Topiramate 25 mg Capsule, 60-count — NDC 24979-211-04 (Billing 24979-0211-04)
This is a package of 60 capsules of Topiramate 25 mg Capsule from Upsher-Smith Laboratories, LLC, marketed since Dec 2023 and currently FDA-listed; retail pharmacies pay about $0.2459 per capsule (NADAC). It is this product's only package size.
Identity & classification
Regulatory identifiers FDA, NLM and CMS codes for this package
Drug-database identifiers Medi-Span GPI and First Databank GCN / HICL / AHFS classification
- GSN (GCN sequence number): 040902
- GCN: 36557
- GPI-14 (Medi-Span): 72600075006830
- HICL (First Databank): 011060
- AHFS class code: 28:12.92.00
- RxCUI (RxNorm): 205315
Where does this data come from?
- FDA openFDA NDC Directory · synced Oct 1, 2026
- FDA label on DailyMed · label index refreshed Oct 1, 2026
- RxNorm (NLM RxNav) · catalog refreshed Oct 1, 2026
- Medi-Span GPI (licensed)
- First Databank (licensed) · refreshed Oct 1, 2026
RxNorm drug class
This medicine belongs to the Centrally acting antiobesity products class.
Where does this data come from?
- RxClass (NLM) · catalog refreshed Oct 1, 2026
Clinical
Topiramate is used to treat certain types of seizures. Topiramate is also used to prevent migraine headaches but not to relieve the pain of migraine headaches when they occur. Topiramate is in a class of medications called anticonvulsants. It works by decreasing abnormal excitement in the brain.
Read the full MedlinePlus article ↗- It treats certain seizures in epilepsy, either alone or added to other medicines. Most products also prevent migraine in people 12 and older. Generic topiramate tablets are labeled...
- Take it by mouth exactly as prescribed. Your doctor will raise the dose slowly. Trokendi XR must be swallowed whole, while Qudexy XR can be sprinkled on soft food. Don't stop sudde...
- Tingling, dizziness, sleepiness, tiredness, appetite and weight loss, and trouble with memory, concentration or speech are common. Tell me if they bother you.
- Call right away for eye pain or vision changes, decreased sweating with a fever, mood changes or suicidal thoughts, a severe rash, or confusion. These can be serious.
Patient education
Supplement & herbal interactions
Some supplements/herbs that may interact with Topiramate — tap one for details:
Topiramate may be associated with lower levels of 1 nutrient — worth a chat with your pharmacist, not a cause for alarm.
Where does this data come from?
- MedlinePlus (NLM) · refreshed Oct 1, 2026
- FDA label on DailyMed · label index refreshed Oct 1, 2026
Ask a licensed pharmacist directly — free, answered by our team.
Pricing
A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.
| Price system | Per ea | Per package |
|---|---|---|
| Retail pharmacies payNADAC · weekly | $0.246 | $14.75 / 60 capsules |
| Medicaid paysCMS SDUD · 12 mo | $0.5437 | $32.62 / 60 capsules |
| Medicare drug plans payPart D · Q2 2026 | $0.4811 | $28.87 / 60 capsules |
Where does this data come from?
- CMS NADAC weekly file · file of Sep 30, 2026
- CMS ASP pricing files · refreshed Sep 20, 2026
- CMS Medicaid State Drug Utilization Data · through Q4 2025
- CMS Part D plan pricing files · refreshed Sep 24, 2026
- VA National Acquisition Center price file
Packaging — all sizes for this product
| Package NDC | Description | Marketing start | Marketing end | Status |
|---|---|---|---|---|
| 24979-0211-04 You're viewing this Main listing | 60 CAPSULE in 1 PACKAGE | 2023-12-05 | — | Active |
Therapeutic equivalents
| Product | Labeler | Pack | NADAC/unit | TE | Status | Price vs. this |
|---|---|---|---|---|---|---|
| Topiramate 25 mgthis 24979-0211-04 | Upsher-Smith | 60 capsules | $0.246 | AB | Availability likely | — |
| Topiramate 25 mg 59651-0453-60 | Aurobindo | 60 capsules | $0.246 | AB | Availability likely | — |
| Topiramate 25 mg 68462-0219-60 | Glenmark | 60 capsules | $0.246 | AB | Availability likely | — |
| Topamax 25 mg 50458-0645-65 | Janssen | 60 capsules | $7.540 | AB | Availability likely | +2967% |
| Topiramate 25 mg 51407-0894-60 | Golden | 60 capsules | — | AB | Discontinued | — |
| topiramate 25 mg 65841-0652-01 | Zydus | 100 capsules | — | AB | FDA listed | — |
| Topiramate 25 mg 67877-0869-05 | Ascend | 500 capsules | — | AB | FDA listed | — |
| topiramate 25 mg 68382-0005-01 | Zydus | 100 capsules | — | AB | FDA listed | — |
| topiramate 25 mg 70518-4247-00 | REMEDYREPACK | 1 capsule | — | AB | FDA listed | — |
| Topiramate 25 mg 72888-0229-05 | Advagen | 500 capsules | — | AB | FDA listed | — |
Where does this data come from?
- FDA openFDA NDC Directory · synced Oct 1, 2026
- FDA Orange Book · refreshed Sep 3, 2026
- CMS NADAC weekly file · file of Sep 30, 2026
Availability & generic status
This product is an FDA-approved generic. Other versions of the same drug are listed under Therapeutic equivalents, least expensive first.
Where does this data come from?
- FDA Orange Book · refreshed Sep 3, 2026
What it looks like
Where does this data come from?
- FDA label on DailyMed · label index refreshed Oct 1, 2026
Inactive Ingredients / Excipients
Inactive ingredients, also called excipients, are components of the drug product other than the active ingredient. They may include fillers, dyes, coatings, preservatives, flavors, or other formulation ingredients.
💡 Tap an ingredient (hover on desktop) to see what it is and why it’s used.
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UNII 3J2P07GVB6
Cellulose acetate is a plant-derived polymer made by chemically modifying cellulose fibers. In medications, it serves as a film-coating material for tablets and capsules to protect the drug, control release, and improve appearance.
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UNII 3OWL53L36A
A natural sugar alcohol derived from seaweed or synthesized in the lab. It's used as a filler to add bulk, a sweetener in sugar-free formulas, and a disintegrant to help tablets break apart in the stomach.
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UNII FZ989GH94E
Povidone is a synthetic polymer made from a plastic-like material. It acts as a binder to hold tablet ingredients together and as a disintegrant to help the tablet break apart in your stomach so the medicine can be absorbed.
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UNII O8232NY3SJ
A plant-based carbohydrate derived from corn kernels. It acts as a filler to add bulk, a binder to hold ingredients together, and a disintegrant to help the tablet break apart in your stomach for absorption.
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UNII C151H8M554
A natural sugar derived from sugar cane or sugar beets. It's used as a sweetener, filler, and binder to improve taste, add bulk, and help hold tablet or capsule ingredients together.
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UNII 15FIX9V2JP
Titanium dioxide is a bright white mineral powder commonly used as a colorant and opacifying agent. It makes pills and tablets white or lighter in color and helps make coatings non-transparent.
6 inactive ingredients listed in the exact product block matched to this NDC.
Where does this data come from?
ingredient classCode="IACT" elements from the exact product block matched by this NDC. Label-section narrative from DailyMed / the openFDA label index is shown separately when available.- FDA label on DailyMed · label index refreshed Oct 1, 2026
- FDA openFDA NDC Directory · synced Oct 1, 2026
Inactive ingredient FAQ
Are inactive ingredients the same for every manufacturer?
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Manufacturer & labeler
Where does this data come from?
- FDA openFDA NDC Directory · synced Oct 1, 2026
- Drugs@FDA
Full prescribing information FDA SPL
🎯 Indications and Usage ▾
1 INDICATIONS AND USAGE Topiramate capsules are indicated for: Epilepsy: initial monotherapy for the treatment of partial-onset or primary generalized tonic-clonic seizures in patients 2 years of age and older (1.1); adjunctive therapy for the treatment of partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome in patients 2 years of age and older (1.2) Preventive treatment of migraine in patients 12 years of age and older (1.3)
1.1Monotherapy Epilepsy Topiramate capsules are indicated as initial monotherapy for the treatment of partial-onset or primary generalized tonic-clonic seizures in patients 2 years of age and older.
1.2Adjunctive Therapy Epilepsy Topiramate capsules are 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.
1.3Migraine Topiramate capsules are indicated for the preventive treatment of migraine in patients 12 years of age and older.
⏱️ Dosage and Administration ▾
2 DOSAGE AND ADMINISTRATION Topiramate capsules initial dose, titration, and recommended maintenance dose varies by indication and age group. See Full Prescribing Information for recommended dosage, and dosing considerations in patients with renal impairment, geriatric patients, and patients undergoing hemodialysis (2.1, 2.2, 2.3, 2.4, 2.5, 2.6)
2.1Dosing in Monotherapy Epilepsy Adults and Pediatric Patients 10 Years of Age and Older The recommended dose for topiramate capsules 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 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 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 topiramate capsules 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 Dose Total Daily Dose (mg/day)* Maximum Maintenance Dose Up to 11 150 250 12 - 22 200 300 23 - 31 200 350 32 - 38 250 350 Greater than 38 250 400 * Administered in two equally divided doses
2.2Dosing in Adjunctive Therapy Epilepsy Adults (17 Years of Age and Older) The recommended total daily dose of topiramate capsules 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 tonicclonic seizures. Topiramate capsules 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 topiramate capsules 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.
2.3Dosing for the Preventive Treatment of Migraine The recommended total daily dose of topiramate capsules 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 topiramate capsules 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 Dose Evening Dose Week 1 N… [Excerpted — this section continues on DailyMed.]
💊 Dosage Forms and Strengths ▾
3 DOSAGE FORMS AND STRENGTHS Topiramate capsules, USP contain white to off white spherical shaped coated pellets. The hard gelatin capsules are clear cap with white opaque body. They are marked as follows: 15 mg capsule with “TWi T210” and “15 mg” in black ink on the cap and the body 25 mg capsule with “TWi T211” and “25 mg” in black ink on the cap and the body Topiramate Capsules, USP: 15 mg and 25 mg (3)
⛔ Contraindications ▾
4 CONTRAINDICATIONS None. None (4)
⚠️ Warnings and Cautions ▾
5 WARNINGS AND PRECAUTIONS Acute myopia and secondary angle closure glaucoma: can lead to permanent visual loss; discontinue topiramate capsules as soon as possible (5.1) Visual field defects: consider discontinuation of topiramate capsules (5.2) Oligohidrosis and hyperthermia: monitor decreased sweating and increased body temperature, especially in pediatric patients (5.3) Metabolic acidosis: baseline and periodic measurement of serum bicarbonate is recommended; consider dose reduction or discontinuation of topiramate capsules if clinically appropriate (5.4) Suicidal behavior and ideation: antiepileptic drugs increase the risk of suicidal behavior or ideation (5.5) Cognitive/neuropsychiatric adverse reactions: use caution when operating machinery including cars; depression and mood problems may occur (5.6) Fetal Toxicity: use during pregnancy can cause cleft lip and/or palate and being small for gestational age (5.7) Withdrawal of AEDs: withdraw topiramate capsules gradually (5.8) Decrease in Bone Mineral Density: has been shown to decrease bone mineral density and bone mineral content in pediatric patients (5.9) Negative effects on growth (height and weight): may slow height increase and weight gain; carefully monitor children receiving prolonged therapy (5.10) Serious skin reactions: If SJS or TEN is suspected, discontinue topiramate capsules (5.11) Hyperammonemia/encephalopathy: measure ammonia if encephalopathic symptoms occur (5.12) Kidney stones: avoid use with other carbonic anhydrase inhibitors, drugs causing metabolic acidosis, or in patients on a ketogenic diet (5.13) Hypothermia has been reported with and without hyperammonemia during topiramate treatment with concomitant valproic acid use (5.14)
5.1Acute Myopia and Secondary Angle Closure Glaucoma Syndrome A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving topiramate capsules. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include some or all of the following: myopia, mydriasis, anterior chamber shallowing, ocular hyperemia (redness), choroidal detachments, retinal pigment epithelial detachments, macular striae, and increased intraocular pressure.
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 topiramate capsules 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 topiramate capsules as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation of topiramate capsules, may be helpful. Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss.
5.2Visual Field Defects Visual field defects (independent of elevated intraocular pressure) have been reported in clinical trials and in postmarketing experience in patients receiving topiramate. In clinical trials, most of these events were reversible after topiramate discontinuation. If visual problems occur at any time during topiramate treatment, consideration should be given to discontinuing the drug.
5.3Oligohidrosis and Hyperthermia Oligohidrosis (decreased sweating), infrequently resulting in hospitalization, has been reported in association with topiramate capsules 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 pediatric patients. Patients (especially pediatric patients) treated with topiramate… [Excerpted — this section continues on DailyMed.]
🤒 Adverse Reactions ▾
6 ADVERSE REACTIONS The following serious adverse reactions are discussed in more detail in other sections of the labeling: Acute Myopia and Secondary Angle Closure Glaucoma [see Warnings and Precautions (5.1)] Visual Field Defects [see Warnings and Precautions (5.2)] Oligohidrosis and Hyperthermia [see Warnings and Precautions (5.3)] Metabolic Acidosis [see Warnings and Precautions (5.4)] Suicidal Behavior and Ideation [see Warnings and Precautions (5.5)] Cognitive/Neuropsychiatric Adverse Reactions [see Warnings and Precautions (5.6)] Decrease of Bone Mineral Density [see Warnings and Precautions (5.9)] Negative Effects on Growth (Height and Weight) [see Warnings and Precautions (5.10)] Serious Skin Reactions [see Warnings and Precautions (5.11)] Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid [VPA] Use) [see Warnings and Precautions (5.12)] Kidney Stones [see Warnings and Precautions (5.13)] Hypothermia with Concomitant Valproic Acid (VPA) Use [see Warnings and Precautions (5.14)] The data described in the following sections were obtained using topiramate tablets.
Epilepsy : Most common (≥10% more frequent than placebo or low-dose topiramate capsules) adverse reactions in adult and pediatric patients were: paresthesia, anorexia, weight loss, speech disorders/related speech problems, fatigue, dizziness, somnolence, nervousness, psychomotor slowing, abnormal vision and fever (6.1) Migraine : Most common (≥5% more frequent than placebo) adverse reactions in adult and pediatric patients were: paresthesia, anorexia, weight loss, difficulty with memory, taste perversion, diarrhea, hypoesthesia, nausea, abdominal pain and upper respiratory tract infection (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Upsher-Smith Laboratories, LLC at 1-855-899-9180 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the incidence of adverse reactions observed in the clinical trials of a drug cannot be directly compared to the incidence of adverse reactions in the clinical trials of another drug, and may not reflect the incidence of adverse reactions observed in practice. Monotherapy Epilepsy Adults 16 Years of Age and Older The most common adverse reactions in the controlled clinical trial (Study 1) that occurred in adults in the 400 mg/day topiramate group and at an incidence higher ( 10 %) than in the 50 mg/day group were: paresthesia, weight loss and anorexia (see Table 5).
Approximately 21% of the 159 adult patients in the 400 mg/day group who received topiramate as monotherapy in Study 1 discontinued therapy due to adverse reactions. The most common ( 2% more frequent than low-dose 50 mg/day topiramate) adverse reactions causing discontinuation were difficulty with memory, fatigue, asthenia, insomnia, somnolence, and paresthesia. Pediatric Patients 6 to 15 Years of Age The most common adverse reactions in the controlled clinical trial (Study 1) that occurred in pediatric patients in the 400 mg/day topiramate group and at an incidence higher (10%) than in the 50 mg/day group were fever and weight loss (see Table 5).
Approximately 14% of the 77 pediatric patients in the 400 mg/day group who received topiramate as monotherapy in the controlled clinical trial discontinued therapy due to adverse reactions. The most common (2% more frequent than low-dose 50 mg/day topiramate) adverse reactions resulting in discontinuation were difficulty with concentration/attention, fever, flushing, and confusion. Table 5 presents the incidence of adverse reactions occurring in at least 3% of adult and pediatric patients treated with 400 mg/day topiramate and occurring with greater incidence than 50 mg/day topiramate.
Table 5: Adverse Reactions in the High Dose Group As Compared to the Low Dose Group, in Monotherapy Epilepsy Trial (Study 1) in Adult and Pediatric Patients Age Group Pediatric (6 to 15 Years) Adult (Age ³16 Years)… [Excerpted — this section continues on DailyMed.]
🔄 Drug Interactions ▾
7 DRUG INTERACTIONS Contraceptives: decreased ontraceptive efficacy and increased breakthrough bleeding, especially at doses greater than 200 mg/day (7.4) Monitor lithium levels if lithium is used with high-dose topiramate capsules (7.7)
7.1Antiepileptic Drugs Concomitant administration of phenytoin or carbamazepine with topiramate capsules resulted in a clinically significant decrease in plasma concentrations of topiramate when compared to topiramate capsules given alone. A dosage adjustment may be needed [see Dosage and Administration (2.1), Clinical Pharmacology (12.3)] . Concomitant administration of valproic acid and topiramate capsules 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 (5.12, 5.14), Clinical Pharmacology (12.3)] .
7.2Other 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 topiramate capsules concomitantly with another carbonic anhydrase inhibitor should be monitored particularly closely for the appearance or worsening of metabolic acidosis [see Clinical Pharmacology (12.3)] .
7.3CNS Depressants Concomitant administration of topiramate capsules 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, topiramate capsules should be used with extreme caution if used in combination with alcohol and other CNS depressants.
7.4Contraceptives The possibility of decreased contraceptive efficacy and increased breakthrough bleeding may occur in patients taking contraceptive products with topiramate capsules. Patients taking estrogen-containing or progestin-only 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 (12.3)] .
7.5Hydrochlorothiazide (HCTZ) Topiramate C max and AUC increased when HCTZ was added to topiramate capsules. The clinical significance of this change is unknown. The addition of HCTZ to topiramate capsules may require a decrease in the topiramate capsules dose [see Clinical Pharmacology (12.3)] .
7.6Pioglitazone A decrease in the exposure of pioglitazone and its active metabolites were noted with the concurrent use of pioglitazone and topiramate capsules in a clinical trial. The clinical relevance of these observations is unknown; however, when topiramate capsules are added to pioglitazone therapy or pioglitazone is added to topiramate capsules therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state [see Clinical Pharmacology (12.3)] .
7.7Lithium An increase in systemic exposure of lithium following topiramate capsules doses of up to 600 mg/day can occur. Lithium levels should be monitored when co-administered with high-dose topiramate capsules [see Clinical Pharmacology (12.3)] .
7.8Amitriptyline Some patients may experience a large increase in amitriptyline concentration in the presence of topiramate capsules 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 (12.3)] .
👥 Use in Specific Populations ▾
8 USE IN SPECIFIC POPULATIONS
8.1Pregnancy Risk Summary Topiramate capsules can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk of major congenital malformations, including but not limited to cleft lip and/or cleft palate (oral clefts), and of being small for gestational age (SGA) [see Human Data]. SGA has been observed at all doses and appears to be dose-dependent.
The prevalence of SGA is greater in infants of women who received higher doses of topiramate during pregnancy. In addition, the prevalence of SGA in infants of women who continued topiramate use until later in pregnancy is higher compared to the prevalence in infants of women who stopped topiramate use before the third trimester. In multiple animal species, topiramate produced developmental toxicity, including increased incidences of fetal malformations, in the absence of maternal toxicity at clinically relevant doses [see Animal Data] .
All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively.
Clinical Considerations Fetal/Neonatal Adverse Reactions Consider the benefits and risks of topiramate when prescribing this drug to women of childbearing potential, particularly when topiramate is considered for a condition not usually associated with permanent injury or death. Because of the risk of oral clefts to the fetus, which occur in the first trimester of pregnancy, all women of childbearing potential should be informed of the potential risk to the fetus from exposure to topiramate. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of topiramate use during pregnancy, and alternative therapeutic options should be considered for these patients.
Labor or Delivery Although the effect of topiramate capsules on labor and delivery in humans has not been established, the development of topiramate-induced metabolic acidosis in the mother and/or in the fetus might affect the fetus’ ability to tolerate labor. Topiramate capsules treatment can cause metabolic acidosis [see Warnings and Precautions (5.4)] . The effect of topiramate-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus’ ability to tolerate labor.
Pregnant patients should be monitored for metabolic acidosis and treated as in the nonpregnant state [see Warnings and Precautions (5.4)] . Newborns of mothers treated with topiramate capsules should be monitored for metabolic acidosis because of transfer of topiramate to the fetus and possible occurrence of transient metabolic acidosis following birth. Based on limited information, topiramate has also been associated with pre-term labor and premature delivery.
Data Human Data Data from pregnancy registries indicate an increased risk of major congenital malformations, including but not limited to oral clefts in infants exposed to topiramate during the first trimester of pregnancy. Other than oral clefts, no specific pattern of major congenital malformations or grouping of major congenital malformation types were observed. In the NAAED pregnancy registry, when topiramate-exposed infants with only oral clefts were excluded, the prevalence of major congenital malformations (4.1%) was higher than that in infants exposed to a reference AED (1.8%) or in infants with mothers without epilepsy and without exposure to AEDs (1.1%).
The prevalence of oral clefts among topiramate-exposed infants (1.4%) was higher than the prevalence in infan… [Excerpted — this section continues on DailyMed.]
🤰 Pregnancy ▾
8.1Pregnancy Risk Summary Topiramate capsules can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk of major congenital malformations, including but not limited to cleft lip and/or cleft palate (oral clefts), and of being small for gestational age (SGA) [see Human Data]. SGA has been observed at all doses and appears to be dose-dependent.
The prevalence of SGA is greater in infants of women who received higher doses of topiramate during pregnancy. In addition, the prevalence of SGA in infants of women who continued topiramate use until later in pregnancy is higher compared to the prevalence in infants of women who stopped topiramate use before the third trimester. In multiple animal species, topiramate produced developmental toxicity, including increased incidences of fetal malformations, in the absence of maternal toxicity at clinically relevant doses [see Animal Data] .
All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively.
Clinical Considerations Fetal/Neonatal Adverse Reactions Consider the benefits and risks of topiramate when prescribing this drug to women of childbearing potential, particularly when topiramate is considered for a condition not usually associated with permanent injury or death. Because of the risk of oral clefts to the fetus, which occur in the first trimester of pregnancy, all women of childbearing potential should be informed of the potential risk to the fetus from exposure to topiramate. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of topiramate use during pregnancy, and alternative therapeutic options should be considered for these patients.
Labor or Delivery Although the effect of topiramate capsules on labor and delivery in humans has not been established, the development of topiramate-induced metabolic acidosis in the mother and/or in the fetus might affect the fetus’ ability to tolerate labor. Topiramate capsules treatment can cause metabolic acidosis [see Warnings and Precautions (5.4)] . The effect of topiramate-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus’ ability to tolerate labor.
Pregnant patients should be monitored for metabolic acidosis and treated as in the nonpregnant state [see Warnings and Precautions (5.4)] . Newborns of mothers treated with topiramate capsules should be monitored for metabolic acidosis because of transfer of topiramate to the fetus and possible occurrence of transient metabolic acidosis following birth. Based on limited information, topiramate has also been associated with pre-term labor and premature delivery.
Data Human Data Data from pregnancy registries indicate an increased risk of major congenital malformations, including but not limited to oral clefts in infants exposed to topiramate during the first trimester of pregnancy. Other than oral clefts, no specific pattern of major congenital malformations or grouping of major congenital malformation types were observed. In the NAAED pregnancy registry, when topiramate-exposed infants with only oral clefts were excluded, the prevalence of major congenital malformations (4.1%) was higher than that in infants exposed to a reference AED (1.8%) or in infants with mothers without epilepsy and without exposure to AEDs (1.1%).
The prevalence of oral clefts among topiramate-exposed infants (1.4%) was higher than the prevalence in infants exposed to a reference AED… [Excerpted — this section continues on DailyMed.]
🧒 Pediatric Use ▾
8.4Pediatric Use Adjunctive Treatment for Epilepsy Pediatric Patients 2 Years of Age and Older The safety and effectiveness of topiramate capsules as adjunctive therapy for the treatment of partial- onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox- Gastaut syndrome have been established in pediatric patients 2 years of age and older [see Adverse Reactions (6.1) and Clinical Studies (14.2)] . Pediatric Patients Below the Age of 2 Years 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.
In a single randomized, double-blind, placebo-controlled investigational trial, the efficacy, safety, and tolerability of topiramate oral liquid and sprinkle formulations as an adjunct to concurrent antiepileptic drug therapy in pediatric patients 1 to 24 months of age with refractory partial-onset seizures were assessed. After 20 days of double-blind treatment, topiramate (at fixed doses of 5, 15, and 25 mg/kg/day) did not demonstrate efficacy compared with placebo in controlling seizures. In general, the adverse reaction profile for topiramate capsules in this population was similar to that of older pediatric patients, although results from the above controlled study and an open-label, longterm extension study in these pediatric patients 1 to 24 months old suggested some adverse reactions/toxicities (not previously observed in older pediatric patients and adults; i.e., growth/length retardation, certain clinical laboratory abnormalities, and other adverse reactions/toxicities that occurred with a greater frequency and/or greater severity than had been recognized previously from studies in older pediatric patients or adults for various indications).
These very young pediatric patients appeared to experience an increased risk for infections (any topiramate dose 12%, placebo 0%) and of respiratory disorders (any topiramate dose 40%, placebo 16%). The following adverse reactions were observed in at least 3% of patients on topiramate and were 3% to 7% more frequent than in patients on placebo: viral infection, bronchitis, pharyngitis, rhinitis, otitis media, upper respiratory infection, cough, and bronchospasm. A generally similar profile was observed in older pediatric patients [see Adverse Reactions (6)] .
Topiramate resulted in an increased incidence of patients with increased creatinine (any topiramate dose 5%, placebo 0%), BUN (any topiramate dose 3%, placebo 0%), and protein (any topiramate dose 34%, placebo 6%), and an increased incidence of decreased potassium (any topiramate dose 7%, placebo 0%). This increased frequency of abnormal values was not dose-related. Creatinine was the only analyte showing a noteworthy increased incidence (topiramate 25 mg/kg/day 5%, placebo 0%) of a markedly abnormal increase.
The significance of these findings is uncertain. Topiramate treatment also produced a dose-related increase in the percentage of patients who had a shift from normal at baseline to high/increased (above the normal reference range) in total eosinophil count at the end of treatment. The incidence of these abnormal shifts was 6 % for placebo, 10% for 5 mg/kg/day, 9% for 15 mg/kg/day, 14% for 25 mg/kg/day, and 11% for any topiramate dose.
There was a mean dose-related increase in alkaline phosphatase. The significance of these findings is uncertain. Topiramate produced a dose-related increased incidence of hyperammonemia [see Warnings and Precautions (5.12)] .
Treatment with topiramate for up to 1 year was associated with reductions in Z SCORES for length, weight, and head circumference [see Warnings and Precautions (5.4), Adverse Reactions (6)] . In open-label, uncontrolled experience, increasing impairment of adaptive behavior was documented in behavioral testing over time in this population. There was… [Excerpted — this section continues on DailyMed.]
🧓 Geriatric Use ▾
8.5Geriatric Use In clinical trials, 3% of patients were over age 60. No age-related differences in effectiveness or adverse effects were evident. However, clinical studies of topiramate did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently than younger subjects.
Dosage adjustment may be necessary for elderly with age-related renal impairment (creatinine clearance rate <70 mL/min/1.73 m 2 ) resulting in reduced clearance [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)].
🆘 Overdosage ▾
10 OVERDOSAGE Overdoses of topiramate capsules 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 topiramate capsules.
Topiramate capsules overdose has resulted in severe metabolic acidosis [see Warnings and Precautions (5.4)] . A patient who ingested a dose of topiramate capsules 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, topiramate capsules 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.
🧬 Clinical Pharmacology ▾
12 CLINICAL PHARMACOLOGY
12.1Mechanism 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.
12.2Pharmacodynamics 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 GABA A 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.
12.3Pharmacokinetics 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… [Excerpted — this section continues on DailyMed.]
🧬 Mechanism of Action ▾
12.1Mechanism 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.
📦 How Supplied / Storage and Handling ▾
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1How Supplied Topiramate Capsules, USP Topiramate capsules, USP contain white to off white spherical shaped coated pellets. The gelatin capsules with clear cap and white opaque body are marked as follows: 15 mg capsule with “TWi T210” and “15 mg” in black ink on the cap and the body and are available in bottles of 60 (NDC 24979-210-04) 25 mg capsule with “TWi T211” and “25 mg” in black ink on the cap and the body and are available in bottles of 60 (NDC 24979-211-04)
16.2Storage and Handling Topiramate Capsules, USP Topiramate capsules, USP should be stored in tightly-closed containers at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Protect from moisture.
16.1How Supplied Topiramate Capsules, USP Topiramate capsules, USP contain white to off white spherical shaped coated pellets. The gelatin capsules with clear cap and white opaque body are marked as follows: 15 mg capsule with “TWi T210” and “15 mg” in black ink on the cap and the body and are available in bottles of 60 (NDC 24979-210-04) 25 mg capsule with “TWi T211” and “25 mg” in black ink on the cap and the body and are available in bottles of 60 (NDC 24979-211-04)
📦 Storage and Handling ▾
16.2Storage and Handling Topiramate Capsules, USP Topiramate capsules, USP should be stored in tightly-closed containers at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Protect from moisture.
📋 Description ▾
11 DESCRIPTION Topiramate is a sulfamate-substituted monosaccharide. Topiramate capsules, USP 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 C 12 H 21 NO 8 S 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: Topiramate capsules, USP contain topiramate-coated beads in a hard gelatin capsule.
The inactive ingredients are black ink, cellulose acetate, gelatin, mannitol, povidone, sodium lauryl sulfate, sugar spheres (sucrose and starch) and titanium dioxide. FDA approved dissolution test specifications differ from USP. structure
💬 Medication Guide ▾
Medication Guide Topiramate (TOE-PIR′-A-MATE) Capsules, for oral use What is the most important information I should know about topiramate capsules? Topiramate capsules 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. Topiramate capsules 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.
Topiramate capsules 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 feel changes in heartbeat not feel hungry (loss of appetite) 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 topiramate capsules. If you are pregnant, you should talk to your healthcare provider about whether you have metabolic acidosis. Like other antiepileptic drugs, topiramate capsules 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 trouble sleeping (insomnia) attempts to commit suicide new or worse irritability new or worse depression acting aggressive, being angry, or violent new or worse anxiety acting on dangerous impulses feeling agitated or restless an extreme increase in activity and talking (mania) panic attacks other unusual changes in behavior or mood Do not stop topiramate capsules without first talking to a healthcare provider.
Stopping topiramate capsules 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. Topiramate capsules can harm your unborn baby. If you take topiramate capsules during pregnancy, your baby has a higher risk for birth defects including cleft lip and cleft palate.
These defects can begin early in pregnancy, even before you know you are pregnant. Birth defects 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 topiramate capsules. If the decision is made to use topiramate capsules, 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 topiramate capsules.
Tell your healthcare provider right away if you become… [Excerpted — this section continues on DailyMed.]
🧬 Pharmacokinetics ▾
12.3Pharmacokinetics 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 m 2 ) and by 54% in subjects with severe renal impairment (creatinine clearance <30 mL/min/1.73 m 2 ) compared to subjects with normal renal function (creatinine clearance >70 mL/min/1.73 m 2 ) [see Dosage and Administration (2.4) and (2.5)] .
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 (2.6), Use in Specific Populations (8.7)] .
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 (2.… [Excerpted — this section continues on DailyMed.]
🧬 Pharmacodynamics ▾
12.2Pharmacodynamics 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 GABA A 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.
🔬 Clinical Studies ▾
14 CLINICAL STUDIES The studies described in the following sections were conducted using topiramate tablets.
14.1Monotherapy Epilepsy Patients with Partial-Onset or Primary Generalized Tonic-Clonic Seizures Adults and Pediatric Patients 10 Years of Age and Older The effectiveness of topiramate 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 topiramate 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 topiramate 400 mg/day group over the topiramate 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 Pediatric Patients 2 to 9 Years of Age The conclusion that topiramate 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 topiramate 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 topiramate 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 topiramate initial monotherapy [see Dosage and Administration (2.1)]. figure1
14.2Adjunctive Therapy Epilepsy Adult 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 (Studies 2, 3, 4, 5, 6, and 7), 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 topiramate 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 topiramate tablet… [Excerpted — this section continues on DailyMed.]
🧪 Nonclinical Toxicology ▾
13 NONCLINICAL TOXICOLOGY
13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis An increase in urinary bladder tumors was observed in mice given topiramate (0, 20, 75, and 300 mg/kg/day) in the diet for 21 months. The increase in the incidence of bladder tumors in males and females receiving 300 mg/kg/day was primarily due to the increased occurrence of a smooth muscle tumor considered histomorphologically unique to mice. The higher of the doses not associated with an increase in tumors (75 mg/kg/day) is equivalent to the maximum recommended human dose (MRHD) for epilepsy (400 mg), and approximately 4 times the MRHD for migraine (100 mg) on a mg/m2 basis.
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 2 years at doses up to 120 mg/kg/day (approximately 3 times the MRHD for epilepsy and 12 times the MRHD for migraine on a mg/m2basis). Mutagenesis 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 DNA synthesis in rat hepatocytes in vitro; and it did not increase chromosomal aberrations in human lymphocytes in vitro or in rat bone marrow in vivo. Impairment of Fertility No adverse effects on male or female fertility were observed in rats administered topiramate orally at doses up to 100 mg/kg/day (2.5 times the MRHD for epilepsy and 10 times the MRHD for migraine on a mg/m2 basis) prior to and during mating and early pregnancy.
📄 Package Label / Principal Display Panel ▾
PRINCIPAL DISPLAY PANEL —Topiramate Capsules, USP, 15 mg Bottle Label DC 24979-210-04 Topiramate Capsules, USP 15 mg Rx Only 60 Capsules image description
PPRINCIPAL DISPLAY PANEL —Topiramate Capsules, USP, 25 mg Bottle Label NDC 24979-211-04 Topiramate Capsules, USP 25 mg Rx Only 60 Capsules image description