Trokendi xr

Overdose

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

Topiramate overdose has resulted in severe metabolic acidosis.

A patient who ingested a dose between 96 g and 110 g of topiramate was admitted to hospital with 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™. Therefore, in acute Trokendi XR™ overdose, if the ingestion is recent, the stomach should be emptied immediately by lavage or by induction of emesis. Activated charcoal has been shown to adsorb topiramate in vitro. Treatment should be appropriately supportive. Hemodialysis is an effective means of removing topiramate from the body.

Contraindications

Trokendi XR™ is contraindicated in patients:

• With recent alcohol use (i.e., within 6 hours prior to and 6 hours after Trokendi XR™ use)
• With metabolic acidosis who are taking concomitant metformin

Trokendi XR price

Undesirable effects

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

• Acute Myopia and Secondary Angle Closure
• Oligohydrosis and Hyperthermia
• Metabolic Acidosis
• Suicidal Behavior and Ideation
• Cognitive/Neuropsychiatric Adverse Reactions
• Fetal Toxicity
• Withdrawal of Antiepileptic Drugs
• Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid Use
• Kidney Stones
• Hypothermia with Concomitant Valproic Acid Use
• Paresthesia

The data described in the following sections were obtained using immediate-release topiramate tablets in studies of patients with epilepsy. Trokendi XR™ has not been studied in a randomized, placebo-controlled Phase III clinical study in the epilepsy patient population. However, it is expected that Trokendi XR™ would produce a similar adverse reaction profile as immediate-release topiramate.

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 clinical practice.

The adverse reactions in the controlled trial (Study 1) that occurred most commonly in adults in the 400 mg per day group (incidence greater than or equal to 5%) and at a rate higher than the 50 mg per day group were paresthesia, weight decrease, somnolence, anorexia, dizziness, and difficulty with memory (see Table 2).

Approximately 21% of the 159 adult patients in the 400 mg per day group who received topiramate as monotherapy in Study 1 discontinued therapy due to adverse reactions. The most common (greater than or equal to 2% more frequent than low-dose 50 mg per day topiramate) adverse reactions causing discontinuation in this trial were difficulty with memory, fatigue, asthenia, insomnia, somnolence and paresthesia.

The adverse reactions in the controlled trial (Study 1) that occurred most commonly in children (10 years up to 16 years of age) in the 400 mg per day topiramate group (incidence greater than or equal to 5%) and at a rate higher than in the 50 mg per day group were weight decrease, upper respiratory tract infection, paresthesia, anorexia, diarrhea, and mood problems (see Table 3).

Approximately 12% of the 57 pediatric patients in the 400 mg per day group who received topiramate as monotherapy in the controlled clinical trial discontinued therapy due to adverse reactions. The most common (greater than 5%) adverse reactions resulting in discontinuation in this trial were difficulty with concentration/attention.

Table 2: Incidence of Treatment-Emergent Adverse Reaction in the Monotherapy Epilepsy Trial in Adultsa Where Incidence Was at Least 2% in the 400 mg/day Immediate-Release Topiramate Group and Greater Than the Rate in the 50 mg/day Immediate-Release Topiramate Group

Table 3: Incidence of Treatment-Emergent Adverse Reactions in the Monotherapy Epilepsy Trial in Pediatric Patients (Ages 10 up to 16 Years)a Where Incidence Was at Least 5% in the 400 mg/day Immediate-Release Topiramate Group and Greater than the Rate in the 50mg/day Immediate-Release Topiramate Group

The most commonly observed adverse reactions associated with the use of topiramate at dosages of 200 to 400 mg per day in controlled trials in adults with partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome that were seen at greater frequency in topiramate-treated patients and did not appear to be dose-related were: somnolence, ataxia, speech disorders and related speech problems, psychomotor slowing, abnormal vision, difficulty with memory, paresthesia and diplopia. The most common dose-related adverse reactions at dosages of 200 mg to 1,000 mg per day were: fatigue, nervousness, difficulty with concentration or attention, confusion, depression, anorexia, language problems, anxiety, mood problems, and weight decrease.

Adverse reactions associated with the use of topiramate at dosages of 5 mg/kg/day to 9 mg/kg/day in controlled trials in pediatric patients with partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome that were seen at greater frequency in topiramate-treated patients were: fatigue, somnolence, anorexia, nervousness, difficulty with concentration/attention, difficulty with memory, aggressive reaction, and weight decrease.

In controlled clinical trials in adults, 11% of patients receiving topiramate 200 to 400mg per day as adjunctive therapy discontinued due to adverse reactions. This rate appeared to increase at dosages above 400mg per day. Adverse events associated with discontinuing therapy included somnolence, dizziness, anxiety, difficulty with concentration or attention, fatigue, and paresthesia and increased at dosages above 400 mg per day. None of the pediatric patients who received topiramate adjunctive therapy at 5 mg/kg/day to 9 mg/kg/day in controlled clinical trials discontinued due to adverse reactions.

Approximately 28% of the 1757 adults with epilepsy who received topiramate at dosages of 200 mg to 1,600 mg per day in clinical studies discontinued treatment because of adverse reactions; an individual patient could have reported more than one adverse reaction. These adverse reactions were: psychomotor slowing (4.0%), difficulty with memory (3.2%), fatigue (3.2%), confusion (3.1%), somnolence (3.2%), difficulty with concentration/attention (2.9%), anorexia (2.7%), depression (2.6%), dizziness (2.5%), weight decrease (2.5%), nervousness (2.3%), ataxia (2.1%), and paresthesia (2.0%). Approximately 11% of the 310 pediatric patients who received topiramate at dosages up to 30 mg/kg/day discontinued due to adverse reactions. Adverse reactions associated with discontinuing therapy included aggravated convulsions (2.3%), difficulty with concentration/attention (1.6%), language problems (1.3%), personality disorder (1.3%), and somnolence (1.3%).

Table 4 lists adverse reactions that occurred in at least 1% of adults treated with 200 to 400 mg per day topiramate in controlled trials that were numerically more common at this dose than in the patients treated with placebo. In general, most patients who experienced adverse reactions during the first eight weeks of these trials no longer experienced them by their last visit. Table 7 lists adverse reactions that occurred in at least 1% of pediatric patients treated with 5 mg/kg to 9 mg/kg topiramate in controlled trials that were numerically more common than in patients treated with placebo.

Other adverse reactions that occurred in more than 1% of adults treated with 200 mg to 400 mg of topiramate in placebo-controlled epilepsy trials but with equal or greater frequency in the placebo group were headache, injury, anxiety, rash, pain, convulsions aggravated, coughing, fever, diarrhea, vomiting, muscle weakness, insomnia, personality disorder, dysmenorrhea, upper respiratory tract infection, and eye pain.

Table 4: Incidence of Adverse Reactions in Placebo-Controlled, Adjunctive Epilepsy Trials in Adultsa,b,c

Study 7 was a randomized, double-blind, adjunctive, placebo-controlled, parallel group study with 3 treatment arms: 1) placebo; 2) topiramate 200 mg per day with a 25 mg per day starting dose, increased by 25 mg per day each week for 8 weeks until the 200 mg per day maintenance dose was reached; and 3) topiramate 200 mg per day with a 50 mg per day starting dose, increased by 50 mg per day each week for 4 weeks until the 200 mg per day maintenance dose was reached. All patients were maintained on concomitant carbamazepine with or without another concomitant antiepileptic drug.

The incidence of adverse reactions (Table 5) did not differ significantly between the 2 topiramate regimens. Because the frequencies of adverse reactions reported in this study were markedly lower than those reported in the previous epilepsy studies, they cannot be directly compared with data obtained in other studies.

Table 5: Incidence of Adverse Reactions in Study 7a,b,c

Table 6: Incidence (%) of Dose-Related Adverse Reactions From Placebo-Controlled, Adjunctive Trials in Adults With Partial Onset Seizures (Studies 2 through 7)a

Table 7: Incidence (%) of Adverse Reaction in Placebo-Controlled, Adjunctive Epilepsy Trial in Pediatric Patients (Ages 2 Years to 16 Years)a,b,c (Study 8)

Therapeutic indications

Trokendi XR™ (topiramate) extended-release capsules are indicated as initial monotherapy in patients 10 years of age and older with partial onset or primary generalized tonic-clonic seizures and adjunctive therapy in patients 6 years of age and older with partial onset or primary generalized tonic-clonic seizures. Safety and effectiveness in patients who were converted to monotherapy from a previous regimen of other anticonvulsant drugs have not been established in controlled trials.

Trokendi XR™ (topiramate) extended-release capsules are indicated as adjunctive therapy in patients 6 years of age and older with seizures associated with Lennox-Gastaut syndrome.

Pharmacodynamic properties

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 GABAA 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.

Pharmacokinetic properties

Linear pharmacokinetics of topiramate from Trokendi XR™ were observed following a single oral dose over the range of 50 mg to 200 mg. At 25 mg, the pharmacokinetics of Trokendi XR™ is nonlinear possibly due to the binding of topiramate to carbonic anhydrase in red blood cells.

The peak plasma concentrations (Cmax) of topiramate occurred at approximately 24 hours following a single 200 mg oral dose of Trokendi XR™. At steady-state, the (AUC0-24hr, Cmax, and Cmin) of topiramate from Trokendi XR™ administered once-daily and the immediate-release tablet administered twice-daily were shown to be bioequivalent. Fluctuation of topiramate plasma concentrations at steady-state for Trokendi XR™ administered once-daily was approximately 26% and 42% in healthy subjects and in epileptic patients, respectively, compared to approximately 40% and 51%, respectively, for immediate-release topiramate.

Compared to the fasted state, high-fat meal increased the Cmax of topiramate by 37% and shortened the Tmax to approximately 8 hour following a single dose of Trokendi XR™, while having no effect on the AUC. Modeling of the observed single dose fed data with simulation to steady state showed that the effect on Cmax is significantly reduced following repeat administrations. Trokendi XR™ can be taken without regard to meals.

Topiramate is 15% to 41% bound to human plasma proteins over the blood concentration range of 0.5 mcg/mL to 250 mcg/mL. The fraction bound decreased as blood concentration increased.

Carbamazepine and phenytoin do not alter the binding of immediate-release topiramate. Sodium valproate, at 500 mcg/mL (a concentration 5 to 10 times higher than considered therapeutic for valproate) decreased the protein binding of immediate-release topiramate from 23% to 13%. Immediate-release topiramate does not influence the binding of sodium valproate.

Topiramate is not extensively metabolized and is primarily eliminated unchanged in the urine (approximately 70% of an administered dose). Six metabolites have been identified in humans, none of which constitutes more than 5% of an administered dose. The metabolites are formed via hydroxylation, hydrolysis, and glucuronidation. There is evidence of renal tubular reabsorption of topiramate. In rats, given probenecid to inhibit tubular reabsorption, along with topiramate, a significant increase in renal clearance of topiramate was observed. This interaction has not been evaluated in humans. Overall, oral plasma clearance (CL/F) is approximately 20 mL/min to 30 mL/min in adults following oral administration. The mean elimination half-life of topiramate was approximately 31 hours following repeat administration of Trokendi XR™.

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Fertility, pregnancy and lactation

Pregnancy Category D

Topiramate can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have increased risk for cleft lip and/or cleft palate (oral clefts). When multiple species of pregnant animals received topiramate at clinically relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring. Topiramate 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 the fetus.

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.massgeneral.org/aed/.

Data from the NAAED Pregnancy Registry indicate an increased risk of oral clefts in infants exposed to topiramate monotherapy during the first trimester of pregnancy. The prevalence of oral clefts was 1.2% compared to a prevalence of 0.39% -0.46% in infants exposed to other AEDs, and a prevalence of 0.12% in infants of mothers without epilepsy or treatment with other AEDs. For comparison, the Centers for Disease Control and Prevention (CDC) reviewed available data on oral clefts in the United States and found a similar background rate of 0.17%. The relative risk of oral clefts in topiramate-exposed pregnancies in the NAAED Pregnancy Registry was 9.6 (95% Confidence Interval=CI 3.6-25.7) as compared to the risk in a background population of untreated women. The UK Epilepsy and Pregnancy Register reported a similarly increased prevalence of oral clefts of 3.2% among infants exposed to topiramate monotherapy. The observed rate of oral clefts was 16 times higher than the background rate in the UK, which is approximately 0.2%.

Topiramate treatment can cause metabolic acidosis (see WARNINGS AND PRECAUTIONS]. The effect of topiramate-induced metabolic acidosis has not been studied in pregnancy; however, metabolic acidosis in pregnancy (due to other causes) can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the fetus' ability to tolerate labor. Pregnant patients should be monitored for metabolic acidosis and treated as in the nonpregnant state. Newborns of mothers treated with topiramate should be monitored for metabolic acidosis because of transfer of topiramate to the fetus and possible occurrence of transient metabolic acidosis following birth.

Topiramate has demonstrated selective developmental toxicity, including teratogenicity, in multiple animal species at clinically relevant doses. When oral doses of 20 mg/kg, 100 mg/kg, or 500 mg/kg were administered to pregnant mice during the period of organogenesis, the incidence of fetal malformations (primarily craniofacial defects) was increased at all doses. The low dose is approximately 0.2 times the recommended human dose (RHD) 400mg per day on a mg/m² basis. Fetal body weights and skeletal ossification were reduced at 500 mg/kg in conjunction with decreased maternal body weight gain.

In rat studies (oral doses of 20 mg/kg, 100 mg/kg, and 500 mg/kg or 0.2 mg/kg, 2.5 mg/kg, 30 mg/kg, and 400 mg/kg), the frequency of limb malformations (ectrodactyly, micromelia, and amelia) was increased among the offspring of dams treated with 400 mg/kg (10 times the RHD on a mg/m² basis) or greater during the organogenesis period of pregnancy. Embryotoxicity (reduced fetal body weights, increased incidence of structural variations) was observed at doses as low as 20 mg/kg (0.5 times the RHD on a mg/m² basis). Clinical signs of maternal toxicity were seen at 400 mg/kg and above, and maternal body weight gain was reduced during treatment with 100 mg/kg or greater.

In rabbit studies (20 mg/kg, 60 mg/kg, and 180 mg/kg or 10 mg/kg, 35 mg/kg, and 120 mg/kg orally during organogenesis), embryo/fetal mortality was increased at 35 mg/kg (2 times the RHD on a mg/m² basis) or greater, and teratogenic effects (primarily rib and vertebral malformations) were observed at 120 mg/kg (6 times the RHD on a mg/m² basis). Evidence of maternal toxicity (decreased body weight gain, clinical signs, and/or mortality) was seen at 35 mg/kg and above.

When female rats were treated during the latter part of gestation and throughout lactation (0.2 mg/kg, 4 mg/kg, 20 mg/kg, and 100 mg/kg or 2, 20, and 200 mg/kg), offspring exhibited decreased viability and delayed physical development at 200 mg/kg (5 times the RHD on a mg/m² basis) and reductions in pre-and/or postweaning body weight gain at 2mg/kg (0.05 times the RHD on a mg/m² basis) and above. Maternal toxicity (decreased body weight gain, clinical signs) was evident at 100 mg/kg or greater.

In a rat embryo/fetal development study with a postnatal component (0.2 mg/kg, 2.5 mg/kg, 30 mg/kg, or 400mg/kg during organogenesis; noted above), pups exhibited delayed physical development at 400 mg/kg (10 times the RHD on a mg/m² basis) and persistent reductions in body weight gain at 30 mg/kg (1 times the RHD on a mg/m² basis) and higher.

Although the effect of topiramate on labor and delivery in humans has not been established, the development of topiramate-induced metabolic acidosis in the mother and/or in the fetus might affect the fetus' ability to tolerate labor.

Qualitative and quantitative composition

Trokendi XR™ (topiramate) 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)

Trokendi XR™ (topiramate) extended-release capsules are available as extended-release capsules in the following strengths and colors:

25 mg (light green opaque body/yellow opaque cap) topiramate extended-release capsules (black print “SPN” and “25”) -bottles of 100 count (NDC-17772-101-01)

50 mg (light green opaque body/orange opaque cap) topiramate extended-release capsules (black print “SPN” and “50”) -bottles of 100 count (NDC-17772-102-01)

100 mg (green opaque body/blue opaque cap) topiramate extended-release capsules (black print “SPN” and “100”) -bottles of 100 count (NDC-17772-103-01)

200 mg (pink opaque body/blue opaque cap) topiramate extended-release capsules (black print “SPN” and “200”) -bottles of 100 count (NDC-17772-104-01)

25 mg (light green opaque body/yellow opaque cap) topiramate extended-release capsules (black print “SPN” and “25”) – blister packages of 30-count (NDC-17772-101-15)

50 mg (light green opaque body/orange opaque cap) topiramate extended-release capsules (black print “SPN” and “50”) – blister packages of 30-count (NDC-17772-102-15)

100 mg (green opaque body/blue opaque cap) topiramate extended-release capsules (black print “SPN” and “100”) – blister packages of 30-count (NDC-17772-103-15)

200 mg (pink opaque body/blue opaque cap) topiramate extended-release capsules (black print “SPN” and “200”) – blister packages of 30-count (NDC-17772-104-15)

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.

Manufactured by: Catalent Pharma Solutions, Winchester, Kentucky 40391. Manufactured for: Supernus Pharmaceuticals, Inc., Rockville, Maryland 20850. Revised: Aug 2013

Special warnings and precautions for use

Included as part of the PRECAUTIONS section.

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 myopia, anterior chamber shallowing, ocular hyperemia (redness) and increased intraocular pressure. Mydriasis may or may not be present. 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.

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 prescribed 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.

Hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis) is associated with topiramate, and can be expected with treatment with Trokendi XR™. This metabolic acidosis is caused by renal bicarbonate loss due to the inhibitory effect of topiramate on carbonic anhydrase. Such electrolyte imbalance has been observed with the use of topiramate in placebo-controlled clinical trials and in the post-marketing period. Generally, topiramate-induced metabolic acidosis occurs early in treatment although cases can occur at any time during treatment. Bicarbonate decrements are usually mild-moderate (average decrease of 4 mEq/L at daily doses of 400 mg in adults and at approximately 6 mg/kg/day in pediatric patients); rarely, patients can experience severe decrements to values below 10 mEq/L. Conditions or therapies that predispose patients to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, ketogenic diet or specific drugs) may be additive to the bicarbonate lowering effects of topiramate.

In adults, the incidence of persistent treatment-emergent decreases in serum bicarbonate (levels of less than 20 mEq/L at two consecutive visits or at the final visit) in controlled clinical trials for adjunctive treatment of epilepsy was 32% for 400 mg per day, and 1% for placebo. Metabolic acidosis has been observed at doses as low as 50 mg per day. The incidence of persistent treatment-emergent decreases in serum bicarbonate in adults in the epilepsy controlled clinical trial for monotherapy was 15% for 50 mg per day and 25% for 400 mg per day. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value less than 17 mEq/L and greater than 5 mEq/L decrease from pretreatment) in the adjunctive therapy trials was 3% for 400 mg per day, and 0% for placebo and in the monotherapy trial was 1% for 50 mg per day and 7% for 400 mg per day. Serum bicarbonate levels have not been systematically evaluated at daily doses greater than 400 mg per day.

Although Trokendi XR™ is not approved for use in patients below the age of 6, the incidence of persistent treatment-emergent decreases in serum bicarbonate in placebo-controlled trials for adjunctive treatment of Lennox-Gastaut syndrome or refractory partial onset seizures in patients age 2 years to 16 years was 67% for topiramate (at approximately 6 mg/kg/day), and 10% for placebo. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value less than17 mEq/L and greater than 5 mEq/L decrease from pretreatment) in these trials was 11% for topiramate and 0% for placebo. Cases of moderately severe metabolic acidosis have been reported in patients as young as 5 months old, especially at daily doses above 5 mg/kg/day.

In pediatric patients (6 years to 15 years of age), the incidence of persistent treatment-emergent decreases in serum bicarbonate in the epilepsy controlled clinical trial for monotherapy performed with topiramate was 9% for 50 mg per day and 25% for 400 mg per day. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value less than 17 mEq/L and greater than 5 mEq/L decrease from pretreatment) in this trial was 1% for 50 mg per day and 6% for 400 mg per day.

Although Trokendi XR™ is not approved for use in patients less than 6 years of age with partial onset seizures, a study of topiramate as adjunctive use in patients under 2 years of age revealed that topiramate produced a metabolic acidosis that is notably greater in magnitude than that observed in controlled trials in older children and adults. The mean treatment difference (25 mg/kg/day topiramate-placebo) was -5.9 mEq/L for bicarbonate. The incidence of metabolic acidosis (defined by a serum bicarbonate less than 20 mEq/L) was 0% for placebo, 30% for 5 mg/kg/day, 50% for 15 mg/kg/day, and 45% for 25 mg/kg/day.

Some 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. Chronic metabolic acidosis in pediatric patients may also reduce growth rates. A reduction in growth rate may eventually decrease the maximal height achieved. The effect of topiramate on growth and bone-related sequelae has not been systematically investigated in long-term, placebo-controlled trials. Long-term, open-label treatment of infants/toddlers, with intractable partial epilepsy, for up to 1 year, showed reductions from baseline in Z SCORES for 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 infants. Reductions in Z SCORES for length and weight were correlated to the degree of acidosis. Topiramate treatment that causes metabolic acidosis during pregnancy can possibly produce adverse effects on the fetus and might also cause metabolic acidosis in the neonate from possible transfer of topiramate to the fetus.

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 topiramate (using dose tapering). If the decision is made to continue patients on topiramate in the face of persistent acidosis, alkali treatment should be considered.

In vitro data 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.

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 1 shows absolute and relative risk by indication for all evaluated AEDs.

Table 1: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis

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.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior or the emergence of suicidal thoughts, behavior or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

Adverse reactions most often associated with the use of topiramate, and therefore expected to be associated with the use of Trokendi XR™ were related to the central nervous system and were observed in the epilepsy population. In adults, 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.

Cognitive Related Dysfunction

The majority of cognitive-related adverse reactions were mild to moderate in severity, and they frequently occurred in isolation. Rapid titration rate and higher initial dose were associated with higher incidences of these reactions. Many of these reactions contributed to withdrawal from treatment.

In the adjunctive epilepsy controlled trials conducted with topiramate (using rapid titration such as 100 mg per day to 200mg per day weekly increments), the proportion of patients who experienced one or more cognitive-related adverse reactions was 42% for 200mg per day, 41% for 400mg per day, 52% for 600mg per day, 56% for 800 and 1,000 mg per day, and 14% for placebo. These dose-related adverse reactions began with a similar frequency in the titration or in the maintenance phase, although in some patients the events began during titration and persisted into the maintenance phase. Some patients who experienced one or more cognitive-related adverse reactions in the titration phase had a dose-related recurrence of these reactions in the maintenance phase.

In the monotherapy epilepsy controlled trial conducted with topiramate, the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50mg per day and 26% for 400mg per day.

Psychiatric/Behavioral Disturbances

Psychiatric/behavioral disturbances (depression or mood) were dose-related for the epilepsy population treated with topiramate.

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 somnolence did not differ substantially between 200 mg per day and 1,000 mg per day, but the incidence of fatigue was dose-related and increased at dosages above 400 mg per day. For the monotherapy epilepsy population in the 50 mg per day and 400 mg per day groups, the incidence of somnolence was dose-related (9% for the 50 mg per day group and 15% for the 400 mg per day group) and the incidence of fatigue was comparable in both treatment groups (14% each). For other uses not approved for Trokendi XR™, somnolence and fatigue were more common in the titration phase.

Additional nonspecific CNS events commonly observed with topiramate in the adjunctive epilepsy population include dizziness or ataxia.

In double-blind adjunctive therapy and monotherapy epilepsy clinical studies conducted with topiramate, the incidences of cognitive/neuropsychiatric adverse reactions in pediatric patients were generally lower than 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 patients during adjunctive therapy double-blind studies were somnolence and fatigue. The most frequently reported neuropsychiatric reactions in pediatric patients in the 50 mg per day and 400 mg per day groups during the monotherapy double-blind study were headache, dizziness, anorexia, and somnolence.

No patients discontinued treatment due to any adverse events in the adjunctive epilepsy double-blind trials. In the monotherapy epilepsy double-blind trial conducted with immediate-release topiramate product, 1 pediatric patient (2%) in the 50 mg per day group and 7 pediatric patients (12%) in the 400 mg per day group discontinued treatment due to any adverse events. The most common adverse reaction associated with discontinuation of therapy was difficulty with concentration/attention; all occurred in the 400 mg per day group.

Topiramate can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk for cleft lip and/or cleft palate (oral clefts). When multiple species of pregnant animals received topiramate at clinically relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring.

Consider the benefits and risks of topiramate when administering the drug in women of childbearing potential, particularly when topiramate is considered for a condition not usually associated with permanent injury or death. Topiramate 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.

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 . In situations where rapid withdrawal of Trokendi XR™ is medically required, appropriate monitoring is recommended.

Topiramate treatment has produced hyperammonemia (in some instances dose-related) in clinical investigational programs in very young pediatric patients (1 month to 24 months) who were treated with adjunctive topiramate for partial onset epilepsy (8% for placebo, 10% for 5 mg/kg/day, 0% for 15 mg/kg/day, 9 % for 25 mg/kg/day). Trokendi XR™ is not approved as adjunctive treatment of partial onset seizures in pediatric patients less than 6 years old. In some patients, ammonia was markedly increased (greater than 50 % above upper limit of normal). The hyperammonemia associated with topiramate treatment occurred with and without encephalopathy in placebo-controlled trials, and in an open-label, extension trial. Dose-related hyperammonemia was also observed in the extension trial in pediatric patients up to 2 years old. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting.

Hyperammonemia with and without encephalopathy has also been observed in post-marketing reports in patients who were taking topiramate without concomitant valproic acid (VPA).

Concomitant administration of topiramate and valproic acid (VPA) has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone based upon post-marketing reports. Although hyperammonemia may be asymptomatic, clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. In most cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is not due to a pharmacokinetic interaction.

Although Trokendi XR™ is not indicated for use in infants/toddlers (1month to 24 months), topiramate with concomitant VPA clearly produced a dose-related increase in the incidence of treatment-emergent hyperammonemia (above the upper limit of normal, 0% for placebo, 12% for 5 mg/kg/day, 7% for 15 mg/kg/day, 17% for 25 mg/kg/day) in an investigational program using topiramate. Markedly increased, dose-related hyperammonemia (0% for placebo and 5 mg/kg/day, 7% for 15 mg/kg/day, and 8% for 25 mg/kg/day) also occurred in these infants/toddlers. Dose-related hyperammonemia was similarly observed in a long-term, extension trial utilizing topiramate in these very young, pediatric patients.

Hyperammonemia with and without encephalopathy has also been observed in post-marketing reports in patients taking topiramate with valproic acid (VPA).

The hyperammonemia associated with topiramate treatment appears to be more common when used concomitantly with VPA.

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.

A total of 32/2086 (1.5%) of adults exposed to topiramate during its adjunctive epilepsy therapy development reported the occurrence of kidney stones, an incidence about 2 to 4 times greater than expected in a similar, untreated population. In the double-blind monotherapy epilepsy study, a total of 4/319 (1.3%) of adults exposed to topiramate reported the occurrence of kidney stones. 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. During long-term (up to 1 year) topiramate treatment in an open-label extension study of 284 pediatric patients 1 month to 24 months old with epilepsy, 7% developed kidney or bladder stones that were diagnosed clinically or by sonogram. Trokendi XR™ is not approved for pediatric patients less than 6 years old.

Trokendi XR™ would be expected to have the same effect as topiramate on the formation of kidney stones. An explanation for the association of topiramate and kidney stones may lay in the fact that topiramate is a carbonic anhydrase inhibitor. Carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) can promote stone formation by reducing urinary citrate excretion and by increasing urinary pH. 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.

Hypothermia, defined as an unintentional drop in body core temperature to less than 35°C (95°F) has been reported in association with topiramate use with concomitant valproic acid (VPA) both in the presence 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. Consideration should be given to stopping topiramate or valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels.

Paresthesia (usually tingling of the extremities), an effect associated with the use of other carbonic anhydrase inhibitors, appears to be a common effect of topiramate. Paresthesia was more frequently reported in the monotherapy epilepsy trials conducted with topiramate than in the adjunctive therapy epilepsy trials conducted with the same product. In the majority of instances, paresthesia did not lead to treatment discontinuation.

Topiramate is a CNS depressant. Concomitant administration of topiramate with other CNS depressant drugs can result in significant CNS depression. Patients should be watched carefully when Trokendi XR™ is coadministered with other CNS depressant drugs.

See FDA-approved patient labeling (Medication Guide)

Counsel patients to swallow Trokendi XR™ capsules whole and intact. Trokendi XR™ should not be sprinkled on food, chewed or crushed..

Advise patients to completely avoid consumption of alcohol at least 6 hours prior to and 6 hours after taking Trokendi XR™.

Advise patients taking Trokendi XR™ to seek immediate medical attention if they experience blurred vision, visual disturbances or periorbital pain.

Counsel patients that Trokendi XR™, especially pediatric patients, can cause decreased sweating and increased body temperature, especially in hot weather, and they should seek medical attention if this is noticed.

Inform patients about the potentially significant risk for metabolic acidosis that may be asymptomatic and may be associated with adverse effects on kidneys (e.g., kidney stones, nephrocalcinosis), bones (e.g., osteoporosis, osteomalacia, and/or rickets in children), and growth (e.g., growth delay/retardation) in pediatric patients, and on the fetus

Counsel patients, their caregivers, and families that AEDs, including Trokendi XR™, may increase the risk of suicidal thoughts and behavior and they should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior or the emergence of suicidal thoughts, behavior or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers..

Warn patients about the potential for somnolence, dizziness, confusion, difficulty concentrating, visual effects and advise them not to drive or operate machinery until they have gained sufficient experience on Trokendi XR™ to gauge whether it adversely affects their mental performance, motor performance, and/or vision..

Advise patients that even when taking Trokendi XR™ or other anticonvulsants, some patients with epilepsy will continue to have unpredictable seizures. Therefore, counsel all patients taking Trokendi XR™ for epilepsy to exercise appropriate caution when engaging in any activities where loss of consciousness could result in serious danger to themselves or those around them (including swimming, driving a car, climbing in high places, etc.). Some patients with refractory epilepsy will need to avoid such activities altogether. Physicians should discuss the appropriate level of caution with their patients, before patients with epilepsy engage in such activities.

Counsel pregnant women and women of childbearing potential that use of topiramate during pregnancy can cause fetal harm, including an increased risk for cleft lip and/or cleft palate (oral clefts), which occur early in pregnancy before many women know they are pregnant. When appropriate, prescribers should counsel pregnant women and women of childbearing potential about alternative therapeutic options.

Advise women of childbearing potential who are not planning a pregnancy to use effective contraception while using topiramate, keeping in mind that there is a potential for decreased contraceptive efficacy when using estrogen-containing birth control with topiramate.

Encourage pregnant women using topiramate to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The 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.massgeneral.org/aed/.

Warn patients about the possible development of hyperammonemia with or without encephalopathy. Although hyperammonemia may be asymptomatic, clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. This hyperammonemia and encephalopathy can develop with topiramate treatment alone or with topiramate treatment with concomitant valproic acid (VPA). Patients should be instructed to contact their physician if they develop unexplained lethargy, vomiting, or changes in mental status.

Instruct patients, particularly those with predisposing factors, to maintain an adequate fluid intake in order to minimize the risk of kidney stone formation.

Counsel patients that Trokendi XR™ can cause a reduction in body temperature, which can lead to alterations in mental status. If they note such changes, they should call their health care professional and measure their body temperature. Patients taking concomitant valproic acid should be specifically counseled on this potential adverse reaction.

Counsel patients that they may experience tingling in the arms and legs. If this symptom occurs, they should consult with their physician .

An increase in urinary bladder tumors was observed in mice given topiramate (20 mg/kg, 75 mg/kg, and 300 mg/kg) in the diet for 21 months. The elevated bladder tumor incidence, which was statistically significant in males and females receiving 300 mg/kg, was primarily due to the increased occurrence of a smooth muscle tumor considered histomorphologically unique to mice. Plasma exposures in mice receiving 300 mg/kg were approximately 0.5 to 1 times steady-state exposures measured in patients receiving topiramate monotherapy at the recommended human dose (RHD) of 400 mg, and 1.5 to 2 times steady-state topiramate exposures in patients receiving 400 mg of topiramate plus phenytoin. The relevance of this finding to human carcinogenic risk

Dosage (Posology) and method of administration

The recommended dose for topiramate monotherapy in adults and 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

The recommended total daily dose of Trokendi XR™ as adjunctive therapy in adults with partial onset seizures or Lennox-Gaustaut Syndrome is 200 mg to 400 mg orally once daily 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 50mg every week. Daily topiramate doses above 1,600 mg have not been studied.

In the study of primary generalized tonic-clonic seizures using topiramate, the assigned dose was reached at the end of 8 weeks.

The recommended total daily dose of Trokendi XR™ as adjunctive therapy for pediatric patients with partial onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome is approximately 5 mg/kg to 9 mg/kg orally once daily. Begin titration at 25 mg once daily (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 2week intervals by increments of 1 mg/kg to 3 mg/kg to achieve optimal clinical response. Dose titration should be guided by clinical outcome. If required, longer intervals between dose adjustments can be used.

In the study of primary generalized tonic-clonic seizures, the assigned dose of 6 mg/kg once daily was reached at the end of 8 weeks.

Alcohol use should be completely avoided within 6 hours prior to and 6 hours after Trokendi XR™ administration.

In patients with renal impairment (creatinine clearance less than 70 mL/min/1.73 m²), one-half of the usual adult dose is recommended. Such patients will require a longer time to reach steady-state at each dose.

Prior to dosing, obtain an estimated GFR measurement in patients at high risk for renal insufficiency (e.g., older patients, or those with diabetes mellitus, hypertension, or autoimmune disease).

Topiramate is cleared by hemodialysis at a rate that is 4 to 6 times greater than in patients with normal renal function. Accordingly, a prolonged period of dialysis may cause topiramate concentration to fall below that required to maintain an anti-seizure effect. To avoid rapid drops in topiramate plasma concentration during hemodialysis, a supplemental dose of topiramate may be required. The actual adjustment should take into account the:

• duration of dialysis period
• clearance rate of the dialysis system being used
• effective renal clearance of topiramate in the patient being dialyzed.

Measurement of baseline and periodic serum bicarbonate during Trokendi XR™ treatment is recommended.

The co-administration of Trokendi XR™ with phenytoin may require an adjustment of the dose of phenytoin to achieve optimal clinical outcome. Addition or withdrawal of phenytoin and/or carbamazepine during adjunctive therapy with Trokendi XR™ may require adjustment of the dose of Trokendi XR™.

It is not necessary to monitor topiramate plasma concentrations to optimize Trokendi XR™ therapy.

Trokendi XR™ can be taken without regard to meals.

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

Interaction with other medicinal products and other forms of interaction

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

• Acute Myopia and Secondary Angle Closure
• Oligohydrosis and Hyperthermia
• Metabolic Acidosis
• Suicidal Behavior and Ideation
• Cognitive/Neuropsychiatric Adverse Reactions
• Fetal Toxicity
• Withdrawal of Antiepileptic Drugs
• Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid Use
• Kidney Stones
• Hypothermia with Concomitant Valproic Acid Use
• Paresthesia

The data described in the following sections were obtained using immediate-release topiramate tablets in studies of patients with epilepsy. Trokendi XR™ has not been studied in a randomized, placebo-controlled Phase III clinical study in the epilepsy patient population. However, it is expected that Trokendi XR™ would produce a similar adverse reaction profile as immediate-release topiramate.

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 clinical practice.

The adverse reactions in the controlled trial (Study 1) that occurred most commonly in adults in the 400 mg per day group (incidence greater than or equal to 5%) and at a rate higher than the 50 mg per day group were paresthesia, weight decrease, somnolence, anorexia, dizziness, and difficulty with memory (see Table 2).

Approximately 21% of the 159 adult patients in the 400 mg per day group who received topiramate as monotherapy in Study 1 discontinued therapy due to adverse reactions. The most common (greater than or equal to 2% more frequent than low-dose 50 mg per day topiramate) adverse reactions causing discontinuation in this trial were difficulty with memory, fatigue, asthenia, insomnia, somnolence and paresthesia.

The adverse reactions in the controlled trial (Study 1) that occurred most commonly in children (10 years up to 16 years of age) in the 400 mg per day topiramate group (incidence greater than or equal to 5%) and at a rate higher than in the 50 mg per day group were weight decrease, upper respiratory tract infection, paresthesia, anorexia, diarrhea, and mood problems (see Table 3).

Approximately 12% of the 57 pediatric patients in the 400 mg per day group who received topiramate as monotherapy in the controlled clinical trial discontinued therapy due to adverse reactions. The most common (greater than 5%) adverse reactions resulting in discontinuation in this trial were difficulty with concentration/attention.

Table 2: Incidence of Treatment-Emergent Adverse Reaction in the Monotherapy Epilepsy Trial in Adultsa Where Incidence Was at Least 2% in the 400 mg/day Immediate-Release Topiramate Group and Greater Than the Rate in the 50 mg/day Immediate-Release Topiramate Group

Table 3: Incidence of Treatment-Emergent Adverse Reactions in the Monotherapy Epilepsy Trial in Pediatric Patients (Ages 10 up to 16 Years)a Where Incidence Was at Least 5% in the 400 mg/day Immediate-Release Topiramate Group and Greater than the Rate in the 50mg/day Immediate-Release Topiramate Group

The most commonly observed adverse reactions associated with the use of topiramate at dosages of 200 to 400 mg per day in controlled trials in adults with partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome that were seen at greater frequency in topiramate-treated patients and did not appear to be dose-related were: somnolence, ataxia, speech disorders and related speech problems, psychomotor slowing, abnormal vision, difficulty with memory, paresthesia and diplopia. The most common dose-related adverse reactions at dosages of 200 mg to 1,000 mg per day were: fatigue, nervousness, difficulty with concentration or attention, confusion, depression, anorexia, language problems, anxiety, mood problems, and weight decrease.

Adverse reactions associated with the use of topiramate at dosages of 5 mg/kg/day to 9 mg/kg/day in controlled trials in pediatric patients with partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome that were seen at greater frequency in topiramate-treated patients were: fatigue, somnolence, anorexia, nervousness, difficulty with concentration/attention, difficulty with memory, aggressive reaction, and weight decrease.

In controlled clinical trials in adults, 11% of patients receiving topiramate 200 to 400mg per day as adjunctive therapy discontinued due to adverse reactions. This rate appeared to increase at dosages above 400mg per day. Adverse events associated with discontinuing therapy included somnolence, dizziness, anxiety, difficulty with concentration or attention, fatigue, and paresthesia and increased at dosages above 400 mg per day. None of the pediatric patients who received topiramate adjunctive therapy at 5 mg/kg/day to 9 mg/kg/day in controlled clinical trials discontinued due to adverse reactions.

Approximately 28% of the 1757 adults with epilepsy who received topiramate at dosages of 200 mg to 1,600 mg per day in clinical studies discontinued treatment because of adverse reactions; an individual patient could have reported more than one adverse reaction. These adverse reactions were: psychomotor slowing (4.0%), difficulty with memory (3.2%), fatigue (3.2%), confusion (3.1%), somnolence (3.2%), difficulty with concentration/attention (2.9%), anorexia (2.7%), depression (2.6%), dizziness (2.5%), weight decrease (2.5%), nervousness (2.3%), ataxia (2.1%), and paresthesia (2.0%). Approximately 11% of the 310 pediatric patients who received topiramate at dosages up to 30 mg/kg/day discontinued due to adverse reactions. Adverse reactions associated with discontinuing therapy included aggravated convulsions (2.3%), difficulty with concentration/attention (1.6%), language problems (1.3%), personality disorder (1.3%), and somnolence (1.3%).

Table 4 lists adverse reactions that occurred in at least 1% of adults treated with 200 to 400 mg per day topiramate in controlled trials that were numerically more common at this dose than in the patients treated with placebo. In general, most patients who experienced adverse reactions during the first eight weeks of these trials no longer experienced them by their last visit. Table 7 lists adverse reactions that occurred in at least 1% of pediatric patients treated with 5 mg/kg to 9 mg/kg topiramate in controlled trials that were numerically more common than in patients treated with placebo.

Other adverse reactions that occurred in more than 1% of adults treated with 200 mg to 400 mg of topiramate in placebo-controlled epilepsy trials but with equal or greater frequency in the placebo group were headache, injury, anxiety, rash, pain, convulsions aggravated, coughing, fever, diarrhea, vomiting, muscle weakness, insomnia, personality disorder, dysmenorrhea, upper respiratory tract infection, and eye pain.

Table 4: Incidence of Adverse Reactions in Placebo-Controlled, Adjunctive Epilepsy Trials in Adultsa,b,c

Study 7 was a randomized, double-blind, adjunctive, placebo-controlled, parallel group study with 3 treatment arms: 1) placebo; 2) topiramate 200 mg per day with a 25 mg per day starting dose, increased by 25 mg per day each week for 8 weeks until the 200 mg per day maintenance dose was reached; and 3) topiramate 200 mg per day with a 50 mg per day starting dose, increased by 50 mg per day each week for 4 weeks until the 200 mg per day maintenance dose was reached. All patients were maintained on concomitant carbamazepine with or without another concomitant antiepileptic drug.

The incidence of adverse reactions (Table 5) did not differ significantly between the 2 topiramate regimens. Because the frequencies of adverse reactions reported in this study were markedly lower than those reported in the previous epilepsy studies, they cannot be directly compared with data obtained in other studies.

Table 5: Incidence of Adverse Reactions in Study 7a,b,c

Table 6: Incidence (%) of Dose-Related Adverse Reactions From Placebo-Controlled, Adjunctive Trials in Adults With Partial Onset Seizures (Studies 2 through 7)a

Table 7: Incidence (%) of Adverse Reaction in Placebo-Controlled, Adjunctive Epilepsy Trial in Pediatric Patients (Ages 2 Years to 16 Years)a,b,c (Study 8)