Topiramate

Brand names: QUDEXY, TOPAMAX, Topamax, Trokendi XR, topiramate, TOPIRAMATE, Topiramate, QUDEXY XR, Eprontia

Warnings

No boxed warning; contraindications are listed as "none." Major warnings include "acute myopia and secondary angle closure glaucoma," which can cause "permanent vision loss" if untreated; "fetal toxicity," as use "during pregnancy can cause cleft lip and/or cleft palate"; "metabolic acidosis" from decreased serum bicarbonate, which can be severe; the class-wide warning that "antiepileptic drugs increase the risk of suicidal thoughts or behavior"; and "oligohidrosis and hyperthermia," primarily reported in pediatric patients, requiring monitoring for decreased sweating and elevated body temperature.

Contraindications

4 CONTRAINDICATIONS None None

Overdose

10 OVERDOSAGE Overdoses of topiramate tablets have been reported. Signs and symptoms included convulsions, drowsiness, speech disturbance, blurred vision, diplopia, mentation impaired, lethargy, abnormal coordination, stupor, hypotension, abdominal pain, agitation, dizziness and depression. The clinical consequences were not severe in most cases, but deaths have been reported after poly-drug overdoses involving Topiramate. Topiramate overdose has resulted in severe metabolic acidosis [see Warnings and Precautions ( 5.4 )] . A patient who ingested a dose between 96 and 110 g topiramate was admitted to a hospital with a coma lasting 20 to 24 hours followed by full recovery after 3 to 4 days. In acute topiramate overdose, if the ingestion is recent, the stomach should be emptied immediately by lavage or by induction of emesis. Activated charcoal has been shown to adsorb topiramate in vitro . Treatment should be appropriately supportive. Hemodialysis is an effective means of removing topiramate from the body

Drug interactions

7 DRUG INTERACTIONS Summary of antiepileptic drug (AED) interactions with topiramate tablets ( 7.1 ) AED Co-administered AED Concentration Topiramate Concentration Phenytoin NCor25%increase a 48%decrease Carbamazepine(CBZ) NC 40%decrease CBZepoxide b NC NE Valproic acid 11%decrease 14%decrease Phenobarbital NC NE Primidone NC NE Lamotrigine NCatTPM dosesupto400 mg/day 13%decrease • Oral contraceptives: Decreased contraceptive efficacy and increased breakthrough bleeding should be considered, especially at doses greater than 200 mg/day ( 7.3 ) • Metformin is contraindicated with metabolic acidosis, an effect of topiramate tablets ( 7.4 ) • Lithium levels should be monitored when co-administered with high-dose topiramate tablets ( 7.5 ) • Other carbonic anhydrase inhibitors: Monitor the patient for the appearance or worsening of metabolic acidosis ( 7.6 ) In vitro studies indicate that topiramate does not inhibit enzyme activity for CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4/5 isozymes. In vitro studies indicate that topiramate is a mild inhibitor of CYP2C19 and a mild inducer of CYP3A4. Drug interactions with some antiepileptic drugs, CNS depressants and oral contraceptives are described here. For other drug interactions, please refer to Clinical Pharmacology ( 12.3 ) . 7.1 Antiepileptic Drugs Potential interactions between topiramate and standard AEDs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. Concomitant administration of phenytoin or carbamazepine with topiramate decreased plasma concentrations of Topiramate by 48% and 40%, respectively when compared to topiramate given alone [see Clinical Pharmacology ( 12.3 ).] Concomitant administration of valproic acid and topiramate tablets has been associated with hyperammonemia with and without encephalopathy. Concomitant administration of topiramate tablets with valproic acid has also been associated with hypothermia (with and without hyperammonemia) in patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported [see Warnings and Precautions ( 5.10 ), ( 5.12 ) or Clinical Pharmacology ( 12.3 )] . 7.2 CNS Depressants Concomitant administration of topiramate tablets 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 tablets should be used with extreme caution if used in combination with alcohol and other CNS depressants. 7.3 Oral Contraceptives Exposure to ethinyl estradiol was statistically significantly decreased at doses of 200, 400, and 800 mg/day (18%, 21%, and 30%, respectively) when topiramate tablets was given as adjunctive therapy in patients taking valproic acid. However, norethindrone exposure was not significantly affected. In another pharmacokinetic interaction study in healthy volunteers with a concomitantly administered combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 mcg ethinyl estradiol (EE), topiramate tablets, given in the absence of other medications at doses of 50 to 200 mg/day, was not associated with statistically significant changes in mean exposure (AUC) to either component of the oral contraceptive. The possibility of decreased contraceptive efficacy and increased breakthrough bleeding should be considered in patients taking combination oral contraceptive products with topiramate tablets. 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 ( 12.3 )]. 7.4 Metformin Topiramate treatment can frequently cause metabolic acidosis, a condition for which the use of metformin is contraindicated [ see Clinical Pharmacology ( 12.3 )] . 7.5 Lithium In patients, lithium levels were unaffected during treatment with topiramate at doses of 200 mg/day; however, there was an observed increase in systemic exposure of lithium (27% for Cmax and 26% for AUC) following topiramate doses of up to 600 mg/day. Lithium levels should be monitored when co-administered with high-dose topiramate tablets [see Clinical Pharmacology ( 12.3 )] . 7.6 Other Carbonic Anhydrase Inhibitors Concomitant use of topiramate, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., zonisamide, acetazolamide, or dichlorphenamide) may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Therefore, if topiramate tablets is given concomitantly with another carbonic anhydrase inhibitor, the patient should be monitored for the appearance or worsening of metabolic acidosis [see Clinical Pharmacology ( 12.3 )] .

Uses

Topiramate tablets are indicated for: - "Initial monotherapy" in patients ≥2 years with partial-onset or primary generalized tonic-clonic seizures - "Adjunctive therapy" in adults and pediatric patients 2-16 years with partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome - "Prophylaxis of migraine headache" in adults

Dosage forms & strengths

C42896 Capsule, Extended Release Tablet Tablet, Coated Tablet, Film Coated TABLET TABLET, FILM COATED CAPSULE, EXTENDED RELEASE POWDER CAPSULE, COATED PELLETS CAPSULE TABLET, COATED SOLUTION BEAD

TOPIRAMATE 100 mg TOPIRAMATE 15 mg TOPIRAMATE 200 mg TOPIRAMATE 25 mg TOPIRAMATE 50 mg Topiramate 100 mg Topiramate 150 mg Topiramate 200 mg Topiramate 25 mg Topiramate 50 mg topiramate 100 mg topiramate 15 mg topiramate 200 mg topiramate 25 mg topiramate 50 mg TOPIRAMATE 50 mg/1 TOPIRAMATE 200 mg/1 TOPIRAMATE 25 mg/1 TOPIRAMATE 40 kg/40kg TOPIRAMATE 100 mg/1 TOPIRAMATE 1 kg/kg TOPIRAMATE 150 mg/1 TOPIRAMATE 15 mg/1 TOPIRAMATE 50 kg/50kg TOPIRAMATE 1 g/g TOPIRAMATE 25 mg/mL TOPIRAMATE 1000 g/1000g TOPIRAMATE 25 kg/25kg

2 DOSAGE AND ADMINISTRATION See DOSAGE AND ADMINISTRATION, Epilepsy: Monotherapy and Adjunctive Therapy Use for additional details Initial Dose Titration Recommended Dose Epilepsy monotherapy: children 2to<10years (2.1 ) 25mg/day administered nightly for the first week The dosage should betitratedover5–7 weeks Daily doses in two divided doses based on weight(Table2) Epilepsy monotherapy: adults and pediatric patients≥10years (2.1 ) 50mg/day in two divided doses The dosage should be increased weekly by increments of 50mg for the first 4 weeks then100mgfor weeks 5to6. 400 mg/day in two divided doses Epilepsy adjunctive therapy :adults with partial onset seizures or LGS( 2.1 ) 25to50mg/day The dosage should be increased weekly to an effective dose by incrementsof25to50mg. 200–400 mg/day in two divided doses Epilepsy adjunctive therapy: adults with primary generalized tonic- clonic seizures (2.1 ) 25to50mg/day The dosage should be increased weekly to an effective dose by incrementsof25to50mg. 400 mg/day in two divided doses Epilepsy adjunctive therapy: pediatric Patients with partial onset seizures, primary generalized tonic-clonic seizures or LGS(186 Error! Hyperlink reference not valid. 25mg/day(or less, based on a range of1to3mg/kg/day) nightly for the first week The dosage should beincreasedat1-or 2-weekintervalsby incrementsof1to3 mg/kg/day(administered in two divided doses).Dose titration should be guided by clinical outcome. 5to9mg/kg/day in two divided doses 2.1 Epilepsy It is not necessary to monitor topiramate plasma concentrations to optimize topiramate therapy. On occasion, the addition of topiramate to phenytoin may require an adjustment of the dose of phenytoin to achieve optimal clinical outcome. Addition or withdrawal of phenytoin and/or carbamazepine during adjunctive therapy with topiramate may require adjustment of the dose of topiramate. Because of the bitter taste, tablets should not be broken. Topiramate tablets USP can be taken without regard to meals. Monotherapy Use Adults and Pediatric Patients 10 Years and Older The recommended dose for topiramate monotherapy in adults and pediatric patients 10 years of age and older is 400 mg/day in two divided doses. Approximately 58% of patients randomized to 400 mg/day achieved this maximal dose in the monotherapy controlled trial; the mean dose achieved in the trial was 275 mg/day. The dose should be achieved by 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 Children Ages 2 to <10 Years Dosing of topiramate as initial monotherapy in children 2 to < 10 years of age with partial onset or primary generalized tonic-clonic seizures was based on a pharmacometric bridging approach [see Clinical Studies ( 14.1 ) ] Dosing in patients 2 to <10 years is based on weight. During the titration period, the initial dose of topiramate should be 25 mg/day administered 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 seizure control, 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 <10 Years * Administered in two equally divided doses 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 Adjunctive Therapy Use Adults 17 Years of Age and Over - Partial Onset Seizures, Primary Generalized Tonic-Clonic Seizures, or Lennox-Gastaut Syndrome The recommended total daily dose of topiramate as adjunctive therapy in adults with partial onset seizures 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. It is recommended that therapy 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 (600, 800 or 1,000 mg/day) have not been shown to improve responses in dose-response studies in adults with partial onset seizures. Daily doses above 1,600 mg have not been studied. In the study of primary generalized tonic-clonic seizures, the initial titration rate was slower than in previous studies; the assigned dose was reached at the end of 8 weeks [see Clinical Studies ( 14.1 )] Pediatric Patients Ages 2 – 16 Years – Partial Onset Seizures, Primary Generalized Tonic-Clonic Seizures, or Lennox-Gastaut Syndrome The recommended total daily dose of Topiramate as adjunctive therapy for pediatric patients 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. In the study of primary generalized tonic-clonic seizures, the initial titration rate was slower than in previous studies; the assigned dose of 6 mg/kg/day was reached at the end of 8 weeks [see Clinical Studies ( 14.1 )] . 2.4 Patients with Renal Impairment In renally impaired subjects (creatinine clearance less than 70 mL/min/1.73 m 2 ), one-half of the usual adult dose is recommended. Such patients will require a longer time to reach steady-state at each dose. 2.5 Geriatric Patients (Ages 65 Years and Over) Dosage adjustment may be indicated in the elderly patient when impaired renal function (creatinine clearance rate <70 mL/min/1.73 m2) is evident [see Clinical Pharmacology ( 12.3 )] . 2.6 Patients Undergoing Hemodialysis Topiramate is cleared by hemodialysis at a rate that is 4 to 6 times greater than a normal individual. Accordingly, a prolonged period of dialysis may cause topiramate concentration to fall below that required to maintain an anti-seizure effect. To avoid rapid drops in topiramate plasma concentration during hemodialysis, a supplemental dose of topiramate may be required. The actual adjustment should take into account 1) the duration of dialysis period, 2) the clearance rate of the dialysis system being used, and 3) the effective renal clearance of topiramate in the patient being dialyzed. 2.7 Patients with Hepatic Disease In hepatically impaired patients, topiramate plasma concentrations may be increased. The mechanism is not well understood.