These Highlights Do Not Include All The Information Needed To Use Trokendi Xr ®

Adults and Pediatric Patients 10 Years of Age and Older with Partial Onset or Primary Generalized Tonic-Clonic Seizures

The recommended dose for TROKENDI XR monotherapy in adults and in pediatric patients 10 years of age and older is 400 mg orally once daily. Titrate TROKENDI XR ^®according to the following schedule:

Alcohol use is contraindicated within 6 hours prior to and 6 hours after TROKENDI XR ^®administration [see Contraindications (4)and Warnings and Precautions (5.5)].

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 TROKENDI XR ^® [see Clinical Pharmacology (12.3)].

TROKENDI XR ^®is indicated for the preventive treatment of migraine in patients 12 years of age and older [see Clinical Studies (14.4)] .

Overdoses of topiramate have been reported. Signs and symptoms included convulsions, drowsiness, speech disturbance, blurred vision, diplopia, impaired mentation, lethargy, abnormal coordination, stupor, hypotension, abdominal pain, agitation, dizziness, and depression. The clinical consequences were not severe in most cases, but deaths have been reported after overdoses involving topiramate.

Topiramate overdose has resulted in severe metabolic acidosis [see Warnings and Precautions (5.4)] .

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

Similar signs, symptoms, and clinical consequences are expected to occur with overdosage of TROKENDI XR ^®. In the event of overdose, TROKENDI XR ^®should be discontinued and general supportive treatment given until clinical toxicity has been diminished or resolved. Hemodialysis is an effective means of removing topiramate from the body.

Topiramate, USP, is a sulfamate-substituted monosaccharide. TROKENDI XR ^®(topiramate) extended-release capsules are available as 25 mg, 50 mg, 100 mg, and 200 mg capsules for oral administration.

Topiramate is a white to off-white powder. Topiramate is freely soluble in polar organic solvents such as acetonitrile and acetone; and very slightly soluble to practically insoluble in non-polar organic solvents such as hexanes. Topiramate has the molecular formula C ₁₂H ₂₁NO ₈S and a molecular weight of 339.4. Topiramate is designated chemically as 2,3:4,5-Di- O-isopropylidene-β-D-fructopyranose sulfamate and has the following structural formula:

TROKENDI XR ^®(topiramate) is an extended-release capsule. TROKENDI XR ^®capsules contain the following inactive ingredients:

Sugar Spheres, NF

Hypromellose (Type 2910), USP

Mannitol, USP

Docusate Sodium, USP

Sodium Benzoate, NF

Ethylcellulose, NF

Oleic Acid, NF

Medium Chain Triglycerides, NF

Polyethylene Glycol, NF

Polyvinyl Alcohol, USP

Titanium Dioxide, USP

Talc, USP

Lecithin, NF

Xanthan Gum, NF

Glycerin, USP-NF

The capsule shells contain gelatin, USP; Titanium Dioxide, USP; and Colorants.

The colorants are:

FD&C Blue #1 (all strength capsules)

Yellow Iron Oxide, USP (25 mg and 50 mg capsules)

FD&C Red #3 (50 mg, 100 mg and 200 mg capsules)

FD&C Yellow #6 (50 mg, 100 mg and 200 mg capsules)

Riboflavin, USP (25 mg capsules)

All capsule shells are imprinted with black print that contains shellac, NF, and black iron oxide, NF.

A decrease in the exposure of pioglitazone and its active metabolites were noted with the concurrent use of pioglitazone and immediate-release topiramate in a clinical trial. The clinical relevance of these observations is unknown; however, when TROKENDI XR ^®is added to pioglitazone therapy or pioglitazone is added to TROKENDI XR ^®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)] .

TROKENDI XR ^®(topiramate) extended-release capsules are available in the following strengths and colors:

25 mg (light green opaque body/yellow opaque cap with black print "SPN" and "25"):

• bottles of 7 count (NDC-17772-101-70), 30 count (NDC-17772-101-30) and 100 count (NDC-17772-101-01)
• blister packages of 30-count (NDC-17772-101-15)

50 mg (light green opaque body/orange opaque cap with black print "SPN" and "50"):

• bottles of 7 count (NDC-17772-102-70), 30 count (NDC-17772-102-30) and 100 count (NDC-17772-102-01)
• blister packages of 30-count (NDC-17772-102-15)

100 mg (green opaque body/blue opaque cap with black print "SPN" and "100"):

• bottles of 7 count (NDC-17772-103-70), 30 count (NDC-17772-103-30) and 100 count (NDC-17772-103-01)
• blister packages of 30-count (NDC-17772-103-15)

200 mg (pink opaque body/blue opaque cap with black print "SPN" and "200"):

• bottles of 7 count (NDC-17772-104-70), 30 count (NDC-17772-104-30) and 100 count (NDC-17772-104-01)
• blister packages of 30-count (NDC-17772-104-15)

Some patients may experience a large increase in amitriptyline concentration in the presence of TROKENDI XR ^®and any adjustments in amitriptyline dose should be made according to the patients' clinical response and not on the basis of plasma levels [see Clinical Pharmacology (12.3)] .

Clinical studies of immediate-release topiramate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Dosage adjustment may be necessary for elderly with creatinine clearance less than 70 mL/min/1.73 m ². Estimate GFR should be measured prior to dosing [see Dosage and Administration (2.5)and Clinical Pharmacology (12.3)] .

Topiramate increases the risk of kidney stones. During adjunctive epilepsy trials, the risk for kidney stones in immediate-release 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. TROKENDI XR ^®would be expected to have the same effect as immediate-release topiramate on the formation of kidney stones. TROKENDI XR ^®is not approved for treatment of epilepsy in pediatric patients less than 6 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 TROKENDI XR ^®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 immediate-release 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.

TROKENDI XR can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in uterohave 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 risks of TROKENDI XR ^®when administering the drug in women of childbearing potential, particularly when TROKENDI XR ^®is considered for a condition not usually associated with permanent injury or death [see Use in Specific Populations (8.1)] . TROKENDI XR ^®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 informed of the potential hazard to a fetus [see Use in Specific Populations (8.1)] .

The possibility of decreased contraceptive efficacy and increased breakthrough bleeding may occur in patients taking contraceptive products with TROKENDI XR ^®. 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)] .

TROKENDI XR ^®is contraindicated in patients with recent alcohol use (i.e., within 6 hours prior to and 6 hours after TROKENDI XR ^®use) [see Warnings and Precautions (5.5)]

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

• Acute Myopia and Secondary Angle Closure Glaucoma [see Warnings and Precautions (5.1)]
• Visual Field Defects [see Warnings and Precautions 5.2]
• Oligohydrosis and Hyperthermia [see Warnings and Precautions (5.3) ]
• Metabolic Acidosis [see Warnings and Precautions (5.4)]
• Interaction With Alcohol [see Warnings and Precautions (5.5)]
• Suicidal Behavior and Ideation [see Warnings and Precautions (5.6)]
• Cognitive/Neuropsychiatric Adverse Reactions [see Warnings and Precautions (5.7)]
• Fetal Toxicity [see Warnings and Precautions (5.8)]
• Withdrawal of Antiepileptic Drugs [see Warnings and Precautions (5.9)]
• Decrease of Bone Mineral Density [see Warnings and Precautions (5.10)]
• Negative Effects on Growth (Height and Weight) [see Warnings and Precautions (5.11)]
• Serious Skin Reactions [see Warnings and Precautions (5.12)]
• Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid Use) [see Warnings and Precautions (5.13)]
• Kidney Stones [see Warnings and Precautions (5.14)]
• Hypothermia With Concomitant Valproic Acid Use [see Warnings and Precautions (5.15)]

The data described in the following sections were obtained using immediate-release topiramate tablets. TROKENDI XR ^®has not been studied in a randomized, placebo-controlled Phase III clinical study; however, it is expected that TROKENDI XR ^®would produce a similar adverse reaction profile as immediate-release topiramate.

• Contraceptives: Decreased contraceptive efficacy and increased breakthrough bleeding, especially at doses greater than 200 mg per day ( 7.5)
• Monitor lithium levels if lithium is used with high-dose TROKENDI XR ( 7.8)

Concomitant administration of topiramate with other CNS depressant drugs or alcohol 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, TROKENDI XR ^®should be used with extreme caution if used in combination with alcohol and other CNS depressants [see Contraindications (4)and Warnings and Precautions (5.7)].

The clearance of topiramate is reduced in patients with moderate (creatinine clearance 30 to 69 mL/min/1.73m ²) and severe (creatinine clearance less than 30 mL/min/1.73m ²) renal impairment. A dosage adjustment is recommended in patients with moderate or severe renal impairment [see Dosage and Administration (2.5)and Clinical Pharmacology (12.3)] .

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.

TROKENDI XR ^®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 carbonic anhydrase inhibition by TROKENDI XR. TROKENDI XR ^®-induced metabolic acidosis can occur at any time during treatment. Bicarbonate decrements are usually mild to 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 TROKENDI XR.

Metabolic acidosis was commonly observed in adult and pediatric patients treated with immediate-release 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 immediate-release 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 (5.10, 5.14)] . A one-year, active-controlled study of pediatric patients treated with immediate-release topiramate demonstrated that immediate-release 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 (5.10), 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 pediatrics. Reductions in length and weight were correlated to the degree of acidosis [see Use in Specific Populations (8.4)] . TROKENDI XR 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 (5.8)and Use in Specific Populations (8.1)] .

TROKENDI XR ^®is indicated for:

• Epilepsy: initial monotherapy for the treatment of partial-onset or primary generalized tonic-clonic seizures in patients 6 years of age and older ( 1.1); adjunctive therapy for the treatment of partial-onset, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome (LGS) in patients 6 years of age and older ( 1.2)
• Preventive treatment of migraine in patients 12 years of age and older ( 1.3)

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 (5.13, 5.15)and Clinical Pharmacology (12.3)] .

TROKENDI XR ^®is indicated as initial monotherapy for the treatment of partial-onset or primary generalized tonic-clonic seizures in patients 6 years of age and older [see Clinical Studies (14.2)] .

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.

Visual field defects (independent of elevated intraocular pressure) have been reported in clinical trials and in postmarketing experience in patients receiving topiramate. In clinical trials, most of these events were reversible after topiramate discontinuation. If visual problems occur at any time during treatment with TROKENDI XR, consideration should be given to discontinuing the drug.

TROKENDI XR ^®(topiramate) extended-release capsules should be stored in well closed containers at controlled room temperature [25°C (77°F); excursions 15°C-30°C (59°F-86°F)]. Protect from moisture and light.

• Acute myopia and secondary angle closure glaucoma: can lead to permanent visual loss; discontinue TROKENDI XR ^®as soon as possible ( 5.1)
• Visual field defects: consider discontinuation of TROKENDI XR ( 5.2)
• Oligohydrosis 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 TROKENDI XR ^®if clinically appropriate ( 5.4)
• Suicidal behavior and ideation: antiepileptic drugs increase the risk of suicidal behavior or ideation ( 5.6)
• Cognitive/neuropsychiatric adverse reactions: use caution when operating machinery including cars; depression and mood problems may occur ( 5.7)
• 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 ( 5.8)
• Withdrawal of AEDs: withdraw TROKENDI XR ^®gradually ( 5.9)
• Decrease in Bone Mineral Density: has been shown to decrease bone mineral density and bone mineral content in pediatric patients ( 5.10)
• Negative effects on growth (height and weight): may slow height increase and weight gain; carefully monitor children receiving prolonged therapy ( 5.11)
• Serious skin reactions: If SJS or TEN is suspected, discontinue TROKENDI XR ( 5.12)
• Hyperammonemia/encephalopathy: measure ammonia if encephalopathic symptoms occur ( 5.13)
• Kidney stones: avoid use with other carbonic anhydrase inhibitors, other drugs causing metabolic acidosis, or in patients on a ketogenic diet ( 5.14)
• Hypothermia has been reported with and without hyperammonemia during topiramate treatment with concomitant valproic acid use ( 5.15)

• TROKENDI XR ^®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)
• Swallow capsule whole and intact. Do not sprinkle on food, chew, or crush ( 2.7)

Serious skin reactions (Stevens-Johnson Syndrome [SJS] and Toxic Epidermal Necrolysis [TEN]) have been reported in patients receiving topiramate. TROKENDI XR 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.

TROKENDI XR ^®extended-release capsules are available in the following strengths and colors:

• 25 mg: Size 2 capsules, light green opaque body/yellow opaque cap (printed "SPN" on the cap, "25" on the body)
• 50 mg: Size 0 capsules, light green opaque body/orange opaque cap (printed "SPN" on the cap, "50" on the body)
• 100 mg: Size 00 capsules, green opaque body/blue opaque cap (printed "SPN" on the cap, "100" on the body)
• 200 mg: Size 00 capsules, pink opaque body/blue opaque cap (printed "SPN" on the cap, "200" on the body)

In vitrodata show that, in the presence of alcohol, the pattern of topiramate release from TROKENDI XR ^®capsules is significantly altered. As a result, plasma levels of topiramate with TROKENDI XR ^®may be markedly higher soon after dosing and subtherapeutic later in the day. Therefore, alcohol use should be completely avoided within 6 hours prior to and 6 hours after TROKENDI XR ^®administration .

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

Body as a Whole-General Disorders: oligohydrosis and hyperthermia [see Warnings and Precautions (5.3)] , hyperammonemia, hyperammonemic encephalopathy [see Warnings and Precautions (5.13)] , hypothermia with concomitant valproic acid [see Warnings and Precautions 5.15)] .

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

Skin and Appendage Disorders: bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis) [see Warnings and Precautions (5.12)] , pemphigus

Urinary System Disorders: kidney stones, nephrocalcinosis [see Warnings and Precautions (5.14)]

Vision disorders: acute myopia, secondary angle closure glaucoma [see Warnings and Precautions (5.1)], maculopathy

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

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

Topiramate C _maxand AUC increased when HCTZ was added to immediate-release topiramate. The clinical significance of this change is unknown. The addition of HCTZ to TROKENDI XR ^®may require a decrease in the TROKENDI XR ^®dose [see Clinical Pharmacology (12.3)] .

TROKENDI XR ^®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 6 years of age and older [see Clinical Studies (14.3)] .

Alcohol use should be completely avoided within 6 hours prior to and 6 hours after TROKENDI XR ^®administration [see Warnings and Precautions (5.5)] .

TROKENDI XR ^®can be taken without regard to meals.

Swallow capsule whole and intact. Do not sprinkle on food, chew, or crush.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Oligohydrosis (decreased sweating), resulting in hospitalization in some cases, has been reported in association with topiramate 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 TROKENDI XR ^®should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. Caution should be used when TROKENDI XR ^®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 .

Antiepileptic drugs (AEDs) increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED, including TROKENDI XR ^®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 2 shows absolute and relative risk by indication for all evaluated AEDs.

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 TROKENDI XR ^®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.

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)and Clinical Pharmacology (12.3)] .

Results of a one-year active-controlled study in pediatric patients (N=63) demonstrated negative effects of immediate-release 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 immediate-release 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 immediate-release 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.

In patients with or without a history of seizures or epilepsy, antiepileptic drugs, including TROKENDI XR ^®, should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency [see Clinical Studies (14)] . In situations where rapid withdrawal of TROKENDI XR ^®is medically required, appropriate monitoring is recommended.

Concomitant use of topiramate, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., zonisamide or acetazolamide) may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Patients should be monitored for the appearance or worsening of metabolic acidosis when TROKENDI XR ^®is given concomitantly with another carbonic anhydrase inhibitor [see Clinical Pharmacology (12.3)].

Immediate-release topiramate can cause, and therefore expected to be caused by TROKENDI XR ^®, 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.

The recommended total daily dose of TROKENDI XR ^®as treatment for the preventive treatment of migraine in patients 12 years of age and older is 100 mg once daily. Titrate TROKENDI XR ^®for the preventive treatment of migraine according to the following schedule:

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

Results of a one-year active-controlled study of pediatric patients (N=63) demonstrated negative effects of immediate-release 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 immediate-release 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 immediate-release topiramate group compared to the control group. Negative effects on weight and height were seen across all immediate-release topiramate age subgroups. Growth (height and weight) of children receiving prolonged TROKENDI XR ^®therapy should be carefully monitored.

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 (VPA) both in conjunction with 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 (7.2)] . Consideration should be given to stopping TROKENDI XR 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.

30 Capsules

NDC 17772-101-30

Trokendi XR _®

(topiramate) extended-release capsules

Once daily.

Swallow capsule

whole and intact.

Do not open, crush,

chew, or sprinkle

capsule contents on food.

25 mg

ATTENTION PHARMACIST: Dispense

the Accompanying Medication Guide

to Each Patient

Supernus ^®

Pharmaceuticals

Rx only

30 Capsules

NDC 17772-102-30

Trokendi XR _®

(topiramate) extended-release capsules

Once daily.

Swallow capsule

whole and intact.

Do not open, crush,

chew, or sprinkle

capsule contents on food.

50 mg

ATTENTION PHARMACIST: Dispense

the Accompanying Medication Guide

to Each Patient

Supernus ^®

Pharmaceuticals

Rx only

30 Capsules

NDC 17772-103-30

Trokendi XR _®

(topiramate) extended-release capsules

Once daily.

Swallow capsule

whole and intact.

Do not open, crush,

chew, or sprinkle

capsule contents on food.

100 mg

ATTENTION PHARMACIST: Dispense

the Accompanying Medication Guide

to Each Patient

Supernus ^®

Pharmaceuticals

Rx only

30 Capsules

NDC 17772-104-30

Trokendi XR _®

(topiramate) extended-release capsules

Once daily.

Swallow capsule

whole and intact.

Do not open, crush,

chew, or sprinkle

capsule contents on food.

200 mg

ATTENTION PHARMACIST: Dispense

the Accompanying Medication Guide

to Each Patient

Supernus ^®

Pharmaceuticals

Rx only

In patients with renal impairment (creatinine clearance less than 70 mL/min/1.73 m ²), one-half of the usual adult dose of TROKENDI XR 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 TROKENDI XR 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)] .

A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving 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 topiramate 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 TROKENDI XR ^®as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation of TROKENDI XR ^®, may be helpful.

Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss.

Topiramate 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 (7.2)] .

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.

The basis for approval of the extended-release formulation (TROKENDI XR ^®) included the studies described below using an immediate-release formulation and the demonstration of the pharmacokinetic equivalence of TROKENDI XR ^®to immediate-release topiramate through the analysis of concentrations and cumulative AUCs at multiple time points [see Clinical Pharmacology (12.6)].

The clinical studies described in the following sections were conducted using immediate-release topiramate.

Adults and Pediatric Patients 10 Years of Age and Older with Partial Onset or Primary Generalized Tonic-Clonic Seizures

The recommended dose for TROKENDI XR monotherapy in adults and in pediatric patients 10 years of age and older is 400 mg orally once daily. Titrate TROKENDI XR ^®according to the following schedule:

Alcohol use is contraindicated within 6 hours prior to and 6 hours after TROKENDI XR ^®administration [see Contraindications (4)and Warnings and Precautions (5.5)].

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 TROKENDI XR ^® [see Clinical Pharmacology (12.3)].

TROKENDI XR ^®is indicated for the preventive treatment of migraine in patients 12 years of age and older [see Clinical Studies (14.4)] .

Overdoses of topiramate have been reported. Signs and symptoms included convulsions, drowsiness, speech disturbance, blurred vision, diplopia, impaired mentation, lethargy, abnormal coordination, stupor, hypotension, abdominal pain, agitation, dizziness, and depression. The clinical consequences were not severe in most cases, but deaths have been reported after overdoses involving topiramate.

Topiramate overdose has resulted in severe metabolic acidosis [see Warnings and Precautions (5.4)] .

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

Similar signs, symptoms, and clinical consequences are expected to occur with overdosage of TROKENDI XR ^®. In the event of overdose, TROKENDI XR ^®should be discontinued and general supportive treatment given until clinical toxicity has been diminished or resolved. Hemodialysis is an effective means of removing topiramate from the body.

Topiramate, USP, is a sulfamate-substituted monosaccharide. TROKENDI XR ^®(topiramate) extended-release capsules are available as 25 mg, 50 mg, 100 mg, and 200 mg capsules for oral administration.

Topiramate is a white to off-white powder. Topiramate is freely soluble in polar organic solvents such as acetonitrile and acetone; and very slightly soluble to practically insoluble in non-polar organic solvents such as hexanes. Topiramate has the molecular formula C ₁₂H ₂₁NO ₈S and a molecular weight of 339.4. Topiramate is designated chemically as 2,3:4,5-Di- O-isopropylidene-β-D-fructopyranose sulfamate and has the following structural formula:

TROKENDI XR ^®(topiramate) is an extended-release capsule. TROKENDI XR ^®capsules contain the following inactive ingredients:

Sugar Spheres, NF

Hypromellose (Type 2910), USP

Mannitol, USP

Docusate Sodium, USP

Sodium Benzoate, NF

Ethylcellulose, NF

Oleic Acid, NF

Medium Chain Triglycerides, NF

Polyethylene Glycol, NF

Polyvinyl Alcohol, USP

Titanium Dioxide, USP

Talc, USP

Lecithin, NF

Xanthan Gum, NF

Glycerin, USP-NF

The capsule shells contain gelatin, USP; Titanium Dioxide, USP; and Colorants.

The colorants are:

FD&C Blue #1 (all strength capsules)

Yellow Iron Oxide, USP (25 mg and 50 mg capsules)

FD&C Red #3 (50 mg, 100 mg and 200 mg capsules)

FD&C Yellow #6 (50 mg, 100 mg and 200 mg capsules)

Riboflavin, USP (25 mg capsules)

All capsule shells are imprinted with black print that contains shellac, NF, and black iron oxide, NF.

A decrease in the exposure of pioglitazone and its active metabolites were noted with the concurrent use of pioglitazone and immediate-release topiramate in a clinical trial. The clinical relevance of these observations is unknown; however, when TROKENDI XR ^®is added to pioglitazone therapy or pioglitazone is added to TROKENDI XR ^®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)] .

TROKENDI XR ^®(topiramate) extended-release capsules are available in the following strengths and colors:

25 mg (light green opaque body/yellow opaque cap with black print "SPN" and "25"):

• bottles of 7 count (NDC-17772-101-70), 30 count (NDC-17772-101-30) and 100 count (NDC-17772-101-01)
• blister packages of 30-count (NDC-17772-101-15)

50 mg (light green opaque body/orange opaque cap with black print "SPN" and "50"):

• bottles of 7 count (NDC-17772-102-70), 30 count (NDC-17772-102-30) and 100 count (NDC-17772-102-01)
• blister packages of 30-count (NDC-17772-102-15)

100 mg (green opaque body/blue opaque cap with black print "SPN" and "100"):

• bottles of 7 count (NDC-17772-103-70), 30 count (NDC-17772-103-30) and 100 count (NDC-17772-103-01)
• blister packages of 30-count (NDC-17772-103-15)

200 mg (pink opaque body/blue opaque cap with black print "SPN" and "200"):

• bottles of 7 count (NDC-17772-104-70), 30 count (NDC-17772-104-30) and 100 count (NDC-17772-104-01)
• blister packages of 30-count (NDC-17772-104-15)

Some patients may experience a large increase in amitriptyline concentration in the presence of TROKENDI XR ^®and any adjustments in amitriptyline dose should be made according to the patients' clinical response and not on the basis of plasma levels [see Clinical Pharmacology (12.3)] .

Clinical studies of immediate-release topiramate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Dosage adjustment may be necessary for elderly with creatinine clearance less than 70 mL/min/1.73 m ². Estimate GFR should be measured prior to dosing [see Dosage and Administration (2.5)and Clinical Pharmacology (12.3)] .

Topiramate increases the risk of kidney stones. During adjunctive epilepsy trials, the risk for kidney stones in immediate-release 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. TROKENDI XR ^®would be expected to have the same effect as immediate-release topiramate on the formation of kidney stones. TROKENDI XR ^®is not approved for treatment of epilepsy in pediatric patients less than 6 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 TROKENDI XR ^®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 immediate-release 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.

TROKENDI XR can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in uterohave 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 risks of TROKENDI XR ^®when administering the drug in women of childbearing potential, particularly when TROKENDI XR ^®is considered for a condition not usually associated with permanent injury or death [see Use in Specific Populations (8.1)] . TROKENDI XR ^®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 informed of the potential hazard to a fetus [see Use in Specific Populations (8.1)] .

The possibility of decreased contraceptive efficacy and increased breakthrough bleeding may occur in patients taking contraceptive products with TROKENDI XR ^®. 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)] .

TROKENDI XR ^®is contraindicated in patients with recent alcohol use (i.e., within 6 hours prior to and 6 hours after TROKENDI XR ^®use) [see Warnings and Precautions (5.5)]

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

• Acute Myopia and Secondary Angle Closure Glaucoma [see Warnings and Precautions (5.1)]
• Visual Field Defects [see Warnings and Precautions 5.2]
• Oligohydrosis and Hyperthermia [see Warnings and Precautions (5.3) ]
• Metabolic Acidosis [see Warnings and Precautions (5.4)]
• Interaction With Alcohol [see Warnings and Precautions (5.5)]
• Suicidal Behavior and Ideation [see Warnings and Precautions (5.6)]
• Cognitive/Neuropsychiatric Adverse Reactions [see Warnings and Precautions (5.7)]
• Fetal Toxicity [see Warnings and Precautions (5.8)]
• Withdrawal of Antiepileptic Drugs [see Warnings and Precautions (5.9)]
• Decrease of Bone Mineral Density [see Warnings and Precautions (5.10)]
• Negative Effects on Growth (Height and Weight) [see Warnings and Precautions (5.11)]
• Serious Skin Reactions [see Warnings and Precautions (5.12)]
• Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid Use) [see Warnings and Precautions (5.13)]
• Kidney Stones [see Warnings and Precautions (5.14)]
• Hypothermia With Concomitant Valproic Acid Use [see Warnings and Precautions (5.15)]

The data described in the following sections were obtained using immediate-release topiramate tablets. TROKENDI XR ^®has not been studied in a randomized, placebo-controlled Phase III clinical study; however, it is expected that TROKENDI XR ^®would produce a similar adverse reaction profile as immediate-release topiramate.

• Contraceptives: Decreased contraceptive efficacy and increased breakthrough bleeding, especially at doses greater than 200 mg per day ( 7.5)
• Monitor lithium levels if lithium is used with high-dose TROKENDI XR ( 7.8)

Concomitant administration of topiramate with other CNS depressant drugs or alcohol 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, TROKENDI XR ^®should be used with extreme caution if used in combination with alcohol and other CNS depressants [see Contraindications (4)and Warnings and Precautions (5.7)].

The clearance of topiramate is reduced in patients with moderate (creatinine clearance 30 to 69 mL/min/1.73m ²) and severe (creatinine clearance less than 30 mL/min/1.73m ²) renal impairment. A dosage adjustment is recommended in patients with moderate or severe renal impairment [see Dosage and Administration (2.5)and Clinical Pharmacology (12.3)] .

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.

TROKENDI XR ^®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 carbonic anhydrase inhibition by TROKENDI XR. TROKENDI XR ^®-induced metabolic acidosis can occur at any time during treatment. Bicarbonate decrements are usually mild to 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 TROKENDI XR.

Metabolic acidosis was commonly observed in adult and pediatric patients treated with immediate-release 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 immediate-release 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 (5.10, 5.14)] . A one-year, active-controlled study of pediatric patients treated with immediate-release topiramate demonstrated that immediate-release 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 (5.10), 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 pediatrics. Reductions in length and weight were correlated to the degree of acidosis [see Use in Specific Populations (8.4)] . TROKENDI XR 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 (5.8)and Use in Specific Populations (8.1)] .

TROKENDI XR ^®is indicated for:

• Epilepsy: initial monotherapy for the treatment of partial-onset or primary generalized tonic-clonic seizures in patients 6 years of age and older ( 1.1); adjunctive therapy for the treatment of partial-onset, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome (LGS) in patients 6 years of age and older ( 1.2)
• Preventive treatment of migraine in patients 12 years of age and older ( 1.3)

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 (5.13, 5.15)and Clinical Pharmacology (12.3)] .

TROKENDI XR ^®is indicated as initial monotherapy for the treatment of partial-onset or primary generalized tonic-clonic seizures in patients 6 years of age and older [see Clinical Studies (14.2)] .

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.

Visual field defects (independent of elevated intraocular pressure) have been reported in clinical trials and in postmarketing experience in patients receiving topiramate. In clinical trials, most of these events were reversible after topiramate discontinuation. If visual problems occur at any time during treatment with TROKENDI XR, consideration should be given to discontinuing the drug.

TROKENDI XR ^®(topiramate) extended-release capsules should be stored in well closed containers at controlled room temperature [25°C (77°F); excursions 15°C-30°C (59°F-86°F)]. Protect from moisture and light.

• Acute myopia and secondary angle closure glaucoma: can lead to permanent visual loss; discontinue TROKENDI XR ^®as soon as possible ( 5.1)
• Visual field defects: consider discontinuation of TROKENDI XR ( 5.2)
• Oligohydrosis 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 TROKENDI XR ^®if clinically appropriate ( 5.4)
• Suicidal behavior and ideation: antiepileptic drugs increase the risk of suicidal behavior or ideation ( 5.6)
• Cognitive/neuropsychiatric adverse reactions: use caution when operating machinery including cars; depression and mood problems may occur ( 5.7)
• 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 ( 5.8)
• Withdrawal of AEDs: withdraw TROKENDI XR ^®gradually ( 5.9)
• Decrease in Bone Mineral Density: has been shown to decrease bone mineral density and bone mineral content in pediatric patients ( 5.10)
• Negative effects on growth (height and weight): may slow height increase and weight gain; carefully monitor children receiving prolonged therapy ( 5.11)
• Serious skin reactions: If SJS or TEN is suspected, discontinue TROKENDI XR ( 5.12)
• Hyperammonemia/encephalopathy: measure ammonia if encephalopathic symptoms occur ( 5.13)
• Kidney stones: avoid use with other carbonic anhydrase inhibitors, other drugs causing metabolic acidosis, or in patients on a ketogenic diet ( 5.14)
• Hypothermia has been reported with and without hyperammonemia during topiramate treatment with concomitant valproic acid use ( 5.15)

• TROKENDI XR ^®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)
• Swallow capsule whole and intact. Do not sprinkle on food, chew, or crush ( 2.7)

Serious skin reactions (Stevens-Johnson Syndrome [SJS] and Toxic Epidermal Necrolysis [TEN]) have been reported in patients receiving topiramate. TROKENDI XR 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.

TROKENDI XR ^®extended-release capsules are available in the following strengths and colors:

• 25 mg: Size 2 capsules, light green opaque body/yellow opaque cap (printed "SPN" on the cap, "25" on the body)
• 50 mg: Size 0 capsules, light green opaque body/orange opaque cap (printed "SPN" on the cap, "50" on the body)
• 100 mg: Size 00 capsules, green opaque body/blue opaque cap (printed "SPN" on the cap, "100" on the body)
• 200 mg: Size 00 capsules, pink opaque body/blue opaque cap (printed "SPN" on the cap, "200" on the body)

In vitrodata show that, in the presence of alcohol, the pattern of topiramate release from TROKENDI XR ^®capsules is significantly altered. As a result, plasma levels of topiramate with TROKENDI XR ^®may be markedly higher soon after dosing and subtherapeutic later in the day. Therefore, alcohol use should be completely avoided within 6 hours prior to and 6 hours after TROKENDI XR ^®administration .

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

Body as a Whole-General Disorders: oligohydrosis and hyperthermia [see Warnings and Precautions (5.3)] , hyperammonemia, hyperammonemic encephalopathy [see Warnings and Precautions (5.13)] , hypothermia with concomitant valproic acid [see Warnings and Precautions 5.15)] .

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

Skin and Appendage Disorders: bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis) [see Warnings and Precautions (5.12)] , pemphigus

Urinary System Disorders: kidney stones, nephrocalcinosis [see Warnings and Precautions (5.14)]

Vision disorders: acute myopia, secondary angle closure glaucoma [see Warnings and Precautions (5.1)], maculopathy

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

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

Topiramate C _maxand AUC increased when HCTZ was added to immediate-release topiramate. The clinical significance of this change is unknown. The addition of HCTZ to TROKENDI XR ^®may require a decrease in the TROKENDI XR ^®dose [see Clinical Pharmacology (12.3)] .

TROKENDI XR ^®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 6 years of age and older [see Clinical Studies (14.3)] .

Alcohol use should be completely avoided within 6 hours prior to and 6 hours after TROKENDI XR ^®administration [see Warnings and Precautions (5.5)] .

TROKENDI XR ^®can be taken without regard to meals.

Swallow capsule whole and intact. Do not sprinkle on food, chew, or crush.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Oligohydrosis (decreased sweating), resulting in hospitalization in some cases, has been reported in association with topiramate 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 TROKENDI XR ^®should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. Caution should be used when TROKENDI XR ^®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 .

Antiepileptic drugs (AEDs) increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED, including TROKENDI XR ^®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 2 shows absolute and relative risk by indication for all evaluated AEDs.

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 TROKENDI XR ^®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.

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)and Clinical Pharmacology (12.3)] .

Results of a one-year active-controlled study in pediatric patients (N=63) demonstrated negative effects of immediate-release 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 immediate-release 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 immediate-release 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.

In patients with or without a history of seizures or epilepsy, antiepileptic drugs, including TROKENDI XR ^®, should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency [see Clinical Studies (14)] . In situations where rapid withdrawal of TROKENDI XR ^®is medically required, appropriate monitoring is recommended.

Concomitant use of topiramate, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., zonisamide or acetazolamide) may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Patients should be monitored for the appearance or worsening of metabolic acidosis when TROKENDI XR ^®is given concomitantly with another carbonic anhydrase inhibitor [see Clinical Pharmacology (12.3)].

Immediate-release topiramate can cause, and therefore expected to be caused by TROKENDI XR ^®, 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.

The recommended total daily dose of TROKENDI XR ^®as treatment for the preventive treatment of migraine in patients 12 years of age and older is 100 mg once daily. Titrate TROKENDI XR ^®for the preventive treatment of migraine according to the following schedule:

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

Results of a one-year active-controlled study of pediatric patients (N=63) demonstrated negative effects of immediate-release 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 immediate-release 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 immediate-release topiramate group compared to the control group. Negative effects on weight and height were seen across all immediate-release topiramate age subgroups. Growth (height and weight) of children receiving prolonged TROKENDI XR ^®therapy should be carefully monitored.

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 (VPA) both in conjunction with 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 (7.2)] . Consideration should be given to stopping TROKENDI XR 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.

30 Capsules

NDC 17772-101-30

Trokendi XR _®

(topiramate) extended-release capsules

Once daily.

Swallow capsule

whole and intact.

Do not open, crush,

chew, or sprinkle

capsule contents on food.

25 mg

ATTENTION PHARMACIST: Dispense

the Accompanying Medication Guide

to Each Patient

Supernus ^®

Pharmaceuticals

Rx only

30 Capsules

NDC 17772-102-30

Trokendi XR _®

(topiramate) extended-release capsules

Once daily.

Swallow capsule

whole and intact.

Do not open, crush,

chew, or sprinkle

capsule contents on food.

50 mg

ATTENTION PHARMACIST: Dispense

the Accompanying Medication Guide

to Each Patient

Supernus ^®

Pharmaceuticals

Rx only

30 Capsules

NDC 17772-103-30

Trokendi XR _®

(topiramate) extended-release capsules

Once daily.

Swallow capsule

whole and intact.

Do not open, crush,

chew, or sprinkle

capsule contents on food.

100 mg

ATTENTION PHARMACIST: Dispense

the Accompanying Medication Guide

to Each Patient

Supernus ^®

Pharmaceuticals

Rx only

30 Capsules

NDC 17772-104-30

Trokendi XR _®

(topiramate) extended-release capsules

Once daily.

Swallow capsule

whole and intact.

Do not open, crush,

chew, or sprinkle

capsule contents on food.

200 mg

ATTENTION PHARMACIST: Dispense

the Accompanying Medication Guide

to Each Patient

Supernus ^®

Pharmaceuticals

Rx only

In patients with renal impairment (creatinine clearance less than 70 mL/min/1.73 m ²), one-half of the usual adult dose of TROKENDI XR 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 TROKENDI XR 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)] .

A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving 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 topiramate 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 TROKENDI XR ^®as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation of TROKENDI XR ^®, may be helpful.

Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss.

Topiramate 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 (7.2)] .

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.

The basis for approval of the extended-release formulation (TROKENDI XR ^®) included the studies described below using an immediate-release formulation and the demonstration of the pharmacokinetic equivalence of TROKENDI XR ^®to immediate-release topiramate through the analysis of concentrations and cumulative AUCs at multiple time points [see Clinical Pharmacology (12.6)].

The clinical studies described in the following sections were conducted using immediate-release topiramate.