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Topamax

Last reviewed on RxList: 6/19/2020
Drug Description

What is Topamax and how is it used?

Topamax is a prescription medicine used:

  • to treat certain types of seizures (partial-onset seizures and primary generalized tonic-clonic seizures) in adults and children 2 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 and adolescents 12 years and older.

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?”

  • 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).
  • 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.
  • Serious skin reactions. Topamax may cause a severe rash with blisters and peeling skin, especially around the mouth, nose, eyes, and genitals (Stevens-Johnson syndrome). Topamax may also cause a rash with blisters and peeling skin over much of the body that may cause death (toxic epidermal necrolysis). Call your healthcare provider right away if you develop a skin rash or blisters.
  • Kidney stones. Drink plenty of fluids when taking Topamax to decrease your chances of getting kidney stones.
  • Low body temperature. Taking Topamax when you are also taking valproic acid can cause a drop in body temperature to less than 95°F, or can cause tiredness, confusion, or coma.

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
  • speech problems
  • tiredness
  • dizziness
  • sleepiness/drowsiness
  • slow reactions
  • difficulty with memory
  • pain in the abdomen
  • fever
  • abnormal vision
  • decreased feeling or sensitivity, especially in the skin

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. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Janssen Pharmaceuticals, Inc. at 1-800-JANSSEN (1-800-526-7736).

DESCRIPTION

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, dimethylsulfoxide, and ethanol. The solubility in water is 9.8 mg/mL. Its saturated solution 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) Structural Formula Illustration

TOPAMAX® Tablets contain the following inactive ingredients: carnauba wax, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, pregelatinized starch, purified water, sodium starch glycolate, synthetic iron oxide, and titanium dioxide.

TOPAMAX® Sprinkle Capsules contain topiramate-coated beads in a hard gelatin capsule. The inactive ingredients are black pharmaceutical ink, cellulose acetate, gelatin, povidone, sodium lauryl sulfate, sorbitan monolaurate, sugar spheres (sucrose and starch) and titanium dioxide.

Indications & Dosage

INDICATIONS

Monotherapy Epilepsy

TOPAMAX® is indicated as initial monotherapy for the treatment of partial-onset or primary generalized tonic-clonic seizures in patients 2 years of age and older.

Adjunctive Therapy Epilepsy

TOPAMAX® is indicated as adjunctive therapy for the treatment of partial-onset seizures, primary generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome in patients 2 years of age and older.

Migraine

TOPAMAX® is indicated for the preventive treatment of migraine in patients 12 years of age and older.

DOSAGE AND ADMINISTRATION

Dosing In Monotherapy Epilepsy

Adults And Pediatric Patients 10 Years Of Age And Older

The recommended dose for TOPAMAX® monotherapy in adults and pediatric patients 10 years of age and older is 400 mg/day in two divided doses. The dose should be achieved by titration according to the following schedule (Table 1):

Table 1: Monotherapy Titration Schedule for Adults and Pediatric Patients 10 years and older

Morning DoseEvening Dose
Week 125 mg25 mg
Week 250 mg50 mg
Week 375 mg75 mg
Week 4100 mg100 mg
Week 5150 mg150 mg
Week 6200 mg200 mg

Pediatric Patients 2 To 9 Years Of Age

Dosing in patients 2 to 9 years of age is based on weight. During the titration period, the initial dose of TOPAMAX® is 25 mg/day nightly for the first week. Based upon tolerability, the dosage can be increased to 50 mg/day (25 mg twice daily) in the second week. Dosage can be increased by 25-50 mg/day each subsequent week as tolerated. Titration to the minimum maintenance dose should be attempted over 5-7 weeks of the total titration period. Based upon tolerability and clinical response, additional titration to a higher dose (up to the maximum maintenance dose) can be attempted at 25-50 mg/day weekly increments. The total daily dose should not exceed the maximum maintenance dose for each range of body weight (Table 2).

Table 2: Monotherapy Target Total Daily Maintenance Dosing for Patients 2 to 9 Years of Age

Weight (kg)Total Daily Dose (mg/day)* Minimum Maintenance DoseTotal Daily Dose (mg/day)* Maximum Maintenance Dose
Up to 11150250
12 -22200300
23 - 31200350
32-38250350
Greater than 38250400
* Administered in two equally divided doses

Dosing In Adjunctive Therapy Epilepsy

Adults (17 Years Of Age And Older)

The recommended total daily dose of TOPAMAX® as adjunctive therapy in adults with partial onset seizures or Lennox-Gastaut Syndrome is 200 to 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. TOPAMAX® should be initiated at 25 to 50 mg/day, followed by titration to an effective dose in increments of 25 to 50 mg/day every week. Titrating in increments of 25 mg/day every week may delay the time to reach an effective dose. Doses above 400 mg/day have not been shown to improve responses in adults with partial-onset seizures.

Pediatric Patients 2 To 16 Years Of Age

The recommended total daily dose of TOPAMAX® as adjunctive therapy for pediatric patients 2 to 16 years of age with partial-onset 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/day (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. The total daily dose should not exceed 400 mg/day.

Dosing For The Preventive Treatment Of Migraine

The recommended total daily dose of TOPAMAX® as treatment for patients 12 years of age and older for the preventive treatment of migraine is 100 mg/day administered in two divided doses (Table 3). The recommended titration rate for TOPAMAX® for the preventive treatment of migraine is as follows:

Table 3: Preventive Treatment of Migraine Titration Schedule for Patients 12 Years of Age and Older

Morning DoseEvening Dose
Week 1None25 mg
Week 225 mg25 mg
Week 325 mg50 mg
Week 450 mg50 mg

Dose and titration rate should be guided by clinical outcome. If required, longer intervals between dose adjustments can be used.

Administration Information

TOPAMAX® can be taken without regard to meals.

TOPAMAX® Tablets

Because of the bitter taste, tablets should not be broken.

TOPAMAX® Sprinkle Capsules

TOPAMAX® 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.

Dosing In Patients With Renal Impairment

In patients with renal impairment (creatinine clearance less than 70 mL/min/1.73 m²), one-half of the usual adult dose of TOPAMAX® is recommended [see Use In Specific Populations, CLINICAL PHARMACOLOGY].

Dosing In Patients Undergoing Hemodialysis

To avoid rapid drops in topiramate plasma concentration during hemodialysis, a supplemental dose of TOPAMAX® 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 [see Use In Specific Populations, CLINICAL PHARMACOLOGY].

HOW SUPPLIED

Dosage Forms And Strengths

TOPAMAX® 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)

TOPAMAX® 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

TOPAMAX®Tablets

TOPAMAX® (topiramate) Tablets are available as debossed, coated, round tablets in the following strengths and colors:

25 mg cream tablet (debossed “OMN” on one side; “25” on the other) and are available in bottles of 60 count with desiccant (NDC 50458-639-65)

50 mg light yellow tablet (debossed “OMN” on one side; “50” on the other) and are available in bottles of 60 count with desiccant (NDC 50458-640-65)

100 mg yellow tablet (debossed “OMN” on one side; “100” on the other) and are available in bottles of 60 count with desiccant (NDC 50458-641-65)

200 mg salmon tablet (debossed “OMN” on one side; “200” on the other) and are available in bottles of 60 count with desiccant (NDC 50458-642-65)

TOPAMAX® Sprinkle Capsules

TOPAMAX® (topiramate capsules) Sprinkle Capsules contain small, white to off-white spheres. The gelatin capsules are white and clear and are marked as follows:

15 mg capsule with “TOP” and “15 mg” on the side and are available in bottles of 60 (NDC 50458-647-65)

25 mg capsule with “TOP” and “25 mg” on the side and are available in bottles of 60 (NDC 50458-645-65)

Storage And Handling

TOPAMAX® Tablets

TOPAMAX® Tablets should be stored in tightly-closed containers at controlled room temperature (59° to 86°F, 15° to 30°C). Protect from moisture.

TOPAMAX® Sprinkle Capsules

TOPAMAX® Sprinkle Capsules should be stored in tightly-closed containers at or below 25°C (77°F). Protect from moisture.

Manufactured by: Janssen Ortho LLC, Gurabo, Puerto Rico 00778. Manufactured for: Janssen Pharmaceuticals, Inc., Titusville, NJ 08560.  Revised: Jun 2020

SLIDESHOW

Epilepsy: Symptoms, Causes and Treatment See Slideshow
Side Effects

SIDE EFFECTS

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

  • Acute Myopia and Secondary Angle Closure Glaucoma [see WARNINGS AND PRECAUTIONS]
  • Visual Field Defects [see WARNINGS AND PRECAUTIONS]
  • Oligohidrosis and Hyperthermia [see WARNINGS AND PRECAUTIONS]
  • Metabolic Acidosis [see WARNINGS AND PRECAUTIONS]
  • Suicidal Behavior and Ideation [see WARNINGS AND PRECAUTIONS]
  • Cognitive/Neuropsychiatric Adverse Reactions [see WARNINGS AND PRECAUTIONS]
  • Serious Skin Reactions [see WARNINGS AND PRECAUTIONS]
  • Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid [VPA] Use) [see WARNINGS AND PRECAUTIONS]
  • Kidney Stones [see WARNINGS AND PRECAUTIONS]
  • Hypothermia with Concomitant Valproic Acid (VPA) Use [see WARNINGS AND PRECAUTIONS]

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

Clinical Trials Experience

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

Monotherapy Epilepsy

Adults 16 Years Of Age And Older

The most common adverse reactions in the controlled clinical trial (Study 1) that occurred in adults in the 400 mg/day TOPAMAX® group and at an incidence higher (≥ 10 %) than in the 50 mg/day group were: paresthesia, weight loss and anorexia (see Table 5).

Approximately 21% of the 159 adult patients in the 400 mg/day group who received TOPAMAX® as monotherapy in Study 1 discontinued therapy due to adverse reactions. The most common (≥ 2% more frequent than low-dose 50 mg/day TOPAMAX®) adverse reactions causing discontinuation were difficulty with memory, fatigue, asthenia, insomnia, somnolence, and paresthesia.

Pediatric Patients 6 To 15 Years Of Age

The most common adverse reactions in the controlled clinical trial (Study 1) that occurred in pediatric patients in the 400 mg/day TOPAMAX® group and at an incidence higher (≥10%) than in the 50 mg/day group were fever and weight loss (see Table 5).

Approximately 14% of the 77 pediatric patients in the 400 mg/day group who received TOPAMAX® as monotherapy in the controlled clinical trial discontinued therapy due to adverse reactions. The most common (≥2% more frequent than low-dose 50 mg/day TOPAMAX®) adverse reactions resulting in discontinuation were difficulty with concentration/attention, fever, flushing, and confusion.

Table 5 presents the incidence of adverse reactions occurring in at least 3% of adult and pediatric patients treated with 400 mg/day TOPAMAX® and occurring with greater incidence than 50 mg/day TOPAMAX®.

Table 5: Adverse Reactions in the High Dose Group As Compared to the Low Dose Group, in Monotherapy Epilepsy Trial (Study 1) in Adult and Pediatric Patients

Body System
Adverse Reaction
Age Group Pediatric (6 to 15 Years)Adult (Age ≥16 Years)
TOPAMAX® Daily Dosage Group (mg/day)
5040050400
(N=74) %(N=77) %(N=160) %(N=159) %
Body as a Whole - General Disorders
Asthenia0346
Fever112
Leg pain23
Paresthesia3122140
Dizziness1314
Ataxia34
Hypoesthesia45
Hypertonia03
Involuntary muscle contractions03
Vertigo03
Gastro-Intestinal System Disorders
Constipation14
Diarrhea89
Gastritis03
Dry mouth13
Liver and Biliary System Disorders
Increase in Gamma-GT13
Metabolic and Nutritional Disorders
Weight loss717617
Platelet, Bleeding & Clotting Disorders
Epistaxis04
Psychiatric Disorders
Anorexia414
Anxiety46
Cognitive problems1614
Confusion03
Depression0379
Difficulty with concentration or attention71078
Difficulty with memory13611
Insomnia89
Decrease in libido03
Mood problems1825
Personality disorder (behavior problems)03
Psychomotor slowing35
Somnolence1015
Red Blood Cell Disorders
Anemia13
Reproductive Disorders, Female
Intermenstrual bleeding03
Vaginal hemorrhage03
Resistance Mechanism Disorders
Infection3823
Viral infection3668
Respiratory System Disorders
Bronchitis1534
Upper respiratory tract infection1618
Rhinitis5624
Sinusitis14
Skin and Appendages Disorders
Alopecia1434
Pruritus14
Rash3414
Acne23
Special Senses Other, Disorders
Taste perversion35
Urinary System Disorders
Cystitis13
Micturition frequency03
Renal calculus03
Urinary incontinence13
Vascular (Extracardiac) Disorders
Flushing05

Adjunctive Therapy Epilepsy

Adults 16 Years Of Age And Older

In pooled controlled clinical trials in adults with partial-onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, 183 patients received adjunctive therapy with TOPAMAX® at dosages of 200 to 400 mg/day (recommended dosage range) and 291 patients received placebo. Patients in these trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to TOPAMAX® or placebo.

The most common adverse reactions in the controlled clinical trial that occurred in adult patients in the 200-400 mg/day TOPAMAX® group with an incidence higher (≥ 10 %) than in the placebo group were: dizziness, speech disorders/related speech problems, somnolence, nervousness, psychomotor slowing, and vision abnormal (Table 6).

Table 6 presents the incidence of adverse reactions occurring in at least 3% of adult patients treated with 200 to 400 mg/day TOPAMAX® and was greater than placebo incidence. The incidence of some adverse reactions (e.g., fatigue, dizziness, paresthesia, language problems, psychomotor slowing, depression, difficulty with concentration/attention, mood problems) was dose-related and much greater at higher than recommended TOPAMAX® dosing (i.e., 600 mg - 1000 mg daily) compared to the incidence of these adverse reactions at the recommended dosing (200 mg to 400 mg daily) range.

Table 6: Most Common Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Epilepsy Trials in Adultsa

Body System Adverse ReactionPlacebo
(N=291)
TOPAMAX® Dosage (mg/day) 200-400
(N=183)
Body as a Whole-General Disorders
Fatigue1315
Asthenia     6
Back pain45
Chest pain34
Influenza-like symptoms23
Central & Peripheral Nervous System Disorders
Dizziness1525
Ataxia716
Speech disorders/Related speech problems213
Paresthesia411
Nystagmus710
Tremor69
Language problems16
Coordination abnormal24
Gait abnormal13
Gastro-Intestinal System Disorders
Nausea810
Dyspepsia67
Abdominal pain46
Constipation24
Metabolic and Nutritional Disorders
Weight loss39
Psychiatric Disorders
Somnolence1229
Nervousness616
Psychomotor slowing213
Difficulty with memory312
Confusion511
Anorexia410
Difficulty with concentration/attention26
Mood problems24
Agitation23
Aggressive reaction23
Emotional lability13
Cognitive problems13
Reproductive Disorders
Breast pain24
Respiratory System Disorders
Rhinitis67
Pharyngitis26
Sinusitis45
Vision Disorders
Vision abnormal213
Diplopia510
a Patients in these adjunctive trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to TOPAMAX® or placebo.

In controlled clinical trials in adults, 11% of patients receiving TOPAMAX® 200 to 400 mg/day as adjunctive therapy discontinued due to adverse reactions. This rate appeared to increase at dosages above 400 mg/day. Adverse reactions associated with discontinuing TOPAMAX® included somnolence, dizziness, anxiety, difficulty with concentration or attention, fatigue and paresthesia.

Pediatric Patients 2 To 15 Years Of Age

In pooled, controlled clinical trials in pediatric patients (2 to 15 years of age) with partial-onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, 98 patients received adjunctive therapy with TOPAMAX® at dosages of 5 to 9 mg/kg/day (recommended dose range) and 101 patients received placebo.

The most common adverse reactions in the controlled clinical trial that occurred in pediatric patients in the 5 mg to 9 mg/kg/day TOPAMAX® group with an incidence higher (≥ 10 %) than in the placebo group were: fatigue and somnolence (Table 7).

Table 7 presents the incidence of adverse reactions that occurred in at least 3% of pediatric patients 2 to 15 years of age receiving 5 mg to 9 mg/kg/day (recommended dose range) of TOPAMAX® and was greater than placebo incidence.

Table 7: Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Epilepsy Trials in Pediatric Patients 2 to 15 Years of Agea,b

Body System/ Adverse ReactionPlacebo
(N=101) %
TOPAMAX®
(N=98) %
Body as a Whole - General Disorders
Fatigue516
Injury1314
Central & Peripheral Nervous System Disorders
Gait abnormal58
Ataxia26
Hyperkinesia45
Dizziness24
Speech disorders/Related speech problems24
Gastro-Intestinal System Disorders
Nausea56
Saliva increased46
Constipation45
Gastroenteritis23
Metabolic and Nutritional Disorders
Weight loss19
Platelet, Bleeding, & Clotting Disorders
Purpura48
Epistaxis14
Psychiatric Disorders
Somnolence1626
Anorexia1524
Nervousness714
Personality disorder (behavior problems)911
Difficulty with concentration/attention210
Aggressive reaction49
Insomnia78
Difficulty with memory05
Confusion34
Psychomotor slowing23
Resistance Mechanism Disorders
Infection viral37
Respiratory System Disorders
Pneumonia15
Skin and Appendages Disorders
Skin disorder23
Urinary System Disorders
Urinary incontinence24
a Patients in these adjunctive 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 reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category.

None of the pediatric patients who received TOPAMAX® adjunctive therapy at 5 to 9 mg/kg/day in controlled clinical trials discontinued due to adverse reactions.

Migraine

Adults

In the four multicenter, randomized, double-blind, placebo-controlled, parallel group migraine clinical trials for the preventive treatment of migraine (which included 35 pediatric patients 12 to 15 years of age), most adverse reactions occurred more frequently during the titration period than during the maintenance period.

The most common adverse reactions with TOPAMAX® 100 mg in the clinical trials for the preventive treatment of migraine of predominantly adults that were seen at an incidence higher (≥ 5 %) than in the placebo group were: paresthesia, anorexia, weight loss, taste perversion, diarrhea, difficulty with memory, hypoesthesia, and nausea (see Table 8).

Table 8 includes those adverse reactions that occurred in the placebo-controlled trials where the incidence in any TOPAMAX® treatment group was at least 3% and was greater than that for placebo patients. The incidence of some adverse reactions (e.g., fatigue, dizziness, somnolence, difficulty with memory, difficulty with concentration/attention) was dose-related and greater at higher than recommended TOPAMAX® dosing (200 mg daily) compared to the incidence of these adverse reactions at the recommended dosing (100 mg daily).

Table 8: Adverse Reactions in Pooled, Placebo-Controlled, Migraine Trials in Adultsa,b

Body System/ Adverse ReactionPlacebo
(N=445)%
TOPAMAX® Dosage (mg/day)
50
(N=235)%
100
(N=386)%
Body as a Whole-General Disorders
Fatigue111415
Injury796
Central & Peripheral Nervous System Disorders
Paresthesia63551
Dizziness1089
Hypoesthesia267
Language problems276
Gastro-Intestinal System Disorders
Nausea8913
Diarrhea4911
Abdominal pain566
Dyspepsia345
Dry mouth223
Gastroenteritis133
Metabolic and Nutritional Disorders
Weight loss169
Musculoskeletal System Disorders
Arthralgia273
Psychiatric Disorders
Anorexia6915
Somnolence587
Difficulty with memory277
Insomnia567
Difficulty with concentration/attention236
Mood problems236
Anxiety345
Depression434
Nervousness244
Confusion223
Psychomotor slowing132
Reproductive Disorders, Female
Menstrual disorder232
Reproductive Disorders, Male
Ejaculation premature030
Resistance Mechanism Disorders
Viral infection344
Respiratory System Disorders
Upper respiratory tract infection121314
Sinusitis6106
Pharyngitis456
Coughing224
Bronchitis233
Dyspnea213
Skin and Appendages Disorders
Pruritis242
Special Sense Other, Disorders
Taste perversion1158
Urinary System Disorders
Urinary tract infection242
Vision Disorders
Blurred visionc242
aIncludes 35 adolescent patients age 12 to 15 years.
b Values represent the percentage of patients reporting a given adverse reaction. Patients may have reported more than one adverse reaction during the study and can be included in more than one adverse reaction category.
cBlurred vision was the most common term considered as vision abnormal. Blurred vision was an included term that accounted for >50% of reactions coded as vision abnormal, a preferred term.

Of the 1,135 patients exposed to TOPAMAX® in the adult placebo-controlled studies, 25% of TOPAMAX®-treated patients discontinued due to adverse reactions, compared to 10% of the 445 placebo-treated patients. The adverse reactions associated with discontinuing therapy in the TOPAMAX®-treated patients included paresthesia (7%), fatigue (4%), nausea (4%), difficulty with concentration/attention (3%), insomnia (3%), anorexia (2%), and dizziness (2%).

Patients treated with TOPAMAX® experienced mean percent reductions in body weight that were dose-dependent. This change was not seen in the placebo group. Mean changes of 0%, -2%, -3%, and -4% were seen for the placebo group, TOPAMAX® 50, 100, and 200 mg groups, respectively.

Pediatric Patients 12 To 17 Years Of Age

In five, randomized, double-blind, placebo-controlled, parallel group clinical trials for the preventive treatment of migraine, most adverse reactions occurred more frequently during the titration period than during the maintenance period. Among adverse reactions with onset during titration, approximately half persisted into the maintenance period.

In four, fixed-dose, double-blind clinical trials for the preventive treatment of migraine in TOPAMAX®-treated pediatric patients 12 to 17 years of age, the most common adverse reactions with TOPAMAX® 100 mg that were seen at an incidence higher (≥5%) than in the placebo group were: paresthesia, upper respiratory tract infection, anorexia, and abdominal pain (see Table 9). Table 9 shows adverse reactions from the pediatric trial (Study 13 [see Clinical Studies]) in which 103 pediatric patients were treated with placebo or 50 mg or 100 mg of TOPAMAX®, and three predominantly adult trials in which 49 pediatric patients (12 to 17 years of age) were treated with placebo or 50 mg, 100 mg or 200 mg of TOPAMAX®. Table 9 also shows adverse reactions in pediatric patients in the controlled migraine trials when the incidence in a TOPAMAX® dose group was at least 5 % or higher and greater than the incidence of placebo. Many adverse reactions shown in Table 9 indicate a dose-dependent relationship. The incidence of some adverse reactions (e.g., allergy, fatigue, headache, anorexia, insomnia, somnolence, and viral infection) was dose-related and greater at higher than recommended TOPAMAX® dosing (200 mg daily) compared to the incidence of these adverse reactions at the recommended dosing (100 mg daily).

Table 9: Adverse Reactions in Pooled Double-Blind Studies for the Preventive Treatment of Migraine in Pediatric Patients 12 to 17 Years of Agea,b,c

Body System/ Adverse ReactionPlacebo
(N=45) %
TOPAMAX® Dosage
50 mg/day
(N=46) %
100 mg/day
(N=48) %
Body as a Whole - General Disorders
Fatigue778
Fever246
Central & Peripheral Nervous System Disorders
Paresthesia72019
Dizziness446
Gastrointestinal System Disorders
Abdominal pain9715
Nausea448
Metabolic and Nutritional Disorders
Weight loss274
Psychiatric Disorders
Anorexia4910
Somnolence226
Insomnia292
Resistance Mechanism Disorders
Infection viral448
Respiratory System Disorders
Upper respiratory tract infection112623
Rhinitis276
Sinusitis294
Coughing072
Special Senses Other, Disorders
Taste perversion226
Vision Disorders
Conjunctivitis474
a 35 adolescent patients aged 12 to <16 years were also included in adverse reaction assessment for adults (Tables 10 and 11)
b Incidence is based on the number of subjects experiencing at least 1 adverse event, not the number of events.
c Included studies MIG-3006, MIGR-001, MIGR-002 and MIGR-003

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

Increased Risk For Bleeding

TOPAMAX® is associated with an increased risk for bleeding. In a pooled analysis of placebo-controlled studies of approved and unapproved indications, bleeding was more frequently reported as an adverse reaction for TOPAMAX® than for placebo (4.5% versus 3.0% in adult patients, and 4.4% versus 2.3% in pediatric patients). In this analysis, the incidence of serious bleeding events for TOPAMAX® and placebo was 0.3% versus 0.2% for adult patients, and 0.4% versus 0% for pediatric patients.

Adverse bleeding reactions reported with TOPAMAX® ranged from mild epistaxis, ecchymosis, and increased menstrual bleeding to life-threatening hemorrhages. In patients with serious bleeding events, conditions that increased the risk for bleeding were often present, or patients were often taking drugs that cause thrombocytopenia (other antiepileptic drugs) or affect platelet function or coagulation (e.g., aspirin, nonsteroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, or warfarin or other anticoagulants).

Other Adverse Reactions Observed During Clinical Trials

Other adverse reactions seen during clinical trials were: abnormal coordination, eosinophilia, gingival bleeding, hematuria, hypotension, myalgia, myopia, postural hypotension, scotoma, suicide attempt, syncope, and visual field defect.

Laboratory Test Abnormalities

Adult Patients

In addition to changes in serum bicarbonate (i.e., metabolic acidosis), sodium chloride and ammonia, TOPAMAX® was associated with changes in several clinical laboratory analytes in randomized, double-blind, placebo-controlled studies [see WARNINGS AND PRECAUTIONS]. Controlled trials of adjunctive TOPAMAX® treatment of adults for partial-onset seizures showed an increased incidence of markedly decreased serum phosphorus (6% TOPAMAX® versus 2% placebo), markedly increased serum alkaline phosphatase (3% TOPAMAX® versus 1% placebo), and decreased serum potassium (0.4 % TOPAMAX® versus 0.1 % placebo).

Pediatric Patients

In pediatric patients (1-24 months) receiving adjunctive TOPAMAX® for partial-onset seizures, there was an increased incidence for an increased result (relative to normal analyte reference range) associated with TOPAMAX® (vs placebo) for the following clinical laboratory analytes: creatinine, BUN, alkaline phosphatase, and total protein, The incidence was also increased for a decreased result for bicarbonate (i.e., metabolic acidosis), and potassium with TOPAMAX® (vs placebo) [see Use In Specific Populations]. TOPAMAX® is not indicated for partial-onset seizures in pediatric patients less than 2 years of age.

In pediatric patients (ranging from 6-17 years of age) receiving TOPAMAX® for the preventive treatment of migraine, there was an increased incidence for an increased result (relative to normal analyte reference range) associated with TOPAMAX® (vs placebo) for the following clinical laboratory analytes: creatinine, BUN, uric acid, chloride, ammonia, alkaline phosphatase, total protein, platelets, and eosinophils, The incidence was also increased for a decreased result for phosphorus, bicarbonate, total white blood count, and neutrophils [see Use In Specific Populations]. TOPAMAX® is not indicated for the preventive treatment of migraine in pediatric patients less than 12 years of age.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of TOPAMAX®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole-General Disorders: oligohydrosis and hyperthermia [see WARNINGS AND PRECAUTIONS], hyperammonemia, hyperammonemic encephalopathy [see WARNINGS AND PRECAUTIONS], hypothermia with concomitant valproic acid [see WARNINGS AND PRECAUTIONS]

Gastrointestinal System Disorders: hepatic failure (including fatalities), hepatitis, pancreatitis

Skin and Appendage Disorders: bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis) [see WARNINGS AND PRECAUTIONS], pemphigus

Urinary System Disorders: kidney stones, nephrocalcinosis [see WARNINGS AND PRECAUTIONS]

Vision Disorders: acute myopia, secondary angle closure glaucoma [see WARNINGS AND PRECAUTIONS], maculopathy

Hematological Disorders: decrease of the International Normalized Ratio (INR) or prothrombin time when given concomitantly with vitamin K antagonist anticoagulant medications such as warfarin.

Drug Interactions

DRUG INTERACTIONS

Antiepileptic Drugs

Concomitant administration of phenytoin or carbamazepine with TOPAMAX® resulted in a clinically significant decrease in plasma concentrations of topiramate when compared to TOPAMAX® given alone. A dosage adjustment may be needed [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].

Concomitant administration of valproic acid and TOPAMAX® has been associated with hypothermia and hyperammonemia with and without encephalopathy. Examine blood ammonia levels in patients in whom the onset of hypothermia has been reported [see WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY].

Other Carbonic Anhydrase Inhibitors

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

CNS Depressants

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

Oral Contraceptives

The possibility of decreased contraceptive efficacy and increased breakthrough bleeding may occur in patients taking combination oral contraceptive products with TOPAMAX®. Patients taking estrogen-containing contraceptives should be asked to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding [see CLINICAL PHARMACOLOGY].

Hydrochlorothiazide (HCTZ)

Topiramate Cmax and AUC increased when HCTZ was added to TOPAMAX®. The clinical significance of this change is unknown. The addition of HCTZ to TOPAMAX® may require a decrease in the TOPAMAX® dose [see CLINICAL PHARMACOLOGY].

Pioglitazone

A decrease in the exposure of pioglitazone and its active metabolites were noted with the concurrent use of pioglitazone and TOPAMAX® in a clinical trial. The clinical relevance of these observations is unknown; however, 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 [see CLINICAL PHARMACOLOGY].

Lithium

An increase in systemic exposure of lithium following TOPAMAX® doses of up to 600 mg/day can occur. Lithium levels should be monitored when co-administered with high-dose TOPAMAX® [see CLINICAL PHARMACOLOGY].

Amitriptyline

Some patients may experience a large increase in amitriptyline concentration in the presence of TOPAMAX® and any adjustments in amitriptyline dose should be made according to the patient's clinical response and not on the basis of plasma levels [see CLINICAL PHARMACOLOGY].

Overdosage & Contraindications

OVERDOSE

Overdoses of TOPAMAX® have been reported. Signs and symptoms included convulsions, drowsiness, speech disturbance, blurred vision, diplopia, impaired mentation, 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 overdoses involving TOPAMAX®.

TOPAMAX® overdose has resulted in severe metabolic acidosis [see WARNINGS AND PRECAUTIONS].

A patient who ingested a dose of TOPAMAX® between 96 and 110 g was admitted to a hospital with a coma lasting 20 to 24 hours followed by full recovery after 3 to 4 days.

In the event of overdose, TOPAMAX® should be discontinued and general supportive treatment given until clinical toxicity has been diminished or resolved. Hemodialysis is an effective means of removing topiramate from the body.

CONTRAINDICATIONS

None.

Clinical Pharmacology

CLINICAL PHARMACOLOGY

Mechanism Of Action

The precise mechanisms by which topiramate exerts its anticonvulsant and preventive migraine effects are unknown; however, preclinical studies have revealed four properties that may contribute to topiramate's efficacy for epilepsy and the preventive treatment of migraine. 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 electroshock seizure (MES) tests. Topiramate is only weakly effective in blocking clonic seizures induced by the GABAA receptor antagonist, pentylenetetrazole. 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.

Changes (increases and decreases) from baseline in vital signs (systolic blood pressure-SBP, diastolic blood pressure-DBP, pulse) occurred more frequently in pediatric patients (6 to 17 years) treated with various daily doses of topiramate (50 mg, 100 mg, 200 mg, 2 to 3 mg/kg) than in patients treated with placebo in controlled trials for the preventive treatment of migraine. The most notable changes were SBP <90 mm Hg, DBP <50 mm Hg, SBP or DBP increases or decreases ≥20 mm Hg, and pulse increases or decreases ≥30 beats per minute. These changes were often dose-related, and were most frequently associated with the greatest treatment difference at the 200 mg dose level. Systematic collection of orthostatic vital signs has not been conducted. The clinical significance of these various changes in vital signs has not been clearly established.

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% to 41% bound to human plasma proteins over the blood concentration range of 0.5 to 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 to 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 adults following oral administration.

Specific Populations

Renal Impairment

The clearance of topiramate was reduced by 42% in subjects with moderate renal impairment (creatinine clearance 30 to 69 mL/min/1.73 m²) and by 54% in subjects with severe renal impairment (creatinine clearance <30 mL/min/1.73 m²) compared to subjects with normal renal function (creatinine clearance >70 mL/min/1.73 m²) [see DOSAGE AND ADMINISTRATION].

Hemodialysis

Topiramate is cleared by hemodialysis. Using a high-efficiency, counterflow, single pass-dialysate hemodialysis procedure, topiramate dialysis clearance was 120 mL/min with blood flow through the dialyzer at 400 mL/min. This high clearance (compared to 20 to 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 [see DOSAGE AND ADMINISTRATION, Use In Specific Populations].

Hepatic Impairment

Plasma clearance of topiramate decreased a mean of 26% in patients with moderate to severe hepatic impairment.

Age, Gender, And Race

The pharmacokinetics of topiramate in elderly subjects (65 to 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 to 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 [see DOSAGE AND ADMINISTRATION and Use In Specific Populations].

Clearance of topiramate in adults was not affected by gender or race.

Pediatric Pharmacokinetics

Pharmacokinetics of topiramate were evaluated in patients age 2 to <16 years. Patients received either no or a combination of other antiepileptic drugs. A population pharmacokinetic model was developed on the basis of pharmacokinetic data from relevant topiramate clinical studies. This dataset contained data from 1217 subjects including 258 pediatric patients age 2 to <16 years (95 pediatric patients <10 years of age).

Pediatric patients on adjunctive treatment exhibited a higher oral clearance (L/h) of topiramate compared to patients on monotherapy, presumably because of increased clearance from concomitant enzyme-inducing antiepileptic drugs. In comparison, topiramate clearance per kg is greater in pediatric patients than in adults and in young pediatric patients (down to 2 years) than in older pediatric patients. Consequently, the plasma drug concentration for the same mg/kg/day dose would be lower in pediatric patients compared to adults and also in younger pediatric patients compared to older pediatric patients. Clearance was independent of dose.

As in adults, hepatic enzyme-inducing antiepileptic drugs decrease the steady state plasma concentrations of topiramate.

Drug Interactions

In vitro studies indicate that topiramate does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, or CYP3A4/5 isozymes. In vitro studies indicate that topiramate is a mild inhibitor of CYP2C19 and a mild inducer of CYP3A4.

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 10.

In Table 10, the second column (AED concentration) describes what happens to the concentration of the co-administered AED listed in the first column when topiramate is added. The third column (topiramate concentration) describes how the co-administration of a drug listed in the first column modifies the concentration of topiramate when compared to TOPAMAX® given alone.

Table 10: Summary of AED Interactions with TOPAMAX®

AED Co-administeredAED ConcentrationTopiramate Concentration
PhenytoinNC or 25% increasea48% decrease
Carbamazepine (CBZ)NC40% decrease
CBZ epoxidebNCNE
Valproic acid11% decrease14% decrease
PhenobarbitalNCNE
PrimidoneNCNE
LamotrigineNC at TPM doses up to 400 mg/day13% decrease
a = Plasma concentration increased 25% in some patients, generally those on a twice a day 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

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 and there was no significant dose-dependent change in EE exposure for doses of 50 to 200 mg/day. The clinical significance of the changes observed is not known [see 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.

Hydrochlorothiazide

A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of hydrochlorothiazide (HCTZ) (25 mg every 24 hours) and topiramate (96 mg every 12 hours) 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 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 interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of metformin (500 mg every 12 hours) and topiramate in plasma when metformin was given alone and when metformin and topiramate (100 mg every 12 hours) were given simultaneously. The results of this study indicated that the mean metformin Cmax and AUC0-12h increased by 18% and 25%, respectively, when topiramate was added. Topiramate did not affect metformin tmax. The clinical significance of the effect of topiramate on metformin pharmacokinetics is not known. Oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect of metformin on topiramate pharmacokinetics is unclear.

Pioglitazone

A 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 AUCτ,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 AUCτ,ss respectively, of the active hydroxy-metabolite was noted as well as a 60% decrease in Cmax,ss and AUCτ,ss of the active keto-metabolite. The clinical significance of these findings is not known.

Glyburide

A drug-drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state pharmacokinetics of glyburide (5 mg/day) alone and concomitantly with topiramate (150 mg/day). There was a 22% decrease in Cmax and a 25% reduction in AUC24 for glyburide during topiramate administration. Systemic exposure (AUC) of the active metabolites, 4-trans-hydroxy-glyburide (M1) and 3-cis-hydroxyglyburide (M2), was also reduced by 13% and 15%, and Cmax was reduced by 18% and 25%, respectively. The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide.

Lithium

In patients, the pharmacokinetics of lithium were unaffected during treatment with topiramate at doses of 200 mg/day; however, there was an observed increase in systemic exposure of lithium (27% for Cmax and 26% for AUC) following topiramate doses up to 600 mg/day [see DRUG INTERACTIONS].

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 males, 7 females).

Amitriptyline

There was a 12% increase in AUC and Cmax for amitriptyline (25 mg per day) in 18 healthy subjects (9 males, 9 females) receiving 200 mg/day of TOPAMAX®.

Sumatriptan

Multiple dosing of topiramate (100 mg every 12 hours) in 24 healthy volunteers (14 males, 10 females) did not affect the pharmacokinetics of single-dose sumatriptan either orally (100 mg) or subcutaneously (6 mg).

Risperidone

When administered concomitantly with topiramate at escalating doses of 100, 250, and 400 mg/day, there was a reduction in risperidone systemic exposure (16% and 33% for steady-state AUC at the 250 and 400 mg/day doses of topiramate). No alterations of 9-hydroxyrisperidone levels were observed. Co-administration of topiramate 400 mg/day with risperidone resulted in a 14% increase in Cmax and a 12% increase in AUC12 of topiramate. There were no clinically significant changes in the systemic exposure of risperidone plus 9-hydroxyrisperidone or of topiramate; therefore, this interaction is not likely to be of clinical significance.

Propranolol

Multiple dosing of topiramate (200 mg/day) in 34 healthy volunteers (17 males, 17 females) did not affect the pharmacokinetics of propranolol following daily 160 mg doses. Propranolol doses of 160 mg/day in 39 volunteers (27 males, 12 females) 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 males, 12 females) 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.

Diltiazem

Co-administration of diltiazem (240 mg Cardizem CD®) with topiramate (150 mg/day) resulted in a 10% decrease in Cmax and a 25% decrease in diltiazem AUC, a 27% decrease in Cmax and an 18% decrease in des-acetyl diltiazem AUC, and no effect on N-desmethyl diltiazem. Co-administration of topiramate with diltiazem resulted in a 16% increase in Cmax and a 19% increase in AUC12 of topiramate.

Venlafaxine

Multiple dosing of TOPAMAX® (150 mg/day) in healthy volunteers did not affect the pharmacokinetics of venlafaxine or O-desmethyl venlafaxine. Multiple dosing of venlafaxine (150 mg) did not affect the pharmacokinetics of topiramate.

Clinical Studies

The studies described in the following sections were conducted using TOPAMAX® (topiramate) Tablets.

Monotherapy Epilepsy

Patients With Partial-Onset Or Primary Generalized Tonic-Clonic Seizures

Adults And Pediatric Patients 10 Years Of Age And Older

The effectiveness of TOPAMAX® as initial monotherapy in adults and pediatric patients 10 years of age and older with partial-onset or primary generalized tonic-clonic seizures was established in a multicenter, randomized, double-blind, parallel-group trial (Study 1).

Study 1 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 TOPAMAX® 25 mg/day for 7 days in an open-label fashion. Forty-nine percent of patients had no prior AED treatment and 17% had a diagnosis of epilepsy for greater than 24 months. Any AED therapy used for temporary or emergency purposes was discontinued prior to randomization. In the double-blind phase, 470 patients were randomized to titrate up to 50 mg/day or 400 mg/day. If the target dose could not be achieved, patients were maintained on the maximum tolerated dose. Fifty-eight percent of patients achieved the maximal dose of 400 mg/day for >2 weeks, and patients who did not tolerate 150 mg/day were discontinued.

The primary efficacy assessment was a between-group comparison of time to first seizure during the double-blind phase. Comparison of the Kaplan-Meier survival curves of time to first seizure favored the TOPAMAX® 400 mg/day group over the TOPAMAX® 50 mg/day group (Figure 1). The treatment effects with respect to time to first seizure were consistent across various patient subgroups defined by age, sex, geographic region, baseline body weight, baseline seizure type, time since diagnosis, and baseline AED use.

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

Kaplan-Meier
Estimates of Cumulative Rates for Time to First Seizure in Study 1 - Illustration

Pediatric Patients 2 To 9 Years Of Age

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

Adjunctive Therapy Epilepsy

Adult Patients With Partial-Onset Seizures

The effectiveness of TOPAMAX® as an adjunctive treatment for adults with partial-onset seizures was established in six multicenter, randomized, double-blind, placebo-controlled trials (Studies 2, 3, 4, 5, 6, and 7), two comparing several dosages of TOPAMAX® 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 pre-specified minimum number of partial-onset seizures, with or without secondary generalization, during the baseline phase (12 seizures for 12-week baseline, 8 for 8-week baseline or 3 for 4-week baseline) were randomly assigned to placebo or a specified dose of 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 (Study 7), the 25 or 50 mg/day initial doses of topiramate were followed by respective weekly increments of 25 or 50 mg/day until the target dose of 200 mg/day was reached. After titration, patients entered a 4, 8 or 12-week stabilization period. The numbers of patients randomized to each dose and the actual mean and median doses in the stabilization period are shown in Table 11.

Pediatric Patients 2 To 16 Years Of Age With Partial-Onset Seizures

The effectiveness of TOPAMAX® as an adjunctive treatment for pediatric patients 2 to 16 years of age with partial-onset seizures was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 8), comparing TOPAMAX® and placebo in patients with a history of partial-onset seizures, with or without secondarily generalized seizures (see Table 12).

Patients in this study were permitted a maximum of two antiepileptic drugs (AEDs) in addition to 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/day; the dose was then increased by 25 mg to 150 mg/day increments every other week until the assigned dosage of 125, 175, 225, or 400 mg/day based on patients' weight to approximate a dosage of 6 mg/kg/day was reached, unless intolerance prevented increases. After titration, patients entered an 8-week stabilization period.

Patients With Primary Generalized Tonic-Clonic Seizures

The effectiveness of TOPAMAX® as an adjunctive treatment for primary generalized tonicclonic seizures in patients 2 years of age and older was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 9), comparing a single dosage of TOPAMAX® and placebo (see Table 12).

Patients in Study 9 were permitted a maximum of two antiepileptic drugs (AEDs) in addition to TOPAMAX® or placebo. Patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least three primary generalized tonic-clonic seizures during the baseline phase were randomly assigned to placebo or TOPAMAX® in addition to their other AEDs.

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

Patients With Lennox-Gastaut Syndrome

The effectiveness of TOPAMAX® as an adjunctive treatment for seizures associated with Lennox-Gastaut syndrome was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 10) comparing a single dosage of TOPAMAX® with placebo in patients 2 years of age and older (see Table 12).

Patients in Study 10 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/day for a week; the dose was then increased to 3 mg/kg/day for one week, then to 6 mg/kg/day. After titration, patients entered an 8-week stabilization period.

The primary measures of effectiveness were the percent reduction in drop attacks and a parental global rating of seizure severity.

Table 11: TOPAMAX® Dose Summary During the Stabilization Periods of Each of Six Double-Blind, Placebo-Controlled, Adjunctive Trials in Adults with Partial-Onset Seizuresa

StudyStabilization DosePlacebobTarget TOPAMAX® Dosage (mg/day)
2004006008001,000
2N42424041
Mean Dose5.9200390556----
Median Dose6.0200400600----
3N44----404540
Mean Dose9.7----544739796
Median Dose10.0----6008001,000
4N23--19------
Mean Dose3.8--395------
Median Dose4.0--400------
5N30----28----
Mean Dose5.7----522----
Median Dose6.0----600----
6N28------25--
Mean Dose7.9------568--
Median Dose8.0------600--
7N90157--------
Mean Dose8200--------
Median Dose8200--------
a Dose-response studies were not conducted for other indications or pediatric partial-onset seizures.
b Placebo dosages are given as the number of tablets. Placebo target dosages were as follows: Protocol 3 4 tablets/day; Protocols 1 and 4, 6 tablets/day; Protocols 5 and 6, 8 tablets/day; Protocol 2, 10 tablets/day.

In all adjunctive 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 12. As described above, a global improvement in seizure severity was also assessed in the Lennox-Gastaut trial.

Table 12: Efficacy Results in Double-Blind, Placebo-Controlled, Adjunctive Epilepsy Trials

TargetTOPAMAX Dosage (mg per day
Study ##Placebo2004006008001,000≈6mgl kg/day*
Partial-Onset Seizures Studies in Adults
2N45454546------
Median % Reduction1227a48b45c------
% Responders182444d46d------
3N47----484847--
Median % Reduction2----41c41c36c
% Responders9----40c41c36d
4N24--23--------
Median % Reduction1--41e--------
% Responders8--35d--------
5N30----30------
Median % Reduction-12----46f------
% Responders10----47c------
6N28------28----
Median % Reduction-21------24c----
% Responders0------43c----
7N91168----------
Median % Reduction2044c----------
% Responders2445c
Partial-Onset Seizures Studies in Pediatric Patients
8N45----------41
Median % Reduction11----------33d
% Responders20----------39
Primary Generalized Tonic-Clonich
9N40----------39
Median % Reduction9----------57d
% Responders20----------56c
Lennox-Gastaut Syndromei
10N49----------46
Median % Reduction-5----------15d
% Responders1428g
Improvement in Seizure Severityj2852d
Comparisons with placebo: ap=0.080; bp ≤ 0.010; cp ≤ 0.001; dp ≤ 0.050; ep=0.065; fp ≤0.005; gp=0.071;
hMedian % reduction and % responders are reported for PGTC seizures;
iMedian % reduction and % responders for drop attacks, i.e., tonic or atonic seizures
jPercentage of subjects who were minimally, much, or very much improved from baseline.
*For Studies 8 and 9, specified target dosages (<9.3 mg/kg/day) were assigned based on subject’s weight to approximate a dosage of 6mg/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/day in adults and over a 2-to 8-week period in pediatric patients; transition was permitted to a new antiepileptic regimen when clinically indicated.

Preventive Treatment Of Migraine

Adult Patients

The results of 2 multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trials established the effectiveness of TOPAMAX® in the preventive treatment of migraine. The design of both trials (Study 11 was conducted in the U.S. and Study 12 was conducted in the U.S. and Canada) was identical, enrolling patients with a history of migraine, with or without aura, for at least 6 months, according to the International Headache Society (IHS) diagnostic criteria. Patients with a history of cluster headaches or basilar, ophthalmoplegic, hemiplegic, or transformed migraine headaches were excluded from the trials. Patients were required to have completed up to a 2-week washout of any prior migraine preventive medications before starting the baseline phase.

Patients who experienced 3 to 12 migraine headaches over the 4 weeks in the baseline phase were randomized to either 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 (according to migraines classified by IHS criteria) 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 Study 11, a total of 469 patients (416 females, 53 males), ranging in age from 13 to 70 years, were randomized and provided efficacy data. Two hundred sixty-five patients completed the entire 26-week double-blind phase. The median average daily dosages were 48 mg/day, 88 mg/day, and 132 mg/day in the target dose groups of 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 treatment differences between the TOPAMAX® 100 and 200 mg/day groups versus placebo were similar and statistically significant (p<0.001 for both comparisons).

In Study 12, a total of 468 patients (406 females, 62 males), ranging in age from 12 to 65 years, were randomized and provided efficacy data. Two hundred fifty-five patients completed the entire 26-week double-blind phase. The median average daily dosages were 47 mg/day, 86 mg/day, and 150 mg/day in the target dose groups of 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 similar and statistically significant (p=0.008 and p <0.001, respectively).

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

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

Figure 2: Reduction in 4-Week Migraine Headache Frequency (Studies 11 and 12 for Adults and Adolescents)

Reduction in 4-Week Migraine Headache
Frequency - Illustration

Pediatric Patients 12 To 17 Years Of Age

The effectiveness of TOPAMAX® for the preventive treatment of migraine in pediatric patients 12 to 17 years of age was established in a multicenter, randomized, double-blind, parallel-group trial (Study 13). The study enrolled 103 patients (40 male, 63 female) 12 to 17 years of age with episodic migraine headaches with or without aura. Patient selection was based on IHS criteria for migraines (using proposed revisions to the 1988 IHS pediatric migraine criteria [IHS-R criteria]).

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

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

The mean reduction from baseline to the last 12 weeks of the double-blind phase in average monthly attack rate, a key secondary efficacy endpoint in Study 13 (and the primary efficacy endpoint in Studies 11 and 12, of adults) was 3.0 for 100 mg TOPAMAX® dose and 1.7 for placebo. This 1.3 treatment difference in mean reduction from baseline of monthly migraine rate was statistically significant (p = 0.0087).

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

CategoryPlacebo
(N=33)
TOPAMAX® 50 mg/day
(N=35)
TOPAMAX® 100 mg/day
(N=35)
Baseline
Median3.64.04.0
Last 12 Weeks of Double-Blind Phase
Median2.32.31.0
Percent Reduction (%)
Median44.444.672.2
P-value versus0.79750.0164 c
Placeboa,b
a P-values (two-sided) for comparisons relative to placebo are generated by applying an ANCOVA model on ranks that includes subject's stratified age at baseline, treatment group, and analysis center as factors and monthly migraine attack rate during baseline period as a covariate.
b P-values for the dose groups are the adjusted p-value according to the Hochberg multiple comparison procedure.
c Indicates p-value is <0.05 (two-sided).

Medication Guide

PATIENT INFORMATION

TOPAMAX®
(TOE-PA-MAX)
(topiramate) TABLETS, for oral use

TOPAMAX®
(TOE-PA-MAX) (topiramate capsules) SPRINKLE CAPSULES, for oral use

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, including any new problems with your vision.

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. If a high fever, a fever that does not go away, or decreased sweating develops, call your healthcare provider right away.

TOPAMAX can increase the level of acid in your blood (metabolic acidosis). If left untreated, metabolic acidosis can cause brittle or soft bones (osteoporosis, osteomalacia, osteopenia), kidney stones, can slow the rate of growth in children, and may possibly harm your baby if you are pregnant. Metabolic acidosis can happen with or without symptoms. Sometimes people with metabolic acidosis will:

  • feel tired
  • not feel hungry (loss of appetite)
  • feel changes in heartbeat
  • have trouble thinking clearly

Your healthcare provider should do a blood test to measure the level of acid in your blood before and during your treatment with TOPAMAX. If you are pregnant, you should talk to your healthcare provider about whether you have metabolic acidosis.

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.

TOPAMAX can harm your unborn baby.

  • If you take TOPAMAX during pregnancy, your baby has a higher risk for birth defects called cleft lip and cleft palate. These defects can begin early in pregnancy, even before you know you are pregnant.
  • Cleft lip and cleft palate may happen even in children born to women who are not taking any medicines and do not have other risk factors.
  • There may be other medicines to treat your condition that have a lower chance of birth defects.
  • All women of childbearing age should talk to their healthcare providers about using other possible treatments instead of TOPAMAX. If the decision is made to use TOPAMAX, you should use effective birth control (contraception) unless you are planning to become pregnant. You should talk to your doctor about the best kind of birth control to use while you are taking TOPAMAX.
  • Tell your healthcare provider right away if you become pregnant while taking TOPAMAX. You and your healthcare provider should decide if you will continue to take TOPAMAX while you are pregnant.
  • If you take TOPAMAX during pregnancy, your baby may be smaller than expected at birth. The longterm effects of this are not known. Talk to your healthcare provider if you have questions about this risk during pregnancy.
  • Metabolic acidosis may have harmful effects on your baby. Talk to your healthcare provider if TOPAMAX has caused metabolic acidosis during your pregnancy.
  • Pregnancy Registry: 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. The purpose of this registry is to collect information about the safety of TOPAMAX and other antiepileptic drugs during pregnancy.

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 adults and children 2 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 and adolescents 12 years and older.

Before taking TOPAMAX, tell your healthcare provider about all of your medical conditions, including if you:

  • have or have had depression, mood problems, or suicidal thoughts or behavior.
  • have kidney problems, have kidney stones, or are getting kidney dialysis.
  • have a history of metabolic acidosis (too much acid in the blood).
  • have liver problems.
  • have weak, brittle, or soft bones (osteomalacia, osteoporosis, osteopenia, 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.
  • are breastfeeding or plan to breastfeed. TOPAMAX passes into breast milk. Breastfed babies may be sleepy or have diarrhea. It is not known if the TOPAMAX that passes into breast milk can cause other serious harm to 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 over-the-counter 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 (such as DEPAKENE or 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.
  • Take TOPAMAX Tablets 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 chew the food and medicine mixture.
  • 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 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 provider 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?

  • You should 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 machinery until you know how TOPAMAX affects you. TOPAMAX can slow your thinking and motor skills, and may affect vision.

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?”

  • 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).
  • 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.
  • Serious skin reactions. TOPAMAX may cause a severe rash with blisters and peeling skin, especially around the mouth, nose, eyes, and genitals (Stevens-Johnson syndrome). TOPAMAX may also cause a rash with blisters and peeling skin over much of the body that may cause death (toxic epidermal necrolysis). Call your healthcare provider right away if you develop a skin rash or blisters.
  • Kidney stones. Drink plenty of fluids when taking TOPAMAX to decrease your chances of getting kidney stones.
  • Low body temperature. Taking TOPAMAX when you are also taking valproic acid can cause a drop in body temperature to less than 95°F, or can cause tiredness, confusion, or coma.

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
  • speech problems
  • tiredness
  • dizziness
  • sleepiness/drowsiness
  • slow reactions
  • difficulty with memory
  • pain in the abdomen
  • fever
  • abnormal vision
  • decreased feeling or sensitivity, especially in the skin

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. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Janssen Pharmaceuticals, Inc. at 1-800-JANSSEN (1-800-526-7736).

How should I store TOPAMAX?

  • Store TOPAMAX Tablets at room temperature between 59°F to 86°F (15°C to 30°C).
  • Store TOPAMAX Sprinkle Capsules at or below 77°F (25°C).
  • 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 the safe and effective use of 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.

You can ask your pharmacist or healthcare provider for information about TOPAMAX that is written for health professionals.

What are the ingredients in TOPAMAX?

Active ingredient: topiramate

Inactive ingredients:

  • Tablets -carnauba wax, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, pregelatinized starch, purified water, sodium starch glycolate, synthetic iron oxide, and titanium dioxide.
  • Sprinkle Capsules -black pharmaceutical ink, cellulose acetate, gelatin, povidone, sodium lauryl sulfate, sorbitan monolaurate, sugar spheres (sucrose and starch) and titanium dioxide.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

FDA Logo

Report Problems to the Food and Drug Administration

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.

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