Trokendi Xr

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 Monotherapy Epilepsy

  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)]

  .
  ); 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 Adjunctive Therapy Epilepsy

  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)]

  .
  )
  
• Preventive treatment of migraine in patients 12 years of age and older (
  
  
  1.3 Migraine

  TROKENDI XR^®is indicated for the preventive treatment of migraine in patients 12 years of age and older

  [see Clinical Studies (14.4)]

  .
  )
  

• 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 Dosing in Monotherapy Epilepsy

  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:

  	Week 1:	50 mg once daily
  	Week 2:	100 mg once daily
  	Week 3:	150 mg once daily
  	Week 4:	200 mg once daily
  	Week 5:	300 mg once daily
  	Week 6:	400 mg once daily

  Pediatric Patients Ages 6 to 9 Years of Age

  Dosing in patients 6 to 9 years of age is based on weight. During the titration period, the initial dose of TROKENDI XR^®is 25 mg/day nightly for the first week. Based upon tolerability, the dosage can be increased to 50 mg/day in the second week. Dosage can be increased by 25 mg to 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 mg to 50 mg/day weekly increments. The total daily dose should not exceed the maximum maintenance dose for each range of body weight (see Table 1).

  Table 1: Monotherapy Target Total Daily Maintenance Dosing for Patients 6 to 9 Years of Age

  Weight (kg)	Total Daily Dose (mg/day) Minimum Maintenance Dose	Total Daily Dose (mg/day) Maximum Maintenance Dose
  Up to 11	150	250
  12 - 22	200	300
  23 - 31	200	350
  32 - 38	250	350
  Greater than 38	250	400
  ,
  
  
  2.2 Dosing in Adjunctive Therapy Epilepsy

  Adults (17 Years of Age and Older)

  The recommended total daily dose of TROKENDI XR^®as adjunctive therapy in adults with partial-onset seizures or Lennox-Gastaut Syndrome is 200 mg to 400 mg orally once daily and with primary generalized tonic-clonic seizures is 400 mg orally once daily. Initiate therapy at 25 mg to 50 mg once daily followed by titration to an effective dose in increments of 25 mg to 50 mg 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 6 to 16 Years of Age

  The recommended total daily dose of TROKENDI XR^®as adjunctive therapy for patients 6 to 16 years of age with partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome is approximately 5 mg/kg to 9 mg/kg orally once daily. Begin titration at 25 mg once daily (or less, based on a range of 1 mg/kg/day to 3 mg/kg/day) given nightly for the first week. Subsequently, increase the dosage at 1- or 2-week intervals by increments of 1 mg/kg/day to 3 mg/kg/day to achieve optimal clinical response. Dose titration should be guided by clinical outcome. The total daily dose should not exceed 400 mg/day.
  ,
  
  
  2.3 Dosing for the Preventive Treatment of Migraine

  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:

  	Week 1:	25mg once daily
  	Week 2:	50mg once daily
  	Week 3:	75mg once daily
  	Week 4:	100mg once daily

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

  Alcohol use should be completely avoided within 6 hours prior to and 6 hours after TROKENDI XR^®administration

  [see Warnings and Precautions (5.5)]

  .
  ,
  
  
  2.5 Dose Modifications in Patients With Renal Impairment

  In patients with renal impairment (creatinine clearance less than 70 mL/min/1.73 m²), 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)]

  .
  ,
  
  
  2.6 Dosage Modifications in Patients Undergoing Hemodialysis

  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)]

  .
  )
  
• Swallow capsule whole and intact. Do not sprinkle on food, chew, or crush (
  
  
  2.7 Administration Instructions

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

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

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)

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as TROKENDI XR, 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/.

• Acute myopia and secondary angle closure glaucoma: can lead to permanent visual loss; discontinue TROKENDI XR
  
  ^®as soon as possible (
  
  
  5.1 Acute Myopia and Secondary Angle Closure Glaucoma Syndrome

  A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving topiramate. 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.
  )
  
• Visual field defects: consider discontinuation of TROKENDI XR (
  
  
  5.2 Visual Field Defects

  Visual field defects (independent of elevated intraocular pressure) have been reported in clinical trials and in postmarketing experience in patients receiving topiramate. In clinical trials, most of these events were reversible after topiramate discontinuation. If visual problems occur at any time during treatment with TROKENDI XR, consideration should be given to discontinuing the drug.
  )
  
• Oligohydrosis and hyperthermia: monitor decreased sweating and increased body temperature, especially in pediatric patients (
  
  
  5.3 Oligohydrosis and Hyperthermia

  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

  .
  )
  
• Metabolic acidosis: baseline and periodic measurement of serum bicarbonate is recommended; consider dose reduction or discontinuation of TROKENDI XR
  
  ^®if clinically appropriate (
  
  
  5.4 Metabolic Acidosis

  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)]

  .

  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 TROKENDI XR (using dose tapering). If the decision is made to continue patients on TROKENDI XR in the face of persistent acidosis, alkali treatment should be considered.
  )
  
• Suicidal behavior and ideation: antiepileptic drugs increase the risk of suicidal behavior or ideation (
  
  
  5.6 Suicidal Behavior and Ideation

  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.

  Table 2: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis

  Indication	Placebo Patients with Events per 1,000 Patients	Drug Patients with Events per 1,000 Patients	Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients	Risk Difference: Additional Drug Patients with Events per 1,000 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 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.
  )
  
• Cognitive/neuropsychiatric adverse reactions: use caution when operating machinery including cars; depression and mood problems may occur (
  
  
  5.7 Cognitive/Neuropsychiatric Adverse Reactions

  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.

  Adult Patients

  Cognitive-Related Dysfunction

  Rapid titration rate and higher initial dose were associated with higher incidences of cognitive-related dysfunction.

  In adult adjunctive epilepsy controlled trials, which used rapid titration (100-200 mg/day weekly increments), and target immediate-release topiramate 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 conducted with immediate-release topiramate, the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50 mg per day and 26% for 400 mg per day.

  In the 6-month controlled trials for the preventive treatment of migraine with immediate release topiramate using a slower titration regimen (25mg per day weekly increments), the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50 mg per day, 22% for 100 mg per day (the recommended dose), 28% for 200 mg per 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 treated with topiramate

  [see Warnings and Precautions (5.6)].

  Somnolence/Fatigue

  Somnolence and fatigue were the adverse reactions most frequently reported during clinical trials of topiramate for adjunctive epilepsy. For the adjunctive epilepsy population, the incidence of fatigue was dose-related. For the monotherapy epilepsy population, the incidence of somnolence was dose-related. For the migraine population, the incidences of both somnolence and fatigue were dose-related and more common in the titration phase.

  Pediatric Patients

  In pediatric epilepsy trials (adjunctive and monotherapy) conducted with topiramate, the incidence of cognitive/neuropsychiatric adverse reactions in pediatric patients 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 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 immediate-release 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 of age) to assess the effects of topiramate on cognitive function at baseline at the end of the Study 3

  [see Clinical Studies (14.4)].

  Mean change from baseline in certain CANTAB tests suggests that topiramate treatment may result in psychomotor slowing and decreased verbal fluency.
  )
  
• 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 Fetal Toxicity

  TROKENDI XR 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 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)]

  .
  )
  
• Withdrawal of AEDs: withdraw TROKENDI XR
  
  ^®gradually (
  
  
  5.9 Withdrawal of Antiepileptic Drugs

  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.
  )
  
• Decrease in Bone Mineral Density: has been shown to decrease bone mineral density and bone mineral content in pediatric patients (
  
  
  5.10 Decrease in Bone Mineral Density

  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.
  )
  
• Negative effects on growth (height and weight): may slow height increase and weight gain; carefully monitor children receiving prolonged therapy (
  
  
  5.11 Negative Effects on Growth (Height and Weight)

  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.
  )
  
• Serious skin reactions: If SJS or TEN is suspected, discontinue TROKENDI XR (
  
  
  5.12 Serious Skin Reactions

  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.
  )
  
• Hyperammonemia/encephalopathy: measure ammonia if encephalopathic symptoms occur (
  
  
  5.13 Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid Use)

  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.

  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 or TROKENDI XR^®treatment or an interaction of concomitant topiramate-based product 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.
  )
  
• Kidney stones: avoid use with other carbonic anhydrase inhibitors, other drugs causing metabolic acidosis, or in patients on a ketogenic diet (
  
  
  5.14 Kidney Stones

  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.
  )
  
• Hypothermia has been reported with and without hyperammonemia during topiramate treatment with concomitant valproic acid use (
  
  
  5.15 Hypothermia With Concomitant Valproic Acid Use

  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.
  )