Topiramate Extended-Release Capsules

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

Topiramate overdose has resulted in severe metabolic acidosis [see WARNINGS AND PRECAUTIONS].

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 QUDEXY XR. Therefore, in acute QUDEXY 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.

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

• Acute Myopia and Secondary Angle Closure Glaucoma [see WARNINGS AND PRECAUTIONS]
• Visual Field Defects [see WARNINGS AND PRECAUTIONS]
• Oligohydrosis and Hyperthermia [see WARNINGS AND PRECAUTIONS]
• Metabolic Acidosis [see WARNINGS AND PRECAUTIONS]
• Suicidal Behavior and Ideation [see WARNINGS AND PRECAUTIONS]
• Cognitive/Neuropsychiatric Adverse Reactions [see WARNINGS AND PRECAUTIONS]
• Fetal Toxicity [see WARNINGS AND PRECAUTIONS and Use in Specific Populations]]
• Withdrawal of Antiepileptic Drugs [see WARNINGS AND PRECAUTIONS]
• Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid Use [see WARNINGS AND PRECAUTIONS]
• Kidney Stones [see WARNINGS AND PRECAUTIONS]
• Hypothermia with Concomitant Valproic Acid Use [see WARNINGS AND PRECAUTIONS]
• Paresthesia [see WARNINGS AND PRECAUTIONS]

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.

Clinical Trials Experience

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.

Topiramate treatment is associated with an increased risk for bleeding. In a pooled analysis of placebo-controlled studies of approved and unapproved indications, bleeding was more frequently reported as an adverse event for topiramate than for placebo (4.5% versus 3.0% in adult patients, and 4.4% versus 2.3% in pediatric patients). In this analysis, the incidence of serious bleeding events for topiramate and placebo was 0.3% versus 0.2% for adult patients, and 0.4% versus 0% for pediatric patients.

Adverse bleeding reactions reported with topiramate ranged from mild epistaxis, ecchymosis, and increased menstrual bleeding to life-threatening hemorrhages. In patients with serious bleeding events, conditions that increased the risk for bleeding were often present, or patients were often taking drugs that cause thrombocytopenia (other antiepileptic drugs) or affect platelet function or coagulation (e.g., aspirin, nonsteroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, or warfarin or other anticoagulants).

Clinical Trials Experience In Epilepsy

Adult Patients 16 Years of Age and Older

The adverse reactions in the controlled trial (Study 1) that occurred most commonly in adults in the 400 mg per day group and at an incidence higher ( ≥ 5%) than in the 50 mg per day group were paresthesia, weight decrease, somnolence, anorexia, and difficulty with memory (see Table 3) [see Clinical Studies].

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.

Pediatric Patients 6 Years to Less Than 16 Years of Age

The adverse reactions in the controlled trial (Study 1) that occurred most commonly in pediatric patients in the 400 mg per day topiramate group and at an incidence higher ( ≥ 5%) than in the 50 mg per day group were fever, weight decrease, paresthesia, mood problems, cognitive problems, infection, and flushing (see Table 4) [see Clinical Studies].

Approximately 14% of the 77 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 ( ≥ 2% more frequent than in the 50 mg per day group) adverse reactions resulting in discontinuation in this trial were difficulty with concentration/attention, fever, flushing, and confusion.

Table 3: Incidence (%) of 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 4: Incidence (%) of Adverse Reactions in the Monotherapy Epilepsy Trial in Pediatric Patients (Ages 6 to Less Than 16 Years)a 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

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 [see Table 5] [see Clinical Studies ]. 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 [see Table 7].

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 [see Table 8].

In controlled clinical trials in adults, 11% of patients receiving topiramate 200 to 400 mg per day as adjunctive therapy discontinued due to adverse reactions. This rate appeared to increase at dosages above 400 mg 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%).

Incidence in Epilepsy Controlled Clinical Trials - Adjunctive Therapy - Partial Onset Seizures, Primary Generalized Tonic-Clonic Seizures, and Lennox-Gastaut Syndrome

Table 5 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 8 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 Observed During Double-Blind Epilepsy Adjunctive Therapy Trials

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 5: Incidence (%) of Adverse Reactions in Placebo-Controlled, Adjunctive Epilepsy Trials in Adults a,b,c

Adverse Reactions Observed in Adjunctive Therapy Trial in Adults with Partial Onset Seizures (Study 7)

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 6) 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 6: Incidence (%) of Adverse Reactions in Placebo Controlled, Adjunctive Trial in Adults with Partial Onset Seizures (Study 7) a,b,c

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

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

Clinical Trial Experience In Migraine

Adult Patients In the four multicenter, randomized, double-blind, placebo-controlled, parallel group migraine prophylaxis clinical trials (which included 35 adolescent patients age 12 to 15 years) conducted with immediate-release topiramate, most of the adverse reactions were mild or moderate in severity. Most adverse reactions occurred more frequently during the titration period than during the maintenance period.

The most common ( ≥ 5% more frequent than placebo) adverse reactions associated with the use of the 100 mg topiramate dose in controlled, migraine clinical trials of predominantly adults were paresthesia, anorexia, weight decrease, taste perversion, diarrhea, difficulty with memory, hypoesthesia, and nausea. Table 9 includes those adverse reactions reported for patients in the placebo-controlled trials where the incidence in any immediate-release topiramate group was at least 2% and was greater than that for placebo patients.

Table 9: Incidence (%) of Adverse Reactions in Placebo-Controlled, Migraine Trials Where Incidence Was ≥ 2% in Any Immediate-release Topiramate Group and Greater than the Rate in Placebo Patients*ab

Of the 1135 patients exposed to immediate-release topiramate in the placebo-controlled studies, 25% discontinued due to adverse reactions, compared to 10% of the 445 placebo patients. The adverse reactions associated with discontinuing therapy in patients in these studies included paresthesia (7%), fatigue (4%), nausea (4%), difficulty with concentration/attention (3%), insomnia (3%), anorexia (2%) and dizziness (2%).

Patients treated in these studies experienced mean percent reductions in body weight that were dose-dependent. This change was not seen in the placebo group. Mean changes of 0%, -2%, -3%, and -4% were seen for the placebo group, immediate-release topiramate 50 mg, 100 mg, and 200 mg groups, respectively.

Table 10 shows adverse reactions that were dose-dependent. Several central nervous system adverse reactions, including some that represented cognitive dysfunction, were dose-related. The most common dose-related adverse reactions (treatment difference ≥ 5% for the 100 mg dose) were: paresthesia, nausea, anorexia, difficulty with memory, diarrhea, weight decrease, and hypoesthesia.

Table 10: Incidence (%) of Dose-Related Adverse Reactions From Placebo-Controlled, Migraine Trialsa

Adolescents 12 To 17 Years Of Age

In five randomized, double-blind, placebo-controlled, parallel group migraine prophylaxis clinical trials, most of the adverse reactions with immediate-release topiramate were mild or moderate in severity. Most adverse reactions occurred more frequently during the titration period than during the maintenance period. Among adverse reactions with onset during titration, approximately half persisted into the maintenance period.

In four, fixed-dose, double-blind migraine prophylaxis clinical trials in immediate-release topiramate treated adolescent patients, the most commonly observed adverse reactions associated with the use of 100 mg of immediate-release topiramate that were seen at an incidence higher ( > 5%) than in the placebo group were: paresthesia, upper respiratory tract infection, anorexia, and abdominal pain (see Table 11). Table 11 shows adverse reactions from the adolescent pivotal trial (Study 3) demonstrating the efficacy of immediate-release topiramate in which there were 103 adolescent patients who were treated with placebo or 50 mg or 100 mg of immediate-release topiramate, and three predominantly adult trials in which there were 49 adolescent patients (12 to 17 years) who were treated with placebo or 50 mg, 100 mg or 200 mg of immediate-release topiramate [see Clinical Studies]. Table 11 also shows adverse reactions in adolescents in the controlled migraine trials when the incidence in an immediate-release topiramate dose group was at least 5% or higher than the incidence of placebo. Many adverse reactions shown in Table 11 indicated a dose-dependent relationship.

Table 11: Incidence (%) of Adverse Reactions in at Least 5% or Greater than the Placebo Incidence of Adolescents (12 - 17 Years) in any Immediate-Release Topiramate Group in Pooled Double-Blind Migraine Prophylaxis Studiesab

In the double-blind placebo-controlled studies, adverse reactions led to discontinuation of treatment in 8% of placebo patients compared with 6% of immediate-release topiramate-treated patients. Adverse reactions associated with discontinuing therapy that occurred in more than one immediate-release topiramate-treated patient were fatigue (1%), headache (1%), and somnolence (1%).

Laboratory Abnormalities

Topiramate decreases serum bicarbonate [see WARNINGS AND PRECAUTIONS]

Topiramate treatment with or without concomitant valproic acid (VPA) can cause hyperammonemia with or without encephalopathy [see WARNINGS AND PRECAUTIONS].

Immediate-release topiramate treatment was associated with changes in several clinical laboratory analytes in randomized, double-blind, placebo-controlled studies. Similar effects should be anticipated with use of TROKENDI XR® .

Controlled trials of adjunctive topiramate treatment of adults for partial onset seizures showed an increased incidence of markedly decreased serum phosphorus (6% topiramate, 2% placebo), markedly increased serum alkaline phosphatase (3% topiramate, 1% placebo), and decreased serum potassium (0.4 % topiramate, 0.1 % placebo). The clinical significance of these abnormalities has not been clearly established.

Changes in several clinical laboratory results (increased creatinine, BUN, alkaline phosphatase, total protein, total eosinophil count and decreased potassium) have been observed in a clinical investigational program in very young (2 years and younger) pediatric patients who were treated with adjunctive topiramate for partial onset seizures [see Use in Specific Populations].

In pooled double-blind studies in pediatric patients (6 to 17 years), an increased risk for certain abnormalities (value outside normal reference range) in selected clinical laboratory analytes measured in blood has been observed during topiramate treatment of pediatric patients compared to placebo-treated patients. In some instances, abnormalities were also observed at the end of the trial at the final visit and the changes were considered markedly abnormal.

For patients 12 to 17 years, the following were noted to be abnormally increased more frequently with topiramate than with placebo: BUN, creatinine, uric acid, chloride [see WARNINGS AND PRECAUTIONS], ammonia [see WARNINGS AND PRECAUTIONS], total protein, and platelets. The following were abnormally decreased in some subjects: phosphorus, and bicarbonate [see WARNINGS AND PRECAUTIONS].

For patients 6 to 11 years, the following were noted to be abnormally increased more frequently with topiramate than with placebo: alkaline phosphatase, creatinine and eosinophils. Analytes abnormally decreased were: total white count and neutrophils. There was no testing for serum bicarbonate, chloride, ammonia, or phosphorus in these younger patients.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of topiramate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The listing is alphabetized: bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), hepatic failure (including fatalities), hepatitis, maculopathy, pancreatitis, and pemphigus.

Read the entire FDA prescribing information for Trokendi XR (Topiramate Extended-release Capsules)

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of too much acid in the blood (acidosis) like confusion; fast breathing; fast heartbeat; a heartbeat the does not feel normal; very bad stomach pain, upset stomach, or throwing up; feeling very sleepy; shortness of breath; or feeling very tired or weak.
• Signs of infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal.
• Signs of high ammonia levels like a heartbeat that does not feel normal, breathing that is not normal, feeling confused, pale skin, slow heartbeat, seizures, sweating, throwing up, or twitching.
• Any unexplained bruising or bleeding.
• Black, tarry, or bloody stools.
• Throwing up blood or throw up that looks like coffee grounds.
• Feeling confused.
• Not able to focus.
• Change in balance.
• Very bad dizziness or passing out.
• Not able to eat.
• Back pain, belly pain, or blood in the urine. May be signs of a kidney stone.
• Trouble passing urine.
• A burning, numbness, or tingling feeling that is not normal.
• A big weight loss.
• If seizures are worse or not the same after starting this medicine (topiramate extended-release capsules).
• Bone pain.
• Chest pain or pressure.
• Memory problems or loss.
• Muscle pain or weakness.
• Ringing in ears.
• Trouble speaking.
• Shakiness.
• Trouble walking.
• Not able to control eye movements.