Topiramate

RECENT MAJOR CHANGES • Indications and Usage ( 1 ) 05/2017 • Dosage and Administration (2 ) 05/2017 • Dosage and Administration, • Geriatric Patients • (Ages 65 Years and Over) Removed 05/2017 • Patients with Hepatic Disease Removed 05/2017 • Warnings and Precautions ( 5.4 , 5.6 , 5.9 , 5.10 ) 05/2017 • Warnings and Precautions • Sudden Unexplained Death in • Epilepsy (SUDEP) Removed 05/2017 • Paresthesia Removed 05/2017 • Adjustment of Dose in Renal Failure Removed 05/2017 • Decreased Hepatic Function Removed 05/2017 • Monitoring: Laboratory Tests Removed 05/2017

1 INDICATIONS AND USAGE Topiramate tablets USP is an antiepileptic (AED) agent indicated for: • Monotherapy epilepsy: Initial monotherapy in patients ≥ 2 years of age with partial onset or primary generalized tonic-clonic seizures ( 1.1 ) • Adjunctive therapy epilepsy: Adjunctive therapy for adults and pediatric patients (2 to 16 years of age) with partial onset seizures or primary generalized tonic-clonic seizures, and in patients ≥2 years of age with seizures associated with Lennox-Gastaut syndrome (LGS) ( 1.2 ) 1.1 Monotherapy Epilepsy Topiramate tablets USP are indicated as initial monotherapy in patients 2 years of age and older with partial onset or primary generalized tonic-clonic seizures. Safety and effectiveness in patients who were converted to monotherapy from a previous regimen of other anticonvulsant drugs have not been established in controlled trials [see Clinical Studies (14.1) ] . 1.2 Adjunctive Therapy Epilepsy Topiramate tablets USP are indicated as adjunctive therapy for adults and pediatric patients ages 2 to 16 years with partial onset seizures or primary generalized tonic-clonic seizures, and in patients 2 years of age and older with seizures associated with Lennox-Gastaut syndrome [see Clinical Studies (14.2) ] .

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 …

3 DOSAGE FORMS AND STRENGTHS Tablets: 25 mg, 50 mg, 100 mg, and 200 mg ( 3 ) Topiramate tablets, USP are available in the following strengths and colors: 25 mg, White colored, circular, biconvex film-coated tablets, debossed with "122" on one side and "C" on the other side. 50 mg, Light orange colored, circular, biconvex, film-coated tablets, debossed with "123" on one side and "C" on the other side. 100 mg, Orange colored, circular, biconvex, film-coated tablets, debossed with "124" on one side and "Cipla" on the other side. 200 mg, Pink colored, capsule shaped, biconvex, film-coated tablets, debossed with "125" on one side and "Cipla" on other side.

CONTRAINDICATIONS Topiramate is contraindicated in patients with a history of hypersensitivity to any component of this product.

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. 6.1 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 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 ≥ 16 Years) Topiramate Daily Dosage Group (mg/day) 50 400 50 400 Body System (N=74) (N=77) (N=160) (N=159) Adverse Reaction % % % % Body as a Whole - General Disorders Asthenia 0 3 4 6 Fever 1 12 Leg pain 2 3 Central & Peripheral Nervous System Disorders Paresthesia 3 12 21 40 Dizziness 13 14 Ataxia 3 4 Hypoesthesia 4 5 Hypertonia 0 3 Involuntary muscle contractions 0 3 Vertigo 0 3 Gastro-Intestinal System Disorders Constipation 1 4 Diarrhea 8 9 Gastritis 0 3 Dry mouth 1 3 Liver and Biliary System Disorders Increase in Gamma-GT 1 3 Metabolic and Nutritional Disorders Weight loss 7 17 6 17 Platelet, Bleeding & Clotting Disorders Epistaxis 0 4 Psychiatric Disorders Anorexia 4 14 Anxiety 4 6 Cognitive problems 1 6 1 4 Confusion 0 3 Depression 0 3 7 9 Difficulty with …

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 …

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to topiramate during pregnancy. Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334. Information about the North American Drug Pregnancy Registry can be found at http://www.aedpregnancyregistry.org/. Risk Summary Topiramate 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 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 tablets 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 tablets 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 clef …

12.1 Mechanism of Action The precise mechanisms by which topiramate exerts its anticonvulsant and preventive migraine prophylaxis 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.

DESCRIPTION Topiramate is a sulfamate-substituted monosaccharide. Topiramate Tablets are available as 25 mg, 50 mg, 100 mg, and 200 mg round tablets for oral administration. Topiramate USP is a white crystalline powder with a bitter taste. Topiramate USP 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 USP has the molecular formula C 12 H 21 NO 8 S and a molecular weight of 339.37. Topiramate USP is designated chemically as 2,3:4,5-Di-O-isopropylidene-β-Dfructopyranose sulfamate and has the following structural formula: Topiramate tablets contain the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, pre-gelatinized starch, lactose monohydrate, sodium starch glycolate, magnesium stearate, opadry white (titanium dioxide, hypromellose 3cp, hypromellose 6cp, PEG 400, polysorbate 80) for 25 mg tablets, opadry yellow (titanium dioxide, hypromellose 3cp, hypromellose 6cp, PEG 400, polysorbate 80, iron oxide yellow) for 50 mg tablets, opadry yellow (hypromellose 3cp, hypromellose 6cp titanium dioxide, PEG 400, iron oxide yellow, polysorbate 80, iron oxide red) for 100 mg tablets and), opadry pink (titanium dioxide, hypromellose 6cp, PEG 400, iron oxide red) for 200 mg tablets. 43e1322a-figure-01

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

HOW SUPPLIED Topiramate Tablets are available containing 50 mg, of topiramate USP. The 50 mg tablets are yellow, round, biconvex tablets de-bossed with IG on one side and 279 on other. They are available as follows: NDC 63187-228-30 bottles of 30 tablets NDC 63187-228-60 bottles of 60 tablets NDC 63187-228-90 bottles of 90 tablets Store at 20° to 25°C (68° to 77°F); [See USP Controlled Room Temperature]. Protect from moisture. PATIENT INFORMATION Topiramate Tablets What do TOPIRAMATE Tablets look like? TOPIRAMATE Tablets 25mg 50mg 100mg 200mg White Yellow Light Pink Yellow Note: The pictures above show the shapes and lettering of TOPIRAMATE tablets. The wording describes the strength and colors of the medication. Before taking your medicine, it is important to compare the tablets you receive from your healthcare professional or pharmacist with these pictures to make sure you have received the correct medicine. Please read this patient information carefully before you take TOPIRAMATE and each time you obtain a refill, in case any information has changed. This summary does not contain all the information about TOPIRAMATE and is not meant to take the place of talking with your healthcare professional. If you have any questions about TOPIRAMATE, discuss them with your healthcare professional or pharmacist. What is TOPIRAMATE? TOPIRAMATE is a prescription medicine used: • alone to treat seizures in patients 10 years and older • with other medicines to treat seizures in adults and children over age 2 Who Should Not Take TOPIRAMATE? Do not take TOPIRAMATE if you are allergic to anything in it. See the end of this leaflet for a complete list of ingredients in TOPIRAMATE. What Should I Tell My Healthcare Professional Before Taking TOPIRAMATE? Tell your healthcare professional about all of your medical conditions, including if you: • have kidney problems, especially kidney stones, or are getting kidney dialysis • have a history of metabolic acidosis (blood and body fluid abnormality) • have liver problems • have osteoporosis (weak or brittle bones) and/or soft bones (osteomalacia) or decreased bone density (osteopenia) • have lung or breathing problems • have eye problems, especially glaucoma • have diarrhea • have a growth problem • are on a diet high in fat called a ketogenic diet • are having surgery • are pregnant or planning to become pregnant. It is not known if TOPIRAMATE can harm your unborn baby. • are breastfeeding. TOPIRAMATE may pass into your milk. Talk to your healthcare professional about the best way to feed your baby while taking TOPIRAMATE. • suffer from depression, mood problems or suicidal thoughts or behavior Tell your healthcare professional about all the medicines you take including prescription and nonprescription medicines, vitamins and herbal supplements. TOPIRAMATE and certain other medicines can affect each other. Sometimes the dose of some of your other medicines or TOPIRAMATE will have to be adjusted. Especially, tell your healthcare professional if you are taking: • other medicines that impair or decrease your thinking, concentration, or muscle coordination (e.g. central nervous system depressant medicines). • birth control pills. TOPIRAMATE may make your birth control pills less effective. Tell your healthcare professional if your menstrual bleeding changes while you are taking birth control pills and TOPIRAMATE. Keep a list of all the medicines you take. Show this list to your healthcare professionals and pharmacists before you start a new medicine. How Should I Take TOPIRAMATE? • Take TOPIRAMATE exactly as prescribed. Your healthcare professional will usually start you on a low dose of TOPIRAMATE and slowly increase your dose until the best dose is found for you. • TOPIRAMATE Tablets should be swallowed whole. Avoid, chewing the tablets as they may leave a bitter taste. • Never store any medicine and food mixture for use at a later time. • TOPIRAMATE can be taken before, during, or after a meal. Drink p …