5 WARNINGS AND PRECAUTIONS
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.
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.
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
.
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 >5mEq/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 (5.12)]
. Chronic metabolic acidosis in pediatric patients may also reduce growth rates, which may 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 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.
5.5 Interaction With Alcohol
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
.
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.
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.
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 for cleft lip and/or cleft palate (oral clefts) and for being small for gestational age. 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)]
.
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.
5.10 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.
5.11 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.
5.12 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.
5.13 Hypothermia With Concomitant Valproic Acid Use
Hypothermia, defined as a drop in body core temperature to < 35ºC (95ºF), 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.
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed in more detail in other sections of the labeling:
The data described in the following sections were obtained using immediate-release topiramate tablets. TROKENDI XR
® has not been studied in a randomized, placebo-controlled Phase III clinical study; however, it is expected that TROKENDI XR
® would produce a similar adverse reaction profile as immediate-release topiramate.
6.1 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 practice.
Monotherapy Epilepsy
Adults 16 Years of Age and Older
The most common adverse reactions in the controlled trial (Study 1) that occurred in adults in the 400 mg/day topiramate group and at an incidence higher (≥ 10%) than in the 50 mg per day group were: paresthesia, weight loss, and anorexia (see
Table 3).
Approximately 21% of the 159 adult patients in the 400 mg/day group who received topiramate as monotherapy in Study 1 discontinued therapy due to adverse reactions. The most common (≥ 2% more frequent than low-dose 50 mg/day topiramate) adverse reactions causing discontinuation were difficulty with memory, fatigue, asthenia, insomnia, somnolence, and paresthesia.
Pediatric Patients 6 Years to 15 Years of Age
The most common adverse reactions in the controlled trial (Study 1) that occurred in pediatric patients in the 400 mg/day topiramate group and at an incidence higher (≥ 10%) than in the 50 mg/day group were fever and weight loss (see
Table 3).
Approximately 14% of the 77 pediatric patients in the 400 mg/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/day group) adverse reactions resulting in discontinuation in this trial were difficulty with concentration/attention, fever, flushing, and confusion.
Table 3 represents the incidence of adverse reactions occurring in at least 3% of adult and pediatric patients treated with 400 mg/day immediate-release topiramate and occurring with greater incidence than 50 mg/day topiramate.
Table 3: Adverse Reactions in the High Dose Group as Compared to the Low Dose Group, in Monotherapy Epilepsy Trial in Adult and Pediatric Patients
|
Age Group |
|
Pediatric
(6 to 15 Years)
|
Adult
(Age ≥16 Years)
|
|
Immediate-release Topiramate Daily Dosage Group (mg/day) |
|
50 |
400 |
50 |
400 |
Body System/
Adverse Reaction
|
(N=74)
%
|
(N=77)
%
|
(N=160)
%
|
(N=159)
%
|
Body as a Whole-General Disorders |
Asthenia |
0 |
3 |
4 |
6 |
Fever |
1 |
12 |
|
|
Leg pain |
|
|
2 |
3 |
Central & Peripheral Nervous System Disorders |
Paresthesia |
3 |
12 |
21 |
40 |
Dizziness |
|
|
13 |
14 |
Ataxia |
|
|
3 |
4 |
Hypoesthesia |
|
|
4 |
5 |
Hypertonia |
|
|
0 |
3 |
Involuntary Muscle contraction |
0 |
3 |
|
|
Vertigo |
0 |
3 |
|
|
Gastro-intestinal System Disorders |
Constipation |
|
|
1 |
4 |
Diarrhea |
8 |
9 |
|
|
Gastritis |
|
|
0 |
3 |
Dry mouth |
|
|
1 |
3 |
Liver and Biliary System Disorders |
Increase in Gamma-GT |
|
|
1 |
3 |
Metabolic and Nutritional Disorders |
Weight loss |
7 |
17 |
6 |
17 |
Platelet, Bleeding & Clotting Disorders |
Epistaxis |
0 |
4 |
|
|
Psychiatric Disorders |
Anorexia |
|
|
4 |
14 |
Anxiety |
|
|
4 |
6 |
Cognitive problems |
1 |
6 |
1 |
4 |
Confusion |
0 |
3 |
|
|
Depression |
0 |
3 |
7 |
9 |
Difficulty with concentration or attention |
7 |
10 |
7 |
8 |
Difficulty with memory |
1 |
3 |
6 |
11 |
Insomnia |
|
|
8 |
9 |
Decrease in libido |
|
|
0 |
3 |
Mood problems |
1 |
8 |
2 |
5 |
Personality disorder (behavior problems) |
0 |
3 |
|
|
Psychomotor slowing |
|
|
3 |
5 |
Somnolence |
|
|
10 |
15 |
Red Blood Cell Disorders |
Anemia |
1 |
3 |
|
|
Reproductive Disorders, Female |
Intermenstrual bleeding |
0 |
3 |
|
|
Vaginal hemorrhage |
|
|
0 |
3 |
Resistance Mechanism Disorders |
Infection |
3 |
8 |
2 |
3 |
Viral infection |
3 |
6 |
6 |
8 |
Respiratory System Disorders |
Bronchitis |
1 |
5 |
3 |
4 |
Upper respiratory tract infection |
16 |
18 |
|
|
Rhinitis |
5 |
6 |
2 |
4 |
Sinusitis |
1 |
4 |
|
|
Skin and Appendages Disorders |
Alopecia |
1 |
4 |
3 |
4 |
Pruritus |
|
|
1 |
4 |
Rash |
3 |
4 |
1 |
4 |
Acne |
|
|
2 |
3 |
Special Senses Other, Disorders |
Taste perversion |
|
|
3 |
5 |
Urinary System Disorders |
Cystitis |
|
|
1 |
3 |
Micturition frequency |
0 |
3 |
0 |
2 |
Renal calculus |
|
|
0 |
3 |
Urinary incontinence |
1 |
3 |
|
|
Vascular (Extracardiac) Disorders |
Flushing |
0 |
5 |
|
|
Adjunctive Therapy Epilepsy
Adults 16 Years of Age and Older
In pooled controlled clinical trials in adults with partial-onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, 183 patients received adjunctive therapy with immediate-release topiramate at dosages of 200 to 400 mg/day (recommended dosage range), and 291 patients received placebo. Patients in these trials were receiving 1 to 2 concomitant antiepileptic drugs in addition to immediate-release topiramate or placebo.
The most common adverse reactions in the controlled clinical trial that occurred in adult patients in the 200-400 mg/day topiramate group with an incidence higher (≥10%) than in the placebo group were: dizziness, speech disorders/related speech problems, somnolence, nervousness, psychomotor slowing, and vision abnormal (see
Table 4)
[see
Clinical Studies (14.3)]
.
Table 4 presents the incidence of adverse reactions occurring in at least 3% of adult patients treated with 200 to 400 mg/day topiramate and was greater than placebo incidence. The incidence of some adverse reactions (e.g., fatigue, dizziness, paresthesia, language problems, psychomotor slowing, depression, difficulty with concentration/attention, mood problems) was dose-related and much greater at higher than recommended topiramate dosing (i.e., 600 to 1000 mg/day) compared to the incidence of these adverse reactions at the recommended dosing (200 to 400 mg/day) range.
Table 4: Most Common Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Epilepsy Trials in Adults
*,†
Body System/ |
Placebo |
Topiramate Dosage (mg/day)
200-400
|
Adverse Reaction |
(N=291)
%
|
(N=183)
%
|
|
Body as a Whole-General Disorders |
Fatigue |
13 |
15 |
Asthenia |
1 |
6 |
Back pain |
4 |
5 |
Chest pain |
3 |
4 |
Influenza-like symptoms |
2 |
3 |
Central & Peripheral Nervous System Disorders |
Dizziness |
15 |
25 |
Ataxia |
7 |
16 |
Speech disorders/Related speech problems |
2 |
13 |
Paresthesia |
4 |
11 |
Nystagmus |
7 |
10 |
Tremor |
6 |
9 |
Language problems |
1 |
6 |
Coordination abnormal |
2 |
4 |
Gait abnormal |
1 |
3 |
Gastro-Intestinal System Disorders |
Nausea |
8 |
10 |
Dyspepsia |
6 |
7 |
Abdominal pain |
4 |
6 |
Constipation |
2 |
4 |
Metabolic and Nutritional Disorders |
Weight loss |
3 |
9 |
Psychiatric Disorders |
Somnolence |
12 |
29 |
Nervousness |
6 |
16 |
Psychomotor slowing |
2 |
13 |
Difficulty with memory |
3 |
12 |
Confusion |
5 |
11 |
Anorexia |
4 |
10 |
Difficulty with concentration/attention |
2 |
6 |
Mood problems |
2 |
4 |
Agitation |
2 |
3 |
Aggressive reaction |
2 |
3 |
Emotional liability |
1 |
3 |
Cognitive problems |
1 |
3 |
Reproductive Disorders, Female |
Breast pain |
2 |
4 |
Respiratory System Disorders |
Rhinitis |
6 |
7 |
Pharyngitis |
2 |
6 |
Sinusitis |
4 |
5 |
Vision Disorders |
Vision abnormal |
2 |
13 |
Diplopia |
5 |
10 |
In controlled clinical trials in adults, 11% of patients receiving immediate-release 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 reactions associated with discontinuing therapy included somnolence, dizziness, anxiety, difficulty with concentration or attention, fatigue, and paresthesia.
Pediatric Patients 2 to 15 Years of Age
In pooled, controlled clinical trials in pediatric patients (2 to 15 years of age) with partial-onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, 98 patients received adjunctive therapy with immediate-release topiramate at dosages of 5 mg to 9 mg/kg/day (recommended dosage range) and 101 patients received placebo.
The most common adverse reactions in the controlled clinical trial that occurred in pediatric patients in the 5 mg to 9 mg/kg/day immediate-release topiramate group with an incidence higher (≥10%) than in the placebo group were: fatigue and somnolence (see
Table 5).
Table 5 presents the incidence of adverse reactions that occurred in at least 3% of pediatric patients 2 to 15 years of age receiving 5 mg to 9 mg/kg/day (recommended dosage range) of immediate-release topiramate and was greater than placebo incidence.
Table 5: Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Epilepsy Trial in Pediatric Patients 2 to 15 Years of Age
*,†
Body System/
Adverse Reaction
|
Placebo
(N=101)
%
|
Topiramate
(N=98)
%
|
|
Body as a Whole-General Disorders |
Fatigue |
5 |
16 |
Injury |
13 |
14 |
Central & Peripheral Nervous System Disorders |
Gait abnormal |
5 |
8 |
Ataxia |
2 |
6 |
Hyperkinesia |
4 |
5 |
Dizziness |
2 |
4 |
Speech disorders/Related speech problems |
2 |
4 |
Gastro-Intestinal System Disorders |
Nausea |
5 |
6 |
Saliva increased |
4 |
6 |
Constipation |
4 |
5 |
Gastroenteritis |
2 |
3 |
Metabolic and Nutritional Disorders |
Weight loss |
1 |
9 |
Platelet, Bleeding & Clotting Disorders |
Purpura |
4 |
8 |
Epistaxis |
1 |
4 |
Psychiatric Disorders |
Somnolence |
16 |
26 |
Anorexia |
15 |
24 |
Nervousness |
7 |
14 |
Personality disorder (Behavior Problems) |
9 |
11 |
Difficulty with concentration/attention |
2 |
10 |
Aggressive reaction |
4 |
9 |
Insomnia |
7 |
8 |
Difficulty with memory |
0 |
5 |
Confusion |
3 |
4 |
Psychomotor slowing |
2 |
3 |
Resistance Mechanism Disorders |
|
|
Infection viral |
3 |
7 |
Respiratory System Disorders |
Pneumonia |
1 |
5 |
Skin and Appendages Disorders |
Skin Disorder |
2 |
3 |
Urinary System Disorders |
Urinary incontinence |
2 |
4 |
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.
Migraine
Adults
In the four multicenter, randomized, double-blind, placebo-controlled, parallel group clinical trials for the preventive treatment of migraine (which included 35 pediatric patients 12 to 15 years of age), most adverse reactions occurred more frequently during the titration period than during the maintenance period.
The most common adverse reactions with immediate-release topiramate 100mg in the clinical trials for the preventive treatment of migraine of predominantly adults that were seen at an incidence higher (≥5%) than in the placebo group were: paresthesia, anorexia, weight loss, taste perversion, diarrhea, difficulty with memory, hypoesthesia, and nausea (see
Table 6).
Table 6 includes those adverse reactions that occurred in the placebo-controlled trials where the incidence in any immediate-release topiramate group was at least 3% and was greater than that for placebo patients. The incidence of some adverse reactions (e.g., fatigue, dizziness, somnolence, difficulty with memory, difficulty with concentration/attention) was dose-related and greater at higher than recommended topiramate dosing (200 mg/day) compared to the incidence of these adverse reactions at the recommended dosing (100 mg/day).
Table 6: Adverse Reactions in Pooled, Placebo-Controlled, Migraine Trials in Adults
*,†,‡
|
|
Topiramate Dosage
(mg/day)
|
Body System/
Adverse Reaction
|
Placebo
(N=445)
%
|
50
(N=235)
%
|
100
(N=386)
%
|
|
Body as a Whole-General Disorders |
Fatigue |
11 |
14 |
15 |
Injury |
7 |
9 |
6 |
Central & Peripheral Nervous System Disorders |
Paresthesia |
6 |
35 |
51 |
Dizziness |
10 |
8 |
9 |
Hypoaesthesia |
2 |
6 |
7 |
Language problems |
2 |
7 |
6 |
Gastro-Intestinal System Disorders |
Nausea |
8 |
9 |
13 |
Diarrhea |
4 |
9 |
11 |
Abdominal pain |
5 |
6 |
6 |
Dyspepsia |
3 |
4 |
5 |
Dry mouth |
2 |
2 |
3 |
Gastroenteritis |
1 |
3 |
3 |
Metabolic and Nutritional Disorders |
Weight loss |
1 |
6 |
9 |
Musculoskeletal System Disorders |
Arthralgia |
2 |
7 |
3 |
Psychiatric Disorders |
Anorexia |
6 |
9 |
15 |
Somnolence |
5 |
8 |
7 |
Difficulty with memory |
2 |
7 |
7 |
Insomnia |
5 |
6 |
7 |
Difficulty with concentration/attention |
2 |
3 |
6 |
Mood problems |
2 |
3 |
6 |
Anxiety |
3 |
4 |
5 |
Depression |
4 |
3 |
4 |
Nervousness |
2 |
4 |
4 |
Confusion |
2 |
2 |
3 |
Psychomotor slowing |
1 |
3 |
2 |
Reproductive Disorders, Female |
Menstrual disorder |
2 |
3 |
2 |
Reproductive Disorders, Male |
Ejaculation premature |
0 |
3 |
0 |
Resistance Mechanism Disorders |
Viral Infection |
3 |
4 |
4 |
Respiratory System Disorders |
Upper respiratory tract infection |
12 |
13 |
14 |
Sinusitis |
6 |
10 |
6 |
Pharyngitis |
4 |
5 |
6 |
Coughing |
2 |
2 |
4 |
Bronchitis |
2 |
3 |
3 |
Dyspnea |
2 |
1 |
3 |
Skin and Appendages Disorders |
Pruritis |
2 |
4 |
2 |
Special Sense Other, Disorders |
Taste perversion |
1 |
15 |
8 |
Urinary System Disorders |
Urinary tract infection |
2 |
4 |
2 |
Vision Disorders |
Blurred vision |
2 |
4 |
2 |
Of the 1135 patients exposed to immediate-release topiramate in the adult 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 the immediate-release topiramate-treated 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.
Pediatric Patients 12 to 17 Years of Age
In five randomized, double-blind, placebo-controlled, parallel group clinical trials for the preventive treatment of migraine, most of the 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 clinical trials for the preventive treatment of migraine in pediatric patients 12 to 17 years of age, the most common adverse reactions with immediate-release topiramate 100 mg 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 7). Table 7 shows adverse reactions from the pediatric trial (Study 13
[see
Clinical Studies (14.4)]
) in which 103 pediatric patients were treated with placebo or 50 mg or 100 mg of immediate-release topiramate, and three predominantly adult trials in which 49 pediatric patients (12 to 17 years of age) were treated with placebo or 50 mg, 100 mg or 200 mg of immediate-release topiramate
[see
Clinical Studies (14.4)].
Table 7 also shows adverse reactions in pediatric patients in controlled migraine trials when the incidence in an immediate-release topiramate dose group was at least 5% or higher and greater than the incidence of placebo. Many adverse reactions shown in Table 7 indicate a dose-dependent relationship. The incidence of some adverse reactions (e.g., allergy, fatigue, headache, anorexia, insomnia, somnolence, and viral infection) was dose-related and greater at higher than recommended immediate-release topiramate dosing (200 mg daily) compared to the incidence of these adverse reactions at the recommended dosing (100 mg daily).
Table 7: Adverse Reactions in Pooled Double-Blind Studies for the Preventive Treatment of Migraine in Pediatric Patients 12 to 17 Years of Age)
*†
|
|
Immediate-Release Topiramate Dosage |
Body System/ Adverse Reaction |
Placebo
(N=45)
%
|
50 mg/day
(N=46)
%
|
100 mg/day
(N=48)
%
|
|
Body as a Whole – General Disorders |
Fatigue |
7 |
7 |
8 |
Fever |
2 |
4 |
6 |
Central & Peripheral Nervous System Disorders |
Paresthesia |
7 |
20 |
19 |
Dizziness |
4 |
4 |
6 |
Gastrointestinal System Disorders |
Abdominal pain |
9 |
7 |
15 |
Nausea |
4 |
4 |
8 |
Metabolic and Nutritional Disorders |
Weight loss |
2 |
7 |
4 |
Psychiatric Disorders |
Anorexia |
4 |
9 |
10 |
Somnolence |
2 |
2 |
6 |
Insomnia |
2 |
9 |
2 |
Resistance Mechanism Disorders |
Infection viral |
4 |
4 |
8 |
Respiratory System Disorders |
Upper respiratory tract infection |
11 |
26 |
23 |
Rhinitis |
2 |
7 |
6 |
Sinusitis |
2 |
9 |
4 |
Coughing |
0 |
7 |
2 |
Special Senses Other, Disorders |
Taste perversion |
2 |
2 |
6 |
Vision Disorders |
Conjunctivitis |
4 |
7 |
4 |
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%).
Increased Risk for Bleeding
Topiramate 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 reaction 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).
Other Adverse Reactions Observed During Clinical Trials
Other adverse reactions seen during clinical trials were: abnormal coordination, eosinophilia, gingival bleeding, hematuria, hypotension, myalgia, myopia, postural hypotension, scotoma, suicide attempt, syncope, and visual field defect.
Laboratory Test Abnormalities
Adult Patients
In addition to changes in serum bicarbonate (i.e., metabolic acidosis), sodium chloride, and ammonia, immediate-release topiramate was associated with changes in several clinical laboratory analytes in randomized, double-blind, placebo-controlled studies
[see
Warnings and Precautions (5.4,
5.11)]
. Controlled trials of adjunctive topiramate treatment of adults for partial-onset seizures showed an increased incidence of markedly decreased serum phosphorus (6% topiramate versus 2% placebo), markedly increased serum alkaline phosphatase (3% topiramate versus 1% placebo), and decreased serum potassium (0.4% topiramate versus 0.1% placebo).
Pediatric Patients
In pediatric patients (1-24 months) receiving adjunctive topiramate for partial-onset seizures, there was an increased incidence for an increased result (relative to normal analyte reference range) associated with immediate-release topiramate (vs placebo) for the following clinical laboratory analytes: creatinine, BUN, alkaline phosphatase, and total protein. The incidence was also increased for a decreased result for bicarbonate (i.e., metabolic acidosis) and potassium with immediate-release topiramate (vs. placebo)
[see
Use in Specific Populations (8.4)]
. TROKENDI XR
® is not indicated for partial-onset seizures in pediatric patients less than 6 years of age.
In pediatric patients (ranging from 6-17 years of age) receiving immediate-release topiramate for the preventive treatment of migraine, there was an increased incidence for an increased result (relative to normal analyte reference range) associated with immediate-release topiramate (vs placebo) for the following clinical laboratory analytes: creatinine, BUN, uric acid, chloride, ammonia, alkaline phosphatase, total protein, platelets, and eosinophils. The incidence was also increased for a decreased result for phosphorus, bicarbonate, total white blood count, and neutrophils
[see
Use in Specific Populations (8.4)].
TROKENDI XR
® is not indicated for the preventive treatment of migraine in pediatric patients less than 12 years of age.
6.2 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of immediate-release topiramate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Body as a Whole-General Disorders: oligohydrosis and hyperthermia
[see
Warnings and Precautions (5.3)]
, hyperammonemia, hyperammonemic encephalopathy
[see
Warnings and Precautions (5.11)]
, hypothermia with concomitant valproic acid
[see
Warnings and Precautions 5.13)]
.
Gastrointestinal System Disorders: hepatic failure (including fatalities), hepatitis, pancreatitis
Skin and Appendage Disorders: bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis)
[see
Warnings and Precautions (5.10)]
, pemphigus
Urinary System Disorders: kidney stones, nephrocalcinosis
[see
Warnings and Precautions (5.12)]
Vision disorders: acute myopia, secondary angle closure glaucoma
[see
Warnings and Precautions (5.1)],
maculopathy
Hematological Disorders: decrease of the International Normalized Ratio (INR) or prothrombin time when given concomitantly with vitamin K antagonist anticoagulant medications such as warfarin.
7 DRUG INTERACTIONS
7.2 Antiepileptic Drugs
Concomitant administration of phenytoin or carbamazepine with topiramate resulted in a clinically significant decrease in plasma concentrations of topiramate when compared to topiramate given alone. A dosage adjustment may be needed
[see
Dosage and Administration (2.1),
Clinical Pharmacology (12.3)].
Concomitant administration of valproic acid and topiramate has been associated with hypothermia and hyperammonemia with and without encephalopathy. Examine blood ammonia levels in patients in whom the onset of hypothermia has been reported
[see
Warnings and Precautions (5.11,
5.13) and
Clinical Pharmacology (12.3)]
.
7.3 Other Carbonic Anhydrase Inhibitors
Concomitant use of topiramate, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., zonisamide or acetazolamide) may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Patients should be monitored for the appearance or worsening of metabolic acidosis when TROKENDI XR
® is given concomitantly with another carbonic anhydrase inhibitor
[see
Clinical Pharmacology (12.3)].
7.4 CNS Depressants
Concomitant administration of topiramate with other CNS depressant drugs or alcohol has not been evaluated in clinical studies. Because of the potential of topiramate to cause CNS depression, as well as other cognitive and/or neuropsychiatric adverse reactions, TROKENDI XR
® should be used with extreme caution if used in combination with alcohol and other CNS depressants
[see
Contraindications (4) and
Warnings and Precautions (5.7)].
7.5 Oral Contraceptives
The possibility of decreased contraceptive efficacy and increased breakthrough bleeding may occur in patients taking combination oral contraceptive products with TROKENDI XR
®. Patients taking estrogen-containing contraceptives should be asked to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding
[see
Clinical Pharmacology (12.3)]
.
7.6 Hydrochlorothiazide (HCTZ)
Topiramate C
max and AUC increased when HCTZ was added to immediate-release topiramate. The clinical significance of this change is unknown. The addition of HCTZ to TROKENDI XR
® may require a decrease in the TROKENDI XR
® dose
[see
Clinical Pharmacology (12.3)]
.
7.7 Pioglitazone
A decrease in the exposure of pioglitazone and its active metabolites were noted with the concurrent use of pioglitazone and immediate-release topiramate in a clinical trial. The clinical relevance of these observations is unknown; however, when TROKENDI XR
® is added to pioglitazone therapy or pioglitazone is added to TROKENDI XR
® therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state
[see
Clinical Pharmacology (12.3)]
.
7.8 Lithium
An increase in systemic exposure of lithium following topiramate doses of up to 600 mg/day can occur. Lithium levels should be monitored when co-administered with high-dose TROKENDI XR
® [see
Clinical Pharmacology (12.3)].
7.9 Amitriptyline
Some patients may experience a large increase in amitriptyline concentration in the presence of TROKENDI XR
® and any adjustments in amitriptyline dose should be made according to the patients' clinical response and not on the basis of plasma levels
[see
Clinical Pharmacology (12.3)]
.
10 OVERDOSAGE
Overdoses of topiramate have been reported. Signs and symptoms included convulsions, drowsiness, speech disturbance, blurred vision, diplopia, impaired mentation, lethargy, abnormal coordination, stupor, hypotension, abdominal pain, agitation, dizziness and depression. The clinical consequences were not severe in most cases, but deaths have been reported after overdoses involving topiramate.
Topiramate overdose has resulted in severe metabolic acidosis
[see
Warnings and Precautions (5.4)]
.
A patient who ingested a dose of immediate-release topiramate between 96 g and 110 g was admitted to a hospital with a coma lasting 20 to 24 hours followed by full recovery after 3 to 4 days.
Similar signs, symptoms, and clinical consequences are expected to occur with overdosage of TROKENDI XR
®. In the event of overdose, TROKENDI XR
® should be discontinued and general supportive treatment given until clinical toxicity has been diminished or resolved. Hemodialysis is an effective means of removing topiramate from the body.
11 DESCRIPTION
Topiramate, USP, is a sulfamate-substituted monosaccharide. TROKENDI XR
® (topiramate) extended-release capsules are available as 25 mg, 50 mg, 100 mg and 200 mg capsules for oral administration.
Topiramate is a white to off-white powder. Topiramate is freely soluble in polar organic solvents such as acetonitrile and acetone; and very slightly soluble to practically insoluble in non-polar organic solvents such as hexanes. Topiramate has the molecular formula C
12H
21NO
8S and a molecular weight of 339.4. Topiramate is designated chemically as 2,3:4,5-Di-
O-isopropylidene-β-D-fructopyranose sulfamate and has the following structural formula:

TROKENDI XR
® (topiramate) is an extended-release capsule. TROKENDI XR
® capsules contain the following inactive ingredients:
Sugar Spheres, NF
Hypromellose (Type 2910), USP
Mannitol, USP
Docusate Sodium, USP
Sodium Benzoate, NF
Ethylcellulose, NF
Oleic Acid, NF
Medium Chain Triglycerides, NF
Polyethylene Glycol, NF
Polyvinyl Alcohol, USP
Titanium Dioxide, USP
Talc, USP
Lecithin, NF
Xanthan Gum, NF
Glycerin, USP-NF
The capsule shells contain gelatin, USP; Titanium Dioxide, USP; and Colorants.
The colorants are:
FD&C Blue #1 (all strength capsules)
Yellow Iron Oxide, USP (25 mg and 50 mg capsules)
FD&C Red #3 (50 mg, 100 mg and 200 mg capsules)
FD&C Yellow #6 (50 mg, 100 mg and 200 mg capsules)
Riboflavin, USP (25 mg capsules)
All capsule shells are imprinted with black print that contains shellac, NF, and black iron oxide, NF.
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Administration Instructions
Counsel patients to swallow TROKENDI XR
® capsules whole and intact. TROKENDI XR
® should not be sprinkled on food, chewed or crushed
[see
Dosage and Administration (2.7)]
.
Consumption of Alcohol
Advise patients to completely avoid consumption of alcohol at least 6 hours prior to and 6 hours after taking TROKENDI XR
® [see
Warnings and Precautions (5.5)]
.
Eye Disorders
Advise patients taking TROKENDI XR
® to seek immediate medical attention if they experience blurred vision, visual disturbances or periorbital pain
[see
Warnings and Precautions (5.1,
5.2)]
.
Oligohydrosis and Hyperthermia
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
[see
Warnings and Precautions (5.3)]
.
Metabolic Acidosis
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
[see
Warnings and Precautions (5.4)]
.
Suicidal Behavior and Ideation
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
[see
Warnings and Precautions (5.6)].
Interference With Cognitive and Motor Performance
Warn patients about the potential for somnolence, dizziness, confusion, difficulty concentrating, or 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
[see
Warnings and Precautions (5.7)]
.
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.
Fetal Toxicity
Counsel pregnant women and women of childbearing potential that use of TROKENDI XR 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. Also inform patients that infants exposed to topiramate monotherapy
in utero may be small for their gestational age
[see
Use in Specific Populations (8.1)]
. There may also be risks to the fetus from chronic metabolic acidosis with use of TROKENDI XR during pregnancy
[see
Warnings and Precautions (5.4,
5.8)].
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
[see
Warnings and Precautions (5.8) and
Drug Interactions (7.5)]
.
Encourage pregnant women using TROKENDI XR to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The registry is collecting information about the safety of antiepileptic drugs during pregnancy
[see
Use in Specific Populations (8.1)]
.
Serious Skin Reactions
Inform patients about the signs of serious skin reactions. Instruct patients to immediately inform their healthcare provider at the first appearance of skin rash
[see
Warnings and Precautions (5.10)]
.
Hyperammonemia and Encephalopathy
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
[see
Warnings and Precautions (5.11)]
.
Kidney Stones
Instruct patients, particularly those with predisposing factors, to maintain an adequate fluid intake in order to minimize the risk of kidney stone formation
[see
Warnings and Precautions (5.12)]
.
Hypothermia
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
[see
Warnings and Precautions (5.13)]
.