DailyMed Label: Eprontia

DailyMed Label: Eprontia

2024

DailyMed Prescription

Eprontia

Topiramate

Azurity Pharmaceuticals, Inc.

NDC: 52652-9001

NDC: 52652-9001

EPRONTIA (topiramate) oral solution is available as a 25 mg/mL solution for oral administration. 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 is a white crystalline powder with a bitter taste. Topiramate is a sulfamate-substituted monosaccharide. 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. EPRONTIA oral solution is colorless to slightly yellow colored clear viscous liquid. EPRONTIA contains the following inactive ingredients: glycerin, methylparaben, mixed berry flavor, polyethylene glycol, propylparaben, and sucralose. Structural Formula

EPRONTIA is 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 ). EPRONTIA is indicated as initial monotherapy for the treatment of partial-onset or primary generalized tonic-clonic seizures in patients 2 years of age and older. EPRONTIA is indicated as adjunctive therapy for the treatment of partial-onset seizures, primary generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome in patients 2 years of age and older. EPRONTIA is indicated for the preventive treatment of migraine in patients 12 years of age and older.

EPRONTIA 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 ). Adults and Pediatric Patients 10 Years of Age and Older The recommended dose for EPRONTIA 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 EPRONTIA 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) Administered in two equally divided doses 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 Adults (17 Years of Age and Older) The recommended total daily dose of EPRONTIA as adjunctive therapy in adults with partial onset seizures or Lennox-Gastaut Syndrome is 200 to 400 mg/day in two divided doses, and 400 mg/day in two divided doses as adjunctive treatment in adults with primary generalized tonic-clonic seizures. EPRONTIA 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 EPRONTIA 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. The recommended total daily dose of EPRONTIA 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 EPRONTIA for the preventive treatment of migraine is as follows: Table 3: Preventive Treatment of Migraine Titration Schedule for Patients 12 years and older Morning Dose Evening Dose Week 1 None 25 mg Week 2 25 mg 25 mg Week 3 25 mg 50 mg Week 4 50 mg 50 mg Dose and titration rate should be guided by clinical outcome. If required, longer intervals between dose adjustments can be used. EPRONTIA can be taken without regard to meals. A calibrated measuring device is recommended to measure and deliver the prescribed dose accurately. A household teaspoon or tablespoon is not an adequate measuring device. Discard the unused portion after 90 days [see How Supplied/Storage and Handling ( 16.2 )] . In patients with renal impairment (creatinine clearance less than 70 mL/min/1.73 m 2 ), one-half of the usual adult dose of EPRONTIA is recommended [see Use in Specific Populations ( 8.5 , 8.6 ), Clinical Pharmacology ( 12.3 )] . To avoid rapid drops in topiramate plasma concentration during hemodialysis, a supplemental dose of EPRONTIA may be required. The actual adjustment should take into account 1) the duration of dialysis period, 2) the clearance rate of the dialysis system being used, and 3) the effective renal clearance of topiramate in the patient being dialyzed [see Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3 )] .

EPRONTIA oral solution 25 mg/mL is supplied as a colorless to slightly yellow colored clear viscous liquid in white HDPE bottles. Oral solution: 25 mg/mL ( 3 ).

None. None ( 4 ).

Acute myopia and secondary angle closure glaucoma: can lead to permanent visual loss; discontinue EPRONTIA as soon as possible ( 5.1 ). Visual field defects: consider discontinuation of EPRONTIA ( 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 EPRONTIA 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 major congenital malformations, including but not limited to cleft lip and/or palate, and being small for gestational age ( 5.7 ). Withdrawal of AEDs: withdraw EPRONTIA 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 EPRONTIA ( 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 ). A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving EPRONTIA (topiramate). 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 EPRONTIA 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 EPRONTIA as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation of EPRONTIA, may be helpful. Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss. Visual field defects (independent of elevated intraocular pressure) have been reported in clinical trials and in post-marketing 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. Oligohidrosis (decreased sweating), infrequently resulting in hospitalization, has been reported in association with EPRONTIA 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 EPRONTIA should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. Caution should be used when EPRONTIA is given with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, other carbonic anhydrase inhibitors and drugs with anticholinergic activity. EPRONTIA can cause hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis). This metabolic acidosis is caused by renal bicarbonate loss due to carbonic anhydrase inhibition by EPRONTIA. EPRONTIA induced metabolic acidosis can occur at any time during treatment. Bicarbonate decrements are usually mild-moderate (average decrease of 4 mEq/L at daily doses of 400 mg in adults and at approximately 6 mg/kg/day in pediatric patients); rarely, patients can experience severe decrements to values below 10 mEq/L. Conditions or therapies that predispose patients to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, ketogenic diet, or specific drugs) may be additive to the bicarbonate lowering effects of EPRONTIA. Metabolic acidosis was commonly observed in adult and pediatric patients treated with topiramate in clinical trials. The incidence of decreased serum bicarbonate in pediatric trials, for adjunctive treatment of Lennox-Gastaut syndrome or refractory partial-onset seizures was as high as 67% for topiramate (at approximately 6 mg/kg/day), and 10% for placebo. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value < 17 mEq/L and ≥5 mEq/L decrease from pretreatment) in these trials was up to 11%, compared to ≤ 2% for placebo. Manifestations of acute or chronic metabolic acidosis may include hyperventilation, nonspecific symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or stupor. Chronic, untreated metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis, and may also result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with an increased risk for fractures [see Warnings and Precautions ( 5.9 , 5.13 )] . A one-year, active-controlled study of pediatric patients treated with topiramate demonstrated that topiramate decreased lumbar spine bone mineral density and that this lumbar spine bone mineral density decrease was correlated (using change from baseline for lumbar spine Z score at final visit versus lowest post-treatment serum bicarbonate) with decreased serum bicarbonate, a reflection of metabolic acidosis [see Warnings and Precautions ( 5.9 ), Use in Specific Populations ( 8.4 )] . Chronic metabolic acidosis in pediatric patients may also reduce growth rates, which may decrease the maximal height achieved. Long-term, open-label treatment of pediatric patients 1 to 24 months old with intractable partial epilepsy, for up to 1 year, showed reductions from baseline in length, weight, and head circumference compared to age and sex-matched normative data, although these patients with epilepsy are likely to have different growth rates than normal 1 to 24 month old pediatric patients. Reductions in length and weight were correlated to the degree of acidosis [see Use in Specific Populations ( 8.4 )] . Topiramate treatment that causes metabolic acidosis during pregnancy can possibly produce adverse effects on the fetus and might also cause metabolic acidosis in the neonate from possible transfer of topiramate to the fetus [see Warnings and Precautions ( 5.7 ), Use in Specific Populations ( 8.1 )] . Measurement of Serum Bicarbonate in Epilepsy and Migraine Patients Measurement of baseline and periodic serum bicarbonate during topiramate treatment is recommended. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing EPRONTIA (using dose tapering). If the decision is made to continue patients on EPRONTIA in the face of persistent acidosis, alkali treatment should be considered. Antiepileptic drugs (AEDs), including EPRONTIA, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. Table 4 shows absolute and relative risk by indication for all evaluated AEDs. Table 4: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events per 1000 Patients Drug Patients with Events per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events per 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing EPRONTIA or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. EPRONTIA can cause cognitive/neuropsychiatric adverse reactions. The most frequent of these can be classified into three general categories: 1) Cognitive-related dysfunction (e.g., confusion, psychomotor slowing, difficulty with concentration/attention, difficulty with memory, speech or language problems, particularly word-finding difficulties); 2) Psychiatric/behavioral disturbances (e.g., depression or mood problems); and 3) Somnolence or fatigue. Adult Patients Cognitive-Related Dysfunction Rapid titration rate and higher initial dose were associated with higher incidences of cognitive-related dysfunction. In adult epilepsy adjunctive controlled trials, which used rapid titration (100-200 mg/day weekly increments), and target EPRONTIA doses of 200 mg - 1000 mg/day, 56% of patients in the 800 mg/day and 1000 mg/day dose groups experienced cognitive-related dysfunction compared to approximately 42% of patients in the 200-400 mg/day groups and 14% for placebo. In this rapid titration regimen, these dose-related adverse reactions began in the titration or in the maintenance phase, and in some patients these events began during titration and persisted into the maintenance phase. In the monotherapy epilepsy controlled trial, the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50 mg/day and 26% for 400 mg/day. In the 6-month controlled trials for the preventive treatment of migraine, which used a slower titration regimen (25 mg/day weekly increments), the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50 mg/day, 22% for 100 mg/day (the recommended dose), 28% for 200 mg/day, and 10% for placebo. Cognitive adverse reactions most commonly developed during titration and sometimes persisted after completion of titration. Psychiatric/Behavioral Disturbances Psychiatric/behavioral disturbances (e.g., depression, mood) were dose-related for both the adjunctive epilepsy and migraine populations [see Warnings and Precautions ( 5.5 )] . Somnolence/Fatigue Somnolence and fatigue were the adverse reactions most frequently reported during clinical trials of EPRONTIA for adjunctive epilepsy. For the adjunctive epilepsy population, the incidence of fatigue, appeared dose-related. For the monotherapy epilepsy population, the incidence of somnolence was dose-related. For the migraine population, the incidences of both fatigue and somnolence were dose-related and more common in the titration phase. Pediatric Patients In pediatric epilepsy trials (adjunctive and monotherapy), the incidence of cognitive/neuropsychiatric adverse reactions was generally lower than that observed in adults. These reactions included psychomotor slowing, difficulty with concentration/attention, speech disorders/related speech problems, and language problems. The most frequently reported cognitive/neuropsychiatric reactions in pediatric epilepsy patients during adjunctive therapy double-blind studies were somnolence and fatigue. The most frequently reported cognitive/neuropsychiatric reactions in pediatric epilepsy patients in the 50 mg/day and 400 mg/day groups during the monotherapy double-blind study were headache, dizziness, anorexia, and somnolence. In pediatric migraine patients, the incidence of cognitive/neuropsychiatric adverse reactions was increased in topiramate treated patients compared to placebo. The risk for cognitive/neuropsychiatric adverse reactions was dose-dependent, and was greatest at the highest dose (200 mg). This risk for cognitive/neuropsychiatric adverse reactions was also greater in younger patients (6 to 11 years of age) than in older patients (12 to 17 years of age). The most common cognitive/neuropsychiatric adverse reaction in these trials was difficulty with concentration/attention. Cognitive adverse reactions most commonly developed during titration and sometimes persisted for various durations after completion of titration. The Cambridge Neuropsychological Test Automated Battery (CANTAB) was administered to adolescents (12 to 17 years) to assess the effects of topiramate on cognitive function at baseline and at the end of the Study 13 [see Clinical Studies ( 14.3 )] . Mean change from baseline in certain CANTAB tests suggests that topiramate treatment may result in psychomotor slowing and decreased verbal fluency. EPRONTIA 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). When multiple species of pregnant animals received topiramate at clinically relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring [see Use in Specific Populations ( 8.1 )] . Consider the benefits and the risks of EPRONTIA when administering this drug in women of childbearing potential, particularly when EPRONTIA is considered for a condition not usually associated with permanent injury or death [see Use in Specific Populations ( 8.1 ), Patient Counseling Information ( 17 )] . EPRONTIA should be used during pregnancy only if the potential benefit outweighs the potential risk. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations ( 8.1 )] . In patients with or without a history of seizures or epilepsy, antiepileptic drugs, including EPRONTIA, should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency [see Clinical Studies ( 14 )] . In situations where rapid withdrawal of EPRONTIA is medically required, appropriate monitoring is recommended. Results of a one-year active-controlled study in pediatric patients (N=63) demonstrated negative effects of topiramate monotherapy on bone mineral acquisition via statistically significant decreases in bone mineral density (BMD) measured in lumbar spine and in total body less head [see Use in Specific Populations ( 8.4 )] . Twenty-one percent of topiramate-treated patients experienced clinically important reductions in BMD (Z score change from baseline of -0.5 or greater) compared to 0 patients in the control group. Although decreases in BMD occurred across all pediatric age subgroups, patients 6 to 9 years of age were most commonly affected. The sample size and study duration were too small to determine if fracture risk is increased. Decreased BMD in the lumbar spine was correlated with decreased serum bicarbonate, which commonly occurs with topiramate treatment and reflects metabolic acidosis, a known cause of increased bone resorption [see Warnings and Precautions ( 5.4 )] . Although small decreases in some markers of bone metabolism (e.g., serum alkaline phosphatase, calcium, phosphorus, and 1,25-dihydroxyvitamin D) occurred in topiramate-treated patients, more significant decreases in serum parathyroid hormone and 25-hydroxyvitamin D, hormones involved in bone metabolism, were observed, along with an increased excretion of urinary calcium. Results of a one-year active-controlled study of pediatric patients (N=63) demonstrated negative effects of topiramate monotherapy on growth (i.e., height and weight) [see Use in Specific Populations ( 8.4 )] . Although continued growth was observed in both treatment groups, the topiramate group showed statistically significant reductions in mean annual change from baseline in body weight compared to the control group. A similar trend of attenuation in height velocity and height change from baseline was also observed in the topiramate group compared to the control group. Negative effects on weight and height were seen across all topiramate age subgroups. Growth (height and weight) of children receiving prolonged EPRONTIA therapy should be carefully monitored. Serious skin reactions (Stevens-Johnson Syndrome [SJS] and Toxic Epidermal Necrolysis [TEN]) have been reported in patients receiving topiramate. EPRONTIA should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. Inform patients about the signs of serious skin reactions. EPRONTIA treatment can cause hyperammonemia with or without encephalopathy [see Adverse Reactions ( 6.2 )] . The risk for hyperammonemia with topiramate appears dose-related. Hyperammonemia has been reported more frequently when topiramate is used concomitantly with valproic acid. Postmarketing cases of hyperammonemia with or without encephalopathy have been reported with topiramate and valproic acid in patients who previously tolerated either drug alone [see Drug Interactions ( 7.1 )] . Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy and/or vomiting. In most cases, hyperammonemic encephalopathy abated with discontinuation of treatment. The incidence of hyperammonemia in pediatric patients 12 to 17 years of age in the preventive treatment of migraine trials was 26% in patients taking topiramate monotherapy at 100 mg/day, and 14% in patients taking topiramate at 50 mg/day, compared to 9% in patients taking placebo. There was also an increased incidence of markedly increased hyperammonemia at the 100 mg dose. Dose-related hyperammonemia was also seen in pediatric patients 1 to 24 months of age treated with topiramate and concomitant valproic acid for partial-onset epilepsy and this was not due to a pharmacokinetic interaction. In some patients, hyperammonemia can be asymptomatic. Monitoring for Hyperammonemia Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, topiramate treatment or an interaction of concomitant topiramate and valproic acid treatment may exacerbate existing defects or unmask deficiencies in susceptible persons. In patients who develop unexplained lethargy, vomiting or changes in mental status associated with any topiramate treatment, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. EPRONTIA increases the risk of kidney stones. During adjunctive epilepsy trials, the risk for kidney stones in topiramate -treated adults was 1.5%, an incidence about 2 to 4 times greater than expected in a similar, untreated population. As in the general population, the incidence of stone formation among topiramate -treated patients was higher in men. Kidney stones have also been reported in pediatric patients taking topiramate for epilepsy or migraine. During long-term (up to 1 year) topiramate treatment in an open-label extension study of 284 pediatric patients 1-24 months old with epilepsy, 7% developed kidney or bladder stones. Topiramate is not approved for treatment of epilepsy in pediatric patients less than 2 years old [see Use in Specific Populations ( 8.4 )] . Topiramate is a carbonic anhydrase inhibitor. Carbonic anhydrase inhibitors can promote stone formation by reducing urinary citrate excretion and by increasing urinary pH [see Warnings and Precautions ( 5.4 )] . The concomitant use of topiramate with any other drug producing metabolic acidosis, or potentially in patients on a ketogenic diet, may create a physiological environment that increases the risk of kidney stone formation, and should therefore be avoided. Increased fluid intake increases the urinary output, lowering the concentration of substances involved in stone formation. Hydration is recommended to reduce new stone formation. An increase in urinary calcium and a marked decrease in urinary citrate was observed in topiramate-treated pediatric patients in a one-year active-controlled study [see Use in Specific Populations ( 8.4 )] . This increased ratio of urinary calcium/citrate increases the risk of kidney stones and/or nephrocalcinosis. Hypothermia, defined as a drop in body core temperature to <35°C (95°F), has been reported in association with topiramate use with concomitant valproic acid both in conjunction with hyperammonemia and in the absence of hyperammonemia. This adverse reaction in patients using concomitant topiramate and valproate can occur after starting topiramate treatment or after increasing the daily dose of topiramate [see Drug Interactions ( 7.1 )] . Consideration should be given to stopping topiramate or valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels.

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

Contraceptives: decreased contraceptive 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 EPRONTIA ( 7.7 ). Concomitant administration of phenytoin or carbamazepine with topiramate resulted in a clinically significant decrease in plasma concentrations of topiramate when compared to topiramate 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 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 )] . Concomitant use of EPRONTIA, 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 EPRONTIA concomitantly with another carbonic anhydrase inhibitor should be monitored particularly closely for the appearance or worsening of metabolic acidosis [see Clinical Pharmacology ( 12.3 )] . Concomitant administration of topiramate 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, EPRONTIA should be used with extreme caution if used in combination with alcohol and other CNS depressants. The possibility of decreased contraceptive efficacy and increased breakthrough bleeding may occur in patients taking contraceptive products with EPRONTIA. 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 )] . Topiramate C max and AUC increased when HCTZ was added to topiramate. The clinical significance of this change is unknown. The addition of HCTZ to topiramate may require a decrease in the topiramate dose [see Clinical Pharmacology ( 12.3 )] . A decrease in the exposure of pioglitazone and its active metabolites were noted with the concurrent use of pioglitazone and topiramate in a clinical trial. The clinical relevance of these observations is unknown; however, when topiramate is added to pioglitazone therapy or pioglitazone is added to topiramate 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 )] . An increase in systemic exposure of lithium following topiramate doses of up to 600 mg/day can occur. Lithium levels should be monitored when co-administered with high dose topiramate [see Clinical Pharmacology ( 12.3 )] . Some patients may experience a large increase in amitriptyline concentration in the presence of topiramate and any adjustments in amitriptyline dose should be made according to the patient's clinical response and not on the basis of plasma levels [see Clinical Pharmacology ( 12.3 )] .

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/. 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. 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 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 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. 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 (0.3%) or the prevalence in infants with mothers without epilepsy and without exposure to AEDs (0.11%). It was also higher than the background prevalence in United States (0.17%) as estimated by the Centers for Disease Control and Prevention (CDC). The relative risk of oral clefts in topiramate-exposed pregnancies in the NAAED Pregnancy Registry was 12.5 (95% Confidence Interval [CI] 5.9 – 26.37) as compared to the risk in a background population of untreated women. The UK Epilepsy and Pregnancy Register reported a prevalence of oral clefts among infants exposed to topiramate monotherapy (3.2%) that was 16 times higher than the background rate in the UK (0.2%). Data from the NAAED pregnancy registry and a population-based birth registry cohort indicate that exposure to topiramate in utero is associated with an increased risk of SGA newborns (birth weight <10th percentile). In the NAAED pregnancy registry, 19.7% of topiramate-exposed newborns were SGA compared to 7.9% of newborns exposed to a reference AED and 5.4% of newborns of mothers without epilepsy and without AED exposure. In the Medical Birth Registry of Norway (MBRN), a population-based pregnancy registry, 25% of newborns in the topiramate monotherapy exposure group were SGA compared to 9 % in the comparison group unexposed to AEDs. The long-term consequences of the SGA findings are not known. Animal Data When topiramate (0, 20, 100, or 500 mg/kg/day) was administered to pregnant mice during the period of organogenesis, incidences of fetal malformations (primarily craniofacial defects) were increased at all doses. Fetal body weights and skeletal ossification were reduced at the highest dose tested in conjunction with decreased maternal body weight gain. A no-effect dose for embryofetal developmental toxicity in mice was not identified. The lowest dose tested, which was associated with increased malformations, is less than the maximum recommended human dose (MRHD) for epilepsy (400 mg/day) or migraine (100 mg/day) on a body surface area (mg/m 2 ) basis. In pregnant rats administered topiramate (0, 20, 100, and 500 mg/kg/day or 0, 0.2, 2.5, 30, and 400 mg/kg/day) orally during the period of organogenesis, the frequency of limb malformations (ectrodactyly, micromelia, and amelia) was increased in fetuses at 400 and 500 mg/kg/day. Embryotoxicity (reduced fetal body weights, increased incidences of structural variations) was observed at doses as low as 20 mg/kg/day. Clinical signs of maternal toxicity were seen at 400 mg/kg/day and above, and maternal body weight gain was reduced at doses of 100 mg/kg/day or greater. The no-effect dose (2.5 mg/kg/day) for embryofetal developmental toxicity in rats is less than the MRHD for epilepsy or migraine on a mg/m 2 basis. In pregnant rabbits administered topiramate (0, 20, 60, and 180 mg/kg/day or 0, 10, 35, and 120 mg/kg/day) orally during organogenesis, embryofetal mortality was increased at 35 mg/kg/day, and increased incidences of fetal malformations (primarily rib and vertebral malformations) were observed at 120 mg/kg/day. Evidence of maternal toxicity (decreased body weight gain, clinical signs, and/or mortality) was seen at 35 mg/kg/day and above. The no-effect dose (20 mg/kg/day) for embryofetal developmental toxicity in rabbits is equivalent to the MRHD for epilepsy and approximately 4 times the MRHD for migraine on a mg/m 2 basis. When topiramate (0, 0.2, 4, 20, and 100 mg/kg/day or 0, 2, 20, and 200 mg/kg/day) was administered orally to female rats during the latter part of gestation and throughout lactation, offspring exhibited decreased viability and delayed physical development at 200 mg/kg/day and reductions in pre- and/or postweaning body weight gain at 2 mg/kg/day and above. Maternal toxicity (decreased body weight gain, clinical signs) was evident at 100 mg/kg/day or greater. In a rat embryofetal development study which included postnatal assessment of offspring, oral administration of topiramate (0, 0.2, 2.5, 30, and 400 mg/kg) to pregnant animals during the period of organogenesis resulted in delayed physical development in offspring at 400 mg/kg/day and persistent reductions in body weight gain in offspring at 30 mg/kg/day and higher. The no-effect dose (0.2 mg/kg/day) for pre- and postnatal developmental toxicity in rats is less than the MRHD for epilepsy or migraine on a mg/m 2 basis. Topiramate is excreted in human milk [see Data ] . The effects of topiramate on milk production are unknown. Diarrhea and somnolence have been reported in breastfed infants whose mothers receive topiramate treatment. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for topiramate and any potential adverse effects on the breastfed infant from topiramate or from the underlying maternal condition. Human Data Limited data from 5 women with epilepsy treated with topiramate during lactation showed drug levels in milk similar to those in maternal plasma. Women of childbearing potential who are not planning a pregnancy should use effective contraception because of the risk of major congenital malformations, including oral clefts, and the risk of infants being SGA [see Drug Interactions ( 7.4 ) and Use in Specific Populations ( 8.1 )] . Adjunctive Treatment for Epilepsy Pediatric Patients 2 Years of Age and Older The safety and effectiveness of EPRONTIA 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 in this population was similar to that of older pediatric patients, although results from the above controlled study and an open-label, long-term 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 a suggestion that this effect was dose-related. However, because of the absence of an appropriate control group, it is not known if this decrement in function was treatment-related or reflects the patient's underlying disease (e.g., patients who received higher doses may have more severe underlying disease) [see Warnings and Precautions ( 5.6 )] . In this open-label, uncontrolled study, the mortality was 37 deaths/1000 patient years. It is not possible to know whether this mortality rate is related to topiramate treatment, because the background mortality rate for a similar, significantly refractory, young pediatric population (1-24 months) with partial epilepsy is not known. Monotherapy Treatment for Epilepsy Pediatric Patients 2 Years of Age and Older The safety and effectiveness of EPRONTIA as monotherapy for the treatment of partial-onset seizures or primary generalized tonic-clonic seizures have been established in pediatric patients aged 2 years and older [see Clinical Trials Experience ( 6.1 ), Clinical Studies ( 14.1 )] . A one-year, active-controlled, open-label study with blinded assessments of bone mineral density (BMD) and growth in pediatric patients 4 to 15 years of age, including 63 patients with recent or new onset of epilepsy, was conducted to assess effects of topiramate (N=28, 6-15 years of age) versus levetiracetam (N=35, 4-15 years of age) monotherapy on bone mineralization and on height and weight, which reflect growth. Effects on bone mineralization were evaluated via dual-energy X-ray absorptiometry and blood markers. Table 10 summarizes effects of topiramate at 12 months for key safety outcomes including BMD, height, height velocity, and weight. All Least Square Mean values for topiramate and the comparator were positive. Therefore, the Least Square Mean treatment differences shown reflect a topiramate-induced attenuation of the key safety outcomes. Statistically significant effects were observed for decreases in BMD (and bone mineral content) in lumbar spine and total body less head and in weight. Subgroup analyses according to age demonstrated similar negative effects for all key safety outcomes (i.e., BMD, height, weight). Table 10: Summary of Topiramate Treatment Difference Results at 12 Months for Key Safety Outcomes Safety Parameter Treatment Difference in Least Square Means (95 % Confidence Interval) Annual Change in BMD Lumbar Spine (g/cm 2 ) -0.036 (-0.058, -0.014) Annual Change in BMD TBLH TBLH=total body less head (g/cm 2 ) -0.026 (-0.039, -0.012) Annual Change in Height (cm) (4-9 years, Primary Analysis Population for Height) Whereas no patients were randomized to 2-5 year age subgroup for topiramate, 5 patients (4-5 years) were randomized to the active control group. -0.84 (-2.67, 0.99) Annual Change in Height (cm) (4-15 years) -0.75 (-2.21, 0.71) Annual Change in Height (cm) (10-15 years) -1.01 (-3.64, 1.61) Height Velocity (cm/year) (4-9 years) -1.00 (-2.76, 0.76) Height Velocity (cm/year) (4-15 years) -0.98 (-2.33, 0.37) Height Velocity (cm/year) (10-15 years) -0.96 (-3.24, 1.32) Annual Change in Weight (kg) -2.05 (-3.66, -0.45) Metabolic acidosis (serum bicarbonate < 20 mEq/L) was observed in all topiramate-treated patients at some time in the study [see Warnings and Precautions ( 5.4 )] . Over the whole study, 76% more topiramate-treated patients experienced persistent metabolic acidosis (i.e. 2 consecutive visits with or final serum bicarbonate < 20 mEq/L) compared to levetiracetam-treated patients. Over the whole study, 35% more topiramate-treated patients experienced a markedly abnormally low serum bicarbonate (i.e., absolute value < 17 mEq/L and ≥ 5 mEq/L decrease from pre-treatment), indicating the frequency of more severe metabolic acidosis, compared to levetiracetam-treated patients. The decrease in BMD at 12 months was correlated with decreased serum bicarbonate, suggesting that metabolic acidosis was at least a partial factor contributing to this adverse effect on BMD. Topiramate-treated patients exhibited an increased risk for developing an increased serum creatinine and an increased serum glucose above the normal reference range compared to control patients. 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 monotherapy treatment of epilepsy. Preventive Treatment of Migraine Pediatric Patients 12 to 17 Years of Age Safety and effectiveness of topiramate for the preventive treatment of migraine was studied in 5 double-blind, randomized, placebo-controlled, parallel-group trials in a total of 219 pediatric patients, at doses of 50 to 200 mg/day, or 2 to 3 mg/kg/day. These comprised a fixed dose study in 103 pediatric patients 12 to 17 years of age [see Clinical Studies ( 14.3 )] , a flexible dose (2 to 3 mg/kg/day), placebo-controlled study in 157 pediatric patients 6 to 16 years of age (including 67 pediatric patients 12 to 16 years of age), and a total of 49 pediatric patients 12 to 17 years of age in 3 studies for the preventive treatment of migraine primarily in adults. Open-label extension phases of 3 studies enabled evaluation of long-term safety for up to 6 months after the end of the double-blind phase. Efficacy of topiramate for the preventive treatment of migraine in pediatric patients 12 to 17 years of age is demonstrated for a 100 mg daily dose in Study 13 [see Clinical Studies ( 14.3 )] . Efficacy of topiramate (2 to 3 mg/kg/day) for the preventive treatment of migraine was not demonstrated in a placebo-controlled trial of 157 pediatric patients (6 to 16 years of age) that included treatment of 67 pediatric patients (12 to 16 years of age) for 20 weeks. In the pediatric trials (12 to 17 years of age) in which patients were randomized to placebo or a fixed daily dose of topiramate, the most common adverse reactions with topiramate that were seen at an incidence higher (≥5%) than in the placebo group were: paresthesia, upper respiratory tract infection, anorexia, and abdominal pain [see Adverse Reactions ( 6 )] . The most common cognitive adverse reaction in pooled double-blind studies in pediatric patients 12 to 17 years of age was difficulty with concentration/attention [see Warnings and Precautions ( 5.6 )] . Markedly abnormally low serum bicarbonate values indicative of metabolic acidosis were reported in topiramate-treated pediatric migraine patients [see Warnings and Precautions ( 5.4 )] . In topiramate-treated pediatric patients (12 to 17 years of age) compared to placebo-treated patients, abnormally increased results were more frequent for creatinine, BUN, uric acid, chloride, ammonia, total protein, and platelets. Abnormally decreased results were observed with topiramate vs placebo treatment for phosphorus and bicarbonate [see Clinical Trials Experience ( 6.1 )] . Notable changes (increases and decreases) from baseline in systolic blood pressure, diastolic blood pressure, and pulse were observed occurred more commonly in pediatric patients treated with topiramate compared to pediatric patients treated with placebo [see Clinical Pharmacology ( 12.2 )] . Pediatric Patients Below the Age of 12 Years Safety and effectiveness in pediatric patients below the age of 12 years have not been established for the preventive treatment of migraine. In a double-blind study in 90 pediatric patients 6 to 11 years of age (including 59 topiramate-treated and 31 placebo patients), the adverse reaction profile was generally similar to that seen in pooled double-blind studies of pediatric patients 12 to 17 years of age. The most common adverse reactions that occurred in topiramate -treated pediatric patients 6 to 11 years of age, and at least twice as frequently than placebo, were gastroenteritis (12% topiramate, 6% placebo), sinusitis (10% topiramate, 3% placebo), weight loss (8% topiramate, 3% placebo) and paresthesia (7% topiramate, 0% placebo). Difficulty with concentration/attention occurred in 3 topiramate-treated patients (5%) and 0 placebo-treated patients (0%). The risk for cognitive adverse reaction was greater in younger patients (6 to 11 years of age) than in older patients (12 to 17 years of age) [see Warnings and Precautions ( 5.6 )] . Juvenile Animal Studies When topiramate (0, 30, 90, and 300 mg/kg/day) was administered orally to rats during the juvenile period of development (postnatal days 12 to 50), bone growth plate thickness was reduced in males at the highest dose. The no-effect dose (90 mg/kg/day) for adverse developmental effects is approximately 2 times the maximum recommended pediatric dose (9 mg/kg/day) on a body surface area (mg/m 2 ) basis. 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 )] . The clearance of topiramate is reduced in patients with moderate (creatinine clearance 30 to 69 mL/min/1.73 m 2 ) and severe (creatinine clearance <30 mL/min/1.73 m 2 ) renal impairment. A dosage adjustment is recommended in patients with moderate or severe renal impairment [see Dosage and Administration ( 2.5 ), Clinical Pharmacology ( 12.3 )] . Topiramate is cleared by hemodialysis at a rate that is 4 to 6 times greater than in a normal individual. A dosage adjustment may be required [see Dosage and Administration ( 2.6 ), Clinical Pharmacology ( 12.3 )] .

EPRONTIA oral solution 25 mg/mL is supplied as a colorless to slightly yellow colored clear viscous liquid in white HDPE bottles. It is available as follows: NDC Size NDC 52652-9001-3 120 mL NDC 52652-9001-2 240 mL NDC 52652-9001-1 473 mL EPRONTIA is stored at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Discard unused portion 90 days after first opening.

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. 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. Peak topiramate plasma concentrations (C max ) occurred at approximately 0.5 hour after oral administration of EPRONTIA in healthy male subjects under fasting conditions. Oral administration of EPRONTIA with a high-fat and high calorie meal did not affect topiramate AUC 0-t and AUC 0-∞ , but lowered the C max by 28% and delayed the T max by 5 hours. Overall, the impact of food-intake on topiramate pharmacokinetics is not expected to be clinically significant, and therefore, EPRONTIA can be administered without regard to 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 ( 2.4 ) and Use in Specific Populations ( 8.5 )] . Clearance of topiramate in adults was not affected by gender or race. Pediatric Pharmacokinetics Pharmacokinetics of topiramate were evaluated in patients age 2 to <16 years. Patients received either no or a combination of other antiepileptic drugs. A population pharmacokinetic model was developed on the basis of pharmacokinetic data from relevant topiramate clinical studies. This dataset contained data from 1217 subjects including 258 pediatric patients age 2 to <16 years (95 pediatric patients <10 years of age). Pediatric patients on adjunctive treatment exhibited a higher oral clearance (L/h) of topiramate compared to patients on monotherapy, presumably because of increased clearance from concomitant enzyme-inducing antiepileptic drugs. In comparison, topiramate clearance per kg is greater in pediatric patients than in adults and in young pediatric patients (down to 2 years) than in older pediatric patients. Consequently, the plasma drug concentration for the same mg/kg/day dose would be lower in pediatric patients compared to adults and also in younger pediatric patients compared to older pediatric patients. Clearance was independent of dose. As in adults, hepatic enzyme-inducing antiepileptic drugs decrease the steady state plasma concentrations of topiramate. Drug Interactions In vitro studies indicate that topiramate does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, or CYP3A4/5 isozymes. In vitro studies indicate that topiramate is a mild inhibitor of CYP2C19 and a mild inducer of CYP3A4. Antiepileptic Drugs Potential interactions between topiramate and standard AEDs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. The effects of these interactions on mean plasma AUCs are summarized in Table 11 . In Table 11, the second column (AED concentration) describes what happens to the concentration of the co-administered AED listed in the first column when topiramate is added. The third column (topiramate concentration) describes how the co-administration of a drug listed in the first column modifies the concentration of topiramate when compared to topiramate given alone. Table 11: Summary of AED Interactions with Topiramate AED Co-administered AED Concentration Topiramate Concentration Phenytoin NC or 25% increase Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. 48% decrease Carbamazepine (CBZ) NC 40% decrease CBZ epoxide Is not administered but is an active metabolite of carbamazepine. NC NE Valproic acid 11% decrease 14% decrease Phenobarbital NC NE Primidone NC NE Lamotrigine NC at TPM doses up to 400 mg/day 13% decrease NC = Less than 10% of change in plasma conentration. AED = Antiepileptic drug. NE = Not Evaluated. Oral Contraceptives In a pharmacokinetic interaction study in healthy volunteers with a concomitantly administered combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 mcg ethinyl estradiol (EE), topiramate, given in the absence of other medications at doses of 50 to 200 mg/day, was not associated with statistically significant changes in mean exposure (AUC) to either component of the oral contraceptive. In another study, exposure to EE was statistically significantly decreased at doses of 200, 400, and 800 mg/day (18%, 21%, and 30%, respectively) when given as adjunctive therapy in patients taking valproic acid. In both studies, topiramate (50 mg/day to 800 mg/day) did not significantly affect exposure to NET and there was no significant dose-dependent change in EE exposure for doses of 50 to 200 mg/day. The clinical significance of the changes observed is not known [see Drug Interactions ( 7.4 )] . Digoxin In a single-dose study, serum digoxin AUC was decreased by 12% with concomitant topiramate administration. The clinical relevance of this observation has not been established. Hydrochlorothiazide A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of hydrochlorothiazide (HCTZ) (25 mg every 24 hours) and topiramate (96 mg every 12 hours) when administered alone and concomitantly. The results of this study indicate that topiramate C max increased by 27% and AUC increased by 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not significantly influenced by the concomitant administration of topiramate. Clinical laboratory results indicated decreases in serum potassium after topiramate or HCTZ administration, which were greater when HCTZ and topiramate were administered in combination. Metformin A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of metformin (500 mg every 12 hours) and topiramate in plasma when metformin was given alone and when metformin and topiramate (100 mg every 12 hours) were given simultaneously. The results of this study indicated that the mean metformin C max and AUC 0-12h increased by 18% and 25%, respectively, when topiramate was added. Topiramate did not affect metformin t max . The clinical significance of the effect of topiramate on metformin pharmacokinetics is not known. Oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect of metformin on topiramate pharmacokinetics is unclear. Pioglitazone A drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of topiramate and pioglitazone when administered alone and concomitantly. A 15% decrease in the AUC t,ss of pioglitazone with no alteration in C max, ss was observed. This finding was not statistically significant. In addition, a 13% and 16% decrease in C max,ss and AUC t,ss respectively, of the active hydroxy-metabolite was noted as well as a 60% decrease in C max,ss and AUC t,ss of the active keto-metabolite. The clinical significance of these findings is not known. Glyburide A drug-drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state pharmacokinetics of glyburide (5 mg/day) alone and concomitantly with topiramate (150 mg/day). There was a 22% decrease in C max and a 25% reduction in AUC 24 for glyburide during topiramate administration. Systemic exposure (AUC) of the active metabolites, 4- trans -hydroxy-glyburide (M1) and 3- cis -hydroxyglyburide (M2), was also reduced by 13% and 15%, and C max was reduced by 18% and 25%, respectively. The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide. Lithium In patients, the pharmacokinetics of lithium were unaffected during treatment with topiramate at doses of 200 mg/day; however, there was an observed increase in systemic exposure of lithium (27% for C max and 26% for AUC) following topiramate doses up to 600 mg/day [see Drug Interactions ( 7.7 )] . Haloperidol The pharmacokinetics of a single dose of haloperidol (5 mg) were not affected following multiple dosing of topiramate (100 mg every 12 hr) in 13 healthy adults (6 males, 7 females). Amitriptyline There was a 12% increase in AUC and C max for amitriptyline (25 mg per day) in 18 healthy subjects (9 males, 9 females) receiving 200 mg/day of topiramate. Sumatriptan Multiple dosing of topiramate (100 mg every 12 hours) in 24 healthy volunteers (14 males, 10 females) did not affect the pharmacokinetics of single-dose sumatriptan either orally (100 mg) or subcutaneously (6 mg). Risperidone When administered concomitantly with topiramate at escalating doses of 100, 250, and 400 mg/day, there was a reduction in risperidone systemic exposure (16% and 33% for steady-state AUC at the 250 and 400 mg/day doses of topiramate). No alterations of 9-hydroxyrisperidone levels were observed. Co-administration of topiramate 400 mg/day with risperidone resulted in a 14% increase in C max and a 12% increase in AUC 12 of topiramate. There were no clinically significant changes in the systemic exposure of risperidone plus 9-hydroxyrisperidone or of topiramate; therefore, this interaction is not likely to be of clinical significance. Propranolol Multiple dosing of topiramate (200 mg/day) in 34 healthy volunteers (17 males, 17 females) did not affect the pharmacokinetics of propranolol following daily 160 mg doses. Propranolol doses of 160 mg/day in 39 volunteers (27 males, 12 females) had no effect on the exposure to topiramate, at a dose of 200 mg/day of topiramate. Dihydroergotamine Multiple dosing of topiramate (200 mg/day) in 24 healthy volunteers (12 males, 12 females) did not affect the pharmacokinetics of a 1 mg subcutaneous dose of dihydroergotamine. Similarly, a 1 mg subcutaneous dose of dihydroergotamine did not affect the pharmacokinetics of a 200 mg/day dose of topiramate in the same study. Diltiazem Co-administration of diltiazem (240 mg Cardizem CD ® ) with topiramate (150 mg/day) resulted in a 10% decrease in C max and a 25% decrease in diltiazem AUC, a 27% decrease in C max and an 18% decrease in des-acetyl diltiazem AUC, and no effect on N-desmethyl diltiazem. Co-administration of topiramate with diltiazem resulted in a 16% increase in C max and a 19% increase in AUC 12 of topiramate. Venlafaxine Multiple dosing of topiramate (150 mg/day) in healthy volunteers did not affect the pharmacokinetics of venlafaxine or O-desmethyl venlafaxine. Multiple dosing of venlafaxine (150 mg) did not affect the pharmacokinetics of topiramate.

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/m 2 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/m 2 basis). 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/m 2 basis) prior to and during mating and early pregnancy.

The safety and efficacy of EPRONTIA are based on the relative bioavailability of EPRONTIA compared to topiramate sprinkle capsules in healthy subjects [see Clinical Pharmacology ( 12.3 )] . Topiramate sprinkle capsules have comparable bioavailability to topiramate tablets. The studies described in the following subsections were conducted using topiramate tablets or sprinkle capsules. 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 )] . Figure 1 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 tablets in addition to their other AEDs. Following randomization, patients began the double-blind phase of treatment. In five of the six studies, patients received active drug beginning at 100 mg per day; the dose was then increased by 100 mg or 200 mg/day increments weekly or every other week until the assigned dose was reached, unless intolerance prevented increases. In the sixth study (Study 7), the 25 or 50 mg/day initial doses of topiramate were followed by respective weekly increments of 25 or 50 mg/day until the target dose of 200 mg/day was reached. After titration, patients entered a 4, 8 or 12-week stabilization period. The numbers of patients randomized to each dose and the actual mean and median doses in the stabilization period are shown in Table 12. Pediatric Patients 2 to 16 Years of Age with Partial-Onset Seizures The effectiveness of topiramate as an adjunctive treatment for pediatric patients 2 to 16 years of age with partial-onset seizures was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 8), comparing topiramate and placebo in patients with a history of partial-onset seizures, with or without secondarily generalized seizures (see Table 13 ). Patients in this study were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate tablets or placebo. In this study, patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least six partial-onset seizures, with or without secondarily generalized seizures, during the baseline phase were randomly assigned to placebo or topiramate tablets in addition to their other AEDs. Following randomization, patients began the double-blind phase of treatment. Patients received active drug beginning at 25 or 50 mg/day; the dose was then increased by 25 mg to 150 mg/day increments every other week until the assigned dosage of 125, 175, 225, or 400 mg/day based on patients' weight to approximate a dosage of 6 mg/kg/day was reached, unless intolerance prevented increases. After titration, patients entered an 8-week stabilization period. Patients With Primary Generalized Tonic-Clonic Seizures The effectiveness of topiramate as an adjunctive treatment for primary generalized tonic-clonic seizures in patients 2 years of age and older was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 9), comparing a single dosage of topiramate and placebo (see Table 13). Patients in Study 9 were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate or placebo. Patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least three primary generalized tonic-clonic seizures during the baseline phase were randomly assigned to placebo or topiramate in addition to their other AEDs. Following randomization, patients began the double-blind phase of treatment. Patients received active drug beginning at 50 mg/day for four weeks; the dose was then increased by 50 mg to 150 mg/day increments every other week until the assigned dose of 175, 225, or 400 mg/day based on patients' body weight to approximate a dosage of 6 mg/kg/day was reached, unless intolerance prevented increases. After titration, patients entered a 12-week stabilization period. Patients With Lennox-Gastaut Syndrome The effectiveness of topiramate as an adjunctive treatment for seizures associated with Lennox- Gastaut syndrome was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 10) comparing a single dosage of topiramate with placebo in patients 2 years of age and older (see Table 13 ). Patients in Study 10 were permitted a maximum of two antiepileptic drugs (AEDs) in addition to topiramate or placebo. Patients who were experiencing at least 60 seizures per month before study entry were stabilized on optimum dosages of their concomitant AEDs during a 4-week baseline phase. Following baseline, patients were randomly assigned to placebo or topiramate in addition to their other AEDs. Active drug was titrated beginning at 1 mg/kg/day for a week; the dose was then increased to 3 mg/kg/day for one week, then to 6 mg/kg/day. After titration, patients entered an 8-week stabilization period. The primary measures of effectiveness were the percent reduction in drop attacks and a parental global rating of seizure severity. Table 12: Topiramate Dose Summary During the Stabilization Periods of Each of Six Double-Blind, Placebo-Controlled, Adjunctive Trials in Adults with Partial-Onset Seizures Dose-response studies were not conducted for other indications or pediatric partial-onset seizures. Study Stabilization Dose Placebo Placebo dosages are given as the number of tablets. Placebo target dosages were as follows: Protocol 3 4 tablets/day; Protocols 1 and 4, 6 tablets/day; Protocols 5 and 6, 8 tablets/day; Protocol 2, 10 tablets/day. Target TOPIRAMATE Dosage (mg/day) 200 400 600 800 1,000 2 N Mean Dose Median Dose 42 5.9 6.0 42 200 200 40 390 400 41 556 600 -- -- 3 N Mean Dose Median Dose 44 9.7 10.0 -- -- 40 544 600 45 739 800 40 796 1,000 4 N Mean Dose Median Dose 23 3.8 4.0 -- 19 395 400 -- -- -- 5 N Mean Dose Median Dose 30 5.7 6.0 -- -- 28 522 600 -- -- 6 N Mean Dose Median Dose 28 7.9 8.0 -- -- -- 25 568 600 -- 7 N Mean Dose Median Dose 90 8 8 157 200 200 -- -- -- -- In all adjunctive trials, the reduction in seizure rate from baseline during the entire double-blind phase was measured. The median percent reductions in seizure rates and the responder rates (fraction of patients with at least a 50% reduction) by treatment group for each study are shown below in Table 13 . As described above, a global improvement in seizure severity was also assessed in the Lennox-Gastaut trial. Table 13: Efficacy Results in Double-Blind, Placebo-Controlled, Adjunctive Epilepsy Trials Study# # Target TOPIRAMATE Dosage (mg per day) Placebo 200 400 600 800 1,000 ≈6mg/kg/day For Studies 8 and 9, specified target dosages (<9.3 mg/kg/day) were assigned based on subject's weight to approximate a dosage of 6mg/kg per day; these dosages corresponded to mg/day dosages of 125, 175, 225, and 400 mg/day. Partial-Onset Seizures Studies in Adults 2 N 45 45 45 46 -- -- -- Median % Reduction 12 27 a 48 b 45 c -- -- -- % Responders 18 24 44 d 46 d -- -- -- 3 N 47 -- -- 48 48 47 -- Median % Reduction 2 -- -- 41 c 41 c 36 c % Responders 9 -- -- 40 c 41 c 36 d 4 N 24 -- 23 -- -- -- -- Median % Reduction 1 -- 41 e -- -- -- -- % Responders 8 -- 35 d -- -- -- -- 5 N 30 -- -- 30 -- -- -- Median % Reduction -12 -- -- 46 f -- -- -- % Responders 10 -- -- 47 c -- -- -- 6 N 28 -- -- -- 28 -- -- Median % Reduction -21 -- -- -- 24 c -- -- % Responders 0 -- -- -- 43 c -- -- 7 N 91 168 -- -- -- -- -- Median % Reduction 20 44 c -- -- -- -- -- % Responders 24 45 c Partial-Onset Seizures Studies in Pediatric Patients 8 N 45 -- -- -- -- -- 41 Median % Reduction 11 -- -- -- -- -- 33 d % Responders 20 -- -- -- -- -- 39 Primary Generalized Tonic-Clonic h 9 N 40 -- -- -- -- -- 39 Median % Reduction 9 -- -- -- -- -- 57 d % Responders 20 -- -- -- -- -- 56 c Lennox-Gastaut Syndrome i 10 N 49 -- -- -- -- -- 46 Median % Reduction -5 -- -- -- -- -- 15 d % Responders 14 28 g Improvement in Seizure Severity j 28 52 d Comparisons with placebo: a p=0.080; b p ≤ 0.010; c p ≤ 0.001; d p ≤ 0.050; e p=0.065; f p≤0.005; g p=0.071; h Median % reduction and % responders are reported for PGTC seizures; i Median % reduction and % responders for drop attacks, i.e., tonic or atonic seizures; j Percentage of subjects who were minimally, much, or very much improved from baseline. Subset analyses of the antiepileptic efficacy of topiramate tablets in these studies showed no differences as a function of gender, race, age, baseline seizure rate, or concomitant AED. In clinical trials for epilepsy, daily dosages were decreased in weekly intervals by 50 to 100 mg/day in adults and over a 2- to 8-week period in pediatric patients; transition was permitted to a new antiepileptic regimen when clinically indicated. Adult Patients The results of 2 multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trials established the effectiveness of topiramate in the preventive treatment of migraine. The design of both trials (Study 11 was conducted in the U.S. and Study 12 was conducted in the U.S. and Canada) was identical, enrolling patients with a history of migraine, with or without aura, for at least 6 months, according to the International Headache Society (IHS) diagnostic criteria. Patients with a history of cluster headaches or basilar, ophthalmoplegic, hemiplegic, or transformed migraine headaches were excluded from the trials. Patients were required to have completed up to a 2-week washout of any prior migraine preventive medications before starting the baseline phase. Patients who experienced 3 to 12 migraine headaches over the 4 weeks in the baseline phase were randomized to either topiramate 50 mg/day, 100 mg/day, 200 mg/day, or placebo and treated for a total of 26 weeks (8-week titration period and 18-week maintenance period). Treatment was initiated at 25 mg/day for one week, and then the daily dosage was increased by 25 mg increments each week until reaching the assigned target dose or maximum tolerated dose (administered twice daily). Effectiveness of treatment was assessed by the reduction in migraine headache frequency, as measured by the change in 4-week migraine rate (according to migraines classified by IHS criteria) from the baseline phase to double-blind treatment period in each topiramate treatment group compared to placebo in the Intent-To-Treat (ITT) population. In Study 11, a total of 469 patients (416 females, 53 males), ranging in age from 13 to 70 years, were randomized and provided efficacy data. Two hundred sixty-five patients completed the entire 26-week double-blind phase. The median average daily dosages were 48 mg/day, 88 mg/day, and 132 mg/day in the target dose groups of topiramate 50, 100, and 200 mg/day, respectively. The mean migraine headache frequency rate at baseline was approximately 5.5 migraine headaches/28 days and was similar across treatment groups. The change in the mean 4-week migraine headache frequency from baseline to the double-blind phase was -1.3, -2.1, and -2.2 in the topiramate 50, 100, and 200 mg/day groups, respectively, versus -0.8 in the placebo group (see Figure 2 ). The treatment differences between the topiramate 100 and 200 mg/day groups versus placebo were similar and statistically significant (p<0.001 for both comparisons). In Study 12, a total of 468 patients (406 females, 62 males), ranging in age from 12 to 65 years, were randomized and provided efficacy data. Two hundred fifty-five patients completed the entire 26-week double-blind phase. The median average daily dosages were 47 mg/day, 86 mg/day, and 150 mg/day in the target dose groups of topiramate 50, 100, and 200 mg/day, respectively. The mean migraine headache frequency rate at baseline was approximately 5.5 migraine headaches/28 days and was similar across treatment groups. The change in the mean 4-week migraine headache period frequency from baseline to the double-blind phase was -1.4, -2.1, and -2.4 in the topiramate 50, 100, and 200 mg/day groups, respectively, versus -1.1 in the placebo group (see Figure 2 ). The differences between the topiramate 100 and 200 mg/day groups versus placebo were similar and statistically significant (p=0.008 and p <0.001, respectively). In both studies, there were no apparent differences in treatment effect within age or gender subgroups. Because most patients were Caucasian, there were insufficient numbers of patients from different races to make a meaningful comparison of race. For patients withdrawing from topiramate, daily dosages were decreased in weekly intervals by 25 to 50 mg/day. Figure 2: Reduction in 4-Week Migraine Headache Frequency (Studies 11 and 12 for Adults and Adolescents) Pediatric Patients 12 to 17 Years of Age The effectiveness of topiramate for the preventive treatment of migraine in pediatric patients 12 to 17 years of age was established in a multicenter, randomized, double-blind, parallel-group trial (Study 13). The study enrolled 103 patients (40 male, 63 female) 12 to 17 years of age with episodic migraine headaches with or without aura. Patient selection was based on IHS criteria for migraines (using proposed revisions to the 1988 IHS pediatric migraine criteria [IHS-R criteria]). Patients who experienced 3 to 12 migraine attacks (according to migraines classified by patient reported diaries) and ≤14 headache days (migraine and non-migraine) during the 4-week prospective baseline period were randomized to either topiramate 50 mg/day, 100 mg/day, or placebo and treated for a total of 16 weeks (4-week titration period followed by a 12-week maintenance period). Treatment was initiated at 25 mg/day for one week, and then the daily dosage was increased by 25 mg increments each week until reaching the assigned target dose or maximum tolerated dose (administered twice daily). Approximately 80% or more patients in each treatment group completed the study. The median average daily dosages were 45 and 79 mg/day in the target dose groups of topiramate 50 and 100 mg/day, respectively. Effectiveness of treatment was assessed by comparing each topiramate treatment group to placebo (ITT population) for the percent reduction from baseline to the last 12 weeks of the double-blind phase in the monthly migraine attack rate (primary endpoint). The percent reduction from baseline to the last 12 weeks of the double-blind phase in average monthly migraine attack rate is shown in Table 14 . The 100 mg topiramate dose produced a statistically significant treatment difference relative to placebo of 28% reduction from baseline in the monthly migraine attack rate. The mean reduction from baseline to the last 12 weeks of the double-blind phase in average monthly attack rate, a key secondary efficacy endpoint in Study 13 (and the primary efficacy endpoint in Studies 11 and 12, of adults) was 3.0 for 100 mg topiramate dose and 1.7 for placebo. This 1.3 treatment difference in mean reduction from baseline of monthly migraine rate was statistically significant (p = 0.0087). Table 14: Percent Reduction from Baseline to the Last 12 Weeks of Double-Blind Phase in Average Monthly Attack Rate: Study 13 (Intent-to-Treat Analysis Set) Category Placebo (N=33) TOPIRAMATE 50 mg/day (N=35) TOPIRAMATE 100 mg/day (N=35) Baseline Median 3.6 4.0 4.0 Last 12 Weeks of Double-Blind Phase Median 2.3 2.3 1.0 Percent Reduction (%) Median 44.4 44.6 72.2 P-value vs. Placebo P-values (two-sided) for comparisons relative to placebo are generated by applying an ANCOVA model on ranks that includes subject's stratified age at baseline, treatment group, and analysis center as factors and monthly migraine attack rate during baseline period as a covariate. , P-values for the dose groups are the adjusted p-value according to the Hochberg multiple comparison procedure. 0.7975 0.0164 Indicates p-value is <0.05 (two-sided). Figure 2

Carton Label NDC 52652-9001-2 EPRONTIA ® (topiramate) oral solution 25 mg/mL FOR ORAL USE ONLY ATTENTION PHARMACIST: Dispense the following to each patient: •Oral Dosing Syringe •Medication Guide - available at eprontia.com/medication-guide.pdf READY TO USE 240 mL Rx Only azurity ® pharmaceuticals Manufactured for: Azurity Pharmaceuticals, Inc. Woburn, MA 01801 Principle Display Panel