Version May 2024
Dosage guidance:
Safety: Do not abruptly discontinue therapy; taper dosage gradually to prevent rebound effects.
Dosage form information: Concentrations of oral solution/suspension may vary (commercially available oral solution [25 mg/mL] versus extemporaneously compounded); should be prescribed as mg of topiramate; use caution.
Neonatal seizures, refractory: Limited data available; optimal dose not established; efficacy results variable:
Preterm neonate: Oral: Immediate release: Initial: 0.5 to 1 mg/kg/day titrated up daily or every other day by 0.5 to 1 mg/kg/day until seizure control was achieved; effective doses ranged from 3.5 to 8 mg/kg/day; dosing based on a case series of 3 preterm neonates (GA: 28 to 33 weeks; birthweight: 1,105 to 1,595 g) with refractory seizures; all patients remained seizure free ~1 year after discharge with topiramate monotherapy (Ref). Another case series of 10 preterm neonates used a higher dose of 10 mg/kg/day on day 1 followed by 2 to 5 mg/kg/day, efficacy results not reported; however, 40% of the patients developed necrotizing enterocolitis within 7 days of initiating topiramate (Ref).
Term neonate: Oral: Immediate release: 10 mg/kg/day was used in 5 neonates and 3 mg/kg/day was used in 1 neonate who were refractory to phenobarbital. In 4 of the 5 patients who received the higher dose, an absence or reduction in seizure frequency was observed; the neonate who received low dose (3 mg/kg) had no apparent change in seizures; no adverse effects noted required discontinuation of therapy (Ref).
Neuroprotectant following anoxic injury (with therapeutic hypothermia): Limited data available; optimal dose not established; efficacy results variable:
Term neonate: Oral: Immediate release: 5 mg/kg/dose on day 1 followed by 3 mg/kg/dose once daily for 2 to 5 days; dosing based on a randomized trial and a prospective case control safety trial. In the randomized, placebo, controlled trial, topiramate at a dose of 5 mg/kg/dose on day 1 followed by 3 mg/kg/dose once daily for 5 days was administered to 49 neonates with hypoxic ischemic encephalopathy and compared to placebo. Topiramate achieved therapeutic concentrations (5 to 20 mg/L) within 24 hours in 36.9% of patients and within 48 hours in 75.5% of the patients. Compared to placebo, patients on topiramate experienced fewer seizures; however, this did not reach statistical significance (Ref). The safety study used 5 mg/kg/dose on day 1 followed by 3 mg/kg/dose once daily on day 2 and 3 in 11 neonates; no adverse effects were noted (Ref). In an earlier pharmacokinetic pilot study of 13 neonates, the same investigators used 5 mg/kg/dose once daily for 3 days; results showed targeted serum concentrations (5 to 20 ng/mL) were achieved in 11 of 13 patients with some accumulation in patients treated with deep hypothermia (Ref). A dose of 10 mg/kg/dose once daily for 3 days beginning at the time of therapeutic hypothermia (TH) was studied in a randomized trial which compared topiramate with TH (n=21) and TH alone (n=23) in neonates (GA: ≥36 weeks; birthweight: ≥1,800 g) with moderate to severe hypoxic-ischemic encephalopathy; no statistically significant difference in the combined outcome of mortality and severe neurodevelopmental disability at 18 months was found; however, a trend of lower incidence of epilepsy at 18 to 24 months follow-up (14.3% topiramate with TH versus 30.4% TH alone) was noted (Ref).
Dosage guidance:
Safety: Do not abruptly discontinue therapy; taper dosage gradually to prevent rebound effects.
Dosage form information: Concentration of oral solution/suspension may vary (commercially available oral solution [25 mg/mL] versus extemporaneously compounded); should be prescribed as mg of topiramate; use caution.
Infantile spasms; monotherapy or adjunctive: Limited data available, efficacy results variable. Not first-line therapy, but may be considered in refractory cases (Ref).
Infants and Children <4 years: Oral: Immediate release: Initial dose: 0.5 to 1 mg/kg/day in divided doses twice daily; may titrate based on clinical response and tolerance in 0.5 to 1 mg/kg/day increments at 5- to 7-day intervals; reported range: 2 to 40 mg/kg/day (Ref).
Dosing based on an open-label trial of 544 patients diagnosed with infantile spasms (349 infants; 243 patients on monotherapy); initial topiramate dose was 0.5 to 1 mg/kg/day; doses were titrated as appropriate; reported final dose range: 3.57 to 20 mg/kg/day. After 20 weeks of therapy, 460 patients (84.5%) had a >50% reduction in seizures and seizure freedom was attained in 122 (50.2%) as monotherapy and in 117 (38.9%) as add-on therapy (Ref). A higher median initial dose of 1.6 mg/kg/day was reported in another trial of 100 patients (median age: 11.9 months; range: 3.6 to 45.1 months; 36 patients on monotherapy); patients were titrated to an effective final dose; reported final dose range: 2 to 40 mg/kg/day; results showed reduction in infantile spasms from a median of 40 episodes/week to a median of 15 episodes/week and 47 patients had a >50% reduction in all seizures. No difference in efficacy was observed for final dose stratifications of low dose (n=31; 2 to 8 mg/kg/day), medium dose (n=39; 9 to 17 mg/kg/day), or high dose (n=24; 18 to 40 mg/kg/day) (Ref). However, other trials have reported a poor response to topiramate; in a single-center trial evaluating 31 infants and young children, 9.7% (3/31) achieved remission with topiramate (responder maximum dose range: 25 to 28 mg/kg/day), and all experienced subsequent electroclinical relapse (Ref).
Migraine, prevention:
Note: Pediatric migraine efficacy trials have been observed to have a high placebo response; a meta-analysis has shown that 30% to 61% of subjects receiving placebo report decreased number of migraine attacks or decrease in headache days. Specific to topiramate therapy, trials have shown a reduction in number of headache days and migraine attacks compared to placebo; there is insufficient evidence in pediatric subjects receiving topiramate to demonstrate a 50% reduction in headache frequency, headache day, and migraine disability compared to placebo (Ref).
Children 6 to <12 years; weight: ≥20 kg: Limited data available: Oral: Immediate release: Initial: 15 mg once daily for 1 week; then increase to 15 mg twice daily for 1 week; then increase to 25 mg twice daily for 7 days; continue to gradually titrate to effect up to target dose of 2 to 3 mg/kg/day divided twice daily; maximum daily dose: 200 mg/day has been reported; however, in older pediatric patients, a targeted daily dose of 100 mg/day is recommended (Ref). Dosing based on a double-randomized, placebo-controlled trial of 90 pediatric patients <12 years (treatment arm: n=59; mean age: 11.3 years as part of a larger trial with a total of 108 pediatric patients receiving topiramate compared to 49 receiving placebo) which showed a mean reduction in migraine days/month with topiramate and significantly more topiramate patients experienced ≥75% reduction in mean monthly migraine days compared to placebo (32% vs 14%) for overall study population; mean maintenance dose: 2 mg/kg/day; treatment duration of maintenance dose: 12 weeks (Ref).
Children ≥12 years and Adolescents:
Immediate release: Oral: Initial: 25 mg/day once daily at night for 1 week; increase at weekly intervals in 25 mg/day increments as tolerated and indicated to recommended dose of 50 mg twice daily; in a double-blind, placebo-controlled, dose-finding trial of 103 pediatric patients ≥12 years (mean age: 14.2 years), the daily dose of 100 mg/day was shown to significantly decrease frequency of migraine attacks compared to a lower dose of 50 mg/day (Ref).
Extended release: Qudexy XR, Trokendi: Oral: Initial: 25 mg/day once daily at night for 1 week; increase at weekly intervals in 25 mg/day increments as tolerated and indicated to recommended dose of 100 mg/day; during titration, some patients may require longer intervals prior to dose escalation.
Seizure disorder, adjunctive therapy for partial onset seizures, primary generalized tonic-clonic seizures, or Lennox Gastaut syndrome :
Children and Adolescents 2 to 16 years:
Immediate release: Children and Adolescents 2 to 16 years: Oral: Initial: 1 to 3 mg/kg/day (maximum dose: 25 mg/dose) administered nightly for 1 week; increase at 1- to 2-week intervals in increments of 1 to 3 mg/kg/day in 2 divided doses; titrate dose to response; usual maintenance: 5 to 9 mg/kg/day in 2 divided doses; maximum daily dose: 400 mg/day.
Extended release:
Qudexy XR: Children and Adolescents 2 to 16 years: Oral: Initial: 25 mg once daily (approximately 1 to 3 mg/kg/day) administered nightly for 1 week; increase at 1- to 2-week intervals in increments of 1 to 3 mg/kg/day rounded to the nearest appropriate capsule size administered once daily; titrate dose to response; usual maintenance range: 5 to 9 mg/kg/dose once daily; maximum daily dose: 400 mg/day.
Trokendi XR: Children and Adolescents 6 to 16 years, able to swallow capsule whole: Oral: Initial: 25 mg once daily (approximately 1 to 3 mg/kg/day) administered nightly for 1 week; increase at 1- to 2-week intervals in increments of 1 to 3 mg/kg/day rounded to the nearest appropriate capsule size administered once daily; titrate dose to response; usual maintenance: 5 to 9 mg/kg/dose once daily; maximum daily dose: 400 mg/day.
Adolescents ≥17 years:
Immediate release: Oral: Initial: 25 to 50 mg/day administered daily for 1 week; increase at weekly intervals by 25 to 50 mg/day; administer in 2 divided doses; titrate dose to response. Usual maintenance dose dependent on seizure type; for partial onset seizures or Lennox-Gastaut syndrome: 100 to 200 mg twice daily; usual maintenance dose for primary generalized tonic-clonic seizures 200 mg twice daily; maximum daily dose: 400 mg/day; Note: Doses above 400 mg/day have not been shown to increase efficacy in dose-response studies in adults with partial onset seizures.
Extended release: Qudexy XR, Trokendi XR: Oral: Initial: 25 to 50 mg once daily for 1 week; increase at weekly intervals by 25 to 50 mg/day once daily; titrate dose to response; longer intervals between dosage adjustment may be used; usual maintenance dose for partial onset seizures or Lennox Gastaut syndrome: 200 to 400 mg once daily; usual maintenance dose for primary generalized tonic-clonic seizures: 400 mg once daily; maximum daily dose: 400 mg/day; higher doses have not been studied.
Seizure disorder, monotherapy for partial onset seizures or primary generalized tonic-clonic seizures :
Immediate release:
Children 2 to <10 years: Oral: Initial: 25 mg once daily (in evening); may increase if tolerated to 25 mg twice daily in week 2; thereafter, may increase by 25 to 50 mg/day at weekly intervals over 5 to 7 weeks up to the lower end of the target daily maintenance dosing range (ie, to the minimum recommended maintenance dose); if additional seizure control is needed and therapy is tolerated, may further increase by 25 to 50 mg/day at weekly intervals up to the upper end of the target daily maintenance dosing range (ie, to the maximum recommended maintenance dose):
Target daily fixed maintenance dosing range:
≤11 kg: 150 to 250 mg/day in 2 divided doses.
12 to 22 kg: 200 to 300 mg/day in 2 divided doses.
23 to 31 kg: 200 to 350 mg/day in 2 divided doses.
32 to 38 kg: 250 to 350 mg/day in 2 divided doses.
>38 kg: 250 to 400 mg/day in 2 divided doses.
Children ≥10 years and Adolescents: Oral: Initial: 25 mg twice daily; increase at weekly intervals by 50 mg/day increments up to a dose of 100 mg twice daily (week 4 dose); thereafter, may further increase at weekly intervals by 100 mg/day increments up to the recommended maximum dose of 200 mg twice daily.
Extended release:
Qudexy XR:
Children 2 to 9 years: Oral: Initial: 25 mg once daily (in evening); may increase if tolerated to 50 mg once daily in week 2; thereafter, may increase by 25 to 50 mg/day at weekly intervals over 5 to 7 weeks up to the lower end of the target daily maintenance dosing range (ie, to the minimum recommended maintenance dose); if additional seizure control is needed and therapy is tolerated, may further increase by 25 to 50 mg/day at weekly intervals up to the upper end of the target daily maintenance dosing range (ie, to the maximum recommended maintenance dose); see the following table.
|
Monotherapy Targeted Total Daily Fixed Maintenance Doses for Patients 2 to 9 Years | ||
|---|---|---|
|
Patient Weight |
Total MINimum Daily Dose (mg/day) |
Total MAXimum Daily Dose (mg/day) |
|
≤11 kg |
150 |
250 |
|
12 to 22 kg |
200 |
300 |
|
23 to 31 kg |
200 |
350 |
|
32 to 38 kg |
250 |
350 |
|
>38 kg |
250 |
400 |
Children ≥10 years and Adolescents: Oral: Initial: 50 mg once daily for 1 week; increase at weekly intervals by 50 mg/day increments up to a dose of 200 mg once daily (week 4 dose); thereafter, may increase at weekly intervals by 100 mg/day increments up to the recommended dose of 400 mg once daily.
Trokendi XR:
Children 6 to 9 years able to swallow capsule whole: Oral: Initial: 25 mg once daily (in evening); may increase if tolerated to 50 mg once daily in week 2; thereafter, may increase by 25 to 50 mg/day at weekly intervals over 5 to 7 weeks up to the lower end of the target daily maintenance dosing range (ie, to the minimum recommended maintenance dose); if additional seizure control is needed and therapy is tolerated, may further increase by 25 to 50 mg/day at weekly intervals up to the upper end of the target daily maintenance dosing range (ie, to the maximum recommended maintenance dose); see the following table.
|
Monotherapy Targeted Total Daily Fixed Maintenance Doses for Patients 6 to 9 Years of Age | ||
|---|---|---|
|
Patient Weight |
Total MINimum Daily Dose (mg/day) |
Total MAXimum Daily Dose (mg/day) |
|
≤11 kg |
150 |
250 |
|
12 to 22 kg |
200 |
300 |
|
23 to 31 kg |
200 |
350 |
|
32 to 38 kg |
250 |
350 |
|
>38 kg |
250 |
400 |
Children ≥10 years and Adolescents: Oral: Initial: 50 mg once daily for 1 week; increase at weekly intervals by 50 mg/day increments up to a dose of 200 mg once daily (week 4 dose); thereafter, may increase at weekly intervals by 100 mg/day increments up to the recommended dose of 400 mg once daily.
Discontinuation of antiseizure therapy: There is currently no standard method for the withdrawal of antiseizure medications in pediatric patients. Successful discontinuation of an antiseizure medication is dependent on several factors including but not limited to: Time of seizure freedom, underlying reason for the seizures, neuroimaging abnormalities, underlying neurodevelopmental status, and medication to be withdrawn (including dose, duration of therapy, and other pharmacokinetic/dynamic considerations) (Ref). In general, do not abruptly discontinue topiramate therapy; taper dosage gradually to prevent rebound effects. If rapid discontinuation required (eg, adverse effect management), appropriate monitoring necessary (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Altered Kidney Function:
Children ≥2 years and Adolescents: There are no pediatric-specific dosage adjustments provided in the manufacturer's labeling. Clearance is reduced in patients with CrCl of <70 mL/minute/1.73 m2 and a dosage adjustment is recommended. Based on adult data, a 50% dosage reduction may be required in patients with a CrCl <70 mL/minute/1.73 m2 (Ref).
Hemodialysis: Children ≥2 years and Adolescents: Removed by hemodialysis, supplemental dose may be required (Ref).
Children and Adolescents: There are no dosage adjustments provided in the manufacturer's labeling; however, clearance may be reduced. Carefully adjust dose as plasma concentrations may be increased if normal dosing is used.
(For additional information see "Topiramate: Drug information")
Dosage guidance:
Dosing: The dosing recommendations in this monograph are expressed as the total daily dose (ie, per 24 hours) unless stated otherwise. The total daily oral dose is given in 1 to 2 divided doses per day depending on the type of preparation (immediate release is dosed twice daily and extended release is dosed once daily).
Alcohol use disorder, moderate to severe (alternative agent) (off-label use):
Note: Reserve use for patients who do not tolerate or respond to naltrexone or acamprosate, especially if a concomitant seizure disorder is present (Ref).
Oral: Immediate release: Initial: 25 mg once daily; increase daily dose gradually (eg, in 25 to 50 mg increments weekly) to a maximum of 300 mg/day. Doses >50 mg/day should be administered in 2 divided doses (Ref). Some experts consider alternative therapy if goals are not met within 6 months of treatment (Ref).
Binge eating disorder (alternative agent) (off-label use):
Oral: Initial: 25 mg once daily; increase dose gradually in progressively larger increments of 25 to 100 mg at intervals ≥1 week based on response and tolerability up to 400 mg/day in 1 to 2 divided doses based on chosen formulation (immediate release is dosed twice daily and extended release is dosed once daily) (Ref).
Cluster headache (prevention) (alternative agent; adjunctive therapy) (off-label use):
Note: Some experts often use in combination with verapamil (Ref).
Oral: Initial: 25 to 50 mg once daily; increase dose gradually in 25 to 50 mg increments at intervals ≥1 week based on response and tolerability, up to a recommended dose of 100 mg/day in 1 to 2 divided doses based on chosen formulation (immediate release is dosed twice daily and extended release is dosed once daily); a further increase up to 200 mg/day may be necessary in some patients for optimal response (Ref).
Headache, short-lasting unilateral neuralgiform attacks (prevention) (alternative agent) (off-label use): Based on limited data:
Oral: Initial: 15 to 25 mg once daily; may increase dose based on response and tolerability in 25 mg increments every 2 weeks up to 100 mg/day in 1 to 2 divided doses based on chosen formulation, and thereafter in 50 mg increments every few weeks up to 400 mg/day in 1 to 2 divided doses based on chosen formulation (immediate release is dosed twice daily and extended release is dosed once daily) (Ref).
Migraine, prevention:
Note: An adequate trial for assessment of effect is considered to be at least 2 to 3 months at a therapeutic dose (Ref).
Oral: Initial: 25 mg once daily; increase dose in 25 to 50 mg increments at intervals ≥1 week based on response and tolerability, up to 100 mg/day in 1 to 2 divided doses based on chosen formulation (immediate release is dosed twice daily and extended release is dosed once daily). Some patients may require up to 200 mg/day for optimal response; however, adverse effects may increase (Ref).
Seizures:
Note: FDA-approved as monotherapy and adjunctive therapy for focal (partial) onset seizures and primary generalized tonic-clonic seizures, or as adjunctive therapy for Lennox-Gastaut syndrome; may be used off label for other seizure types.
Monotherapy: Oral: Initial: 50 mg/day; increase dose in 50 mg increments at weekly intervals based on response and tolerability up to 200 mg/day in 1 to 2 divided doses based on chosen formulation; thereafter, may further increase in 100 mg increments at weekly intervals up to 400 mg/day in 1 to 2 divided doses based on chosen formulation (immediate release is dosed twice daily and extended release is dosed once daily).
Adjunctive therapy: Oral: Initial: 25 to 50 mg/day; increase in 25 to 50 mg increments at weekly intervals based on response and tolerability up to 400 mg/day in 1 to 2 divided doses based on chosen formulation (immediate release is dosed twice daily and extended release is dosed once daily).
Tremor, essential (alternative agent for patients who fail preferred therapies) (off-label use):
Oral: Initial: 25 mg once or twice daily; increase dose gradually in increments of 25 to 50 mg at intervals ≥1 week based on response and tolerability up to 400 mg/day in 1 to 2 divided doses based on chosen formulation (immediate release is dosed twice daily and extended release is dosed once daily) (Ref).
Weight gain, antipsychotic-induced (alternative agent; adjunct to behavioral and antipsychotic modifications) (off-label use):
Oral: Initial: 50 mg/day; increase in 25 to 50 mg increments at weekly intervals based on response and tolerability up to a recommended dose of 200 mg/day in 1 to 2 divided doses based on chosen formulation (immediate release is dosed twice daily and extended release is dosed once daily) (Ref).
Dosing conversion:
Between IR and ER formulations: Convert using same total daily dose but adjust frequency as indicated for the IR (2 times daily) and ER (once daily) products.
Between ER formulations: Bioequivalence has not been demonstrated between Trokendi XR and Qudexy XR.
Discontinuation of therapy: In patients receiving topiramate long-term, unless safety concerns require a more rapid withdrawal, topiramate should be withdrawn gradually over a few weeks to several months to minimize the potential of seizures or other withdrawal symptoms (Ref). In clinical trials, adult doses were decreased by 50 to 100 mg each week over 2 to 8 weeks for seizure treatment, and by 25 to 50 mg each week for migraine prophylaxis.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function (Ref):
Oral:
CrCl ≥70 to <130 mL/minute/1.73 m2: No dosage adjustment necessary.
CrCl <70 mL/minute/1.73 m2: Reduce dose to 50% of the indication-specific usual dose and titrate more slowly.
Augmented renal clearance (measured urinary CrCl ≥130 mL/minute/1.73 m2):
Note: Augmented renal clearance (ARC) is a condition that occurs in certain critically ill patients without organ dysfunction and with normal serum creatinine concentrations. Young patients (<55 years of age) admitted post trauma or major surgery are at highest risk for ARC, as well as those with sepsis, burns, or hematologic malignancies. An 8- to 24-hour measured urinary CrCl is necessary to identify these patients (Ref).
Oral: No pharmacokinetic data available; empiric dose increases may be necessary in certain situations (eg, urgent seizure control) (Ref).
Hemodialysis, intermittent (thrice weekly): Dialyzable (50%) (Ref):
Oral: Reduce dose to 50% of the indication-specific usual dose and titrate more slowly. Since topiramate is significantly cleared by hemodialysis, supplemental doses (eg, 50% of the total daily dose) post hemodialysis are recommended (Ref).
Peritoneal dialysis: Likely to be dialyzable (Ref):
Oral: Reduce dose to 50% of the indication-specific usual dose and titrate more slowly (Ref).
CRRT: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Recommendations are based on high-flux dialyzers and effluent flow rates of 20 to 25 mL/kg/hour (or ~1,500 to 3,000 mL/hour) unless otherwise noted.
Oral: Reduce dose to 50% of the indication-specific usual dose and titrate more slowly. Significant removal of topiramate by CRRT is likely, and dose increases may be required based on patient response (Ref).
PIRRT (eg, sustained, low-efficiency diafiltration): Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement.
Oral: Reduce dose to 50% of the indication-specific usual dose and titrate more slowly. Give supplemental dose after completion of PIRRT (eg, 50% of the total daily dose). May titrate based on patient response (Ref).
There are no dosage adjustments provided in the manufacturer's labeling; however, topiramate clearance may be reduced in hepatic impairment. Use with caution.
Topiramate is associated with a range of effects involving the central nervous system (CNS) in all ages. Most common are dose-related sedative effects (eg, dizziness, drowsiness, fatigue). Additionally, topiramate has been associated with both short-term and long-term cognitive dysfunction in both children and adults, even at low doses (≤100 mg/day), including disturbance in attention, memory impairment, and language problems. Topiramate-associated cognitive dysfunction includes declines in verbal fluency, attention/concentration, processing speed, language skills, perception, working memory, reduced IQ, poor verbal fluency, abnormal thinking, and word-finding deficits (Ref). Topiramate is also associated with psychiatric disturbances (eg, aggressive behavior, mood disorder, anxiety, depression, exacerbation of depression), particularly in patients with previous history of depression or cognitive adverse reactions. Topiramate is also associated with paresthesia. The numbness and tingling of topiramate paresthesia are generally self-limiting, resolving over 2 to 3 months of therapy (Ref).
Mechanism: Dose-related (sedative effects; other effects may involve multiple mechanisms). Multiple effects on receptors within the CNS including sodium channel blockade, L-type calcium channel blockade (Ref), potentiation of gamma-amino butyric acid (GABA) transmission, inhibition of glutamate neuroexcitatory pathways through AMPA and kainate receptors (Ref). Topiramate is also a weak inhibitor of type II and type IV carbonic anhydrase (Ref). It has been speculated that rapid titration may increase the relative GABA effects leading to more prominent psychiatric symptoms (Ref).
Onset: Varied. Drowsiness and fatigue may occur early in therapy. Psychiatric effects may be delayed, with an onset up to 6 weeks after initiation of therapy (Ref).
Risk factors:
Sedative effects:
• Dose-related
Cognitive impairment:
• Higher initial dose and/or rapid titration (Ref)
• Older adults (Ref)
• High working memory capacity (Ref)
• Pediatric patients (6 to 11 years of age)
• Serum drug concentrations (Ref)
Psychiatric disturbances:
• Higher initial dose and/or rapid titration (Ref)
• History of febrile seizures (Ref)
• Personal or family history of psychiatric disorder (Ref)
• Previous psychotic history (for psychosis) (Ref)
Paresthesia:
• Females (Ref)
• Higher dose (Ref)
• Patients receiving topiramate for migraine (Ref)
Topiramate is associated with hyperchloremic metabolic acidosis (nonanion gap) in adult and pediatric patients; it may be more common and more severe in infants and children <2 years of age. Metabolic acidosis may be asymptomatic (Ref). Chronic acidosis may predispose individuals to nephrolithiasis, nephrocalcinosis, and osteomalacia/osteoporosis in all ages. Decreased bone mineral density (BMD) has been reported in all pediatric age groups, with ages 6 to 9 years most commonly affected. Linear skeletal growth rate below expectation has been observed in pediatric patients; a similar trend has also been observed for body weight.
Mechanism: May be dose-related; inhibition of carbonic anhydrase with increased renal bicarbonate excretion (Ref).
Onset: Varied; metabolic acidosis can occur at any time during treatment.
Risk factors:
• May be dose-related; however, metabolic acidosis may occur at doses as low as 50 mg/day
• Conditions that predispose to acidosis (eg, hepatic, kidney, and/or respiratory impairment)
• Ketogenic diet (Ref)
• Diarrhea
• Status epilepticus
• Concurrent treatment with other drugs which may cause acidosis (eg, zonisamide, acetazolamide)
Topiramate increases the risk of nephrolithiasis between 2 to 4 times that of the untreated population. Kidney stones have been reported in both adults and pediatric patients.
Mechanism: Dose-related; exhibits weak carbonic anhydrase inhibitory properties and may elevate the pH of the urine while decreasing urinary citrate concentrations, predisposing to calcium phosphate stone formation (Ref).
Onset: Delayed; occurs after long term therapy, usually months to years (Ref).
Risk factors:
• Concurrent medications known to cause metabolic acidosis
• Ketogenic diet (conflicting data) (Ref)
• Males
• Dehydration
Topiramate is associated with acute myopia with secondary angle-closure glaucoma in children and adults. Also associated with choroidal effusion (Ref) and visual field defect, scotoma, and maculopathy, which may occur without elevation of intraocular pressure (Ref). Bilateral hypopyon uveitis and choroidal detachment have also been reported (Ref). Most visual field defects were reversible with discontinuation.
Mechanism: Not established; may be related to alterations in ion transfer (sodium and carbon dioxide), idiosyncratic swelling of the ciliary body, and displacement of lens and ciliary body, leading to acute angle closure and elevation of intraocular pressure (Ref).
Onset: Varied; typically within 1 month of initiation but has occurred as early as 9 days after initiation (2 days after dose increase) (Ref).
Topiramate is associated with decreased sweat production (hypohidrosis) and symptoms of heat intolerance including facial flushing, lethargy, itching sensation, and irritability with hyperthermia in all ages. Some episodes may be severe, requiring hospitalization and/or resulting in long-term sequelae (ataxia and tremor) (Ref).
Mechanism: Dose-related; inhibition of carbonic anhydrase leading to a reduction in sweat production without peripheral nervous system involvement (Ref).
Onset: Varied; from within 2 weeks to 2 months after initiation (Ref).
Risk factors:
• Exercise and higher environmental temperature (Ref)
• Pediatric patients (Ref)
• Concurrent use of other drugs which may inhibit carbonic anhydrase or drugs with anticholinergic activity
Antiseizure drugs (AEDs) have been associated with suicidal ideation and suicidal tendencies. However, the FDA meta-analysis has been criticized due to several limitations (Ref). The risk of suicide is increased in epilepsy (Ref), but the occurrence of suicidal ideation/tendencies in epilepsy is multifactorial. While some AEDs (but not all) have been associated with treatment-emergent psychiatric effects such as anxiety and depression, other factors such as postictal suicidal behavior and pertinent patient history must also be evaluated to provide an accurate assessment of risk for any individual drug (Ref). In one case report, the onset of topiramate-associated suicidal ideation corresponded to an increase in topiramate dose followed by the appearance of depressive symptoms. The patient was described as euthymic with the resolution of this symptom within a week of discontinuation (Ref).
Mechanism: Not established; associated with depression and anxiety, which may potentially be related to suicidal ideation and tendencies (Ref).
Onset: Varied; peak incidence of suicidality across AEDs (not specific to individual agents) has been noted to occur between 1 and 12 weeks of therapy (Ref). A review of clinical trials noted that risk extended from 1 week to 24 weeks of therapy, corresponding to the duration of most trials.
Risk factors:
• May correspond to dose increases (Ref)
• History of depression (Ref)
• Use in conditions other than epilepsy, depression, or bipolar disorder (Ref)
• Higher initial dose and/or rapid titration may increase risk for psychiatric disturbances (Ref)
• Family and personal psychiatric history (Ref)
• Family history of epilepsy (Ref)
• History of febrile seizures (Ref)
Weight loss was originally observed as an adverse reaction in several trials for various indications with topiramate. More recently, topiramate has been explored therapeutically to promote weight loss (Ref). Weight loss may be significant in all ages. In a typical series of adult patients with epilepsy, a loss of 3 kg was reported in the first 3 months of therapy, which increased to 5.9 kg after 1 year (Ref). The exacerbation and development of eating disorder, including anorexia and bulimia, has been reported in adolescents receiving topiramate for migraines or chronic headaches and an adult receiving topiramate for epilepsy (Ref). Of interest, topiramate has been used to successfully decrease binge eating frequency in binge eating disorder (Ref).
Mechanism: Not established; reduced caloric intake has been observed, while additional proposed mechanisms include hormonal influences on energy production (via leptin, adiponectin, and insulin resistance) and changes in glucose and lipid metabolism via carbonic anhydrase inhibition (Ref).
Onset: Varied; typically reported during the first 4 to 6 months of therapy and may continue for at least a year, then trend toward baseline levels (Ref).
Risk factors:
Weight loss:
• Duration of treatment and high baseline body mass index (Ref)
• Daily dose and sex (inconsistent associations) (Ref)
Development of eating disorders:
• History of eating disorder (Ref)
• Dieting (Ref)
• Cognitive symptoms of eating disorders (eg, body image distortion, fear of gaining weight, drive for thinness) (Ref)
• Patients with migraine (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions are reported for monotherapy in adult and pediatric patients unless otherwise specified. A wide range of dosages were studied. Incidence of adverse reactions was frequently lower in the pediatric population studied, unless otherwise specified.
>10%:
Endocrine & metabolic: Decreased serum bicarbonate (children and adolescents: 67%; <17 mEq/L and ≥5 mEq/L decrease from pretreatment: 11%; average decrease of 4 mEq/L at dose of 400 mg/day in adults and 6 mg/kg/day in children) (table 1), hyperammonemia (adolescents: 14% to 26%) (table 2), weight loss (4% to 17%) (table 3)
|
Drug (Topiramate) |
Placebo |
Population |
Dose |
Dosage Form |
Indication |
Comments |
|---|---|---|---|---|---|---|
|
67% |
10% |
Children and adolescents |
~6 mg/kg/day |
Immediate-release oral |
Adjunctive treatment of Lennox-Gastaut syndrome or refractory partial-onset seizures |
N/A |
|
11% |
≤2% |
Children and adolescents |
~6 mg/kg/day |
Immediate-release oral |
Adjunctive treatment of Lennox-Gastaut syndrome or refractory partial-onset seizures |
<17 mEq/L and >5 mEq/L decrease from pretreatment |
|
Drug (Topiramate) |
Placebo |
Population |
Dose |
Dosage Form |
Indication |
|---|---|---|---|---|---|
|
26% |
9% |
Adolescents |
100 mg/day |
Immediate-release oral |
Migraine |
|
14% |
9% |
Adolescents |
50 mg/day |
Immediate-release oral |
Migraine |
|
Drug (Topiramate) |
Placebo |
Population |
Dose |
Dosage Form |
Indication |
Number of Patients (Topiramate) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|---|
|
17% |
N/A |
Children and adolescents |
400 mg/day |
Immediate-release oral |
Epilepsy |
77 |
N/A |
|
7% |
N/A |
Children and adolescents |
50 mg/day |
Immediate-release oral |
Epilepsy |
74 |
N/A |
|
7% |
2% |
Adolescents |
50 mg/day |
Immediate-release oral |
Migraine |
46 |
45 |
|
4% |
2% |
Adolescents |
100 mg/day |
Immediate-release oral |
Migraine |
48 |
45 |
|
17% |
N/A |
Adolescents and adults |
400 mg/day |
Immediate-release oral |
Epilepsy |
159 |
N/A |
|
6% |
N/A |
Adolescents and adults |
50 mg/day |
Immediate-release oral |
Epilepsy |
160 |
N/A |
|
9% |
1% |
Adolescents and adults |
100 mg/day |
Immediate-release oral |
Migraine |
386 |
445 |
|
6% |
1% |
Adolescents and adults |
50 mg/day |
Immediate-release oral |
Migraine |
235 |
445 |
Gastrointestinal: Abdominal pain (adolescents and adults: 6% to 15%), anorexia (adolescents and adults: 4% to 15%) (table 4), diarrhea (2% to 11%), dysgeusia (adolescents and adults: 3% to 15%), nausea (adolescents and adults: 8% to 13%)
|
Drug (Topiramate) |
Placebo |
Population |
Dose |
Dosage Form |
Indication |
Number of Patients (Topiramate) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|---|
|
10% |
4% |
Adolescents |
100 mg/day |
Immediate-release oral |
Migraine |
48 |
45 |
|
9% |
4% |
Adolescents |
50 mg/day |
Immediate-release oral |
Migraine |
46 |
45 |
|
14% |
N/A |
Adolescents and adults |
400 mg/day |
Immediate-release oral |
Epilepsy |
159 |
N/A |
|
4% |
N/A |
Adolescents and adults |
50 mg/day |
Immediate-release oral |
Epilepsy |
160 |
N/A |
|
15% |
6% |
Adolescents and adults |
100 mg/day |
Immediate-release oral |
Migraine |
386 |
445 |
|
9% |
6% |
Adolescents and adults |
50 mg/day |
Immediate-release oral |
Migraine |
235 |
445 |
Nervous system: Dizziness (dose-related) (adolescents and adults: 6% to 14%) (table 5), drowsiness (dose-related) (adolescents and adults: 2% to 15%) (table 6), fatigue (dose-related) (7% to 15%) (table 7), memory impairment (1% to 11%) (table 8), paresthesia (adolescents and adults: 19% to 51%; children and adolescents: 3% to 12%) (table 9)
|
Drug (Topiramate) |
Placebo |
Population |
Dose |
Dosage Form |
Indication |
Number of Patients (Topiramate) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|---|
|
6% |
4% |
Adolescents |
100 mg/day |
Immediate-release oral |
Migraine |
48 |
45 |
|
4% |
4% |
Adolescents |
50 mg/day |
Immediate-release oral |
Migraine |
46 |
45 |
|
14% |
N/A |
Adolescents and adults |
400 mg/day |
Immediate-release oral |
Epilepsy |
159 |
N/A |
|
13% |
N/A |
Adolescents and adults |
50 mg/day |
Immediate-release oral |
Epilepsy |
160 |
N/A |
|
9% |
10% |
Adolescents and adults |
100 mg/day |
Immediate-release oral |
Migraine |
386 |
445 |
|
8% |
10% |
Adolescents and adults |
50 mg/day |
Immediate-release oral |
Migraine |
235 |
445 |
|
Drug (Topiramate) |
Placebo |
Population |
Dose |
Dosage Form |
Indication |
Number of Patients (Topiramate) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|---|
|
10% |
N/A |
Adolescents and adults |
50 mg/day |
Immediate-release oral |
Epilepsy |
160 |
N/A |
|
15% |
N/A |
Adolescents and adults |
400 mg/day |
Immediate-release oral |
Epilepsy |
159 |
N/A |
|
8% |
5% |
Adolescents and adults |
50 mg/day |
Immediate-release oral |
Migraine |
235 |
445 |
|
7% |
5% |
Adolescents and adults |
100 mg/day |
Immediate-release oral |
Migraine |
386 |
445 |
|
2% |
2% |
Adolescents |
50 mg/day |
Immediate-release oral |
Migraine |
46 |
45 |
|
6% |
2% |
Adolescents |
100 mg/day |
Immediate-release oral |
Migraine |
48 |
45 |
|
Drug (Topiramate) |
Placebo |
Population |
Dose |
Dosage Form |
Indication |
Number of Patients (Topiramate) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|---|
|
8% |
7% |
Adolescents |
100 mg/day |
Immediate-release oral |
Migraine |
48 |
45 |
|
7% |
7% |
Adolescents |
50 mg/day |
Immediate-release oral |
Migraine |
46 |
45 |
|
15% |
11% |
Adolescents and adults |
100 mg/day |
Immediate-release oral |
Migraine |
386 |
445 |
|
14% |
11% |
Adolescents and adults |
50 mg/day |
Immediate-release oral |
Migraine |
235 |
445 |
|
Drug (Topiramate) |
Placebo |
Population |
Dose |
Dosage Form |
Indication |
Number of Patients (Topiramate) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|---|
|
3% |
N/A |
Children and adolescents |
400 mg/day |
Immediate-release oral |
Epilepsy |
77 |
N/A |
|
1% |
N/A |
Children and adolescents |
50 mg/day |
Immediate-release oral |
Epilepsy |
74 |
N/A |
|
11% |
N/A |
Adolescents and adults |
400 mg/day |
Immediate-release oral |
Epilepsy |
159 |
N/A |
|
6% |
N/A |
Adolescents and adults |
50 mg/day |
Immediate-release oral |
Epilepsy |
160 |
N/A |
|
7% |
2% |
Adolescents and adults |
50 mg/day |
Immediate-release oral |
Migraine |
235 |
445 |
|
7% |
2% |
Adolescents and adults |
100 mg/day |
Immediate-release oral |
Migraine |
386 |
445 |
|
Drug (Topiramate) |
Placebo |
Population |
Dose |
Dosage Form |
Indication |
Number of Patients (Topiramate) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|---|
|
12% |
N/A |
Children and adolescents |
400 mg/day |
Immediate-release oral |
Epilepsy |
77 |
N/A |
|
3% |
N/A |
Children and adolescents |
50 mg/day |
Immediate-release oral |
Epilepsy |
74 |
N/A |
|
20% |
7% |
Adolescents |
50 mg/day |
Immediate-release oral |
Migraine |
46 |
45 |
|
19% |
7% |
Adolescents |
100 mg/day |
Immediate-release oral |
Migraine |
48 |
45 |
|
40% |
N/A |
Adolescents and adults |
400 mg/day |
Immediate-release oral |
Epilepsy |
159 |
N/A |
|
21% |
N/A |
Adolescents and adults |
50 mg/day |
Immediate-release oral |
Epilepsy |
160 |
N/A |
|
51% |
6% |
Adolescents and adults |
100 mg/day |
Immediate-release oral |
Migraine |
386 |
445 |
|
35% |
6% |
Adolescents and adults |
50 mg/day |
Immediate-release oral |
Migraine |
235 |
445 |
Neuromuscular & skeletal: Decreased bone mineral density (children and adolescents: 21% [n=63])
Respiratory: Upper respiratory tract infection (13% to 26%)
Miscellaneous: Fever (1% to 12%)
1% to 10%:
Cardiovascular: Flushing (children and adolescents: 5%)
Dermatologic: Acne vulgaris (adolescents and adults: 2% to 3%), alopecia (1% to 4%), pruritus (adolescents and adults: 1% to 4%), skin rash (1% to 4%)
Endocrine & metabolic: Decreased libido (adolescents and adults: 3%), intermenstrual bleeding (children and adolescents: 3%), menstrual disease (adolescents and adults: 3%)
Gastrointestinal: Constipation (adolescents and adults: 1% to 4%), dyspepsia (adolescents and adults: 4% to 5%), gastritis (adolescents and adults: 3%), gastroenteritis (adolescents and adults: 3%), xerostomia (adolescents and adults: 1% to 3%)
Genitourinary: Cystitis (adolescents and adults: 1% to 3%), premature ejaculation (adolescents and adults: 3%), urinary frequency (2% to 3%), urinary incontinence (children and adolescents: 1% to 3%), urinary tract infection (adolescents and adults: 4%), vaginal hemorrhage (adolescents and adults: 3%)
Hematologic & oncologic: Anemia (children and adolescents: 1% to 3%), hemorrhage (4% to 5%)
Hepatic: Increased gamma-glutamyl transferase (adolescents and adults: 1% to 3%)
Infection: Infection (2% to 8%), viral infection (3% to 8%)
Nervous system: Anxiety (adolescents and adults: 4% to 6%) (table 10), asthenia (3% to 6%), ataxia (adolescents and adults: 3% to 4%), behavioral problems (children and adolescents: 3%), cognitive dysfunction (1% to 6%) (literature suggests higher incidence; Lee 2006; Mula 2012), confusion (3%), depression (adolescents and adults: 7% to 9%; children and adolescents: 3%), disturbance in attention, hypertonia (adolescents and adults: 3%), hypoesthesia (adolescents and adults: 4% to 7%), insomnia (adolescents and adults: 6% to 9%), lack of concentration, language problems (adolescents and adults: 6% to 7%) (table 11), mood disorder (1% to 8%), nervousness (adolescents and adults: 4%), psychomotor impairment (adolescents and adults: 2% to 5%) (literature suggests higher incidence) (Javed 2015) (table 12), vertigo (children and adolescents: 3%)
|
Drug (Topiramate) |
Placebo |
Population |
Dose |
Dosage Form |
Indication |
Number of Patients (Topiramate) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|---|
|
6% |
N/A |
Adolescents and adults |
400 mg/day |
Immediate-release oral |
Epilepsy |
159 |
N/A |
|
4% |
N/A |
Adolescents and adults |
50 mg/day |
Immediate-release oral |
Epilepsy |
160 |
N/A |
|
5% |
3% |
Adolescents and adults |
100 mg/day |
Immediate-release oral |
Migraine |
386 |
445 |
|
4% |
3% |
Adolescents and adults |
50 mg/day |
Immediate-release oral |
Migraine |
235 |
445 |
|
Drug (Topiramate) |
Placebo |
Population |
Dose |
Dosage Form |
Indication |
Number of Patients (Topiramate) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|---|
|
7% |
2% |
Adolescents and adults |
50 mg/day |
Immediate-release oral |
Migraine |
235 |
445 |
|
6% |
2% |
Adolescents and adults |
100 mg/day |
Immediate-release oral |
Migraine |
386 |
445 |
|
Drug (Topiramate) |
Placebo |
Population |
Dose |
Dosage Form |
Indication |
Number of Patients (Topiramate) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|---|
|
5% |
N/A |
Adolescents and adults |
400 mg/day |
Immediate-release oral |
Epilepsy |
159 |
N/A |
|
3% |
N/A |
Adolescents and adults |
50 mg/day |
Immediate-release oral |
Epilepsy |
160 |
N/A |
|
3% |
1% |
Adolescents and adults |
50 mg/day |
Immediate-release oral |
Migraine |
235 |
445 |
|
2% |
1% |
Adolescents and adults |
100 mg/day |
Immediate-release oral |
Migraine |
386 |
445 |
Neuromuscular & skeletal: Arthralgia (adolescents and adults: 3% to 7%), lower extremity pain (adolescents and adults: 2% to 3%), muscle spasm (3%)
Ophthalmic: Blurred vision (adolescents and adults: 4%), conjunctivitis (adolescents and adults: 7%)
Renal: Nephrolithiasis (adolescents and adults: 3%) (literature suggests higher incidence) (Giannapoulou 2015; Maalouf 2011)
Respiratory: Bronchitis (1% to 5%), cough (adolescents and adults: 2% to 7%), dyspnea (adolescents and adults: 1% to 3%), epistaxis (children and adolescents: 4%), pharyngitis (adolescents and adults: 5% to 6%), rhinitis (2% to 7%), sinusitis (1% to 10%)
Miscellaneous: Accidental injury (adolescents and adults: 6% to 9%)
<1%: Hematologic & oncologic: Major hemorrhage (children)
Frequency not defined:
Cardiovascular: Hypotension, orthostatic hypotension, syncope
Endocrine & metabolic: Abnormal serum phosphorus level (decreased), hyperchloremia, increased serum total protein, increased uric acid
Gastrointestinal: Gingival hemorrhage
Genitourinary: Hematuria
Hematologic & oncologic: Decreased neutrophils, decreased white blood cell count, eosinophilia, thrombocytosis
Hypersensitivity: Hypersensitivity reaction
Nervous system: Headache
Neuromuscular & skeletal: Linear skeletal growth rate below expectation (reductions in mean annual change from baseline in weight and height compared to control group), myalgia
Ophthalmic: Scotoma
Postmarketing:
Dermatologic: Bullous rash, erythema multiforme, hypohidrosis (more common in pediatric patients) (Ben-Zeev 2003), pemphigus (Alkhalifah 2017), Stevens-Johnson syndrome, toxic epidermal necrolysis
Endocrine & metabolic: Hyperchloremic metabolic acidosis (nonanion gap) (Sinha 2018; Ture 2016), severe hypokalemia (Muaddi 2021)
Gastrointestinal: Pancreatitis
Genitourinary: Anorgasmia (Chen 2017), urinary retention (Li 2020)
Hepatic: Hepatic failure (Tsien 2016), hepatitis
Nervous system: Aggressive behavior (Hansen 2018), eating disorder (Lebow 2015), hallucination (Register 2017), hyperammonemic encephalopathy (usually in combination with valproate) (Tantikittichaikul 2015; Yamamoto 2013), hyperthermia (more common in pediatric patients) (Galicia 2005), mania (Duan 2019), myoclonus (Rissardo 2020), psychosis (Mula 2003), restless leg syndrome (Rissardo 2020), suicidal ideation (Abraham 2003), suicidal tendencies
Ophthalmic: Acute myopia with secondary angle-closure glaucoma (Sierra-Rodrigues 2019), choroidal detachment (Tyagi 2021), choroidal effusion (Lau 2018), maculopathy (Gualtieri 2013), uveitis (bilateral hypopyon) (Tyagi 2021), visual field defect (Gualtieri 2013)
Renal: Calcium nephrolithiasis (Barnett 2018), renal tubular acidosis (Muaddi 2021)
Extended release: Recent alcohol use (ie, within 6 hours prior to and 6 hours after administration) (Trokendi XR only); patients with metabolic acidosis who are taking concomitant metformin (Qudexy XR only).
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Immediate release: There are no contraindications listed in the manufacturer's labeling.
Canadian labeling: Hypersensitivity to topiramate or any component of the formulation or container; pregnancy and women in childbearing years not using effective contraception (migraine prophylaxis only).
Disease-related concerns:
• Hepatic impairment: Use caution with hepatic impairment; clearance may be reduced. Dosage adjustment may be required.
• Renal impairment: Use caution with renal impairment; clearance may be reduced. Dosage adjustment may be required.
Special populations:
• Older adults: Use with caution; dosage adjustment may be necessary. Weight loss, cognitive impairment, sedation, and gait/balance disturbances may be more pronounced in the older adult cohort (Sommer 2010).
Other warnings/precautions:
• Withdrawal: Do not discontinue abruptly because of the possibility of increasing seizure frequency; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal. Doses were also gradually withdrawn in migraine prophylaxis studies (decreased in weekly intervals by 25 to 50 mg/day).
Necrotizing enterocolitis (NEC) has been reported in neonates; a case series of 10 preterm neonates (GA: 23 to 36 weeks; birthweight: 440 to 2,100 g) who received topiramate at a dose of 10 mg/kg on day 1, followed by 5 mg/kg/dose once daily for treatment of neonatal seizures reported the development of NEC within 1 to 7 days following topiramate administration in 4 of 10 (40%) of preterm neonates; one patient even developed symptoms suggesting a recurrence of NEC following reintroduction of topiramate. No causal relationship can be determined; monitor closely (Courchia 2018).
Pediatric patients <24 months of age may be at increased risk for topiramate-associated hyperammonemia, especially when used concurrently with valproic acid; monitor closely for lethargy, vomiting, or unexplained changes in mental status.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule ER 24 Hour Sprinkle, Oral:
Qudexy XR: 25 mg, 50 mg, 100 mg, 150 mg, 200 mg
Generic: 25 mg, 50 mg, 100 mg, 150 mg, 200 mg
Capsule Extended Release 24 Hour, Oral:
Trokendi XR: 25 mg [contains fd&c blue #1 (brilliant blue), sodium benzoate]
Trokendi XR: 50 mg, 100 mg, 200 mg [contains fd&c blue #1 (brilliant blue), fd&c yellow #6 (sunset yellow), sodium benzoate]
Generic: 25 mg, 50 mg, 100 mg, 200 mg
Capsule Sprinkle, Oral:
Topamax Sprinkle: 15 mg, 25 mg
Generic: 15 mg, 25 mg
Solution, Oral:
Eprontia: 25 mg/mL (120 mL, 240 mL, 473 mL) [contains methylparaben, polyethylene glycol (macrogol), propylparaben]
Tablet, Oral:
Topamax: 25 mg, 50 mg, 100 mg, 200 mg
Generic: 25 mg, 50 mg, 100 mg, 200 mg
May be product dependent
Capsule ER 24 Hour Sprinkle (Qudexy XR Oral)
25 mg (per each): $11.72
50 mg (per each): $15.27
100 mg (per each): $30.26
150 mg (per each): $37.22
200 mg (per each): $41.39
Capsule ER 24 Hour Sprinkle (Topiramate ER Oral)
25 mg (per each): $9.37 - $9.93
50 mg (per each): $12.21 - $12.94
100 mg (per each): $24.18 - $25.63
150 mg (per each): $29.75 - $31.53
200 mg (per each): $33.08 - $35.07
Capsule ER 24 Hour Therapy Pack (Topiramate ER Oral)
25 mg (per each): $13.28 - $14.02
50 mg (per each): $17.30 - $18.26
100 mg (per each): $34.27 - $36.18
200 mg (per each): $46.88 - $49.49
Capsule ER 24 Hour Therapy Pack (Trokendi XR Oral)
25 mg (per each): $14.76
50 mg (per each): $19.22
100 mg (per each): $38.08
200 mg (per each): $52.09
Capsule, sprinkles (Topamax Sprinkle Oral)
15 mg (per each): $7.44
25 mg (per each): $8.99
Capsule, sprinkles (Topiramate Oral)
15 mg (per each): $2.42
25 mg (per each): $2.92
Solution (Eprontia Oral)
25 mg/mL (per mL): $2.86
Tablets (Topamax Oral)
25 mg (per each): $7.86
50 mg (per each): $15.69
100 mg (per each): $21.43
200 mg (per each): $25.09
Tablets (Topiramate Oral)
25 mg (per each): $0.09 - $2.55
50 mg (per each): $0.14 - $5.10
100 mg (per each): $0.21 - $6.96
200 mg (per each): $0.34 - $8.15
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule Sprinkle, Oral:
Topamax Sprinkle: 15 mg, 25 mg
Tablet, Oral:
Topamax: 25 mg, 100 mg, 200 mg [contains polysorbate 80]
Generic: 25 mg, 50 mg, 100 mg, 200 mg
Note : A topiramate solution (25 mg/mL) for oral administration is commercially available.
20 mg/mL Oral Suspension (ASHP Standard Concentration) (ASHP 2017)
A 20 mg/mL oral suspension may be made with topiramate tablets or powder, Ora-Plus and Ora-Sweet. Measure out 2,000 mg of topiramate (equivalent tablets or powder). If using tablets, crush in a mortar and reduce to a fine powder. Add 10 mL of Ora-Plus and mix to a uniform paste; mix while adding an additional 40 mL of Ora-Plus in incremental proportions. Add a small amount of Ora-Sweet and mix. Transfer to a calibrated, amber bottle; rinse mortar with Ora-Sweet and add sufficient quantity to make 100 mL. Label "shake well." Stable for 90 days refrigerated or at room temperature (Allen 2017).
Oral: May be administered without regard to food.
Immediate release:
Oral solution (Eprontia): Measure dose with a calibrated measuring device for accurate dose delivery (avoid household spoons).
Tablets: Broken tablets have a bitter taste; tablets may be crushed, mixed with water, and administered immediately.
Sprinkle capsules: Swallow sprinkle capsules whole or open and sprinkle contents on small amount of soft food (eg, 1 teaspoonful of applesauce, oatmeal, ice cream, pudding, custard, or yogurt); swallow sprinkle/food mixture immediately; do not chew; do not store for later use; drink fluids after dose to make sure mixture is completely swallowed.
Extended release:
Qudexy XR: May be swallowed whole or may be opened and sprinkled on a small amount (~1 teaspoon) of soft food; swallow immediately and do not chew.
Trokendi XR: Swallow capsules whole; do not sprinkle capsules on food, chew, or crush. Avoid alcohol use within 6 hours prior to and 6 hours after administration.
Oral: Administer without regard to meals. Administer the IR formulation in divided doses. It is not recommended to crush, break, or chew immediate release tablets due to bitter taste. Swallow ER and sprinkle capsules whole. Sprinkle capsules and Qudexy XR capsules may also be opened to sprinkle the entire contents on a small amount (~1 teaspoon) of soft food; swallow immediately and do not chew. Do not store drug/food mixture for future use. Do not sprinkle Trokendi XR capsules on food, chew, or crush. Avoid alcohol use with Trokendi XR capsules within 6 hours prior to and 6 hours after administration. Use a calibrated measuring device to measure oral solution; do not use a household teaspoon or tablespoon.
Bariatric surgery: Capsule, extended release: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. IR tablet and sprinkle capsule formulations are available. If safety and efficacy can be effectively monitored, no change in formulation or administration is required after bariatric surgery; however, if swallowing is an issue after surgery, Qudexy XR formulation may be sprinkled on a small amount of soft food.
Hazardous agent (NIOSH 2016 [group 3]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
Extended release capsules: Store at 15°C to 30°C (59°F to 86°F). Protect from moisture. Protect from light.
Oral solution: Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). Once open discard any part not used after 90 days.
Sprinkle capsules: Store at or below 25°C (77°F). Protect from moisture.
Tablets: Store at 15°C to 30°C (59°F to 86°F). Protect from moisture.
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Qudexy XR: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/205122s012lbl.pdf#page=60
Topamax: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/020505s065,020844s056lbl.pdf#page=56
Trokendi XR: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/201635s030lbl.pdf#page=52
Oral:
Immediate release: Capsules (sprinkle), tablets (Topamax), oral solution (Eprontia): Initial monotherapy of primary generalized tonic-clonic seizures or partial onset seizures (FDA approved in ages ≥2 years and adults); adjunctive treatment of primary generalized tonic-clonic seizures or partial onset seizures (FDA approved in ages ≥2 years and adults); adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (FDA approved in ages ≥2 years and adults); prophylaxis of migraine headache (FDA approved in ages ≥12 years and adults); has also been used for infantile spasms.
Extended release: Initial monotherapy of primary generalized tonic-clonic seizures or partial onset seizures (Qudexy XR: FDA approved in ages ≥2 years and adults; Trokendi XR: FDA approved in ages ≥6 years and adults); adjunctive treatment of primary generalized tonic-clonic seizures, partial onset seizures, or treatment of seizures associated with Lennox-Gastaut syndrome (Qudexy XR: FDA approved in ages ≥2 years and adults; Trokendi XR: FDA approved in ages ≥6 years and adults); prophylaxis of migraine headache (Qudexy XR and Trokendi XR: FDA approved in ages ≥12 years and adults).
Topamax may be confused with Sporanox, TEGretol, TEGretol-XR, Toprol-XL
Bioequivalence has not been demonstrated between Trokendi XR and Qudexy XR.
Qudexy XR capsules may be swallowed whole or opened to sprinkle the entire contents on a small amount (~1 teaspoon) of soft food. Do not open and sprinkle Trokendi XR capsules on food, chew, or crush; doing so may disrupt the triphasic release properties.
Avoid alcohol use with Trokendi XR within 6 hours prior to and 6 hours after administration; concurrent use may result in dose dumping.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alcohol (Ethyl): May enhance the CNS depressant effect of Topiramate. Alcohol (Ethyl) may increase the serum concentration of Topiramate. This applies specifically to use with the extended-release topiramate capsules (Trokendi XR). Also, topiramate concentrations may be subtherapeutic in the later portion of the dosage interval. Management: Concurrent use of alcohol within 6 hours of ingestion of extended-release topiramate (Trokendi XR) is contraindicated. Any use of alcohol with topiramate should be avoided when possible and should only be undertaken with extreme caution. Risk X: Avoid combination
Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Alpha-/Beta-Agonists (Indirect-Acting): Carbonic Anhydrase Inhibitors may increase the serum concentration of Alpha-/Beta-Agonists (Indirect-Acting). Risk C: Monitor therapy
Amantadine: Carbonic Anhydrase Inhibitors may increase the serum concentration of Amantadine. Risk C: Monitor therapy
Amitriptyline: Topiramate may enhance the CNS depressant effect of Amitriptyline. Topiramate may increase serum concentrations of the active metabolite(s) of Amitriptyline. Topiramate may increase the serum concentration of Amitriptyline. Risk C: Monitor therapy
Amphetamines: Carbonic Anhydrase Inhibitors may decrease the excretion of Amphetamines. Risk C: Monitor therapy
Anticholinergic Agents: May enhance the adverse/toxic effect of Topiramate. Risk C: Monitor therapy
Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification
Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy
Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modification
Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy
CarBAMazepine: Topiramate may enhance the CNS depressant effect of CarBAMazepine. CarBAMazepine may decrease the serum concentration of Topiramate. Risk C: Monitor therapy
Carbonic Anhydrase Inhibitors: May enhance the adverse/toxic effect of other Carbonic Anhydrase Inhibitors. The development of acid-base disorders with concurrent use of ophthalmic and oral carbonic anhydrase inhibitors has been reported. Management: Avoid concurrent use of different carbonic anhydrase inhibitors if possible. Monitor patients closely for the occurrence of kidney stones and with regards to severity of metabolic acidosis. Risk X: Avoid combination
Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification
Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy
Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
Desmopressin: Hyponatremia-Associated Agents may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy
DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modification
Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Doxylamine: CNS Depressants may enhance the CNS depressant effect of Doxylamine. Risk C: Monitor therapy
DroPERidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification
Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Flecainide: Carbonic Anhydrase Inhibitors may decrease the excretion of Flecainide. Risk C: Monitor therapy
Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination
Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification
Fosphenytoin: May decrease the serum concentration of Topiramate. Topiramate may increase the serum concentration of Fosphenytoin. Risk C: Monitor therapy
Hormonal Contraceptives: Topiramate may decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing topiramate to ensure contraceptive reliability. Risk D: Consider therapy modification
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification
Ixabepilone: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Lacosamide: Antiseizure Agents (Sodium Channel Blockers) may enhance the adverse/toxic effect of Lacosamide. Specifically the risk for bradycardia, ventricular tachyarrhythmias, or a prolonged PR interval may be increased. Risk C: Monitor therapy
LamoTRIgine: Topiramate may enhance the arrhythmogenic effect of LamoTRIgine. LamoTRIgine may enhance the CNS depressant effect of Topiramate. Management: Consider the risk of serious arrhythmias or death versus any expected benefit of lamotrigine in patients receiving concomitant sodium channel blockers. Additionally, if combined, caution patients that CNS depressant effects may be increased. Risk D: Consider therapy modification
Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification
Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Lithium: Topiramate may increase the serum concentration of Lithium. Risk C: Monitor therapy
Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Loop Diuretics: May enhance the hypokalemic effect of Topiramate. Risk C: Monitor therapy
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Mefloquine: May diminish the therapeutic effect of Antiseizure Agents. Mefloquine may decrease the serum concentration of Antiseizure Agents. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of seizures. If antiseizure drugs are being used for another indication, monitor antiseizure drug concentrations and treatment response closely with concurrent use. Risk D: Consider therapy modification
Memantine: Carbonic Anhydrase Inhibitors may increase the serum concentration of Memantine. Risk C: Monitor therapy
MetFORMIN: Topiramate may enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk for lactic acidosis may be increased. MetFORMIN may increase the serum concentration of Topiramate. Topiramate may increase the serum concentration of MetFORMIN. Risk C: Monitor therapy
Methenamine: Carbonic Anhydrase Inhibitors may diminish the therapeutic effect of Methenamine. Management: Consider avoiding the concomitant use of medications that alkalinize the urine, such as carbonic anhydrase inhibitors, and methenamine. Monitor for decreased therapeutic effects of methenamine if used concomitant with a carbonic anhydrase inhibitor. Risk D: Consider therapy modification
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification
Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
MetyraPONE: Antiseizure Agents may diminish the diagnostic effect of MetyraPONE. Management: Consider alternatives to the use of the metyrapone test in patients taking antiseizure agents. Risk D: Consider therapy modification
MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy
Mianserin: May diminish the therapeutic effect of Antiseizure Agents. Risk C: Monitor therapy
Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Nabilone: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification
Orlistat: May decrease the serum concentration of Antiseizure Agents. Risk C: Monitor therapy
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination
Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modification
OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification
Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination
Perampanel: Topiramate may enhance the CNS depressant effect of Perampanel. Topiramate may decrease the serum concentration of Perampanel. Risk C: Monitor therapy
Phenytoin: Topiramate may increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Topiramate. Risk C: Monitor therapy
Pioglitazone: Topiramate may decrease the serum concentration of Pioglitazone. Risk C: Monitor therapy
Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy
Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy
Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification
ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy
Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy
Salicylates: May enhance the adverse/toxic effect of Carbonic Anhydrase Inhibitors. Salicylate toxicity might be enhanced by this same combination. Management: Avoid these combinations when possible.Dichlorphenamide use with high-dose aspirin as contraindicated. If another combination is used, monitor patients closely for adverse effects. Tachypnea, anorexia, lethargy, and coma have been reported. Risk D: Consider therapy modification
Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination
Thiazide and Thiazide-Like Diuretics: May enhance the hypokalemic effect of Topiramate. Thiazide and Thiazide-Like Diuretics may increase the serum concentration of Topiramate. Risk C: Monitor therapy
Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Ulipristal: Topiramate may decrease the serum concentration of Ulipristal. Risk X: Avoid combination
Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Valproate Products: Topiramate may enhance the adverse/toxic effect of Valproate Products. Specifically, the risk of hypothermia and hyperammonemia, with or without encephalopathy, may be increased. Valproate Products may decrease the serum concentration of Topiramate. Topiramate may decrease the serum concentration of Valproate Products. Risk C: Monitor therapy
Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification
Zuranolone: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects. Risk D: Consider therapy modification
Ketogenic diet may increase the possibility of acidosis and/or kidney stones. Management: Monitor for symptoms of acidosis or kidney stones.
Effective contraception should be used in females of reproductive potential who are not planning a pregnancy; consider use of alternative medications in patients who wish to become pregnant.
Based on limited data (n=5), topiramate was found to cross the placenta and could be detected in neonatal serum (Ohman 2002).
Topiramate may cause fetal harm if administered to a pregnant patient. An increased risk of oral clefts (cleft lip and/or palate) and for being small for gestational age (SGA) has been observed following in utero exposure. Data from the North American Antiepileptic Drug (NAAED) Pregnancy Registry reported that the prevalence of oral clefts was 1.1% for infants exposed to topiramate during the first trimester of pregnancy, versus 0.36% for infants exposed to a reference antiseizure drug, and 0.12% for infants with no exposure born to mothers without epilepsy; the relative risk of oral clefts in infants exposed to topiramate was calculated to be 9.6 (95% CI: 4 to 23). Data from the NAAED Pregnancy Registry reported that the prevalence of small for gestational age newborns was 19.7% for newborns exposed to topiramate in utero, versus 7.9% for newborns exposed to a reference antiseizure drug, and 5.4% for newborns with no exposure born to mothers without epilepsy. Although not evaluated during pregnancy, metabolic acidosis may be induced by topiramate. Metabolic acidosis during pregnancy may result in adverse effects and fetal death. Pregnant patients and their newborns should be monitored for metabolic acidosis. In general, maternal polytherapy with antiseizure drugs may increase the risk of congenital malformations; monotherapy with the lowest effective dose is recommended. Newborns of patients taking antiseizure medications may be at an increased risk of a 1 minute Apgar score <7 (Harden 2009).
Maternal serum concentrations may decrease during the second and third trimesters of pregnancy; therefore, therapeutic drug monitoring should be considered during pregnancy and postpartum in patients who require therapy (Ohman 2009; Westin 2009).
Data collection to monitor pregnancy and infant outcomes following exposure to topiramate is ongoing. Patients may enroll themselves into the NAAED Pregnancy Registry by calling 1-888-233-2334. Additional information is available at www.aedpregnancyregistry.org.
Frequency, duration, and severity of seizure episodes or migraine headaches; renal function; monitor serum electrolytes including baseline and periodic serum bicarbonate, symptoms of metabolic acidosis, complications of chronic acidosis (eg, nephrolithiasis, rickets, reduced growth rates); monitor body temperature and for decreased sweating, especially in warm or hot weather; changes in weight or appetite due to anorexia; monitor serum ammonia concentration in patients with unexplained lethargy, vomiting, or mental status changes; intraocular pressure, symptoms of secondary angle closure glaucoma; signs and symptoms of suicidality (eg, anxiety, depression, behavior changes); signs of skin rash and severe skin reactions.
Not applicable; plasma topiramate concentrations have not been shown to correlate with clinical efficacy.
Antiseizure activity may be due to a combination of potential mechanisms: Blocks neuronal voltage-dependent sodium channels, enhances GABA(A) activity, antagonizes AMPA/kainate glutamate receptors, and weakly inhibits carbonic anhydrase.
Note: Immediate-release preparations are bioequivalent (sprinkle capsule and tablet); extended-release capsules (Trokendi XR) administered once daily is bioequivalent to twice daily administration of immediate-release formulations; however, bioequivalence has not been established between Trokendi XR and Qudexy XR.
Absorption: Good, rapid; immediate release formulation is unaffected by food. A single Trokendi XR dose with a high-fat meal increased the Cmax by 37% and shortened the Tmax to approximately 8 hours; this effect is significantly reduced following repeat administrations. A single Qudexy XR dose with a high-fat meal delayed the Tmax by 4 hours.
Distribution: Vd: 0.6 to 0.8 L/kg.
Protein binding: 15% to 41% (inversely related to plasma concentrations).
Metabolism: Not extensively metabolized. Minor amounts metabolized in liver via hydroxylation, hydrolysis, and glucuronidation; there is evidence of renal tubular reabsorption; percentage of dose metabolized in liver and clearance are increased in patients receiving enzyme inducers (eg, carbamazepine, phenytoin).
Bioavailability: ~80% (immediate release).
Half-life elimination:
Immediate release:
Not receiving concomitant enzyme inducers or valproic acid:
Neonates (full-term) with hypothermia: ~43 hours (Filippi 2009).
Infants and Children 9 months to <4 years: 10.4 hours (range: 8.5 to 15.3 hours) (Mikaeloff 2004).
Children 4 to 7 years: Mean range: 7.7 to 8 hours (Rosenfeld 1999).
Children 8 to 11 years: Mean range: 11.3 to 11.7 hours (Rosenfeld 1999).
Children and Adolescents 12 to 17 years: Mean range: 12.3 to 12.8 hours (Rosenfeld 1999).
Receiving concomitant enzyme inducers (eg, carbamazepine, phenytoin, phenobarbital):
Neonates (full-term) with hypothermia: 26.5 hours (Filippi 2009).
Infants and Children 9 months to <4 years: 6.5 hours (range: 3.75 to 10.2 hours) (Mikaeloff 2004).
Children and Adolescents 4 to 17 years: 7.5 hours (Rosenfeld 1999).
Receiving valproic acid: Infants and Children 9 months to 4 years: 9.2 hours (range: 7.23 to 12 hours) (Mikaeloff 2004).
Adults: 19 to 23 hours (mean: 21 hours).
Adults with renal impairment: 59 ± 11 hours.
Extended release: Qudexy XR: ~56 hours; Trokendi XR: ~31 hours.
Time to peak, serum:
Immediate release:
Neonates (full-term) with hypothermia: 3.8 hours (Filippi 2009).
Infants and Children 9 months to <4 years: 3.7 hours (range: 1.5 to 10.2 hours) (Mikaeloff 2004).
Children 4 to 17 years: Mean range: 1 to 2.8 hours (Rosenfeld 1999).
Adults: Oral solution: 0.5 hours; Tablets: 2 hours; range: 1.4 to 4.3 hours.
Extended release: Qudexy XR: ~20 hours; Trokendi XR: ~24 hours.
Excretion: Urine (~70% as unchanged drug); may undergo renal tubular reabsorption.
Clearance:
Not receiving concomitant enzyme inducers or valproic acid:
Neonates (full-term) with hypothermia: 13.4 mL/kg/hour (Filippi 2009).
Infants and Children 9 months to <4 years: 46.5 mL/kg/hour (range: 30.5 to 70.9 mL/kg/hour) (Mikaeloff 2004).
Children 4 to 17 years: 27.6 mL/kg/hour (Rosenfeld 1999).
Receiving concomitant enzyme inducers:
Neonates (full-term) with hypothermia: 17.9 mL/kg/hour (Filippi 2009).
Infants and Children 9 months to <4 years: 85.4 mL/kg/hour (range: 46.2 to 135 mL/kg/hour) (Mikaeloff 2004).
Children and Adolescents 4 to 17 years: 60.6 mL/kg/hour (Rosenfeld 1999).
Receiving valproic acid: Infants and Children 9 months to <4 years: 49.6 mL/kg/hour (range: 26.6 to 60.2 mL/kg/h) (Mikaeloff 2004).
Adults: 20 to 30 mL/minute.
Altered kidney function: Clearance is reduced 42% in moderately impaired (creatinine clearance [CrCl] 30 to 69 mL/minute/1.73 m2) and 54% in severely impaired (CrCl <30 mL/minute/1.73 m2) patients. Significantly hemodialyzed; dialysis clearance is 120 mL/minute (4-6 times higher than in adults with normal renal function).
Hepatic function impairment: Clearance is reduced by a mean of 26% in patients with moderate to severe hepatic impairment.
Older adult: Half-life elimination is longer. Plasma and renal clearance were reduced 21% and 19%, respectively. Reduced clearance resulted in slightly higher Cmax (23% for immediate release; 30% for Trokendi XR) and AUC (25% for immediate release; 44% for Trokendi XR). Topiramate clearance is decreased only to the extent that renal function is reduced. Tmax for Trokendi XR is shorter (16 hours).
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