TOPAMAX®

(topiramate) Tablets
TOPAMAX®
(topiramate) Capsules
DRUG DESCRIPTION
What are the possible side effects of topiramate (Topamax, Topamax Sprinkle)?
Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.
Call your doctor at once if you have any new or worsening symptoms such as: mood or behavior changes, depression, anxiety, or if you feel agitated, hostile, restless, hyperactive (mentally or physically), or have thoughts about suicide or hurting yourself.
Stop taking topiramate and call your doctor at once if you have any of…
Read All Potential Side Effects and See Pictures of Topamax »
Topiramate is a sulfamate-substituted monosaccharide. TOPAMAX® (topiramate) Tablets are available as 25 mg, 50 mg, 100 mg, and 200 mg round tablets for oral administration. TOPAMAX® (topiramate capsules) Sprinkle Capsules are available as 15 mg and 25 mg sprinkle capsules for oral administration as whole capsules or opened and sprinkled onto soft food.
Topiramate is a white crystalline powder with a bitter taste. Topiramate is most soluble in alkaline solutions containing sodium hydroxide or sodium phosphate and having a pH of 9 to 10. It is freely soluble in acetone, chloroform, dimethyl sulfoxide, and ethanol. The solubility in water is 9.8 mg/mL. Its saturated solu tion has a pH of 6.3. Topiramate has the molecular formula C12H21NO8S and a molecular weight of 339.36. Topiramate is designated chemically as 2,3:4,5-Di-O-isopropylidene-β-D-fructopyranose sulfamate and has the following structural formula:

TOPAMAX® (topiramate) Tablets contain the following inactive ingredients: lactose monohydrate, pregelatinized starch, micro crystalline cellulose, sodium starch glycolate, magnesium stearate, purified water, carnauba wax, hypromellose, titanium dioxide, polyethylene glycol, synthetic iron oxide (25, 50, 100, and 200 mg tablets) and polysorbate 80.
TOPAMAX® (topiramate capsules) Sprinkle Capsules contain topiramate coated beads in a hard gelatin capsule. The inactive ingredients are: sugar spheres (sucrose and starch), povidone, cellulose acetate, gelatin, sorbitan monolaurate, sodium lauryl sulfate, titanium dioxide, and black pharmaceutical ink.
Last reviewed on RxList: 12/28/2009
Topamax Indications & Dosage

INDICATIONS
Monotherapy Epilepsy
TOPAMAX® (topiramate) Tablets and TOPAMAX® (topiramate capsules) Sprinkle Capsules are indicated as initial monotherapy in patients 10 years of age and older with partial onset or primary generalized tonic-clonic seizures.
Effectiveness was demonstrated in a controlled trial in patients with epilepsy who had no more than 2 seizures in the 3 months prior to enrollment. Safety and effectiveness in patients who were converted to monotherapy from a previous regimen of other anticonvulsant drugs have not been established in controlled trials.
Adjunctive Therapy Epilepsy
TOPAMAX® (topiramate) Tablets and TOPAMAX® (topiramate capsules) Sprinkle Capsules are indicated as adjunctive therapy for adults and pediatric patients ages 2-16 years with partial onset seizures, or primary generalized tonic-clonic seizures, and in patients 2 years of age and older with seizures associated with Lennox-Gastaut syndrome.
Migraine
TOPAMAX® (topiramate) Tablets and TOPAMAX® (topiramate capsules) Sprinkle Capsules are indicated for adults for the prophylaxis of migraine headache. The usefulness of TOPAMAX® in the acute treatment of migraine headache has not been studied.
DOSAGE AND ADMINISTRATION
Epilepsy
In the controlled add-on trials, no correlation has been demonstrated between trough plasma concentrations of topiramate and clinical efficacy. No evidence of tolerance has been demonstrated in humans. Doses above 400 mg/day (600, 800, or 1,000 mg/day) have not been shown to improve responses in dose-response studies in adults with partial onset seizures.
It is not necessary to monitor topiramate plasma concentrations to optimize TOPAMAX® therapy. On occasion, the addition of TOPAMAX® to phenytoin may require an adjustment of the dose of phenytoin to achieve optimal clinical outcome. Addition or withdrawal of phenytoin and/or carbamazepine during adjunctive therapy with TOPAMAX® may require adjustment of the dose of TOPAMAX®. Because of the bitter taste, tablets should not be broken.
TOPAMAX® can be taken without regard to meals.
Monotherapy Use
The recommended dose for topiramate monotherapy in adults and children 10 years of age and older is 400 mg/day in two divided doses. Approximately 58% of patients randomized to 400 mg/day achieved this maximal dose in the monotherapy controlled trial; the mean dose achieved in the trial was 275 mg/day. The dose should be achieved by titrating according to the following schedule:
Morning Dose Evening Dose
Week 1 25 mg 25 mg
Week 2 50 mg 50 mg
Week 3 75 mg 75 mg
Week 4 100 mg 100 mg
Week 5 150 mg 150 mg
Week 6 200 mg 200 mg
Adjunctive Therapy Use
Adults (17 Years of Age and Over) – Partial Seizures, Primary Generalized Tonic-Clonic Seizures, or Lennox-Gastaut Syndrome
The recommended total daily dose of TOPAMAX® as adjunctive therapy in adults with partial seizures is 200-400 mg/day in two divided doses, and 400 mg/day in two divided doses as adjunctive treatment in adults with primary generalized tonic-clonic seizures. It is recommended that therapy be initiated at 25-50 mg/day followed by titration to an effective dose in increments of 25-50 mg/week. Titrating in increments of 25 mg/week may delay the time to reach an effective dose. Daily doses above 1,600 mg have not been studied.
In the study of primary generalized tonic-clonic seizures the initial titration rate was slower than in previous studies; the assigned dose was reached at the end of 8 weeks (see Clinical Studies, Adjunctive Therapy Controlled Trials in Patients With Primary Generalized Tonic-Clonic Seizures).
Pediatric Patients (Ages 2-16 Years) – Partial Seizures, Primary Generalized Tonic-Clonic Seizures, or Lennox-Gastaut Syndrome
The recommended total daily dose of TOPAMAX® (topiramate) as adjunctive therapy for patients with partial seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome is approximately 5 to 9 mg/kg/day in two divided doses. Titration should begin at 25 mg (or less, based on a range of 1 to 3 mg/kg/day) nightly for the first week. The dosage should then be increased at 1- or 2-week intervals by increments of 1 to 3 mg/kg/day (administered in two divided doses), to achieve optimal clinical response. Dose titration should be guided by clinical outcome.
In the study of primary generalized tonic-clonic seizures the initial titration rate was slower than in previous studies; the assigned dose of 6 mg/kg/day was reached at the end of 8 weeks (see Clinical Studies, Adjunctive Therapy Controlled Trials in Patients With Primary Generalized Tonic-Clonic Seizures).
Migraine
The recommended total daily dose of TOPAMAX® as treatment for prophylaxis of migraine headache is 100 mg/day administered in two divided doses. The recommended titration rate for topiramate for migraine prophylaxis to 100 mg/day is:
Morning Dose Evening Dose
Week 1 None 25 mg
Week 2 25 mg 25 mg
Week 3 25 mg 50 mg
Week 4 50 mg 50 mg
Dose and titration rate should be guided by clinical outcome. If required, longer intervals between dose adjustments can be used.
Administration of TOPAMAX® Sprinkle Capsules
TOPAMAX® (topiramate capsules) Sprinkle Capsules may be swallowed whole or may be administered by carefully opening the capsule and sprinkling the entire contents on a small amount (teaspoon) of soft food. This drug/food mixture should be swallowed immediately and not chewed. It should not be stored for future use.
Patients with Renal Impairment
In renally impaired subjects (creatinine clearance less than 70 mL/min/1.73 m²), one half of the usual adult dose is recommended. Such patients will require a longer time to reach steady-state at each dose.
Geriatric Patients (Ages 65 Years and Over)
Dosage adjustment may be indicated in the elderly patient when impaired renal function (creatinine clearance rate ≤ 70 mL/min/1.73 m²) is evident (see DOSAGE AND ADMINISTRATION: Patients with Renal Impairment and CLINICAL PHARMACOLOGY: Special Populations: Age, Gender, and Race).
Patients Undergoing Hemodialysis
Topiramate is cleared by hemodialysis at a rate that is 4 to 6 times greater than a normal individual. Accordingly, a prolonged period of dialysis may cause topiramate concentration to fall below that required to maintain an anti-seizure effect. To avoid rapid drops in topiramate plasma concentration during hemo dialysis, a supplemental dose of topiramate may be required. The actual adjustment should take into account 1) the duration of dialysis period, 2) the clearance rate of the dialysis system being used, and 3) the effective renal clearance of topiramate in the patient being dialyzed.
Patients with Hepatic Disease
In hepatically impaired patients topiramate plasma concentrations may be increased. The mechanism is not well understood.
HOW SUPPLIED
TOPAMAX® (topiramate) Tablets are available as debossed, coated, round tablets in the following strengths and colors:
25 mg cream (debossed “OMN” on one side; “25” on the other)
50 mg light-yellow (debossed “OMN” on one side; “50” on the other)
100 mg yellow (debossed “OMN” on one side; “100” on the other)
200 mg salmon (debossed “OMN” on one side; “200” on the other)
They are supplied as follows:
25 mg tablets – bottles of 60 count with desiccant (NDC 50458-639-65)
50 mg tablets – bottles of 60 count with desiccant (NDC 50458-640-65)
100 mg tablets – bottles of 60 count with desiccant (NDC 50458-641-65)
200 mg tablets – bottles of 60 count with desiccant (NDC 50458-642-65)
TOPAMAX® (topiramate capsules) Sprinkle Capsules contain small, white to off white spheres. The gelatin capsules are white and clear.
They are marked as follows:
15 mg capsule with “TOP” and “15 mg” on the side
25 mg capsule with “TOP” and “25 mg” on the side
The capsules are supplied as follows:
15 mg capsules – bottles of 60 (NDC 50458-647-65)
25 mg capsules – bottles of 60 (NDC 50458-645-65)
TOPAMAX® (topiramate) Tablets should be stored in tightly-closed containers at controlled room temperature (59 to 86°F, 15 to 30°C). Protect from moisture.
TOPAMAX® (topiramate capsules) Sprinkle Capsules should be stored in tightly-closed containers at or below 25°C (77°F). Protect from moisture.
TOPAMAX® (topiramate) and TOPAMAX® (topiramate capsules) are trademarks of Ortho-McNeil Neurologics, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc.
TOPAMAX® (topiramate) Tablets and TOPAMAX® (topiramate capsules) Sprinkle Capsules are manufactured by Janssen Ortho, LLC Gurabo, Puerto Rico 00778 and are manufactured for Ortho-McNeil Neurologics, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc., Titusville, NJ 08560. Rev May 2009.
Last reviewed on RxList: 12/28/2009
Topamax Side Effects & Drug Interactions

SIDE EFFECTS
The data described in the following section were obtained using TOPAMAX® (topiramate) Tablets.
Monotherapy Epilepsy
The adverse events in the controlled trial that occurred most commonly in adults in the 400 mg/day group and at a rate higher than the 50 mg/day group were: paresthesia, weight decrease, somnolence, anorexia, dizziness, and difficulty with memory NOS [see Table 5].
The adverse events in the controlled trial that occurred most commonly in children (10 years up to 16 years of age) in the 400 mg/day group and at a rate higher than the 50 mg/day group were: weight decrease, upper respiratory tract infection, paresthesia, anorexia, diarrhea, and mood problems [see Table 6].
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 events. Adverse events associated with discontinuing therapy ( ≥ 2%) included depression, insomnia, difficulty with memory (NOS), somnolence, paresthesia, psychomotor slowing, dizziness, and nausea.
Approximately 12% of the 57 pediatric patients in the 400 mg/day group who received topiramate as monotherapy in the controlled clinical trial discontinued therapy due to adverse events. Adverse events associated with discontinuing therapy ( ≥ 5%) included difficulty with concentration/attention.
The prescriber should be aware that these data cannot be used to predict the frequency of adverse events in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during the clinical study. 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 event incidences in the population studied.
Table 5: Incidence of Treatment-Emergent Adverse Events in the Monotherapy Epilepsy Trial in Adultsa Where Rate Was at Least 2% in the 400 mg/day Topiramate Group and Greater Than the Rate in the 50 mg/day Topiramate Group
Body System/Adverse Event TOPAMAX® Dosage (mg/day)
50
(N=160) 400
(N=159)
Body as a Whole–General Disorders
Asthenia 4 6
Leg Pain 2 3
Chest Pain 1 2
Central & Peripheral Nervous System Disorders
Paresthesia 21 40
Dizziness 13 14
Hypoaesthesia 4 5
Ataxia 3 4
Hypertonia 0 3
Gastro-Intestinal System Disorders
Diarrhea 5 6
Constipation 1 4
Gastritis 0 3
Dry Mouth 1 3
Gastroesophageal Reflux 1 2
Liver and Biliary System Disorders
Gamma-GT Increased 1 3
Metabolic and Nutritional Disorders
Weight Decrease 6 16
Psychiatric Disorders
Somnolence 9 15
Anorexia 4 14
Difficulty with Memory NOS 5 10
Insomnia 8 9
Depression 7 9
Difficulty with Concentration/Attention 7 8
Anxiety 4 6
Psychomotor Slowing 3 5
Mood Problems 2 5
Confusion 3 4
Cognitive Problem NOS 1 4
Libido Decreased 0 3
Reproductive Disorders, Female
Vaginal Hemorrhage 0 3
Red Blood Cell Disorders
Anemia 1 2
Resistance Mechanism Disorders
Infection Viral 6 8
Infection 2 3
Respiratory System Disorders
Bronchitis 3 4
Rhinitis 2 4
Dyspnea 1 2
Skin and Appendages Disorders
Rash 1 4
Pruritus 1 4
Acne 2 3
Special Senses Other, Disorders
Taste Perversion 3 5
Urinary System Disorders
Cystitis 1 3
Renal Calculus 0 3
Urinary Tract Infection 1 2
Dysuria 0 2
Micturition Frequency 0 2
a Values represent the percentage of patients reporting a given adverse event. Patients may have reported more than one adverse event during the study and can be included in more than one adverse event category.
Table 6: Incidence of Treatment-Emergent Adverse Events in the Monotherapy Epilepsy Trial in Children Ages 10 up to 16 YearsaWhere Rate Was at Least 5% in the 400 mg/day Topiramate Group and Greater Than the Rate in the 50 mg/day Topiramate Group
Body System/Adverse Event TOPAMAX® Dosage (mg/day)
50
(N=57) 400
(N=57)
Body as a Whole–General Disorders
Fever 0 9
Central & Peripheral Nervous System Disorders
Paresthesia 2 16
Gastro-Intestinal System Disorders
Diarrhea 5 11
Metabolic and Nutritional Disorders
Weight Decrease 7 21
Psychiatric Disorders
Anorexia 11 14
Mood Problems 2 11
Difficulty with Concentration/Attention 4 9
Cognitive Problems NOS 0 7
Nervousness 4 5
Resistance Mechanism Disorders
Infection Viral 4 9
Infection 2 7
Respiratory System Disorders
Upper Respiratory Tract Infection 16 18
Rhinitis 2 7
Bronchitis 2 7
Sinusitis 2 5
Skin and Appendages Disorders
Alopecia 2 5
a Values represent the percentage of patients reporting a given adverse event. Patients may have reported more than oneadverse event during the study and can be included in more than one adverse event category.
Adjunctive Therapy Epilepsy
The most commonly observed adverse events associated with the use of topiramate 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 topiramate-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 7]. The most common dose-related adverse events at dosages of 200 to 1,000 mg/day were: fatigue, nervousness, difficulty with concentration or attention, confusion, depres sion, anorexia, language problems, anxiety, mood problems, and weight decrease [see Table 9].
Adverse events associated with the use of topiramate 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 topiramate-treated patients were: fatigue, somnolence, anorexia, nervousness, difficulty with concentration/attention, difficulty with memory, aggressive reaction, and weight decrease [see Table 10].
In controlled clinical trials in adults, 11% of patients receiving topiramate 200 to 400 mg/day as adjunctive therapy discontinued due to adverse events. This rate appeared to increase at dosages above 400 mg/day. Adverse events 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 topiramate adjunctive therapy at 5 to 9 mg/kg/day in controlled clinical trials discontinued due to adverse events.
Approximately 28% of the 1,757 adults with epilepsy who received topiramate at dosages of 200 to 1,600 mg/day in clinical studies discontinued treatment because of adverse events; an individual patient could have reported more than one adverse event. These adverse events 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 topiramate at dosages up to 30 mg/kg/day discontinued due to adverse events. Adverse events 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 7 lists treatment-emergent adverse events that occurred in at least 1% of adults treated with 200 to 400 mg/day topiramate 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 events during the first eight weeks of these trials no longer experienced them by their last visit. Table 10 lists treatment-emergent adverse events that occurred in at least 1% of pediatric patients treated with 5 to 9 mg/kg topiramate 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 events 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 event incidences in the population studied.
Other Adverse Events Observed During Double-Blind Epilepsy Adjunctive Therapy Trials
Other events that occurred in more than 1% of adults treated with 200 to 400 mg of topiramate 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 7: Incidence of Treatment-Emergent Adverse Events in Placebo-Controlled, Add-On Epilepsy Trials in Adultsa,b Where Rate Was > 1% in Any Topiramate Group and Greater Than the Rate in Placebo-Treated Patients
Body System/Adverse Eventc Placebo
(N=291) TOPAMAX® Dosage (mg/day)
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 Hypoaesthesia 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 trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to TOPAMAX® or placebo. b Values represent the percentage of patients reporting a given adverse event. Patients may have reported more than one adverse event during the study and can be included in more than one adverse event category. c Adverse events 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, placebo-controlled, parallel group study with 3 treatment arms: 1) placebo; 2) topiramate 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) topiramate 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 events (Table 8) did not differ significantly between the 2 topiramate regimens. Because the frequencies of adverse events 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 8: Incidence of Treatment-Emergent Adverse Events in Study 119a,b Where Rate Was ≥ 2% in the Topiramate Group and Greater Than the Rate in Placebo-Treated Patients Body System/Adverse Event c 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 Hypoasthesia 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 a Patients in these add-on trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to TOPAMAX® or placebo. b Values represent the percentage of patients reporting a given adverse event. Patients may have reported more than one adverse event during the study and can be included in more than one adverse event category. c Adverse events 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 9: Incidence (%) of Dose-Related Adverse Events From Placebo-Controlled, Add-On Trials in Adults with Partial Onset Seizuresa Adverse Event Placebo (N=216) TOPAMAX® Dosage (mg/day) 200 (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 a Dose-response studies were not conducted for other adult indications or for pediatric indications. Table 10: Incidence (%) of Treatment-Emergent Adverse Events in Placebo-Controlled, Add-On Epilepsy Trials in Pediatric Patients Ages 2-16 Yearsa,b (Events that Occurred in at Least 1% of Topiramate-Treated Patients and Occurred More Frequently in Topiramate-Treated Than Placebo-Treated Patients) Body System/Adverse Event Placebo (N=101) Topiramate (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 NOS 0 5 Confusion 3 4 Psychomotor Slowing 2 3 Appetite Increased 0 1 Neurosis 0 1 Reproductive Disorders, Female Leukorrhoea 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 Seborrhoea 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 a Patients in these add-on trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to TOPAMAX® or placebo. b Values represent the percentage of patients reporting a given adverse event. Patients may have reported more than one adverse event during the study and can be included in more than one adverse event category. Other Adverse Events Observed During All Epilepsy Clinical Trials Topiramate has been administered to 2,246 adults and 427 pediatric patients with epilepsy during all clinical studies, only some of which were placebo controlled. During these studies, all adverse events were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse events, similar types of events were grouped into a smaller number of standardized categories using modified WHOART dictionary terminology. The frequencies presented represent the proportion of patients who experienced an event of the type cited on at least one occasion while receiving topiramate. Reported events 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. Events 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, hyper aesthesia, 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, hypo kalemia, alkaline phosphatase increased, hypocalcemia, hyperlipemia, hyperglycemia, xero phthalmia, diabetes mellitus. Rare: hyperchloremia, hyper natremia, hyponatremia, hypo choles terolemia, hypo phosphatemia, 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 accom modation, 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 events with topiramate were mild or moderate in severity. Most adverse events occurred more frequently during the titration period than during the maintenance period. Table 11 includes those adverse events reported for patients in the placebo-controlled trials where the incidence rate in any topiramate treatment group was at least 2 % and was greater than that for placebo patients. Table 11: Incidence of Treatment-Emergent Adverse Events in Placebo-Controlled, Migraine Trials Where Rate Was ≥ 2 % in Any Topiramate Group and Greater than the Rate in Placebo-Treated Patientsa Body System/Adverse Event 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 Hypoaesthesia 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 NOS < 1 2 < 1 < 1 Psychiatric Disorders Anorexia 6 9 15 14 Somnolence 5 8 7 10 Difficulty with Memory NOS 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 NOS 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 Visionb 2 4 2 4 Conjunctivitis 1 1 2 1 a Values represent the percentage of patients reporting a given adverse event. Patients may have reported more than one adverse event during the study and can be included in more than one adverse event category. b Blurred vision was the most common term considered as vision abnormal. Blurred vision was an included term that accounted for > 50 % of events coded as vision abnormal, a preferred term.
Of the 1,135 patients exposed to topiramate in the placebo-controlled studies, 25% discontinued due to adverse events, compared to 10% of the 445 placebo patients. The adverse events 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.
Table 12 shows adverse events that were dose-dependent. Several central nervous system adverse events, including some that represented cognitive dysfunction, were dose-related. The most common dose-related adverse events were paresthesia, fatigue, nausea, anorexia, dizziness, difficulty with memory, diarrhea, weight decrease, difficulty with concentration/attention, and somnolence.
Table 12: Incidence (%) of Dose-Related Adverse Events From Placebo-Controlled, Migraine Trialsa
Adverse Event 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 NOS 2 7 7 11
Diarrhea 4 9 11 11
Difficulty with Concentration/Attention 2 3 6 10
Somnolence 5 8 7 10
Hypoaesthesia 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 a The incidence rate of the adverse event in the 200 mg/day group was ≥ 2% than the rate in both the placebo group and the 50 mg/day group. Other Adverse Events Observed During Migraine Clinical Trials Topiramate, for the treatment of prophylaxis of migraine headache, has been administered to 1,367 patients in all clinical studies (includes double-blind and open-label extension). During these studies, all adverse events were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse events, similar types of events were grouped into a smaller number of standardized categories using modified WHOART dictionary terminology. The following additional adverse events that were not described earlier were reported by greater than 1% of the 1,367 topiramate-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, tooth disorder. 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, pemphigus, and renal tubular acidosis. Drug Abuse And Dependence The abuse and dependence potential of TOPAMAX® has not been evaluated in human studies. DRUG INTERACTIONS In vitro studies indicate that topiramate does not inhibit enzyme activity for CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4/5 isozymes. Antiepileptic Drugs Potential interactions between topiramate and standard AEDs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. The effects of these interactions on mean plasma AUCs are summarized in Table 4. In Table 4, the second column (AED concentration) describes what happens to the concentration of the AED listed in the first column when topiramate is added. The third column (topiramate concentration) describes how the coadministra tion of a drug listed in the first column modifies the concentration of topiramate in experimental settings when TOPAMAX® was given alone. Table 4: Summary of AED Interactions with TOPAMAX® AED Co-administered AED Concentration Topiramate Concentration Phenytoin NC or 25% increasea 48% decrease Carbamazepine (CBZ) NC 40% decrease CBZ epoxideb NC NE Valproic acid 11% decrease 14% decrease Phenobarbital NC NE Primidone NC NE Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease a = Plasma concentration increased 25% in some patients, generally those on a b.i.d. dosing regimen of phenytoin. b = Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. AED = Antiepileptic drug. NE = Not Evaluated. TPM = Topiramate In addition to the pharmacokinetic interaction described in the above table, concomitant administration of valproic acid and topiramate has been associated with hyperammonemia with and without encephalopathy (see PRECAUTIONS, Hyperammonemia and Encephalopathy Associated with Concomitant Valproic Acid Use). Other Drug Interactions Digoxin: In a single-dose study, serum digoxin AUC was decreased by 12% with concomitant TOPAMAX® administration. The clinical relevance of this observation has not been established. 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 events, topiramate should be used with extreme caution if used in combination with alcohol and other CNS depressants. Oral Contraceptives: In a 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. In another study, exposure to EE was statistically significantly decreased at doses of 200, 400, and 800 mg/day (18%, 21%, and 30%, respectively) when given as adjunctive therapy in patients taking valproic acid. In both studies, TOPAMAX® (50 mg/day to 800 mg/day) did not significantly affect exposure to NET. Although there was a dose dependent decrease in EE exposure for doses between 200-800 mg/day, there was no significant dose dependent change in EE exposure for doses of 50-200 mg/day. The clinical significance of the changes observed is not known. 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. Hydrochlorothiazide (HCTZ): A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of HCTZ (25 mg q24h) and topiramate (96 mg q12h) when administered alone and concomitantly. The results of this study indicate that topiramate Cmax increased by 27% and AUC increased by 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The addition of HCTZ to topiramate therapy may require an adjustment of the topiramate dose. The steady-state pharmacokinetics of HCTZ were not significantly influenced by the concomitant administration of topiramate. Clinical laboratory results indicated decreases in serum potassium after topiramate or HCTZ administration, which were greater when HCTZ and topiramate were administered in combination. Metformin: A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of metformin and topiramate in plasma when metformin was given alone and when metformin and topiramate were given simultaneously. The results of this study indicated that metformin mean Cmax and mean AUC0-12h increased by 18% and 25%, respectively, while mean CL/F decreased 20% when metformin was co-administered with topiramate. Topiramate did not affect metformin tmax. The clinical significance of the effect of topiramate on metformin pharmacokinetics is unclear. Oral plasma clearance of topiramate appears to be reduced when administered with metformin. The extent of change in the clearance is unknown. The clinical significance of the effect of metformin on topiramate pharmacokinetics is unclear. When TOPAMAX® is added or withdrawn in patients on metformin therapy, careful attention should be given to the routine monitoring for adequate control of their diabetic disease state. Pioglitazone: A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of topiramate and pioglitazone when administered alone and concomitantly. A 15% decrease in the AUCι,ss of pioglitazone with no alteration in Cmax,ss was observed. This finding was not statistically significant. In addition, a 13% and 16% decrease in Cmax,ss and AUCι,ss respectively, of the active hydroxy-metabolite was noted as well as a 60% decrease in Cmax,ss and AUCι,ss of the active keto-metabolite. The clinical significance of these findings is not known. When TOPAMAX® is added to pioglitazone therapy or pioglitazone is added to TOPAMAX® therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state. Lithium: Multiple dosing of topiramate 100 mg every 12 hrs decreased the AUC and Cmax of Lithium (300 mg every 8 hrs) by 20% (N=12, 6 M; 6 F). Haloperidol: The pharmacokinetics of a single dose of haloperidol (5 mg) were not affected following multiple dosing of topiramate (100 mg every 12 hr) in 13 healthy adults (6 M, 7 F). Amitriptyline: There was a 12% increase in AUC and Cmax for amitriptyline (25 mg per day) in 18 normal subjects (9 male; 9 female) receiving 200 mg/day of topiramate. Some subjects may experience a large increase in amitriptyline concentration in the presence of topiramate and any adjustments in amitriptyline dose should be made according to the patient's clinical response and not on the basis of plasma levels. Sumatriptan: Multiple dosing of topiramate (100 mg every 12 hrs) in 24 healthy volunteers (14 M, 10 F) did not affect the pharmacokinetics of single dose sumatriptan either orally (100 mg) or subcutaneously (6 mg). Risperidone: There was a 25% decrease in exposure to risperidone (2 mg single dose) in 12 healthy volunteers (6 M, 6 F) receiving 200 mg/day of topiramate. Therefore, patients receiving risperidone in combination with topiramate should be closely monitored for clinical response. Propranolol: Multiple dosing of topiramate (200 mg/day) in 34 healthy volunteers (17 M, 17 F) did not affect the pharmacokinetics of propranolol following daily 160 mg doses. Propranolol doses of 160 mg/day in 39 volunteers (27M, 12F) had no effect on the exposure to topiramate at a dose of 200 mg/day of topiramate. Dihydroergotamine: Multiple dosing of topiramate (200 mg/day) in 24 healthy volunteers (12 M, 12 F) did not affect the pharmacokinetics of a 1 mg subcutaneous dose of dihydroergotamine. Similarly, a 1 mg subcutaneous dose of dihydroergotamine did not affect the pharmacokinetics of a 200 mg/day dose of topiramate in the same study. Others: Concomitant use of TOPAMAX®, a carbonic anhydrase inhibitor, with other carbonic anhydrase inhibitors, e.g., aceta zolamide or dichlor phena mide, may create a physiological environment that increases the risk of renal stone formation, and should therefore be avoided. Drug/Laboratory Tests Interactions: There are no known interactions of topiramate with commonly used laboratory tests. Last reviewed on RxList: 12/28/2009 Topamax Warnings & Precautions WARNINGS Metabolic Acidosis Hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis) is associated with topiramate treatment. This metabolic acidosis is caused by renal bicarbonate loss due to the inhibitory effect of topiramate on carbonic anhydrase. Such electrolyte imbalance has been observed with the use of topiramate in placebo-controlled clinical trials and in the post-marketing period. Generally, topiramate-induced metabolic acidosis occurs early in treatment although cases can occur at any time during treatment. Bicarbonate decrements are usually mild-moderate (average decrease of 4 mEq/Lat daily doses of 400 mg in adults and at approximately 6 mg/kg/day in pediatric patients); rarely, patients can experience severe decrements to values below 10 mEq/L. Conditions or therapies that predispose to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, surgery, ketogenic diet, or drugs) may be additive to the bicarbonate lowering effects of topiramate. In adults, the incidence of persistent treatment-emergent decreases in serum bicarbonate (levels of <20 mEq/L at two consecutive visits or at the final visit) in controlled clinical trials for adjunctive treatment of epilepsy was 32% for 400 mg/day, and 1% for placebo. Metabolic acidosis has been observed at doses as low as 50 mg/day. The incidence of persistent treatment-emergent decreases in serum bicarbonate in adults in the epilepsy controlled clinical trial for monotherapy was 15% for 50 mg/day and 25% for 400 mg/day. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value <17 mEq/L and >5 mEq/L decrease from pretreatment) in the adjunctive therapy trials was 3% for 400 mg/day, and 0% for placebo and in the monotherapy trial was 1% for 50 mg/day and 7% for 400 mg/day. Serum bicarbonate levels have not been systematically evaluated at daily doses greater than 400 mg/day.
In pediatric patients (<16 years of age), the incidence of persistent treatment-emergent decreases in serum bicarbonate in placebo-controlled trials for adjunctive treatment of Lennox-Gastaut syndrome or refractory partial onset seizures was 67% for TOPAMAX® (at approximately 6 mg/kg/day), and 10% for placebo. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value <17 mEq/L and >5 mEq/L decrease from pretreatment) in these trials was 11% for TOPAMAX® and 0% for placebo. Cases of moderately severe metabolic acidosis have been reported in patients as young as 5 months old, especially at daily doses above 5 mg/kg/day.
In pediatric patients (10 years up to 16 years of age), the incidence of persistent treatment-emergent decreases in serum bicarbonate in the epilepsy controlled clinical trial for monotherapy was 7% for 50 mg/day and 20% for 400 mg/day. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value <17 mEq/L and >5 mEq/L decrease from pretreatment) in this trial was 4% for 50 mg/day and 4% for 400 mg/day.
The incidence of persistent treatment-emergent decreases in serum bicarbonate in placebo-controlled trials for adults for prophylaxis of migraine was 44% for 200 mg/day, 39% for 100 mg/day, 23% for 50 mg/day, and 7% for placebo. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value <17 mEq/L and >5 mEq/L decrease from pretreatment) in these trials was 11% for 200 mg/day, 9% for 100 mg/day, 2% for 50 mg/day, and <1% for placebo. Some manifestations of acute or chronic metabolic acidosis may include hyperventilation, nonspecific symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or stupor. Chronic, untreated metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis, and may also result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with an increased risk for fractures. Chronic metabolic acidosis in pediatric patients may also reduce growth rates. A reduction in growth rate may eventually decrease the maximal height achieved. The effect of topiramate on growth and bone-related sequelae has not been systematically investigated. Measurement of baseline and periodic serum bicarbonate during topiramate treatment is recommended. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing topiramate (using dose tapering). If the decision is made to continue patients on topiramate in the face of persistent acidosis, alkali treatment should be considered. Acute Myopia and Secondary Angle Closure Glaucoma A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving TOPAMAX® . Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, anterior chamber shallowing, ocular hyperemia (redness) and increased intraocular pressure. Mydriasis may or may not be present. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating TOPAMAX® therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with topiramate has been reported in pediatric patients as well as adults. The primary treatment to reverse symptoms is discontinuation of TOPAMAX® as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation of TOPAMAX® , may be helpful. Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss. Oligohidrosis and Hyperthermia Oligohidrosis (decreased sweating), infrequently resulting in hospitalization, has been reported in association with TOPAMAX® use. Decreased sweating and an elevation in body temperature above normal characterized these cases. Some of the cases were reported after exposure to elevated environmental temperatures. The majority of the reports have been in children. Patients, especially pediatric patients, treated with TOPAMAX® should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. Caution should be used when TOPAMAX® is prescribed with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, other carbonic anhydrase inhibitors and drugs with anticholinergic activity. Withdrawal of AEDs Antiepileptic drugs, including TOPAMAX® , should be withdrawn gradually to minimize the potential of increased seizure frequency. Cognitive/Neuropsychiatric Adverse Events Adults Adverse events most often associated with the use of TOPAMAX® were related to the central nervous system and were observed in both the epilepsy and migraine populations. In adults, the most frequent of these can be classified into three general categories: 1) Cognitive-related dysfunction (e.g., confusion, psychomotor slowing, difficulty with concentration/attention, difficulty with memory, speech or language problems, particularly word-finding difficulties); 2) Psychiatric/behavioral disturbances (e.g., depression or mood problems); and 3) Somnolence or fatigue. Cognitive-Related Dysfunction The majority of cognitive-related adverse events were mild to moderate in severity, and they frequently occurred in isolation. Rapid titration rate and higher initial dose were associated with higher incidences of these events. Many of these events contributed to withdrawal from treatment (see ADVERSE REACTIONS, Table 4, Table 6, and Table 10 ). In the original add-on epilepsy controlled trials (using rapid titration such as 100-200 mg/day weekly increments), the proportion of patients who experienced one or more cognitive-related adverse events was 42% for 200 mg/day, 41% for 400 mg/day, 52% for 600 mg/day, 56% for 800 and 1000 mg/day, and 14% for placebo. These dose-related adverse reactions began with a similar frequency in the titration or in the maintenance phase, although in some patients the events began during titration and persisted into the maintenance phase. Some patients who experienced one or more cognitive-related adverse events in the titration phase had a dose-related recurrence of these events in the maintenance phase. In the monotherapy epilepsy controlled trial, the proportion of patients who experienced one or more cognitive-related adverse events was 19% for TOPAMAX® 50 mg/day and 26% for 400 mg/day. In the 6-month migraine prophylaxis controlled trials using a slower titration regimen (25 mg/day weekly increments), the proportion of patients who experienced one or more cognitive-related adverse events was 19% for TOPAMAX® 50 mg/day, 22% for 100 mg/day, 28% for 200 mg/day, and 10% for placebo. These dose-related adverse reactions typically began in the titration phase and often persisted into the maintenance phase, but infrequently began in the maintenance phase. Some patients experienced a recurrence of one or more of these cognitive adverse events and this recurrence was typically in the titration phase. Arelatively small proportion of topiramate-treated patients experienced more than one concurrent cognitive adverse event. The most common cognitive adverse events occurring together included difficulty with memory along with difficulty with concentration/attention, difficulty with memory along with language problems, and difficulty with concentration/attention along with language problems. Rarely, topiramate-treated patients experienced three concurrent cognitive events. Psychiatric/Behavioral Disturbances Psychiatric/behavioral disturbances (depression or mood problems) were dose-related for both the epilepsy and migraine populations. In the double blind phases of clinical trials with topiramate in approved and investigational indications, suicide attempts occurred at a rate of 3/1000 patient years (13 events/3999 patient years) on topiramate versus 0 (0 events/1430 patient years) on placebo. One completed suicide was reported in a bipolar disorder trial in a patient on topiramate. Somnolence/Fatigue Somnolence and fatigue were the adverse events most frequently reported during clinical trials of TOPAMAX® for adjunctive epilepsy. For the adjunctive epilepsy population, the incidence of somnolence did not differ substantially between 200 mg/day and 1000 mg/day, but the incidence of fatigue was dose-related and increased at dosages above 400 mg/day. For the monotherapy epilepsy population in the 50 mg/day and 400 mg/day groups, the incidence of somnolence was dose-related (9% for the 50 mg/day group and 15% for the 400 mg/day group) and the incidence of fatigue was comparable in both treatment groups (14% each). For the migraine population, fatigue and somnolence were dose-related and more common in the titration phase. Additional nonspecific CNS events commonly observed with topiramate in the add-on epilepsy population include dizziness or ataxia. Pediatric Patients In double-blind adjunctive therapy and monotherapy epilepsy clinical studies, the incidences of cognitive/neuropsychiatric adverse events in pediatric patients were generally lower than observed in adults. These events included psychomotor slowing, difficulty with concentration/attention, speech disorders/related speech problems and language problems. The most frequently reported neuropsychiatric events in pediatric patients during adjunctive therapy double-blind studies were somnolence and fatigue. The most frequently reported neuropsychiatric events in pediatric patients in the 50 mg/day and 400 mg/day groups during the monotherapy double-blind study were headache, dizziness, anorexia, and somnolence. No patients discontinued treatment due to any adverse events in the adjunctive epilepsy double-blind trials. In the monotherapy epilepsy double-blind trial, 1 pediatric patient (2%) in the 50 mg/day group and 7 pediatric patients (12%) in the 400 mg/day group discontinued treatment due to any adverse events. The most common adverse event associated with discontinuation of therapy was difficulty with concentration/attention; all occurred in the 400 mg/day group. Sudden Unexplained Death in Epilepsy (SUDEP) During the course of premarketing development of TOPAMAX® (topiramate) Tablets, 10 sudden and unexplained deaths were recorded among a cohort of treated patients (2,796 subject years of exposure). This represents an incidence of 0.0035 deaths per patient year. Although this rate exceeds that expected in a healthy population matched for age and sex, it is within the range of estimates for the incidence of sudden unexplained deaths in patients with epilepsy not receiving TOPAMAX® (ranging from 0.0005 for the general population of patients with epilepsy, to 0.003 for a clinical trial population similar to that in the TOPAMAX® program, to 0.005 for patients with refractory epilepsy). PRECAUTIONS Hyperammonemia and Encephalopathy Associated with Concomitant Valproic Acid Use Concomitant administration of topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. In most cases, symptoms and signs abated with discontinuation of either drug. This adverse event is not due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, an interaction of topiramate and valproic acid may exacerbate existing defects or unmask deficiencies in susceptible persons. In patients who develop unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. Kidney Stones A total of 32/2,086 (1.5%) of adults exposed to topiramate during its adjunctive epilepsy therapy development reported the occurrence of kidney stones, an incidence about 2-4 times greater than expected in a similar, untreated population. In the double-blind monotherapy epilepsy study, a total of 4/319 (1.3%) of adults exposed to topiramate reported the occurrence of kidney stones. As in the general population, the incidence of stone formation among topiramate treated patients was higher in men. Kidney stones have also been reported in pediatric patients. An explanation for the association of TOPAMAX® and kidney stones may lie in the fact that topiramate is a carbonic anhydrase inhibitor. Carbonic anhydrase inhibitors, e.g., acetazolamide or dichlorphenamide, promote stone formation by reducing urinary citrate excretion and by increasing urinary pH. The concomitant use of TOPAMAX® with other carbonic anhydrase inhibitors or potentially in patients on a ketogenic diet may create a physiological environment that increases the risk of kidney stone formation, and should therefore be avoided. Increased fluid intake increases the urinary output, lowering the concentration of substances involved in stone formation. Hydration is recommended to reduce new stone formation. Paresthesia Paresthesia (usually tingling of the extremities), an effect associated with the use of other carbonic anhydrase inhibitors, appears to be a common effect of TOPAMAX® . Paresthesia was more frequently reported in the monotherapy epilepsy trials and migraine prophylaxis trials versus the adjunctive therapy epilepsy trials. In the majority of instances, paresthesia did not lead to treatment discontinuation. Adjustment of Dose in Renal Failure The major route of elimination of unchanged topiramate and its metabolites is via the kidney. Dosage adjustment may be required in patients with reduced renal function (see DOSAGE AND ADMINISTRATION). Decreased Hepatic Function In hepatically impaired patients, topiramate should be administered with caution as the clearance of topiramate may be decreased. Carcinogenesis, Mutagenesis, Impairment of Fertility An increase in urinary bladder tumors was observed in mice given topiramate (20, 75, and 300 mg/kg) in the diet for 21 months. The elevated bladder tumor incidence, which was statistically significant in males and females receiving 300 mg/kg, was primarily due to the increased occurrence of a smooth muscle tumor considered histomorphologically unique to mice. Plasma exposures in mice receiving 300 mg/kg were approximately 0.5 to 1 times steady-state exposures measured in patients receiving topiramate monotherapy at the recommended human dose (RHD) of 400 mg, and 1.5 to 2 times steady-state topiramate exposures in patients receiving 400 mg of topiramate plus phenytoin. The relevance of this finding to human carcinogenic risk is uncertain. No evidence of carcinogenicity was seen in rats following oral administration of topiramate for 2years at doses up to 120mg/kg (approximately 3 times the RHD on a mg/m² basis). Topiramate did not demonstrate genotoxic potential when tested in a battery of in vitro and in vivo assays. Topiramate was not mutagenic in the Ames test or the in vitro mouse lymphoma assay; it did not increase unscheduled DNAsynthesis in rat hepatocytes in vitro; and it did not increase chromosomal aberrations in human lymphocytes in vitro or in rat bone marrow in vivo. No adverse effects on male or female fertility were observed in rats at doses up to 100 mg/kg (2.5 times the RHD on a mg/m² basis). Pregnancy Pregnancy Category C. Topiramate has demonstrated selective developmental toxicity, including teratogenicity, in experimental animal studies. When oral doses of 20, 100, or 500 mg/kg were administered to pregnant mice during the period of organogenesis, the incidence of fetal malformations (primarily craniofacial defects) was increased at all doses. The low dose is approximately 0.2 times the recommended human dose (RHD=400 mg/day) on a mg/m² basis. Fetal body weights and skeletal ossification were reduced at 500 mg/kg in conjunction with decreased maternal body weight gain. In rat studies (oral doses of 20, 100, and 500 mg/kg or 0.2, 2.5, 30, and 400 mg/kg), the frequency of limb malformations (ectrodactyly, micromelia, and amelia) was increased among the offspring of dams treated with 400 mg/kg (10 times the RHD on a mg/m² basis) or greater during the organogenesis period of pregnancy. Embryotoxicity (reduced fetal body weights, increased incidence of structural variations) was observed at doses as low as 20mg/kg (0.5 times the RHD on a mg/m² basis). Clinical signs of maternal toxicity were seen at 400 mg/kg and above, and maternal body weight gain was reduced during treatment with 100 mg/kg or greater. In rabbit studies (20, 60, and 180 mg/kg or 10, 35, and 120 mg/kg orally during organogenesis), embryo/fetal mortality was increased at 35 mg/kg (2 times the RHD on a mg/m² basis) or greater, and teratogenic effects (primarily rib and vertebral malformations) were observed at 120 mg/kg (6 times the RHD on a mg/m² basis). Evidence of maternal toxicity (decreased body weight gain, clinical signs, and/or mortality) was seen at 35mg/kg and above. When female rats were treated during the latter part of gestation and throughout lactation (0.2, 4, 20, and 100 mg/kg or 2, 20, and 200 mg/kg), offspring exhibited decreased viability and delayed physical development at 200 mg/kg (5 times the RHD on a mg/m² basis) and reductions in pre- and/or postweaning body weight gain at 2 mg/kg (0.05times the RHD on a mg/m² basis) and above. Maternal toxicity (decreased body weight gain, clinical signs) was evident at 100mg/kg or greater. In a rat embryo/fetal development study with a postnatal component (0.2, 2.5, 30, or 400 mg/kg during organogenesis; noted above), pups exhibited delayed physical development at 400 mg/kg (10 times the RHD on a mg/m² basis) and persistent reductions in body weight gain at 30 mg/kg (1 times the RHD on a mg/m² basis) and higher. There are no studies using TOPAMAX® in pregnant women. TOPAMAX® should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus. In post-marketing experience, cases of hypospadias have been reported in male infants exposed in utero to topiramate, with or without other anticonvulsants; however, a causal relationship with topiramate has not been established. Labor and Delivery In studies of rats where dams were allowed to deliver pups naturally, no drug-related effects on gestation length or parturition were observed at dosage levels up to 200mg/kg/day. The effect of TOPAMAX® on labor and delivery in humans is unknown. Nursing Mothers Topiramate is excreted in the milk of lactating rats. The excretion of topiramate in human milk has not been evaluated in controlled studies. Limited observations in patients suggest an extensive secretion of topiramate into breast milk. Since many drugs are excreted in human milk, and because the potential for serious adverse reactions in nursing infants to TOPAMAX® is unknown, the potential benefit to the mother should be weighed against the potential risk to the infant when considering recommendations regarding nursing. Pediatric Use Safety and effectiveness in patients below the age of 2 years have not been established for the adjunctive therapy treatment of partial onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome. Safety and effectiveness in patients below the age of 10 years have not been established for the monotherapy treatment of epilepsy. Topiramate is associated with metabolic acidosis. Chronic untreated metabolic acidosis in pediatric patients may cause osteomalacia/rickets and may reduce growth rates. A reduction in growth rate may eventually decrease the maximal height achieved. The effect of topiramate on growth and bone-related sequelae has not been systematically investigated (see WARNINGS). Safety and effectiveness in pediatric patients have not been established for the prophylaxis treatment of migraine headache. Geriatric Use In clinical trials, 3% of patients were over 60. No age related difference in effectiveness or adverse effects were evident. However, clinical studies of topiramate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Dosage adjustment may be necessary for elderly with impaired renal function (creatinine clearance rate ≤70 mL/min/1.73 m² ) due to reduced clearance of topiramate (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). Race and Gender Effects Evaluation of effectiveness and safety in clinical trials has shown no race or gender related effects. Last reviewed on RxList: 12/28/2009 Topamax Overdosage & Contraindications OVERDOSE Overdoses of TOPAMAX® have been reported. Signs and symptoms included convulsions, drowsiness, speech disturbance, blurred vision, diplopia, mentation impaired, lethargy, abnormal coordination, stupor, hypotension, abdominal pain, agitation, dizziness and depression. The clinical consequences were not severe in most cases, but deaths have been reported after poly-drug overdoses involving TOPAMAX®. Topiramate overdose has resulted in severe metabolic acidosis (see WARNINGS). A patient who ingested a dose between 96 and 110 g topiramate was admitted to hospital with coma lasting 20-24 hours followed by full recovery after 3 to 4 days. In acute TOPAMAX® overdose, if the ingestion is recent, the stomach should be emptied immediately by lavage or by induction of emesis. Activated charcoal has been shown to adsorb topiramate in vitro. Treatment should be appropriately supportive. Hemodialysis is an effective means of removing topiramate from the body. CONTRAINDICATIONS TOPAMAX® is contraindicated in patients with a history of hypersensitivity to any component of this product. Last reviewed on RxList: 12/28/2009 Topamax Clinical Pharmacology CLINICAL PHARMACOLOGY Mechanism of Action The precise mechanisms by which topiramate exerts its anticonvulsant and migraine prophylaxis effects are unknown; however, preclinical studies have revealed four properties that may contribute to topiramate's efficacy for epilepsy and migraine prophylaxis. Electrophysiological and biochemical evidence suggests that topiramate, at pharmacologically relevant concentrations, blocks voltage-dependent sodium channels, augments the activity of the neurotransmitter gamma-aminobutyrate at some subtypes of the GABA-A receptor, antagonizes the AMPA/kainate subtype of the glutamate receptor, and inhibits the carbonic anhydrase enzyme, particularly isozymes II and IV. Pharmacodynamics Topiramate has anticonvulsant activity in rat and mouse maximal electro shock seizure (MES) tests. Topiramate is only weakly effective in blocking clonic seizures induced by the GABAA receptor antagonist, pentylene tetrazole. Topiramate is also effective in rodent models of epilepsy, which include tonic and absence-like seizures in the spontaneous epileptic rat (SER) and tonic and clonic seizures induced in rats by kindling of the amygdala or by global ischemia. Pharmacokinetics The sprinkle formulation is bioequivalent to the immediate release tablet formulation and, therefore, may be substituted as a therapeutic equivalent. Absorption of topiramate is rapid, with peak plasma concentrations occurring at approximately 2 hours following a 400 mg oral dose. The relative bioavailability of topiramate from the tablet formulation is about 80% compared to a solution. The bioavailability of topiramate is not affected by food. The pharmacokinetics of topiramate are linear with dose proportional increases in plasma concentration over the dose range studied (200 to 800 mg/day). The mean plasma elimination half-life is 21 hours after single or multiple doses. Steady state is thus reached in about 4 days in patients with normal renal function. Topiramate is 15-41% bound to human plasma proteins over the blood concentration range of 0.5-250 μg/mL. The fraction bound decreased as blood concentration increased. Carbamazepine and phenytoin do not alter the binding of topiramate. Sodium valproate, at 500 μg/mL (a concentration 5-10 times higher than considered therapeutic for valproate) decreased the protein binding of topiramate from 23% to 13%. Topiramate does not influence the binding of sodium valproate. Metabolism and Excretion Topiramate is not extensively metabolized and is primarily eliminated unchanged in the urine (approximately 70% of an administered dose). Six metabolites have been identified in humans, none of which constitutes more than 5% of an administered dose. The metabolites are formed via hydroxylation, hydrolysis, and glucuronidation. There is evidence of renal tubular reabsorption of topiramate. In rats, given probenecid to inhibit tubular reabsorption, along with topiramate, a significant increase in renal clearance of topiramate was observed. This interaction has not been evaluated in humans. Overall, oral plasma clearance (CL/F) is approximately 20 to 30 mL/min in humans following oral administration. Pharmacokinetic Interactions (see also DRUG INTERACTIONS) Antiepileptic Drugs Potential interactions between topiramate and standard AEDs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. The effect of these interactions on mean plasma AUCs are summarized under PRECAUTIONS (Table 3). Special Populations Renal Impairment The clearance of topiramate was reduced by 42% in moderately renally impaired (creatinine clearance 30-69 mL/min/1.73m²) and by 54% in severely renally impaired subjects (creatinine clearance < 30 mL/min/1.73m²) compared to normal renal function subjects (creatinine clearance > 70 mL/min/1.73m²). Since topiramate is presumed to undergo significant tubular reabsorption, it is uncertain whether this experience can be generalized to all situations of renal impairment. It is conceivable that some forms of renal disease could differentially affect glomerular filtration rate and tubular reabsorption resulting in a clearance of topiramate not predicted by creatinine clearance. In general, however, use of one-half the usual starting and maintenance dose is recommended in patients with moderate or severe renal impairment (see PRECAUTIONS: Adjustment of Dose in Renal Failure and DOSAGE AND ADMINISTRATION).
Hemodialysis
Topiramate is cleared by hemodialysis. Using a high efficiency, counterflow, single pass-dialysate hemo dialysis procedure, topiramate dialysis clearance was 120 mL/min with blood flow through the dialyzer at 400 mL/min. This high clearance (compared to 20-30 mL/min total oral clearance in healthy adults) will remove a clinically significant amount of topiramate from the patient over the hemodialysis treatment period. Therefore, a supplemental dose may be required (see DOSAGE AND ADMINISTRATION).
Hepatic Impairment
In hepatically impaired subjects, the clearance of topiramate may be decreased; the mechanism underlying the decrease is not well understood.
Age, Gender, and Race
The pharmacokinetics of topiramate in elderly subjects (65-85 years of age, N=16) were evaluated in a controlled clinical study. The elderly subject population had reduced renal function [creatinine clearance (-20%)] compared to young adults. Following a single oral 100 mg dose, maximum plasma concentration for elderly and young adults was achieved at approximately 1-2 hours. Reflecting the primary renal elimination of topiramate, topiramate plasma and renal clearance were reduced 21% and 19%, respectively, in elderly subjects, compared to young adults. Similarly, topiramate half-life was longer (13%) in the elderly. Reduced topiramate clearance resulted in slightly higher maximum plasma concentration (23%) and AUC (25%) in elderly subjects than observed in young adults. Topiramate clearance is decreased in the elderly only to the extent that renal function is reduced. As recommended for all patients, dosage adjustment may be indicated in the elderly patient when impaired renal function (creatinine clearance rate ≤ 70 mL/min/1.73 m²) is evident. It may be useful to monitor renal function in the elderly patient (see Special Populations: Renal Impairment, PRECAUTIONS: Adjustment of Dose in Renal Failure and DOSAGE AND ADMINISTRATION).
Clearance of topiramate in adults was not affected by gender or race.
Pediatric Pharmacokinetics
Pharmacokinetics of topiramate were evaluated in patients ages 4 to 17 years receiving one or two other antiepileptic drugs. Pharmacokinetic profiles were obtained after one week at doses of 1, 3, and 9 mg/kg/day. Clearance was independent of dose.
Pediatric patients have a 50% higher clearance and consequently shorter elimination half-life than adults. Consequently, the plasma concentration for the same mg/kg dose may be lower in pediatric patients compared to adults. As in adults, hepatic enzyme-inducing antiepileptic drugs decrease the steady state plasma concentrations of topiramate.
Clinical Studies
The studies described in the following sections were conducted using TOPAMAX® (topiramate) Tablets.
Epilepsy
Monotherapy Controlled Trial
The effectiveness of topiramate as initial monotherapy in adults and children 10 years of age and older with partial onset or primary generalized seizures was established in a multicenter, randomized, double-blind, parallel-group trial.
The trial was conducted in 487 patients diagnosed with epilepsy (6 to 83 years of age) who had 1 or 2 well-documented seizures during the 3-month retrospective baseline phase who then entered the study and received topiramate 25 mg/day for 7 days in an open-label fashion. Forty-nine percent of subjects had no prior AED treatment and 17% had a diagnosis of epilepsy for greater than 24 months. Any AED therapy used for temporary or emergency purposes was discontinued prior to randomization. In the double-blind phase, 470 patients were randomized to titrate up to 50 mg/day or 400 mg/day. If the target dose could not be achieved, patients were maintained on the maximum tolerated dose. Fifty eight percent of patients achieved the maximal dose of 400 mg/day for ≥ 2 weeks, and patients who did not tolerate 150 mg/day were discontinued. The primary efficacy assessment was a between group comparison of time to first seizure during the double-blind phase. Comparison of the Kaplan-Meier survival curves of time to first seizure favored the topiramate 400 mg/day group over the topiramate 50 mg/day group (p=0.0002, log rank test; Figure 1). The treatment effects with respect to time to first seizure were consistent across various patient subgroups defined by age, sex, geographic region, baseline body weight, baseline seizure type, time since diagnosis, and baseline AED use.
Figure 1: Kaplan-Meier Estimates of Cumulative Rates for Time to First Seizure

Adjunctive Therapy Controlled Trials in Patients With Partial Onset Seizures
The effectiveness of topiramate as an adjunctive treatment for adults with partial onset seizures was established in six multicenter, randomized, double-blind, placebo-controlled trials, two comparing several dosages of topiramate and placebo and four comparing a single dosage with placebo, in patients with a history of partial onset seizures, with or without secondarily generalized seizures.
Patients in these studies were permitted a maximum of two antiepileptic drugs (AEDs) in addition to TOPAMAX® Tablets or placebo. In each study, patients were stabilized on optimum dosages of their concomitant AEDs during baseline phase lasting between 4 and 12 weeks. Patients who experienced a prespecified minimum number of partial onset seizures, with or without secondary generalization, during the baseline phase (12 seizures for 12-week baseline, 8 for 8-week baseline, or 3 for 4-week baseline) were randomly assigned to placebo or a specified dose of TOPAMAX® Tablets in addition to their other AEDs.
Following randomization, patients began the double-blind phase of treatment. In five of the six studies, patients received active drug beginning at 100 mg per day; the dose was then increased by 100 mg or 200 mg/day increments weekly or every other week until the assigned dose was reached, unless intolerance prevented increases. In the sixth study (119), the 25 or 50 mg/day initial doses of topiramate were followed by respective weekly increments of 25 or 50 mg/day until the target dose of 200 mg/day was reached. After titration, patients entered a 4, 8, or 12-week stabilization period. The numbers of patients randomized to each dose, and the actual mean and median doses in the stabilization period are shown in Table 1.
Adjunctive Therapy Controlled Trial in Pediatric Patients Ages 2 -16 Years With Partial Onset Seizures
The effectiveness of topiramate as an adjunctive treatment for pediatric patients ages 2 -16 years with partial onset seizures was established in a multi center, randomized, double-blind, placebo-controlled trial, comparing topiramate and placebo in patients with a history of partial onset seizures, with or without secondarily generalized seizures.
Patients in this study were permitted a maximum of two antiepileptic drugs (AEDs) in addition to TOPAMAX® Tablets or placebo. In this study, patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least six partial onset seizures, with or without secondarily generalized seizures, during the baseline phase were randomly assigned to placebo or TOPAMAX® Tablets in addition to their other AEDs.
Following randomization, patients began the double-blind phase of treatment. Patients received active drug beginning at 25 or 50 mg per day; the dose was then increased by 25 mg to 150 mg/day increments every other week until the assigned dosage of 125, 175, 225, or 400 mg/day based on patients’ weight to approximate a dosage of 6 mg/kg per day was reached, unless intolerance prevented increases. After titration, patients entered an 8-week stabilization period.
Adjunctive Therapy Controlled Trial in Patients With Lennox-Gastaut Syndrome
The effectiveness of topiramate as an adjunctive treatment for seizures associated with Lennox-Gastaut syndrome was established in a multicenter, randomized, double-blind, placebo-controlled trial comparing a single dosage of topiramate with placebo in patients 2 years of age and older.
Patients in this study were permitted a maximum of two antiepileptic drugs (AEDs) in addition to TOPAMAX® or placebo. Patients who were experiencing at least 60 seizures per month before study entry were stabilized on optimum dosages of their concomitant AEDs during a 4-week baseline phase. Following baseline, patients were randomly assigned to placebo or TOPAMAX® in addition to their other AEDs. Active drug was titrated beginning at 1 mg/kg per day for a week; the dose was then increased to 3 mg/kg per day for one week then to 6 mg/kg per day. After titration, patients entered an 8-week stabilization period. The primary measures of effectiveness were the percent reduction in drop attacks and a parental global rating of seizure severity.
Table 1: Topiramate Dose Summary During the Stabilization Periods of Each of Six Double-Blind, Placebo-Controlled, Add-On Trials in Adults with Partial Onset Seizuresb
Protocol Stabilization Dose Placeboa Target Topiramate Dosage (mg/day)
200 400 600 800 1,000
YD N 42 42 40 41 – –
Mean Dose 5.9 200 390 556 – –
Median Dose 6.0 200 400 600 – –
YE N 44 – – 40 45 40
Mean Dose 9.7 – – 544 739 796
Median Dose 10.0 – – 600 800 1,000
Y1 N 23 – 19 – – –
Mean Dose 3.8 – 395 – – –
Median Dose 4.0 – 400 – – –
Y2 N 30 – – 28 – –
Mean Dose 5.7 – – 522 – –
Median Dose 6.0 – – 600 – –
Y3 N 28 – – – 25 –
Mean Dose 7.9 – – – 568 –
Median Dose 8.0 – – – 600 –
119 N 90 157 – – – –
Mean Dose 8 200 – – – –
Median Dose 8 200 – – – –
a Placebo dosages are given as the number of tablets. Placebo target dosages were as follows: Protocol Y1, 4 tablets/day; Protocols YD and Y2, 6 tablets/day; Protocol Y3 and 119, 8 tablets/day; Protocol YE, 10 tablets/day.
b Dose-response studies were not conducted for other indications or pediatric partial onset seizures.
In all add-on trials, the reduction in seizure rate from baseline during the entire double-blind phase was measured. The median percent reductions in seizure rates and the responder rates (fraction of patients with at least a 50% reduction) by treatment group for each study are shown below in Table 2. As described above, a global improvement in seizure severity was also assessed in the Lennox-Gastaut trial.
Table 2: Efficacy Results in Double-Blind, Placebo-Controlled, Add-On Epilepsy Trials
Protocol Efficacy Results Placebo Target Topiramate Dosage (mg/day) ≈6mg /kg/day*
200 400 600 800 1,000
Partial Onset Seizures
Studies in Adults
YD N 45 45 45 46 – – –
Median % Reduction 11.6 27.2a 47.5b 44.7c – – –
% Responders 18 24 44d 46d – – –
YE N 47 – – 48 48 47 –
Median % Reduction 1.7 – – 40.8c 41.0c 36.0c –
% Responders 9 – – 40c 41c 36d –
Y1 N 24 – 23 – – – –
Median % Reduction 1.1 – 40.7e – – – –
% Responders 8 – 35d – – – –
Y2 N 30 – – 30 – – –
Median % Reduction -12.2 – – 46.4f – – –
% Responders 10 – – 47c – – –
Y3 N 28 – – – 28 – –
Median % Reduction -20.6 – – – 24.3c – –
% Responders 0 – – – 43c – –
119 N 91 168 – – – – –
Median % Reduction 20.0 44.2c – – – – –
% Responders 24 45c – – – – –
Studies in Pediatric Patients
YP N 45 – – – – – 41
Median % Reduction 10.5 – – – – – 33.1d
% Responders 20 – – – – – 39
Primary Generalized Tonic-Clonich
YTC N 40 – – – – – 39
Median % Reduction 9.0 – – – – – 56.7d
% Responders 20 – – – – – 56c
Lennox-Gastaut Syndromei
YL N 49 – – – – – 46
Median % Reduction -5.1 – – – – – 14.8d
% Responders 14 – – – – – 28g
Improvement in Seizure Severityj 28 – – – – – 52d
Comparisons with placebo: a p=0.080; b p ≤ 0.010; c p ≤ 0.001; d p ≤ 0.050; e p=0.065; f p ≤ 0.005; g p=0.071; h Median % reduction and % responders are reported for PGTC Seizures; i Median % reduction and % responders for drop attacks, i.e., tonic or atonic seizures; j Percent of subjects who were minimally, much, or very much improved from baseline
* For Protocols YP and YTC, protocol-specified target dosages ( < 9.3 mg/kg/day) were assigned based on subject's weight to approximate a dosage of 6 mg/kg per day; these dosages corresponded to mg/day dosages of 125, 175, 225, and 400 mg/day. Subset analyses of the antiepileptic efficacy of TOPAMAX® Tablets in these studies showed no differences as a function of gender, race, age, baseline seizure rate, or concomitant AED. In clinical trials for epilepsy, daily dosages were decreased in weekly intervals by 50 to 100 mg in adults and over a 2 to 8 week period in children; transition was permitted to a new antiepileptic regimen when clinically indicated. Migraine The results of 2 multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trials established the effectiveness of TOPAMAX® in the prophylactic treatment of migraine headache. The design of both trials (one study was conducted in the U.S. and one study was conducted in the U.S. and Canada) was identical, enrolling patients with a history of migraine, with or without aura, for at least 6 months, according to the International Headache Society diagnostic criteria. Patients with a history of cluster headaches or basilar, ophthalmoplegic, hemiplegic, or transformed migraine headaches were excluded from the trials. Patients were required to have completed up to a 2 week washout of any prior migraine preventive medications before starting the baseline phase. Patients who experienced 3 to 12 migraine headaches over the 4-weeks in the baseline phase were equally randomized to either TOPAMAX® 50 mg/day, 100 mg/day, 200 mg/day, or placebo and treated for a total of 26 weeks (8-week titration period and 18-week maintenance period). Treatment was initiated at 25 mg/day for one week, and then the daily dosage was increased by 25-mg increments each week until reaching the assigned target dose or maximum tolerated dose (administered twice daily). Effectiveness of treatment was assessed by the reduction in migraine headache frequency, as measured by the change in 4-week migraine rate from the baseline phase to double-blind treatment period in each TOPAMAX® treatment group compared to placebo in the intent to treat (ITT) population. In the first study a total of 469 patients (416 females, 53 males), ranging in age from 13 to 70 years, were randomized and provided efficacy data. Two hundred sixty five patients completed the entire 26-week double-blind phase. The median average daily dosages were 47.8 mg/day, 88.3 mg/day, and 132.1 mg/day in the target dose groups of TOPAMAX® 50, 100, and 200 mg/day, respectively. The mean migraine headache frequency rate at baseline was approximately 5.5 migraine headaches/28 days and was similar across treatment groups. The change in the mean 4-week migraine headache frequency from baseline to the double-blind phase was -1.3, -2.1, and -2.2 in the TOPAMAX® 50, 100, and 200 mg/day groups, respectively, versus -0.8 in the placebo group (see Figure 2). The differences between the TOPAMAX® 100 and 200 mg/day groups versus placebo were statistically significant (p < 0.001 for both comparisons). In the second study a total of 468 patients (406 females, 62 males), ranging in age from 12 to 65 years, were randomized and provided efficacy data. Two hundred fifty five patients completed the entire 26-week double-blind phase. The median average daily dosages were 46.5 mg/day, 85.6 mg/day, and 150.2 mg/day in the target dose groups of TOPAMAX® 50, 100, and 200 mg/day, respectively. The mean migraine headache frequency rate at baseline was approximately 5.5 migraine headaches/28 days and was similar across treatment groups. The change in the mean 4-week migraine headache period frequency from baseline to the double-blind phase was -1.4, -2.1, and -2.4 in the TOPAMAX® 50, 100, and 200 mg/day groups, respectively, versus -1.1 in the placebo group (see Figure 2). The differences between the TOPAMAX® 100 and 200 mg/day groups versus placebo were statistically significant (p=0.008 and < 0.001, respectively). In both studies, there were no apparent differences in treatment effect within age, or gender, subgroups. Because most patients were Caucasian, there were insufficient numbers of patients from different races to make a meaningful comparison of race. For patients withdrawing from TOPAMAX®, daily dosages were decreased in weekly intervals by 25 to 50 mg. Figure 2: Reduction in 4-Week Migraine Headache Frequency (Studies TOPMAT-MIGR-001 and TOPMAT-MIGR-002) Last reviewed on RxList: 12/28/2009 Topamax Medication Guide PATIENT INFORMATION MEDICATION GUIDE TOPAMAX® (Toe-pa-max) (topiramate) Tablets and Sprinkle Capsules Read this Medication Guide before you start taking TOPAMAX and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. If you have any questions about TOPAMAX, talk to your healthcare provider or pharmacist. What is the most important information I should know about TOPAMAX? TOPAMAX may cause eye problems. Serious eye problems include: any sudden decrease in vision with or without eye pain and redness, a blockage of fluid in the eye causing increased pressure in the eye (secondary angle closure glaucoma). These eye problems can lead to permanent loss of vision if not treated. You should call your healthcare provider right away if you have any new eye symptoms. TOPAMAX may cause decreased sweating and increased body temperature (fever). People, especially children, should be watched for signs of decreased sweating and fever, especially in hot temperatures. Some people may need to be hospitalized for this condition. Like other antiepileptic drugs, TOPAMAX may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: thoughts about suicide or dying attempts to commit suicide new or worse depression new or worse anxiety feeling agitated or restless panic attacks trouble sleeping (insomnia) new or worse irritability acting aggressive, being angry, or violent acting on dangerous impulses an extreme increase in activity and talking (mania) other unusual changes in behavior or mood Do not stop TOPAMAX without first talking to a healthcare provider. Stopping TOPAMAX suddenly can cause serious problems. Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes. How can I watch for early symptoms of suicidal thoughts and actions? Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you are worried about symptoms. What is TOPAMAX? TOPAMAX is a prescription medicine used: to treat certain types of seizures (partial onset seizures and primary generalized tonic-clonic seizures) in people 10 years and older, with other medicines to treat certain types of seizures (partial onset seizures, primary generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome) in adults and children 2 years and older, to prevent migraine headaches in adults. What should I tell my healthcare provider before taking TOPAMAX? Before taking TOPAMAX, tell your healthcare provider about all your medical conditions, including if you: have or have had depression, mood problems or suicidal thoughts or behavior have kidney problems, kidney stones or are getting kidney dialysis have a history of metabolic acidosis (too much acid in the blood) have liver problems have osteoporosis, soft bones, or decreased bone density have lung or breathing problems have eye problems, especially glaucoma have diarrhea have a growth problem are on a diet high in fat and low in carbohydrates, which is called a ketogenic diet are having surgery are pregnant or plan to become pregnant. It is not known if TOPAMAX will harm your unborn baby. If you become pregnant while taking TOPAMAX, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334 begin_of_the_skype_highlighting 1-888-233-2334 end_of_the_skype_highlighting. The purpose of this registry is to collect information about the safety of antiepileptic medicine during pregnancy. are breastfeeding. It is not known if TOPAMAX passes into breast milk and if it can harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take TOPAMAX. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. TOPAMAX and other medicines may affect each other causing side effects. Especially, tell your healthcare provider if you take: Valproic acid (Depakene, Depakote) any medicines that impair or decrease your thinking, concentration, or muscle coordination. birth control pills. TOPAMAX may make your birth control pills less effective. Tell your healthcare provider if your menstrual bleeding changes while you are taking birth control pills and TOPAMAX. Ask your healthcare provider if you are not sure if your medicine is listed above. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist each time you get a new medicine. Do not start a new medicine without talking with your healthcare provider. How should I take TOPAMAX? Take TOPAMAX exactly as prescribed. Your healthcare provider may change your dose. Do not change your dose without talking to your healthcare provider. TOPAMAX tablets should be swallowed whole. Do not chew the tablets. They may leave a bitter taste. TOPAMAX sprinkle capsules may be swallowed whole or may be opened and sprinkled on a teaspoon of soft food. Drink fluids right after eating the food and medicine mixture to make sure it is all swallowed. Do not store any medicine and food mixture for later use. TOPAMAX can be taken before, during, or after a meal. Drink plenty of fluids during the day. This may help prevent kidney stones while taking TOPAMAX. If you take too much TOPAMAX, call your healthcare provider or poison control center right away or go to the nearest emergency room. If you miss a single dose of TOPAMAX, take it as soon as you can. However, if you are within 6 hours of taking your next scheduled dose, wait until then to take your usual dose of TOPAMAX, and skip the missed dose. Do not double your dose. If you have missed more than one dose, you should call your healthcare professional for advice. Do not stop taking TOPAMAX without talking to your healthcare provider. Stopping TOPAMAX suddenly may cause serious problems. If you have epilepsy and you stop taking TOPAMAX suddenly, you may have seizures that do not stop. Your healthcare provider will tell you how to stop taking TOPAMAX slowly. Your healthcare provider may do blood tests while you take TOPAMAX. What should I avoid while taking TOPAMAX? Do not drink alcohol while taking TOPAMAX. TOPAMAX and alcohol can affect each other causing side effects such as sleepiness and dizziness. Do not drive a car or operate heavy machinery until you know how TOPAMAX affects you. TOPAMAX can slow your thinking and motor skills. What are the possible side effects of TOPAMAX? TOPAMAX may cause serious side effects including: See “What is the most important information I should know about TOPAMAX?” Metabolic Acidosis. Metabolic acidosis can cause: tiredness loss of appetite irregular heartbeat impaired consciousness High blood ammonia levels. High ammonia in the blood can affect your mental activities, slow your alertness, make you feel tired, or cause vomiting. This has happened when TOPAMAX is taken with a medicine called valproic acid (DEPAKENE and DEPAKOTE). Kidney stones. Drink plenty of fluids when taking TOPAMAX to decrease your chances of getting kidney stones. Effects on Thinking and Alertness. TOPAMAX may affect how you think, and cause confusion, problems with concentration, attention, memory, or speech. TOPAMAX may cause depression or mood problems, tiredness, and sleepiness. Dizziness or Loss of Muscle Coordination. Call your healthcare provider right away if you have any of the symptoms above. The most common side effects of TOPAMAX include: tingling of the arms and legs (paresthesia) not feeling hungry nausea a change in the way foods taste diarrhea weight loss nervousness upper respiratory tract infection Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all the possible side effects of TOPAMAX. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 begin_of_the_skype_highlighting 1-800-FDA-1088 end_of_the_skype_highlighting. How should I store TOPAMAX? Store TOPAMAX tablets at room temperature, 59°F to 86°F (15°C to 30°C). Store TOPAMAX Sprinkle Capsules at or below 25°C (77°F). Keep TOPAMAX in a tightly closed container. Keep TOPAMAX dry and away from moisture. Keep TOPAMAX and all medicines out of the reach of children. General information about TOPAMAX. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use TOPAMAX for a condition for which it was not prescribed. Do not give TOPAMAX to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about TOPAMAX. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about TOPAMAX that is written for health professionals. For more information, go to www.topamax.com or call 1-800-526-7736 begin_of_the_skype_highlighting 1-800-526-7736 end_of_the_skype_highlighting. What are the ingredients in TOPAMAX? Active ingredient: topiramate Inactive ingredients: Tablets - lactose monohydrate, pregelatinized starch, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, purified water, carnauba wax, hypromellose, titanium dioxide, polyethylene glycol, synthetic iron oxide and polysorbate 80. Sprinkle Capsules - sugar spheres (sucrose and starch), povidone, cellulose acetate, gelatin, sorbitan monolaurate, sodium lauryl sulfate, titanium dioxide, and black pharmaceutical ink. Last reviewed on RxList: 12/28/2009 Topamax Consumer IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you. TOPIRAMATE - ORAL (toe-PEER-uh-mate) COMMON BRAND NAME(S): Topamax USES: Topiramate is used alone or with other medications to prevent and control seizures (epilepsy). This medication is also used to prevent migraine headaches and reduce how often you may get them. Topiramate will not work to treat a migraine headache once it occurs. If you get a migraine headache, treat it as directed by your doctor (e.g., take pain medications, decrease sound and light). Topiramate is an anti-seizure medication (anticonvulsant) that works in several ways to prevent seizures and migraines. HOW TO USE: Read the Medication Guide and, if available, the Patient Information Leaflet provided by your pharmacist before you start using topiramate and each time you get a refill. If you have any questions regarding the information, consult your doctor or pharmacist. Take this medication by mouth with or without food, usually twice daily or as directed by your doctor. Swallow the tablets whole. Do not crush, chew or break the tablets because they have a bitter taste. To prevent kidney stones from forming, drink plenty of liquids while taking this medication unless your doctor instructs you otherwise. The dosage is based on your medical condition and response to therapy. In children, dosage may also be based on body weight. Your doctor may gradually increase your dose to lower your risk of side effects such as drowsiness and memory problems. It may take several weeks to reach the best dose for you. Take this medication exactly as directed. Take this medication regularly in order to get the most benefit from it. To help you remember, take it at the same times each day. Do not stop taking this medication without consulting your doctor. Some conditions may become worse when this drug is suddenly stopped. Your dose may need to be gradually decreased. Inform your doctor if your condition persists or worsens. Topamax Consumer (continued) SIDE EFFECTS: Weakness, tiredness, drowsiness, dizziness, confusion, difficulty concentrating, tingling of the hands/feet, loss of appetite, diarrhea, impotence, and weight loss may occur. If any of these symptoms persist or worsen, notify your doctor promptly. Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects. Tell your doctor immediately if any of these unlikely but serious side effects occur: slow/unsteady movement, speech/language problems. A small number of people who take anticonvulsants for any condition (such as seizure, bipolar disorder, pain) may experience depression, suicidal thoughts/attempts, or other mental/mood problems. Tell your doctor immediately if you or your family/caregiver notice any unusual/sudden changes in your mood, thoughts, or behavior including signs of depression, suicidal thoughts/attempts, thoughts about harming yourself. Tell your doctor immediately if any of these rare but very serious side effects occur: severe back/side pain, rapid breathing, bone pain/breakage, loss of consciousness, fast/slow/irregular heartbeat, stomach/abdominal pain, painful urination, bloody or pink-colored urine, chest pain. Seek immediate medical attention if either of these rare but very serious eye problems occur: sudden vision changes (e.g., blurred vision), eye pain/redness. This medication can rarely cause a serious metabolic problem (hyperammonemia), especially if you are also taking valproic acid. Tell your doctor immediately if you experience sudden/unexplained tiredness, vomiting, or mental changes (e.g., difficulty staying awake). A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing. This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist. In the US - Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 begin_of_the_skype_highlighting 1-800-FDA-1088 end_of_the_skype_highlighting. In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345 begin_of_the_skype_highlighting 1-866-234-2345 end_of_the_skype_highlighting. PRECAUTIONS: Before taking topiramate, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. Before using this medication, tell your doctor or pharmacist your medical history, especially of: eye problems (e.g., glaucoma), kidney problems, liver problems, severe lung/breathing problems, metabolism problems (e.g., metabolic acidosis, born with metabolism disease), long-term diarrhea problem, any special diet (e.g., high-protein, ketogenic). This drug may make you dizzy or drowsy or cause blurred vision. Do not drive, use machinery, or do any activity that requires alertness or clear vision until you are sure you can perform such activities safely. Avoid alcoholic beverages. Topiramate can infrequently cause decreased sweating, which could raise your body temperature to unsafe levels (hyperthermia). The risk of this serious side effect is greater in hot weather and/or during vigorous exercise, especially in children. Drink plenty of fluids and dress lightly in hot weather or when exercising. Check carefully for signs of decreased sweating. If this occurs, immediately stop exercising and seek cooler shelter. Seek immediate medical attention if your body temperature is above normal or if you have mental/mood changes, headache, or dizziness. Consult your doctor for more details. Before having surgery, tell your doctor or dentist that you are using this medication. Monitor your weight while taking this medication, and share the results with your doctor. If you lose weight unexpectedly, discuss with your doctor. You may need to change your diet. Caution is advised when using this drug in children because they may be more sensitive to its side effects, especially effects on bone health, growth rate, and temperature. Consult your doctor or pharmacist for more details. Kidney function declines as you grow older. This medication is removed by the kidneys. Therefore, elderly people may be at greater risk for side effects such as drowsiness and dizziness while using this drug. This medication should be used only when clearly needed during pregnancy. Discuss the risks and benefits with your doctor. This medication passes into breast milk and may have undesirable effects on a nursing infant. Consult your doctor before breast-feeding. Topamax Consumer (continued) DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop or change the dosage of any medicine before checking with them first. Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially: amitriptyline, carbamazepine, metformin, phenytoin, pioglitazone, risperidone, valproic acid, "water pills" (diuretics such as hydrochlorothiazide, acetazolamide, dichlorphenamide), other drugs that cause decreased sweating (e.g., anticholinergics such as belladonna alkaloids/scopolamine, antihistamines such as hydroxyzine, phenothiazines such as chlorpromazine). This medication may decrease the effectiveness of combination-type birth control (e.g., pills, patches). This can result in pregnancy. You may need to use an additional form of reliable birth control while using this medication. Report any unusual vaginal bleeding to your doctor. Consult your doctor or pharmacist for details. Tell your doctor or pharmacist if you also take drugs that cause drowsiness such as: certain antihistamines (e.g., diphenhydramine), anti-seizure drugs (e.g., phenobarbital), medicine for sleep or anxiety (e.g., alprazolam, diazepam, zolpidem), muscle relaxants, narcotic pain relievers (e.g., codeine), psychiatric medicines (e.g., haloperidol, nortriptyline, trazodone). Check the labels on all your medicines (e.g., cough-and-cold products) because they may contain drowsiness-causing ingredients. Ask your pharmacist about the safe use of those products. This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist. OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222 begin_of_the_skype_highlighting 1-800-222-1222 end_of_the_skype_highlighting. Canadian residents should call their local poison control center directly. NOTES: Do not share this medication with others. Laboratory and/or medical tests (e.g., eye exams, serum bicarbonate level) should be performed to monitor your progress and check for side effects. MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is within 6 hours of your next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up. If you have missed more than one dose, you should call your doctor for advice. STORAGE: Store in a tightly closed container at room temperature between 59-86 degrees F (15-30 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets. Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product. MEDICAL ALERT: Your condition can cause complications in a medical emergency. For enrollment information call MedicAlert at 1-800-854-1166 begin_of_the_skype_highlighting 1-800-854-1166 end_of_the_skype_highlighting (USA) or 1-800-668-1507 begin_of_the_skype_highlighting 1-800-668-1507 end_of_the_skype_highlighting (Canada).