 adolescent patients aged 12 to < 16 years were also included in adverse reaction assessment for adults (Tables 10 and 11)
bIncidence is based on the number of subjects experiencing at least 1 adverse event, not the number of events.
cIncluded studies MIG-3006, MIGR-001, MIGR-002 and MIGR-003

In the double-blind placebo-controlled studies, adverse reactions led to discontinuation of treatment in 8% of placebo patients compared with 6% of TOPAMAX®-treated patients. Adverse reactions associated with discontinuing therapy that occurred in more than one TOPAMAX®-treated patient were fatigue (1%), headache (1%), and somnolence (1%).

Other Adverse Reactions Observed During Migraine Clinical Trials
Adults

TOPAMAX®, for the treatment of prophylaxis of migraine headache, has been administered to 1367 patients (including 33 adolescent patients aged 12 to < 16 years) 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 in Table 10 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.

Adolescents 12 to 17 Years of Age

In two clinical studies for the treatment of prophylaxis of migraine headache in pediatric patients only, TOPAMAX® has been administered to 134 adolescent patients (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 in Table 12 were reported by at least 2% of the 134 TOPAMAX®-treated patients in the controlled clinical trials:

Body as a Whole: Injury, influenza-like symptoms, back pain, pain.

Gastrointestinal System Disorders: Gastroenteritis, vomiting.

Musculoskeletal system disorders: Myalgia.

Psychiatric disorders: Nervousness.

Resistance Mechanism Disorders: Infection.

Respiratory System Disorders: Pharyngitis, asthma, bronchitis.

Skin and Appendages Disorders: Pruritus, rash.

Urinary System Disorders: Urinary incontinence, urinary tract infection.

Vision Disorders: Eye pain, vision abnormal.

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.

Read the Topamax (topiramate) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

In vitro studies indicate that topiramate does not inhibit enzyme activity for CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4/5 isozymes. In vitro studies indicate that topiramate is a mild inhibitor of CYP2C19 and a mild inducer of CYP3A4. Drug interactions with some antiepileptic drugs, CNS depressants and oral contraceptives are described here. For other drug interactions, please refer to Clinical Pharmacology (12.3).

Antiepileptic Drugs

Potential interactions between topiramate and standard AEDs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. Concomitant administration of phenytoin or carbamazepine with topiramate decreased plasma concentrations of topiramate by 48% and 40%, respectively when compared to TOPAMAX® given alone [see CLINICAL PHARMACOLOGY]

Concomitant administration of valproic acid and TOPAMAX® has been associated with hyperammonemia with and without encephalopathy. Concomitant administration of TOPAMAX® with valproic acid has also been associated with hypothermia (with and without hyperammonemia) in patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

CNS Depressants

Concomitant administration of TOPAMAX® and alcohol or other CNS depressant drugs has not been evaluated in clinical studies. Because of the potential of topiramate to cause CNS depression, as well as other cognitive and/or neuropsychiatric adverse reactions, TOPAMAX®should be used with extreme caution if used in combination with alcohol and other CNS depressants.

Oral Contraceptives

Exposure to ethinyl estradiol was statistically significantly decreased at doses of 200, 400, and 800 mg/day (18%, 21%, and 30%, respectively) when TOPAMAX® was given as adjunctive therapy in patients taking valproic acid. However, norethindrone exposure was not significantly affected. In another pharmacokinetic interaction study in healthy volunteers with a concomitantly administered combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 mcg ethinyl estradiol (EE), TOPAMAX® , given in the absence of other medications at doses of 50 to 200 mg/day, was not associated with statistically significant changes in mean exposure (AUC) to either component of the oral contraceptive. The possibility of decreased contraceptive efficacy and increased breakthrough bleeding should be considered in patients taking combination oral contraceptive products with TOPAMAX®. Patients taking estrogen-containing contraceptives should be asked to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding [see CLINICAL PHARMACOLOGY].

Metformin

Topiramate treatment can frequently cause metabolic acidosis, a condition for which the use of metformin is contraindicated [see CLINICAL PHARMACOLOGY].

Lithium

In patients, lithium levels were unaffected during treatment with topiramate at doses of 200 mg/day; however, there was an observed increase in systemic exposure of lithium (27% for Cmax and 26% for AUC) following topiramate doses of up to 600 mg/day. Lithium levels should be monitored when co-administered with high-dose TOPAMAX® [see CLINICAL PHARMACOLOGY].

Other Carbonic Anhydrase Inhibitors

Concomitant use of topiramate, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., zonisamide, acetazolamide, or dichlorphenamide) may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Therefore, if TOPAMAX® is given concomitantly with another carbonic anhydrase inhibitor, the patient should be monitored for the appearance or worsening of metabolic acidosis [see CLINICAL PHARMACOLOGY].

Drug Abuse And Dependence

Controlled Substance

TOPAMAX® (topiramate) is not a controlled substance.

Abuse

The abuse and dependence potential of TOPAMAX®has not been evaluated in human studies.

Dependence

TOPAMAX® has not been systematically studied in animals or humans for its potential for tolerance or physical dependence.

Read the Topamax Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 11/7/2014
This monograph has been modified to include the generic and brand name in many instances.

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