Trokendi Xr

— THERAPEUTIC CATEGORIES —
  • Migraine and headache
  • Seizure disorders
PAGE CONTENTS
  • Jump to Section
  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Trokendi Xr Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Topiramate 25mg, 50mg, 100mg, 200mg; ext-rel caps.

    Pharmacological Class

    Sulfamate.

    How Supplied

    XR caps—7, 30, 100

    How Supplied

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

    • 25 mg (light green opaque body/yellow opaque cap with black print "SPN" and "25"):

      • Bottles of 7-, 30-, and 100-count

      • Blister packages of 30-count

    • 50 mg (light green opaque body/orange opaque cap with black print "SPN" and "50"):

      • Bottles of 7-, 30-, and 100-count

      • Blister packages of 30-count

    • 100 mg (green opaque body/blue opaque cap with black print "SPN" and "100"):

      • Bottles of 7-, 30-, and 100-count

      • Blister packages of 30-count

    • 200 mg (pink opaque body/blue opaque cap with black print "SPN" and "200"):

      • Bottles of 7-, 30-, and 100-count

      • Blister packages of 30-count

    Storage

    Trokendi XR (topiramate) extended-release capsules should be stored in well closed containers at controlled room temperature [25°C (77°F); excursions 15°C-30°C (59°F-86°F)]. Protect from moisture and light.

    Manufacturer

    Supernus Pharmaceuticals, Inc.

    Trokendi Xr Indications

    Indications

    Prophylaxis of migraine headache.

    Trokendi Xr Dosage and Administration

    Adult

    Swallow whole. Do not sprinkle on food, chew, or crush. Initially 25mg once daily, increase at 1-week intervals by increments of 25mg/week to target dose of 100mg once daily. Renal impairment (CrCl <70mL/min): reduce dose by ½. Hemodialysis: may need extra dose.

    Children

    <12yrs: not established.

    Renal Impairment

    • The clearance of topiramate is reduced in patients with moderate (creatinine clearance 30 to 69 mL/min/1.73m2) and severe (creatinine clearance less than 30 mL/min/1.73m2) renal impairment. A dosage adjustment is recommended in patients with moderate or severe renal impairment.

    • 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.

    Other Modifications

    Females and Males of Reproductive Potential 

    • Contraception: Advise women of childbearing potential who are not planning a pregnancy to use effective contraception due to risks of the fetus of oral clefts and of being small for gestational age.

    Trokendi Xr Contraindications

    Contraindications

    Recent alcohol use (within 6hrs prior to and 6hrs after topiramate ext-rel).

    Trokendi Xr Boxed Warnings

    Not Applicable

    Trokendi Xr Warnings/Precautions

    Warnings/Precautions

    Discontinue if acute myopia and secondary angle-closure glaucoma syndrome occur. Consider discontinuing if visual problems occur. Measure baseline and periodic serum bicarbonate during therapy; consider reducing dose or discontinuing if acidosis occurs. Inborn errors of metabolism, reduced hepatic mitochondrial activity: increased risk of hyperammonemia; measure ammonia levels if encephalopathic symptoms occur. Monitor on growth (during prolonged therapy), oligohidrosis, and hyperthermia esp. in children. Suicidal tendencies (monitor). Discontinue at the 1st sign of a rash. Kidney stones. Maintain adequate hydration; avoid ketogenic diets. Renal impairment; obtain CrCl prior to initiation. Avoid abrupt cessation. Fetal toxicity (eg, congenital malformations, oral clefts, small for gestational age). Labor & delivery. Pregnancy. Advise females of reproductive potential to use effective contraception during therapy. Nursing mothers.

    Warnings/Precautions

    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 typically occur within 1 month of initiating topiramate therapy.

    • Discontinue if acute myopia and secondary angle-closure glaucoma syndrome occur.

    Visual Field Defects

    • Consider discontinuing if visual problems occur at any time during treatment.

    Oligohydrosis and Hyperthermia 

    • Majority of cases were reported in pediatric patients.

    • Monitor closely for evidence of decreased sweating and increased body temperature, especially in hot weather.

    • Use caution when Trokendi XR is given with other drugs that predispose patients to heat-related disorders; these drugs include, but not limited to, other carbonic anhydrase inhibitors and drugs with anticholinergic activity.

    Metabolic Acidosis  

    • May cause hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis).

    • Increased risk of metabolic acidosis in patients with renal disease, severe respiratory disorders, status epilepticus, diarrhea, ketogenic diet, or specific drugs.

    • Measure baseline and periodic serum bicarbonate during therapy; consider reducing dose or discontinuing if acidosis occurs. If the decision is made to continue treatment with Trokendi XR in the face of persistent acidosis, alkali treatment should be considered.

    Interaction With Alcohol 

    • Completely avoid alcohol use within 6 hours prior to or after Trokendi XR administration.

    Suicidal Behavior and Ideation

    • Increased risk of suicidal thoughts or behavior.

    • Monitor for the emergence or worsening of depression, suicidal thoughts, or behavior, and/or any unusual changes in mood or behavior.

    Cognitive/Neuropsychiatric Adverse Reactions

    • Use caution when operating machinery including cars. Depression and mood problems may occur.

    Fetal Toxicity 

    • May cause fetal harm. Consider the benefits and risks of Trokendi XR when administering the drug in women of childbearing potential.

    Withdrawal of Antiepileptic Drugs

    • Gradually withdraw to minimize the potential for seizures or increased seizure frequency.

    • Monitor appropriately is recommended in situations where rapid withdrawal of Trokendi XR is medically required.

    Negative Effects on Growth (Height and Weight) 

    • 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.

    • Discontinue at the first sign of a rash, unless the rash is clearly not drug-realted.

    • Do not resume treatment and consider alternative therapy if signs or symptoms suggest SJS/TEN.

    Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid Use)

    • Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk of hyperammonemia with or without encephalopathy.

    • Measure ammonia levels if patients develop unexplained lethargy, vomiting, or changes in mental status associated with any topiramate treatment and consider hyperammonemic encephalopathy. 

    Kidney Stones 

    • Increased risk of kidney stones especially concomitant use with any other drug producing metabolic acidosis, or potentially in patients on a ketogenic diet, and should be avoided.

    • Hydration is recommended.

    Hypothermia With Concomitant Valproic Acid Use

    • 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.

    Pregnancy Considerations

    Pregnancy Exposure Registry  

    • 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 

    • May cause fetal harm. Infants exposed to topiramate in utero have increased risk for cleft lip and/or cleft palate and for being small for gestational age.

    • The prevalence of SGA in infants of women is higher with topiramate use until later in pregnancy compared with the prevalence in infants of women who stopped topiramate use before the third trimester.

    Clinical Considerations

    • Fetal/Neonatal Adverse reactions: Consider the benefits and risks of topiramate when prescribing this drug to women of childbearing potential. Counsel women on the relative risks and benefits during pregnancy, and consider alternative therapeutic options.

    • Labor or Delivery: The effect of topiramate on labor and delivery in humans has not been established. Monitor pregnant patients and newborns of mothers treated with Trokendi XR for metabolic acidosis.

    Nursing Mother Considerations

    Risk Summary

    • Consider the developmental and health benefits of breastfeeding 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.

    Pediatric Considerations

    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 younger than 6 years of age has not been established.

    Preventive Treatment of Migraine in Pediatric Patients 12 to 17 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.

    Geriatric Considerations

    Dosage adjustment may be necessary for elderly with creatinine clearance less than 70 mL/min/1.73 m2. Estimate GFR should be measured prior to dosing.

    Renal Impairment Considerations

    • The clearance of topiramate is reduced in patients with moderate (creatinine clearance 30 to 69 mL/min/1.73m2) and severe (creatinine clearance less than 30 mL/min/1.73m2) renal impairment. A dosage adjustment is recommended in patients with moderate or severe renal impairment.

    • 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.

    Other Considerations for Specific Populations

    Females and Males of Reproductive Potential 

    • Contraception: Advise women of childbearing potential who are not planning a pregnancy to use effective contraception due to risks of the fetus of oral clefts and of being small for gestational age.

    Trokendi Xr Pharmacokinetics

    Absorption

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

    Distribution

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

    Metabolism

    Topiramate is not extensively metabolized and is primarily eliminated unchanged in the urine (approximately 70% of an administered dose). The metabolites are formed via hydroxylation, hydrolysis, and glucuronidation. 

     

    Elimination

    Overall, oral plasma clearance (CL/F) is approximately 20 mL/min to 30 mL/min in adults following oral administration. The mean elimination half-life of topiramate was approximately 31 hours following repeat administration of Trokendi XR. 

    Trokendi Xr Interactions

    Interactions

    See Contraindications. Increased severity of metabolic acidosis and risk of kidney stone formation with concomitant other carbonic anhydrase inhibitors (eg, zonisamide, acetazolamide, dichlorphenamide); monitor. Phenytoin, carbamazepine reduce topiramate levels; may need to adjust dose. May potentiate amitriptyline, phenytoin levels. May antagonize oral contraceptives, valproic acid. May be potentiated by HCTZ. CNS depression potentiated with alcohol, other CNS depressants; avoid. Hyperammonemia (w/ or w/o encephalopathy) and/or hypothermia possible with valproic acid. Monitor glucose with pioglitazone. Caution with other drugs that interfere with temperature regulation (eg, anticholinergics, carbonic anhydrase inhibitors). Monitor lithium levels with high-dose topiramate. May be antagonized by valproic acid, lamotrigine.

    Trokendi Xr Adverse Reactions

    Adverse Reactions

    Paresthesia, anorexia, weight decrease, speech disorders/related speech problems, fatigue, dizziness, somnolence, nervousness, psychomotor slowing, abnormal vision, difficulty with memory/concentration/attention, fever, taste perversion, upper RTI, abdominal pain, diarrhea, hypoesthesia, nausea; metabolic acidosis, cognitive/neuropsychiatric reactions, serious skin reactions (eg, SJS, TEN), decrease in bone mineral density.

    Trokendi Xr Clinical Trials

    Clinical Trials

    Preventive Treatment of Migraine 

    Adult Patients

    • The efficacy of immediate-release topiramate in the preventive treatment of migraine was evaluated in 2 identical, multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trials conducted in the US (Study 11) or the US and Canada (Study 12).

    • The trials included patients with a history of migraine with or without aura for at least 6 months. Patients were required to have completed up to a 2-week washout of any prior migraine preventative medications before starting the baseline phase.

    • Patients who experienced 3 to 12 migraine headaches over the 4 weeks in the baseline phase were randomly assigned to either immediate-release topiramate 50mg/day, 100mg/day, 200mg/day or placebo for a total of 26 weeks. Effectiveness was assessed by the reduction in migraine headache frequency, as measured by the change in 4-week migraine rate from the baseline phase to double-blind period.

    • In Study 11, the change in the mean 4-week migraine headache frequency from baseline to the double-blind phase was -1.3, -2.1, and -2.2 in the topiramate 50mg/day, 100mg/day, and 200mg/day treatment arms vs -0.8 in the placebo arm. The placebo-adjusted treatment differences for the 100mg and 200mg arms were similar and statistically significant (P <.001 for both).

    • In Study 12, the change in the mean 4-week migraine headache frequency from baseline to the double-blind phase was -1.4, -2.1, and -2.4 in the topiramate 50mg/day, 100mg/day, and 200mg/day treatment arms vs -1.1 in the placebo arm. The placebo-adjusted treatment differences for the 100mg and 200mg arms were similar and statistically significant (P =.008 and P <.001, respectively).

    Pediatric Patients 12 to 17 Years of Age 

    • The efficacy of immediate-release topiramate in the preventive treatment of migraine was evaluated in a multicenter, randomized, double-blind, parallel-group clinical trial (Study 13).

    • The trials included patients 12 to 17 years of age with episodic migraine headaches with or without aura. Patients who experienced 3 to 12 migraine attacks and ≤14 headache days during the 4-week prospective baseline period over the 4 weeks in the baseline phase were randomly assigned to either immediate-release topiramate 50mg/day, 100mg/day or placebo for a total of 16 weeks. Effectiveness was assessed by the percent reduction from baseline to the last 12 weeks of the double-blind phase in the monthly migraine attack rate.

    • In Study 13, patients treated with topiramate 100mg/day achieved a 72.2% median reduction in the monthly migraine attack rate vs 44.4% median reduction for patients treated with placebo (P =.0164).

    • The mean reduction from baseline to the last 12 weeks of the double-blind phase in average monthly attack rate was 3.0 for 100mg and 1.7 for placebo (treatment difference, 1.3; P =.0087).

    Trokendi Xr Note

    Not Applicable

    Trokendi Xr Patient Counseling

    Cost Savings Program

    Trokendi Co-pay Savings and Support

    Trokendi Xr Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Topiramate 25mg, 50mg, 100mg, 200mg; ext-rel caps.

    Pharmacological Class

    Sulfamate.

    How Supplied

    XR caps—7, 30, 100

    How Supplied

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

    • 25 mg (light green opaque body/yellow opaque cap with black print "SPN" and "25"):

      • Bottles of 7-, 30-, and 100-count

      • Blister packages of 30-count

    • 50 mg (light green opaque body/orange opaque cap with black print "SPN" and "50"):

      • Bottles of 7-, 30-, and 100-count

      • Blister packages of 30-count

    • 100 mg (green opaque body/blue opaque cap with black print "SPN" and "100"):

      • Bottles of 7-, 30-, and 100-count

      • Blister packages of 30-count

    • 200 mg (pink opaque body/blue opaque cap with black print "SPN" and "200"):

      • Bottles of 7-, 30-, and 100-count

      • Blister packages of 30-count

    Storage

    Trokendi XR (topiramate) extended-release capsules should be stored in well closed containers at controlled room temperature [25°C (77°F); excursions 15°C-30°C (59°F-86°F)]. Protect from moisture and light.

    Manufacturer

    Supernus Pharmaceuticals, Inc.

    Trokendi Xr Indications

    Indications

    Initial monotherapy and adjunct in partial-onset or primary generalized tonic-clonic seizures. Adjunct in Lennox-Gastaut Syndrome.

    Trokendi Xr Dosage and Administration

    Adult

    Swallow whole. Do not sprinkle on food, chew, or crush. Monotherapy: initially 50mg once daily, increase at 1-week intervals by increments of 50mg/week for the first 4 weeks, then increase by 100mg/week for Weeks 5–6 to target dose of 400mg once daily. Adjunctive therapy: ≥17yrs: initially 25–50mg once daily, increase at 1-week intervals by 25–50mg/week until target dose of 200–400mg once daily (partial onset seizures or Lennox-Gastaut) or 400mg once daily (primary generalized tonic-clonic seizures). Renal impairment (CrCl <70mL/min): reduce dose by ½. Hemodialysis: may need extra dose.

    Children

    Swallow whole. Do not sprinkle on food, chew, or crush. Monotherapy: <6yrs: not established. 6–9yrs (dosing based on weight): Titration period: initially 25mg/day in the PM for the first week, if tolerated, can increase to 50mg/day in second week. Dosage can be increased by 25–50mg/day each subsequent week as tolerated. Attempt titration to the minimum maintenance dose over 5–7 weeks and to the maximum maintenance dose by 25–50mg/day weekly increments (see full labeling). Total daily maintenance dose: (up to 11kg): 150–250mg/day; (12–22kg): 200–300mg/day; (23–31kg): 200–350mg/day; (32–38kg): 250–350mg/day; (>38kg): 250–400mg/day. ≥10yrs: initially 50mg once daily, increase at 1-week intervals by increments of 50mg/week for the first 4 weeks, then increase by increments of 100mg/week for Weeks 5–6 to target dose of 400mg once daily. Adjunctive therapy: <6yrs: not established. 6–16yrs: initially 1–3mg/kg (max 25mg) once daily in the PM for one week, increase at 1- or 2-week intervals by increments of 1–3mg/kg to target range of 5–9mg/kg once daily or until optimal clinical response; max 400mg/day. Renal impairment (CrCl <70mL/min): reduce dose by ½. Hemodialysis: may need extra dose.

    Renal Impairment

    • The clearance of topiramate is reduced in patients with moderate (creatinine clearance 30 to 69 mL/min/1.73m2) and severe (creatinine clearance less than 30 mL/min/1.73m2) renal impairment. A dosage adjustment is recommended in patients with moderate or severe renal impairment.

    • 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.

    Other Modifications

    Females and Males of Reproductive Potential 

    • Contraception: Advise women of childbearing potential who are not planning a pregnancy to use effective contraception due to risks of the fetus of oral clefts and of being small for gestational age.

    Trokendi Xr Contraindications

    Contraindications

    Recent alcohol use (within 6hrs prior to and 6hrs after topiramate ext-rel).

    Trokendi Xr Boxed Warnings

    Not Applicable

    Trokendi Xr Warnings/Precautions

    Warnings/Precautions

    Discontinue if acute myopia and secondary angle-closure glaucoma syndrome occur. Consider discontinuing if visual problems occur. Measure baseline and periodic serum bicarbonate during therapy; consider reducing dose or discontinuing if acidosis occurs. Inborn errors of metabolism, reduced hepatic mitochondrial activity: increased risk of hyperammonemia; measure ammonia levels if encephalopathic symptoms occur. Monitor on growth (during prolonged therapy), oligohidrosis, and hyperthermia esp. in children. Suicidal tendencies (monitor). Discontinue at the 1st sign of a rash. Kidney stones. Maintain adequate hydration; avoid ketogenic diets. Renal impairment; obtain CrCl prior to initiation. Avoid abrupt cessation. Fetal toxicity (eg, congenital malformations, oral clefts, small for gestational age). Labor & delivery. Pregnancy. Advise females of reproductive potential to use effective contraception during therapy. Nursing mothers.

    Warnings/Precautions

    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 typically occur within 1 month of initiating topiramate therapy.

    • Discontinue if acute myopia and secondary angle-closure glaucoma syndrome occur.

    Visual Field Defects

    • Consider discontinuing if visual problems occur at any time during treatment.

    Oligohydrosis and Hyperthermia 

    • Majority of cases were reported in pediatric patients.

    • Monitor closely for evidence of decreased sweating and increased body temperature, especially in hot weather.

    • Use caution when Trokendi XR is given with other drugs that predispose patients to heat-related disorders; these drugs include, but not limited to, other carbonic anhydrase inhibitors and drugs with anticholinergic activity.

    Metabolic Acidosis  

    • May cause hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis).

    • Increased risk of metabolic acidosis in patients with renal disease, severe respiratory disorders, status epilepticus, diarrhea, ketogenic diet, or specific drugs.

    • Measure baseline and periodic serum bicarbonate during therapy; consider reducing dose or discontinuing if acidosis occurs. If the decision is made to continue treatment with Trokendi XR in the face of persistent acidosis, alkali treatment should be considered.

    Interaction With Alcohol 

    • Completely avoid alcohol use within 6 hours prior to or after Trokendi XR administration.

    Suicidal Behavior and Ideation

    • Increased risk of suicidal thoughts or behavior.

    • Monitor for the emergence or worsening of depression, suicidal thoughts, or behavior, and/or any unusual changes in mood or behavior.

    Cognitive/Neuropsychiatric Adverse Reactions

    • Use caution when operating machinery including cars. Depression and mood problems may occur.

    Fetal Toxicity 

    • May cause fetal harm. Consider the benefits and risks of Trokendi XR when administering the drug in women of childbearing potential.

    Withdrawal of Antiepileptic Drugs

    • Gradually withdraw to minimize the potential for seizures or increased seizure frequency.

    • Monitor appropriately is recommended in situations where rapid withdrawal of Trokendi XR is medically required.

    Negative Effects on Growth (Height and Weight) 

    • 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.

    • Discontinue at the first sign of a rash, unless the rash is clearly not drug-realted.

    • Do not resume treatment and consider alternative therapy if signs or symptoms suggest SJS/TEN.

    Hyperammonemia and Encephalopathy (Without and With Concomitant Valproic Acid Use)

    • Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk of hyperammonemia with or without encephalopathy.

    • Measure ammonia levels if patients develop unexplained lethargy, vomiting, or changes in mental status associated with any topiramate treatment and consider hyperammonemic encephalopathy. 

    Kidney Stones 

    • Increased risk of kidney stones especially concomitant use with any other drug producing metabolic acidosis, or potentially in patients on a ketogenic diet, and should be avoided.

    • Hydration is recommended.

    Hypothermia With Concomitant Valproic Acid Use

    • 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.

    Pregnancy Considerations

    Pregnancy Exposure Registry  

    • 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 

    • May cause fetal harm. Infants exposed to topiramate in utero have increased risk for cleft lip and/or cleft palate and for being small for gestational age.

    • The prevalence of SGA in infants of women is higher with topiramate use until later in pregnancy compared with the prevalence in infants of women who stopped topiramate use before the third trimester.

    Clinical Considerations

    • Fetal/Neonatal Adverse reactions: Consider the benefits and risks of topiramate when prescribing this drug to women of childbearing potential. Counsel women on the relative risks and benefits during pregnancy, and consider alternative therapeutic options.

    • Labor or Delivery: The effect of topiramate on labor and delivery in humans has not been established. Monitor pregnant patients and newborns of mothers treated with Trokendi XR for metabolic acidosis.

    Nursing Mother Considerations

    Risk Summary

    • Consider the developmental and health benefits of breastfeeding 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.

    Pediatric Considerations

    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 younger than 6 years of age has not been established.

    Preventive Treatment of Migraine in Pediatric Patients 12 to 17 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.

    Geriatric Considerations

    Dosage adjustment may be necessary for elderly with creatinine clearance less than 70 mL/min/1.73 m2. Estimate GFR should be measured prior to dosing.

    Renal Impairment Considerations

    • The clearance of topiramate is reduced in patients with moderate (creatinine clearance 30 to 69 mL/min/1.73m2) and severe (creatinine clearance less than 30 mL/min/1.73m2) renal impairment. A dosage adjustment is recommended in patients with moderate or severe renal impairment.

    • 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.

    Other Considerations for Specific Populations

    Females and Males of Reproductive Potential 

    • Contraception: Advise women of childbearing potential who are not planning a pregnancy to use effective contraception due to risks of the fetus of oral clefts and of being small for gestational age.

    Trokendi Xr Pharmacokinetics

    Absorption

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

    Distribution

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

    Metabolism

    Topiramate is not extensively metabolized and is primarily eliminated unchanged in the urine (approximately 70% of an administered dose). The metabolites are formed via hydroxylation, hydrolysis, and glucuronidation. 

     

    Elimination

    Overall, oral plasma clearance (CL/F) is approximately 20 mL/min to 30 mL/min in adults following oral administration. The mean elimination half-life of topiramate was approximately 31 hours following repeat administration of Trokendi XR. 

    Trokendi Xr Interactions

    Interactions

    See Contraindications. Increased severity of metabolic acidosis and risk of kidney stone formation with concomitant other carbonic anhydrase inhibitors (eg, zonisamide, acetazolamide, dichlorphenamide); monitor. Phenytoin, carbamazepine reduce topiramate levels; may need to adjust dose. May potentiate amitriptyline, phenytoin levels. May antagonize oral contraceptives, valproic acid. May be potentiated by HCTZ. CNS depression potentiated with alcohol, other CNS depressants; avoid. Hyperammonemia (w/ or w/o encephalopathy) and/or hypothermia possible with valproic acid. Monitor glucose with pioglitazone. Caution with other drugs that interfere with temperature regulation (eg, anticholinergics, carbonic anhydrase inhibitors). Monitor lithium levels with high-dose topiramate. May be antagonized by valproic acid, lamotrigine.

    Trokendi Xr Adverse Reactions

    Adverse Reactions

    Paresthesia, anorexia, weight decrease, speech disorders/related speech problems, fatigue, dizziness, somnolence, nervousness, psychomotor slowing, abnormal vision, difficulty with memory/concentration/attention, fever, taste perversion, upper RTI, abdominal pain, diarrhea, hypoesthesia, nausea; metabolic acidosis, cognitive/neuropsychiatric reactions, serious skin reactions (eg, SJS, TEN), decrease in bone mineral density.

    Trokendi Xr Clinical Trials

    Clinical Trials

    Monotherapy Epilepsy

    Patients With Partial-Onset or Primary Generalized Tonic-Clonic Seizures (Patients Aged ≥10yrs)

    • The efficacy of topiramate as initial monotherapy in adults and pediatric patients10 years of age and older with partial onset or primary generalized tonic-clonic seizures in a multicenter, randomized, double-blind, dose-controlled, parallel-group trial (Study 1).

    • Study 1 included 487 patients diagnosed with epilepsy who were randomly assigned to titrate up to 50mg/day or 400mg/day of topiramate. The primary endpoint was a between-group comparison of time to first seizure during the double-blind phase.

    • Results showed that the treatment effects with respect to time to first seizure were consistent across various patient subgroups defined by age, sex, geographic region, baseline body weight, baseline seizure type, time since diagnosis, and baseline AED use.

    Patients With Partial-Onset or Primary Generalized Tonic-Clonic Seizures (Pediatric Patients 6 to 9 Years of Age)

    • Topiramate was found to be effective as initial monotherapy in pediatric patients 6 to 9 years of age with partial-onset or primary generalized tonic-clonic seizures based on a pharmacometric bridging approach using data from the controlled epilepsy trials conducted with immediate-release topiramate.

     

    Adjunctive Therapy Epilepsy 

    Adult Patients With Partial-Onset Seizures

    • The efficacy of topiramate as an adjunctive treatment for adults with a history of partial-onset seizures, with or without secondarily generalized seizures, was established in 6 multicenter, randomized, double-blind, placebo-controlled trials (Studies 2, 3, 4, 5, 6, and 7). In 2 of the studies, several doses of topiramate were compared with placebo. In 4 of the studies, a single dosage of topiramate was compared with placebo.

    • In these studies, patients were allowed to take a maximum of 2 antiepileptic drugs (AEDs) in addition to topiramate or placebo. Patients who experienced a prespecified minimum number of partial-onset seizures with or without secondary generalized seizures during the baseline phase were randomly assigned to receive either placebo or a specified dose of topiramate in addition to their AEDs.

    • The median percent reductions in seizure rates and the responder rates (fraction of patients with at least a 50% reduction) for topiramate and placebo were measured.

    • Study 2: 

      • Median % reduction:

        • 27% for 200mg/day; 48% for 400mg/day; 45% for 600mg/day vs 12% for placebo

      • % responders: 

        • 24% for 200mg/day; 44% for 400mg/day; 46% for 600mg/day vs 18% for placebo

    • Study 3: 

      • Median % reduction:

        • 48% for 600mg/day; 48% for 800mg/day; 47% for 1000mg/day vs 2% for placebo

      • % responders: 

        • 40% for 600mg/day; 41% for 800mg/day; 36% for 1000mg/day vs 9% for placebo

    • Study 4: 

      • Median % reduction:

        • 41% for 400mg/day vs 1% for placebo

      • % responders: 

        • 35% for 400mg/day vs 8% for placebo

    • Study 5: 

      • Median % reduction:

        • 46% for 600mg/day vs -12% for placebo

      • % responders: 

        • 47% for 600mg/day vs 10% for placebo

    • Study 6: 

      • Median % reduction:

        • 24% for 800mg/day vs -21% for placebo

      • % responders: 

        • 43% for 800mg/day vs 0% for placebo

    • Study 7: 

      • Median % reduction:

        • 44% for 200mg/day vs 20% for placebo

      • % responders: 

        • 45% for 200mg/day vs 24% for placebo

    Pediatric Patients 6 to 16 Years of Age With Partial-Onset Seizures

    • The efficacy of topiramate as an adjunctive treatment for pediatric patients 6 to 16 years of age with a history of partial-onset seizures, with or without secondarily generalized seizures, was established in a multicenter, randomized, double-blind, placebo-controlled trials (Study 8).

    • In the study, patients were allowed to take a maximum of 2 AEDs in addition to topiramate or placebo. Patients whoexperienced at least 6 partial-onset seizures with or without secondary generalized seizures during the baseline phase were randomly assigned to receive either placebo or a specified dose of topiramate in addition to their AEDs.

    • The median percent reductions in seizure rates and the responder rates (fraction of patients with at least a 50% reduction) for topiramate and placebo were measured.

    • Study 8: 

      • Median % reduction:

        • 33% for 6mg/kg/day vs 11% for placebo

      • % responders: 

        • 39% for 6mg/kg/day vs 20% for placebo

    Patients With Primary Generalized Tonic-Clonic Seizures

    • The efficacy of topiramate as an adjunctive treatment for patients 6 years of age and older with primary generalized tonic-clonic seizures was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 9).

    • In the study, patients were allowed to take a maximum of 2 AEDs in addition to topiramate or placebo. Patients who experienced at least 3 primary generalized tonic-clonic seizures during the baseline phase were randomly assigned to receive either placebo or a specified dose of topiramate in addition to their AEDs.

    • The median percent reductions in seizure rates and the responder rates (fraction of patients with at least a 50% reduction) for topiramate and placebo were measured.

    • Study 9: 

      • Median % reduction:

        • 57% for 6mg/kg/day vs 9% for placebo

      • % responders: 

        • 56% for 6mg/kg/day vs 20% for placebo

    Patients With Lennox-Gastaut Syndrome

    • The efficacy of topiramate as an adjunctive treatment for patients 6 years of age and older with seizures associated with Lennox-Gastaut syndrome was established in a multicenter, randomized, double-blind, placebo-controlled trial (Study 10).

    • In the study, patients were allowed to take a maximum of 2 AEDs in addition to topiramate or placebo. Patients who experienced at least 60 seizures per month before study entry.

    • The median percent reductions in seizure rates and the responder rates (fraction of patients with at least a 50% reduction) for topiramate and placebo were measured.

    • Study 10: 

      • Median % reduction:

        • 15% for 6mg/kg/day vs -5% for placebo

      • % responders: 

        • 28% for 6mg/kg/day vs 14% for placebo

      • Improvement in Seizure Severity:

        • 52% for 6mg/kg/day vs 28% for placebo

    Trokendi Xr Note

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