Trokendi Xr
(topiramate)Dosage & Administration
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Trokendi XR Prescribing Information
Monotherapy Epilepsy
TROKENDI XR ®is indicated as initial monotherapy for the treatment of partial-onset or primary generalized tonic-clonic seizures in patients 6 years of age and older [see Clinical Studies (14.2)] .
Adjunctive Therapy Epilepsy
TROKENDI XR ®is indicated as adjunctive therapy for the treatment of partial-onset seizures, primary generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome in patients 6 years of age and older [see Clinical Studies (14.3)] .
Migraine
TROKENDI XR ®is indicated for the preventive treatment of migraine in patients 12 years of age and older [see Clinical Studies (14.4)] .
Dosing in Monotherapy Epilepsy
Adults and Pediatric Patients 10 Years of Age and Older with Partial Onset or Primary Generalized Tonic-Clonic Seizures
The recommended dose for TROKENDI XR monotherapy in adults and in pediatric patients 10 years of age and older is 400 mg orally once daily. Titrate TROKENDI XR ®according to the following schedule:
| Week 1: | 50 mg once daily | |
| Week 2: | 100 mg once daily | |
| Week 3: | 150 mg once daily | |
| Week 4: | 200 mg once daily | |
| Week 5: | 300 mg once daily | |
| Week 6: | 400 mg once daily |
Pediatric Patients Ages 6 to 9 Years of Age
Dosing in patients 6 to 9 years of age is based on weight. During the titration period, the initial dose of TROKENDI XR ®is 25 mg/day nightly for the first week. Based upon tolerability, the dosage can be increased to 50 mg/day in the second week. Dosage can be increased by 25 mg to 50 mg/day each subsequent week as tolerated. Titration to the minimum maintenance dose should be attempted over 5-7 weeks of the total titration period. Based upon tolerability and clinical response, additional titration to a higher dose (up to the maximum maintenance dose) can be attempted at 25 mg to 50 mg/day weekly increments. The total daily dose should not exceed the maximum maintenance dose for each range of body weight (see Table 1).
| Weight (kg) | Total Daily Dose (mg/day) Minimum Maintenance Dose | Total Daily Dose (mg/day) Maximum Maintenance Dose |
|---|---|---|
| Up to 11 | 150 | 250 |
| 12 - 22 | 200 | 300 |
| 23 - 31 | 200 | 350 |
| 32 - 38 | 250 | 350 |
| Greater than 38 | 250 | 400 |
Dosing in Adjunctive Therapy Epilepsy
Adults (17 Years of Age and Older)
The recommended total daily dose of TROKENDI XR ®as adjunctive therapy in adults with partial-onset seizures or Lennox-Gastaut Syndrome is 200 mg to 400 mg orally once daily and with primary generalized tonic-clonic seizures is 400 mg orally once daily. Initiate therapy at 25 mg to 50 mg once daily followed by titration to an effective dose in increments of 25 mg to 50 mg every week. Titrating in increments of 25 mg/day every week may delay the time to reach an effective dose. Doses above 400 mg/day have not been shown to improve responses in adults with partial-onset seizures.
Pediatric Patients 6 to 16 Years of Age
The recommended total daily dose of TROKENDI XR ®as adjunctive therapy for patients 6 to 16 years of age with partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome is approximately 5 mg/kg to 9 mg/kg orally once daily. Begin titration at 25 mg once daily (or less, based on a range of 1 mg/kg/day to 3 mg/kg/day) given nightly for the first week. Subsequently, increase the dosage at 1- or 2-week intervals by increments of 1 mg/kg/day to 3 mg/kg/day to achieve optimal clinical response. Dose titration should be guided by clinical outcome. The total daily dose should not exceed 400 mg/day.
Dosing for the Preventive Treatment of Migraine
The recommended total daily dose of TROKENDI XR ®as treatment for the preventive treatment of migraine in patients 12 years of age and older is 100 mg once daily. Titrate TROKENDI XR ®for the preventive treatment of migraine according to the following schedule:
| Week 1: | 25mg once daily | |
| Week 2: | 50mg once daily | |
| Week 3: | 75mg once daily | |
| Week 4: | 100mg once daily |
Dose and titration rate should be guided by clinical outcome. If required, longer intervals between dose adjustments can be used.
Administration With Alcohol
Alcohol use should be completely avoided within 6 hours prior to and 6 hours after TROKENDI XR ®administration [see Warnings and Precautions (5.5)] .
Dose Modifications in Patients With Renal Impairment
In patients with renal impairment (creatinine clearance less than 70 mL/min/1.73 m 2), one-half of the usual adult dose of TROKENDI XR is recommended [see Use in Specific Populations (8.5, 8.6), Clinical Pharmacology (12.3)] .
Dosage Modifications in Patients Undergoing Hemodialysis
To avoid rapid drops in topiramate plasma concentration during hemodialysis, a supplemental dose of TROKENDI XR may be required. The actual adjustment should take into account 1) the duration of dialysis period, 2) the clearance rate of the dialysis system being used, and 3) the effective renal clearance of topiramate in the patient being dialyzed [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)] .
Administration Instructions
TROKENDI XR ®can be taken without regard to meals.
Swallow capsule whole and intact. Do not sprinkle on food, chew, or crush.
TROKENDI XR ®extended-release capsules are available in the following strengths and colors:
- 25 mg: Size 2 capsules, light green opaque body/yellow opaque cap (printed "SPN" on the cap, "25" on the body)
- 50 mg: Size 0 capsules, light green opaque body/orange opaque cap (printed "SPN" on the cap, "50" on the body)
- 100 mg: Size 00 capsules, green opaque body/blue opaque cap (printed "SPN" on the cap, "100" on the body)
- 200 mg: Size 00 capsules, pink opaque body/blue opaque cap (printed "SPN" on the cap, "200" on the body)
Pregnancy
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as TROKENDI XR, during pregnancy. Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334. Information about the North American Drug Pregnancy Registry can be found at http://www.aedpregnancyregistry.org/.
Risk Summary
TROKENDI XR can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in uterohave increased risk of major congenital malformations, including but not limited to cleft lip and/or cleft palate (oral clefts), and of being small for gestational age (SGA) [see Human Data] . SGA has been observed at all doses and appears to be dose-dependent. The prevalence of SGA is greater in infants of women who received higher doses of topiramate during pregnancy. In addition, the prevalence of SGA in infants of women who continued topiramate use until later in pregnancy is higher compared to the prevalence in infants of women who stopped topiramate use before the third trimester.
In multiple animal species, topiramate demonstrated developmental toxicity, including increased incidences of fetal malformations, in the absence of maternal toxicity at clinically relevant doses [see Animal Data] .
All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively.
Clinical Considerations
Fetal/Neonatal Adverse reactions
Consider the benefits and risks of topiramate when prescribing this drug to women of childbearing potential, particularly when topiramate is considered for a condition not usually associated with permanent injury or death. Because of the risk of oral clefts to the fetus, which occur in the first trimester of pregnancy before many women know they are pregnant, all women of childbearing potential should be informed of the potential risk to the fetus from exposure to topiramate. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of topiramate use during pregnancy, and alternative therapeutic options should be considered for these patients.
Labor or Delivery
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.
TROKENDI XR treatment can cause metabolic acidosis [see Warnings and Precautions (5.4)] . 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 [see Warnings and Precautions (5.4)] . Newborns of mothers treated with TROKENDI XR should be monitored for metabolic acidosis because of transfer of topiramate to the fetus and possible occurrence of transient metabolic acidosis following birth.
Based on limited information, topiramate has also been associated with pre-term labor and premature delivery.
Data
Human Data
Data from pregnancy registries indicate an increased risk of major congenital malformations, including but not limited to oral clefts in infants exposed to topiramate during the first trimester of pregnancy. Other than oral clefts, no specific pattern of major congenital malformations or grouping of major congenital malformation types were observed. In the NAAED pregnancy registry, when topiramate-exposed infants with only oral clefts were excluded, the prevalence of major congenital malformations (4.1%) was higher than that in infants exposed to a reference AED (1.8%) or in infants with mothers without epilepsy and without exposure to AEDs (1.1%). The prevalence of oral clefts among topiramate-exposed infants (1.4%) was higher than the prevalence in infants exposed to reference AEDs (0.3%), or the prevalence in infants with mothers without epilepsy and without exposure to AEDs (0.11%). It was also higher than the background prevalence in United States (0.17%) as estimated by the Centers for Disease Control and Prevention (CDC). The relative risk of oral clefts in topiramate-exposed pregnancies in the NAAED Pregnancy Registry was 12.5 (95% Confidence Interval=[CI] 5.9-26.37) as compared to the risk in a background population of untreated women. The UK Epilepsy and Pregnancy Register reported a prevalence of oral clefts among infants exposed to topiramate monotherapy (3.2%) that was 16 times higher than the background rate in the UK (0.2%).
Data from the NAAED pregnancy registry and a population-based birth registry cohort indicate that exposure to topiramate in uterois associated with an increased risk of SGA newborns (birth weight <10th percentile). In the NAAED pregnancy registry, 19.7% of topiramate-exposed newborns were SGA compared to 7.9% of newborns exposed to a reference AED, and 5.4% of newborns of mothers without epilepsy and without AED exposure. In the Medical Birth Registry of Norway (MBRN), a population-based pregnancy registry, 25% of newborns in the topiramate monotherapy exposure group were SGA compared to 9% in the comparison group who were unexposed to AEDs. The long-term consequences of the SGA findings are not known.
Animal Data
When topiramate (0, 20, 100, or 500 mg/kg/day) was administered orally to pregnant mice during the period of organogenesis, incidences of fetal malformations (primarily craniofacial defects) were increased at all doses. Fetal body weights and skeletal ossification were reduced at the highest dose tested in conjunction with decreased maternal body weight gain. A no-effect dose for embryofetal developmental toxicity in mice was not identified. The lowest dose tested, which was associated with an increased incidence of malformations, is less than the maximum recommended human dose (MRHD) for epilepsy (400 mg/day) or migraine (100 mg/day) on a body surface area (mg/m 2) basis.
In pregnant rats administered topiramate (0, 20, 100, and 500 mg/kg/day or 0, 0.2, 2.5, 30, and 400 mg/kg/day) orally during the period of organogenesis, the frequency of limb malformations (ectrodactyly, micromelia, and amelia) was increased in fetuses at 400 and 500 mg/kg/day. Embryotoxicity (reduced fetal body weights, increased incidences of structural variations) was observed at doses as low as 20 mg/kg/day. Clinical signs of maternal toxicity were seen at 400 mg/kg/day and above, and maternal body weight gain was reduced at doses of 100 mg/kg/day or greater. The no-effect dose (2.5 mg/kg/day) for embryofetal developmental toxicity in rats is less than the MRHD for epilepsy or migraine on a mg/m 2basis.
In pregnant rabbits administered topiramate (0, 20, 60, and 180 mg/kg/day or 0, 10, 35, and 120 mg/kg/day) orally during organogenesis, embryofetal mortality was increased at 35 mg/kg/day and an increased incidence of fetal malformations (primarily rib and vertebral malformations) was observed at 120 mg/kg/day. Evidence of maternal toxicity (decreased body weight gain, clinical signs, and/or mortality) was seen at 35 mg/kg/day and above. The no-effect dose (20 mg/kg/day) for embryofetal developmental toxicity in rabbits is equivalent to the MRHD for epilepsy and approximately 4 times the MRHD for migraine on a mg/m 2basis.
When topiramate (0, 0.2, 4, 20, and 100 mg/kg/day or 0, 2, 20, and 200 mg/kg/day) was administered orally to female rats during the latter part of gestation and throughout lactation, offspring exhibited decreased viability and delayed physical development at 200 mg/kg/day and reductions in pre-and/or postweaning body weight gain at 2 mg/kg/day and above. Maternal toxicity (decreased body weight gain, clinical signs) was evident at 100 mg/kg/day or greater.
In a rat embryofetal development study which included postnatal assessment of offspring, oral administration of topiramate (0, 0.2, 2.5, 30, and 400 mg/kg/day) to pregnant animals during the period of organogenesis resulted in delayed physical development in offspring at 400 mg/kg/day and persistent reductions in body weight gain in offspring at 30 mg/kg/day and higher. The no-effect dose (0.2 mg/kg/day) for pre- and postnatal developmental toxicity is less than the MRHD for epilepsy or migraine on a mg/m 2basis.
Lactation
Risk Summary
Topiramate is excreted in human milk [see Data]. The effects of topiramate on milk production are unknown. Diarrhea and somnolence have been reported in breastfed infants whose mothers receive topiramate treatment.
The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for TROKENDI XR and any potential adverse effects on the breastfed infant from TROKENDI XR or from the underlying maternal condition.
Data
Limited data from 5 women with epilepsy treated with topiramate during lactation showed drug levels in milk similar to those in maternal plasma.
Females and Males of Reproductive Potential
Contraception
Women of childbearing potential who are not planning a pregnancy should use effective contraception because of the risk of major congenital malformations, including oral clefts, and the risk of infants being SGA [see Drug Interactions (7.5)and Use in Specific Populations (8.1)] .
Pediatric Use
Seizures in Pediatric Patients 6 Years of Age and Older
The safety and effectiveness of TROKENDI XR ®for treatment of partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndromes in pediatric patients at least 6 years of age is based on controlled trials with immediate-release topiramate [see Adverse Reactions (6.1), Clinical Studies (14.2, 14.3)] .
The adverse reactions in pediatric patients treated for partial onset seizure, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome are similar to those seen in adults [see Warnings and Precautions (5)and Adverse Reactions (6)] .
These include, but are not limited to:
- oligohydrosis and hyperthermia [see Warnings and Precautions (5.3)]
- dose-related increased incidence of metabolic acidosis [see Warnings and Precautions (5.4)]
- dose-related increased incidence of hyperammonemia [see Warnings and Precautions (5.13)]
Not Recommended for Pediatric Patients Younger than 6 Years of Age
The safety and effectiveness of TROKENDI XR for treatment of partial-onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndromes in pediatric patients younger than 6 years of age has not been established.
Because the capsule must be swallowed whole, and may not be sprinkled on food, crushed or chewed, TROKENDI XR ®is recommended only for children age 6 or older.
The following pediatric use information for adjunctive treatment for partial onset epilepsy in infants and toddlers (1 to 24 months) is based on studies conducted with immediate-release topiramate, which failed to demonstrate efficacy.
Safety and effectiveness of immediate-release topiramate in patients below the age of 2 years have not been established for the adjunctive therapy treatment of partial onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome. In a single randomized, double-blind, placebo-controlled investigational trial, the efficacy, safety, and tolerability of immediate-release topiramate oral liquid and sprinkle formulations as an adjunct to concurrent antiepileptic drug therapy in pediatric patients 1 to 24 months of age with refractory partial-onset seizures were assessed. After 20 days of double-blind treatment, immediate-release topiramate (at fixed doses of 5, 15, and 25 mg/kg per day) did not demonstrate efficacy compared with placebo in controlling seizures.
In general, the adverse reaction profile for immediate-release topiramate in this population was similar to that of older pediatric patients, although results from the above controlled study, and an open-label, long-term extension study in these pediatric patients 1 to 24 months old suggested some adverse reactions not previously observed in older pediatric patients and adults; i.e., growth/length retardation, certain clinical laboratory abnormalities, and other adverse reactions that occurred with a greater frequency and/or greater severity than had been recognized previously from studies in older pediatric patients or adults for various indications.
These very young pediatric patients appeared to experience an increased risk for infections (any topiramate dose 12%, placebo 0%) and of respiratory disorders (any topiramate dose 40%, placebo 16%). The following adverse reactions were observed in at least 3% of patients on immediate-release topiramate and were 3% to 7% more frequent than in patients on placebo: viral infection, bronchitis, pharyngitis, rhinitis, otitis media, upper respiratory infection, cough, and bronchospasm. A generally similar profile was observed in older pediatric patients [see Adverse Reactions (6.1)].
Immediate-release topiramate resulted in an increased incidence of patients with increased creatinine (any topiramate dose 5%, placebo 0%), BUN (any topiramate dose 3%, placebo 0%), and protein (any topiramate dose 34%, placebo 6%), and an increased incidence of decreased potassium (any topiramate dose 7%, placebo 0%). This increased frequency of abnormal values was not dose related. Creatinine was the only analyte showing a noteworthy increased incidence (topiramate 25 mg/kg/day 5%, placebo 0%) of a markedly abnormal increase [see Adverse Reactions (6.1)] . The significance of these findings is uncertain.
Immediate-release topiramate treatment also produced a dose-related increase in the percentage of patients who had a shift from normal at baseline to high/increased (above the normal reference range) in total eosinophil count at the end of treatment. The incidence of these abnormal shifts was 6 % for placebo, 10% for 5 mg/kg/day, 9% for 15 mg/kg/day, 14% for 25 mg/kg/day, and 11% for any topiramate dose [see Adverse Reactions (6.1)] . There was a mean dose-related increase in alkaline phosphatase. The significance of these findings is uncertain.
Topiramate produced a dose-related increased incidence of hyperammonemia [see Warnings and Precautions (5.13)] .
Treatment with immediate-release topiramate for up to 1 year was associated with reductions in Z SCORES for length, weight, and head circumference [see Warnings and Precautions (5.4)and Adverse Reactions (6)] .
In open-label, uncontrolled experience, increasing impairment of adaptive behavior was documented in behavioral testing over time in this population. There was a suggestion that this effect was dose-related. However, because of the absence of an appropriate control group, it is not known if this decrement in function was treatment related or reflects the patient's underlying disease (e.g., patients who received higher doses may have more severe underlying disease) [see Warnings and Precautions (5.7)] .
In this open-label, uncontrolled study, the mortality was 37 deaths/1000 patient years. It is not possible to know whether this mortality rate is related to immediate-release topiramate treatment, because the background mortality rate for a similar, significantly refractory, young pediatric population (1 month to 24 months) with partial epilepsy is not known.
Other Pediatric Studies
Topiramate treatment produced a dose-related increased shift in serum creatinine from normal at baseline to an increased value at the end of 4 months treatment in adolescent patients (ages 12 years to 16 years) in a double-blind, placebo-controlled study [see Adverse Reactions (6.1)] .
A one-year, active-controlled, open-label study with blinded assessments of bone mineral density (BMD) and growth in pediatric patients 4 to 15 years of age, including 63 patients with recent or new onset of epilepsy, was conducted to assess effects of immediate-release topiramate (N=28, 6-15 years of age) versus levetiracetam (N=35, 4-15 years of age) monotherapy on bone mineralization and on height and weight, which reflect growth. Effects on bone mineralization were evaluated via dual-energy X-ray absorptiometry and blood markers. Table 8 summarizes effects of immediate-release topiramate at 12 months for key safety outcomes including BMD, height, height velocity, and weight. All Least Square Mean values for immediate-release topiramate and the comparator were positive. Therefore, the Least Square Mean treatment differences shown reflect an immediate-release topiramate-induced attenuation of the key safety outcomes. Statistically significant effects were observed for decreases in BMD (and bone mineral content) in lumbar spine and total body less head and in weight. Subgroup analyses according to age demonstrated similar negative effects for all key safety outcomes (i.e., BMD, height, weight).
| Safety Parameter | Treatment Difference in Least Square Means (95 % Confidence Interval) | ||
|---|---|---|---|
| |||
| Annual Change in BMD Lumbar Spine (g/cm 2) | -0.036 | (-0.058, -0.014) | |
| Annual Change in BMD TBLH *(g/cm 2) | -0.026 | (-0.039, -0.012) | |
| Annual Change in Height (cm) (4-9 years, Primary Analysis Population for Height) † | -0.84 | (-2.67, 0.99) | |
| Annual Change in Height (cm) (4-15 years) | -0.75 | (-2.21, 0.71) | |
| Annual Change in Height (cm) (10-15 years) | -1.01 | (-3.64, 1.61) | |
| Height Velocity (cm/year) (4-9 years) | -1.00 | (-2.76, 0.76) | |
| Height Velocity (cm/year) (4-15 years) | -0.98 | (-2.33, 0.37) | |
| Height Velocity (cm/year) (10-15 years) | -0.96 | (-3.24, 1.32) | |
| Annual Change in Weight (kg) | -2.05 | (-3.66, -0.45) | |
Metabolic acidosis (serum bicarbonate <20 mEq/L) was observed in all immediate-release topiramate-treated patients at some time in the study [see Warnings and Precautions (5.4)]. Over the whole study, 76% more immediate-release topiramate-treated patients experienced persistent metabolic acidosis (i.e., 2 consecutive visits with or final serum bicarbonate < 20 mEq/L) compared to levetiracetam-treated patients. Over the whole study, 35% more immediate-release topiramate-treated patients experienced a markedly abnormally low serum bicarbonate (i.e., absolute value <17 mEq/L and ≥ 5mEq/L decrease from pre-treatment), indicating the frequency of more severe metabolic acidosis, compared to levetiracetam-treated patients. The decrease in BMD at 12 months was correlated with decreased serum bicarbonate, suggesting that metabolic acidosis was at least a partial factor contributing to this adverse effect on BMD.
Immediate-release topiramate-treated patients exhibited an increased risk for developing an increased serum creatinine and an increased serum glucose above the normal reference range compared to control patients.
Preventive Treatment of Migraine in Pediatric Patients 12 to 17 Years of Age
Safety and effectiveness of topiramate for the preventive treatment of migraine was studied in 5 double-blind, randomized, placebo-controlled, parallel-group trials in a total of 219 pediatric patients, at doses of 50 mg/day to 200 mg/day, or 2 to 3 mg/kg/day. These comprised a fixed dose study in 103 pediatric patients 12 to 17 years of age [see Clinical Studies (14.4)], a flexible dose (2 to 3 mg/kg/day), placebo-controlled study in 157 pediatric patients 6 to 16 years of age (including 67 pediatric patients 12 to 16 years of age), and a total of 49 pediatric patients 12 to 17 years of age in 3 studies for the preventive treatment of migraine primarily in adults. Open-label extension phases of 3 studies enabled evaluation of long-term safety for up to 6 months after the end of the double-blind phase.
Efficacy of topiramate for the preventive treatment of migraine in pediatric patients 12 to 17 years of age is demonstrated for a 100 mg daily dose in Study 3 [see Clinical Studies (14.4)]. Efficacy of topiramate (2 to 3 mg/kg/day) for the preventive treatment of migraine was not demonstrated in a placebo-controlled trial of 157 pediatric patients (6 to 16 years of age) that included treatment of 67 pediatric patients 12 to 16 years of age) for 20 weeks.
In the pediatric trials (12 to 17 years of age) in which patients were randomized to placebo or a fixed daily dose of immediate-release topiramate, the most common adverse reactions with 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 Adverse Reactions (6.1)] .
The most common cognitive adverse reaction in pooled double-blind studies in pediatric patients 12 to 17 years of age was difficulty with concentration/attention [see Warnings and Precautions (5.7)] .
Markedly abnormally low serum bicarbonate values indicative of metabolic acidosis were reported in topiramate-treated pediatric migraine patients [see Warnings and Precautions (5.4)] .
In topiramate-treated pediatric patients (12 to 17 years of age) compared to placebo-treated patients, abnormally increased results were more frequent for creatinine, BUN, uric acid, chloride, ammonia, total protein, and platelets. Abnormally decreased results were observed with topiramate vs placebo treatment for phosphorus and bicarbonate [see Adverse Reactions (6.1)] .
Notable changes (increases and decreases) from baseline in systolic blood pressure, diastolic blood pressure, and pulse that were observed occurred more commonly in pediatric patients treated with topiramate compared to pediatric patients treated with placebo [see Clinical Pharmacology (12.2)] .
Preventive Treatment of Migraine in Pediatric Patients 6 to 11 Years of Age
Safety and effectiveness in pediatric patients below the age of 12 years have not been established for the preventive treatment of migraine.
In a double-blind study in 90 pediatric patients 6 to 11 years of age (including 59 topiramate-treated and 31 placebo patients), the adverse reaction profile was generally similar to that seen in pooled double-blind studies of pediatric patients 12 to 17 years of age. The most common adverse reactions that occurred in immediate-release topiramate-treated pediatric patients 6 to 11 years of age, and at least twice as frequently than placebo, were gastroenteritis (12% topiramate, 6% placebo), sinusitis (10% topiramate, 3% placebo), weight loss (8% topiramate, 3% placebo) and paresthesia (7% topiramate, 0% placebo). Difficulty with concentration/attention occurred in 3 topiramate-treated patients (5%) and 0 placebo-treated patients.
The risk for cognitive adverse reactions was greater in younger patients (6 to 11 years of age) than in older patients (12 to 17 years of age) [see Warnings and Precautions (5.7)] .
Juvenile Animal Studies
When topiramate (30, 90, and 300 mg/kg/day) was administered orally to rats during the juvenile period of development (postnatal days 12 to 50), bone growth plate thickness was reduced in males at the highest dose, which is approximately 5-8 times the maximum recommended pediatric dose (9 mg/kg/day) on a body surface area (mg/m 2) basis.
Geriatric Use
Clinical studies of immediate-release topiramate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Dosage adjustment may be necessary for elderly with creatinine clearance less than 70 mL/min/1.73 m 2. Estimate GFR should be measured prior to dosing [see Dosage and Administration (2.5)and Clinical Pharmacology (12.3)] .
Renal Impairment
The clearance of topiramate is reduced in patients with moderate (creatinine clearance 30 to 69 mL/min/1.73m 2) and severe (creatinine clearance less than 30 mL/min/1.73m 2) renal impairment. A dosage adjustment is recommended in patients with moderate or severe renal impairment [see Dosage and Administration (2.5)and Clinical Pharmacology (12.3)] .
Patients Undergoing Hemodialysis
Topiramate is cleared by hemodialysis at a rate that is 4 to 6 times greater than in a normal individual. A dosage adjustment may be required [see Dosage and Administration (2.6)and Clinical Pharmacology (12.3)] .
TROKENDI XR ®is contraindicated in patients with recent alcohol use (i.e., within 6 hours prior to and 6 hours after TROKENDI XR ®use) [see Warnings and Precautions (5.5)]
Acute Myopia and Secondary Angle Closure Glaucoma Syndrome
A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving topiramate. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include some or all of the following: myopia, mydriasis, anterior chamber shallowing, ocular hyperemia (redness), choroidal detachments, retinal pigment epithelial detachments, macular striae, and increased intraocular pressure. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating topiramate therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with topiramate has been reported in pediatric patients as well as adults. The primary treatment to reverse symptoms is discontinuation of TROKENDI XR ®as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation of TROKENDI XR ®, may be helpful.
Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss.
Visual Field Defects
Visual field defects (independent of elevated intraocular pressure) have been reported in clinical trials and in postmarketing experience in patients receiving topiramate. In clinical trials, most of these events were reversible after topiramate discontinuation. If visual problems occur at any time during treatment with TROKENDI XR, consideration should be given to discontinuing the drug.
Oligohydrosis and Hyperthermia
Oligohydrosis (decreased sweating), resulting in hospitalization in some cases, has been reported in association with topiramate use. Decreased sweating and an elevation in body temperature above normal characterized these cases. Some of the cases were reported after exposure to elevated environmental temperatures.
The majority of the reports have been in pediatric patients. Patients, especially pediatric patients, treated with TROKENDI XR ®should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. Caution should be used when TROKENDI XR ®is given with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, other carbonic anhydrase inhibitors and drugs with anticholinergic activity .
Metabolic Acidosis
TROKENDI XR ®can cause hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis). This metabolic acidosis is caused by renal bicarbonate loss due carbonic anhydrase inhibition by TROKENDI XR. TROKENDI XR ®-induced metabolic acidosis can occur at any time during treatment. Bicarbonate decrements are usually mild to moderate (average decrease of 4 mEq/L at daily doses of 400 mg in adults and at approximately 6 mg/kg/day in pediatric patients); rarely, patients can experience severe decrements to values below 10 mEq/L. Conditions or therapies that predispose patients to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, ketogenic diet, or specific drugs) may be additive to the bicarbonate lowering effects of TROKENDI XR.
Metabolic acidosis was commonly observed in adult and pediatric patients treated with immediate-release topiramate in clinical trials. The incidence of decreased serum bicarbonate in pediatric trials for adjunctive treatment of Lennox-Gastaut syndrome or refractory partial onset seizures was as high as 67% for immediate-release topiramate (at approximately 6 mg/kg/day), and 10% for placebo. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value <17 mEq/L and ≥ 5 mEq/L decrease from pretreatment) in these trials was up to 11%, compared to ≤ 2% for placebo.
Manifestations of acute or chronic metabolic acidosis may include hyperventilation, nonspecific symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or stupor. Chronic, untreated metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis and may also result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with an increased risk for fractures [see Warnings and Precautions (5.10, 5.14)] . A one-year, active-controlled study of pediatric patients treated with immediate-release topiramate demonstrated that immediate-release topiramate decreased lumbar spine bone mineral density and that this lumbar spine bone mineral density decrease was correlated (using change from baseline for lumbar spine Z score at final visit versus lowest post-treatment serum bicarbonate) with decreased serum bicarbonate, a reflection of metabolic acidosis [see Warnings and Precautions (5.10), Use in Specific Populations (8.4)]. Chronic metabolic acidosis in pediatric patients may also reduce growth rates, which may decrease the maximal height achieved. Long-term, open-label treatment of pediatric patients 1 to 24 months old with intractable partial epilepsy, for up to 1 year, showed reductions from baseline in length, weight, and head circumference compared to age and sex-matched normative data, although these patients with epilepsy are likely to have different growth rates than normal 1 to 24 month old pediatrics. Reductions in length and weight were correlated to the degree of acidosis [see Use in Specific Populations (8.4)] . TROKENDI XR treatment that causes metabolic acidosis during pregnancy can possibly produce adverse effects on the fetus and might also cause metabolic acidosis in the neonate from possible transfer of topiramate to the fetus [see Warnings and Precautions (5.8)and Use in Specific Populations (8.1)] .
Measurement of Serum Bicarbonate in Epilepsy and Migraine Patients
Measurement of baseline and periodic serum bicarbonate during topiramate treatment is recommended. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing TROKENDI XR (using dose tapering). If the decision is made to continue patients on TROKENDI XR in the face of persistent acidosis, alkali treatment should be considered.
Interaction With Alcohol
In vitrodata show that, in the presence of alcohol, the pattern of topiramate release from TROKENDI XR ®capsules is significantly altered. As a result, plasma levels of topiramate with TROKENDI XR ®may be markedly higher soon after dosing and subtherapeutic later in the day. Therefore, alcohol use should be completely avoided within 6 hours prior to and 6 hours after TROKENDI XR ®administration .
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.
| Indication | Placebo Patients with Events per 1,000 Patients | Drug Patients with Events per 1,000 Patients | Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients | Risk Difference: Additional Drug Patients with Events per 1,000 Patients |
|---|---|---|---|---|
| Epilepsy | 1.0 | 3.4 | 3.5 | 2.4 |
| Psychiatric | 5.7 | 8.5 | 1.5 | 2.9 |
| Other | 1.0 | 1.8 | 1.9 | 0.9 |
| Total | 2.4 | 4.3 | 1.8 | 1.9 |
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing TROKENDI XR ®or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Cognitive/Neuropsychiatric Adverse Reactions
Immediate-release topiramate can cause, and therefore expected to be caused by TROKENDI XR ®, cognitive/neuropsychiatric adverse reactions. The most frequent of these can be classified into three general categories: 1) Cognitive-related dysfunction (e.g., confusion, psychomotor slowing, difficulty with concentration/attention, difficulty with memory, speech or language problems, particularly word-finding difficulties); 2) Psychiatric/behavioral disturbances (e.g., depression or mood problems); and 3) Somnolence or fatigue.
Adult Patients
Cognitive-Related Dysfunction
Rapid titration rate and higher initial dose were associated with higher incidences of cognitive-related dysfunction.
In adult adjunctive epilepsy controlled trials, which used rapid titration (100-200 mg/day weekly increments), and target immediate-release topiramate doses of 200 mg – 1000 mg/day, 56% of patients in the 800 mg/day and 1000 mg/day dose groups experienced cognitive-related dysfunction compared to approximately 42% of patients in the 200 - 400 mg/day groups and 14% for placebo. In this rapid titration regimen, these dose-related adverse reactions began in the titration or in the maintenance phase, and in some patients these events began during titration and persisted into the maintenance phase.
In the monotherapy epilepsy controlled trial conducted with immediate-release topiramate, the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50 mg per day and 26% for 400 mg per day.
In the 6-month controlled trials for the preventive treatment of migraine with immediate release topiramate using a slower titration regimen (25mg per day weekly increments), the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50 mg per day, 22% for 100 mg per day (the recommended dose), 28% for 200 mg per day and 10% for placebo. Cognitive adverse reactions most commonly developed during titration and sometimes persisted after completion of titration.
Psychiatric/Behavioral Disturbances
Psychiatric/behavioral disturbances (e.g., depression, mood) were dose-related for both the adjunctive epilepsy and migraine populations treated with topiramate [see Warnings and Precautions (5.6)].
Somnolence/Fatigue
Somnolence and fatigue were the adverse reactions most frequently reported during clinical trials of topiramate for adjunctive epilepsy. For the adjunctive epilepsy population, the incidence of fatigue was dose-related. For the monotherapy epilepsy population, the incidence of somnolence was dose-related. For the migraine population, the incidences of both somnolence and fatigue were dose-related and more common in the titration phase.
Pediatric Patients
In pediatric epilepsy trials (adjunctive and monotherapy) conducted with topiramate, the incidence of cognitive/neuropsychiatric adverse reactions in pediatric patients was generally lower than that observed in adults. These reactions included psychomotor slowing, difficulty with concentration/attention, speech disorders/related speech problems and language problems. The most frequently reported neuropsychiatric reactions in pediatric epilepsy patients during adjunctive therapy double-blind studies were somnolence and fatigue. The most frequently reported cognitive/neuropsychiatric reactions in pediatric epilepsy patients in the 50 mg/day and 400 mg/day groups during the monotherapy double-blind study were headache, dizziness, anorexia, and somnolence.
In pediatric migraine patients, the incidence of cognitive/neuropsychiatric adverse reactions was increased in immediate-release topiramate-treated patients compared to placebo.
The risk for cognitive/neuropsychiatric adverse reactions was dose-dependent, and was greatest at the highest dose (200 mg). This risk for cognitive/neuropsychiatric adverse reactions was also greater in younger patients (6 to 11 years of age) than in older patients (12 to 17 years of age). The most common cognitive/neuropsychiatric adverse reaction in these trials was difficulty with concentration/attention. Cognitive adverse reactions most commonly developed during titration and sometimes persisted for various durations after completion of titration. The Cambridge Neuropsychological Test Automated Battery (CANTAB) was administered to adolescents (12 to 17 years of age) to assess the effects of topiramate on cognitive function at baseline at the end of the Study 3 [see Clinical Studies (14.4)]. Mean change from baseline in certain CANTAB tests suggests that topiramate treatment may result in psychomotor slowing and decreased verbal fluency.
Fetal Toxicity
TROKENDI XR can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in uterohave an increased risk of major congenital malformations, including but not limited to cleft lip and/or cleft palate (oral clefts), and of being small for gestational age (SGA). When multiple species of pregnant animals received topiramate at clinically relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring [see Use in Specific Populations (8.1)] .
Consider the benefits and risks of TROKENDI XR ®when administering the drug in women of childbearing potential, particularly when TROKENDI XR ®is considered for a condition not usually associated with permanent injury or death [see Use in Specific Populations (8.1)] . TROKENDI XR ®should be used during pregnancy only if the potential benefit outweighs the potential risk. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to a fetus [see Use in Specific Populations (8.1)] .
Withdrawal of Antiepileptic Drugs
In patients with or without a history of seizures or epilepsy, antiepileptic drugs, including TROKENDI XR ®, should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency [see Clinical Studies (14)] . In situations where rapid withdrawal of TROKENDI XR ®is medically required, appropriate monitoring is recommended.
Decrease in Bone Mineral Density
Results of a one-year active-controlled study in pediatric patients (N=63) demonstrated negative effects of immediate-release topiramate monotherapy on bone mineral acquisition via statistically significant decreases in bone mineral density (BMD) measured in lumbar spine and in total body less head [see Use in Specific Populations (8.4)]. Twenty-one percent of immediate-release topiramate-treated patients experienced clinically important reductions in BMD (Z score change from baseline of -0.5 or greater) compared to 0 patients in the control group. Although decreases in BMD occurred across all pediatric age subgroups, patients 6 to 9 years of age were most commonly affected. The sample size and study duration were too small to determine if fracture risk is increased. Decreased BMD in the lumbar spine was correlated with decreased serum bicarbonate, which commonly occurs with topiramate treatment and reflects metabolic acidosis, a known cause of increased bone resorption [see Warnings and Precautions (5.4)]. Although small decreases in some markers of bone metabolism (e.g., serum alkaline phosphatase, calcium, phosphorus, and 1,25-dihydroxyvitamin D) occurred in immediate-release topiramate-treated patients, more significant decreases in serum parathyroid hormone and 25-hydroxyvitamin D, hormones involved in bone metabolism, were observed, along with an increased excretion of urinary calcium.
Negative Effects on Growth (Height and Weight)
Results of a one-year active-controlled study of pediatric patients (N=63) demonstrated negative effects of immediate-release topiramate monotherapy on growth (i.e., height and weight) [see Use in Specific Populations (8.4)]. Although continued growth was observed in both treatment groups, the immediate-release topiramate group showed statistically significant reductions in mean annual change from baseline in body weight compared to the control group. A similar trend of attenuation in height velocity and height change from baseline was also observed in the immediate-release topiramate group compared to the control group. Negative effects on weight and height were seen across all immediate-release topiramate age subgroups. Growth (height and weight) of children receiving prolonged TROKENDI XR ®therapy should be carefully monitored.
Serious Skin Reactions
Serious skin reactions (Stevens-Johnson Syndrome [SJS] and Toxic Epidermal Necrolysis [TEN]) have been reported in patients receiving topiramate. TROKENDI XR should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. Inform patients about the signs of serious skin reactions.
Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid Use)
Topiramate treatment can cause hyperammonemia with or without encephalopathy [see Adverse Reactions (6.2)] . The risk for hyperammonemia with topiramate appears dose-related. Hyperammonemia has been reported more frequently when topiramate is used concomitantly with valproic acid. Postmarketing cases of hyperammonemia with or without encephalopathy have been reported with topiramate and valproic acid in patients who previously tolerated either drug alone [see Drug Interactions (7.2)] .
Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy and/or vomiting. In most cases, hyperammonemic encephalopathy abated with discontinuation of treatment.
The incidence of hyperammonemia in pediatric patients 12 to 17 years of age in the preventive treatment of migraine trials was 26% in patients taking topiramate monotherapy at 100 mg/day, and 14% in patients taking topiramate at 50 mg/day, compared to 9% in patients taking placebo. There was also an increased incidence of markedly increased hyperammonemia at the 100 mg dose.
Dose-related hyperammonemia was also seen in pediatric patients 1 to 24 months of age treated with topiramate and concomitant valproic acid for partial onset epilepsy, and this was not due to a pharmacokinetic interaction.
In some patients, hyperammonemia can be asymptomatic.
Monitoring for Hyperammonemia
Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, topiramate or TROKENDI XR ®treatment or an interaction of concomitant topiramate-based product and valproic acid treatment may exacerbate existing defects or unmask deficiencies in susceptible persons.
In patients who develop unexplained lethargy, vomiting, or changes in mental status associated with any topiramate treatment, hyperammonemic encephalopathy should be considered and an ammonia level should be measured.
Kidney Stones
Topiramate increases the risk of kidney stones. During adjunctive epilepsy trials, the risk for kidney stones in immediate-release topiramate-treated adults was 1.5%, an incidence about 2 to 4 times greater than expected in a similar, untreated population. As in the general population, the incidence of stone formation among topiramate-treated patients was higher in men. Kidney stones have also been reported in pediatric patients taking topiramate for epilepsy or migraine. During long-term (up to 1 year) topiramate treatment in an open-label extension study of 284 pediatric patients 1-24 months old with epilepsy, 7% developed kidney or bladder stones. TROKENDI XR ®would be expected to have the same effect as immediate-release topiramate on the formation of kidney stones. TROKENDI XR ®is not approved for treatment of epilepsy in pediatric patients less than 6 years old [see Use in Specific Populations (8.4)] .
Topiramate is a carbonic anhydrase inhibitor. Carbonic anhydrase inhibitors can promote stone formation by reducing urinary citrate excretion and by increasing urinary pH [see Warnings and Precautions (5.4)] . The concomitant use of TROKENDI XR ®with any other drug producing metabolic acidosis, or potentially in patients on a ketogenic diet, may create a physiological environment that increases the risk of kidney stone formation, and should therefore be avoided.
Increased fluid intake increases the urinary output, lowering the concentration of substances involved in stone formation. Hydration is recommended to reduce new stone formation.
An increase in urinary calcium and a marked decrease in urinary citrate was observed in immediate-release topiramate-treated pediatric patients in a one-year active-controlled study [see Use in Specific Populations (8.4)]. This increased ratio of urinary calcium/citrate increases the risk of kidney stones and/or nephrocalcinosis.
Hypothermia With Concomitant Valproic Acid Use
Hypothermia, defined as a drop in body core temperature to < 35°C (95°F), has been reported in association with topiramate use with concomitant valproic acid (VPA) both in conjunction with and in the absence of hyperammonemia. This adverse reaction in patients using concomitant topiramate and valproate can occur after starting topiramate treatment or after increasing the daily dose of topiramate [see Drug Interactions (7.2)] . Consideration should be given to stopping TROKENDI XR or valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels.