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  • CLASSES

    Anticonvulsants, Miscellaneous
    Other Anti-migraine Agents

    DEA CLASS

    Rx

    DESCRIPTION

    Oral anticonvulsant; weak carbonic anhydrase inhibitor
    Used for partial and generalized seizures, Lennox-Gastaut, refractory seizures, and migraine prophylaxis; off-label uses include binge-eating disorder and alcohol use disorder
    Close monitoring for emerging or worsening suicidal thoughts/behavior or depression recommended

    COMMON BRAND NAMES

    EPRONTIA, Qudexy XR, Topamax, Topamax Sprinkle, Topiragen, Trokendi XR

    HOW SUPPLIED

    EPRONTIA Oral Sol: 1mL, 25mg
    Qudexy XR/Topiramate/Trokendi XR Oral Cap ER: 25mg, 50mg, 100mg, 150mg, 200mg
    Topamax Sprinkle/Topiramate Oral Cap Coated Pellets: 15mg, 25mg
    Topamax/Topiragen/Topiramate Oral Tab: 25mg, 50mg, 100mg, 200mg

    DOSAGE & INDICATIONS

    For the treatment of partial seizures (monotherapy or adjunctive therapy).
    For monotherapy treatment of partial seizures.
    Oral dosage (immediate-release)
    Adults

    25 mg PO twice daily for 1 week, initially. Titrate dose by 50 mg/day weekly for 3 weeks, then by 100 mg/day weekly for 2 weeks. Usual Dose: 200 mg PO twice daily.

    Children and Adolescents 10 to 17 years

    25 mg PO twice daily for 1 week, initially. Titrate dose by 50 mg/day weekly for 3 weeks, then by 100 mg/day weekly for 2 weeks. Usual Dose: 200 mg PO twice daily.

    Children 2 to 9 years weighing more than 38 kg

    25 mg PO once daily in the evening for 1 week, initially. Titrate dose by 25 mg/day weekly for 1 week, then by 25 to 50 mg/day weekly as tolerated. Usual Dose: 125 to 200 mg PO twice daily.

    Children 2 to 9 years weighing 32 to 38 kg

    25 mg PO once daily in the evening for 1 week, initially. Titrate dose by 25 mg/day weekly for 1 week, then by 25 to 50 mg/day weekly as tolerated. Usual Dose: 125 to 175 mg PO twice daily.

    Children 2 to 9 years weighing 23 to 31 kg

    25 mg PO once daily in the evening for 1 week, initially. Titrate dose by 25 mg/day weekly for 1 week, then by 25 to 50 mg/day weekly as tolerated. Usual Dose: 100 to 175 mg PO twice daily.

    Children 2 to 9 years weighing 12 to 22 kg

    25 mg PO once daily in the evening for 1 week, initially. Titrate dose by 25 mg/day weekly for 1 week, then by 25 to 50 mg/day weekly as tolerated. Usual Dose: 100 to 150 mg PO twice daily.

    Children 2 to 9 years weighing 11 kg or less

    25 mg PO once daily in the evening for 1 week, initially. Titrate dose by 25 mg/day weekly for 1 week, then by 25 to 50 mg/day weekly as tolerated. Usual Dose: 75 to 125 mg PO twice daily.

    Oral dosage (extended-release, Trokendi XR)
    Adults

    50 mg PO once daily for 1 week, initially. Titrate dose by 50 mg/day weekly for 3 weeks, then 100 mg/day weekly for 2 weeks. Usual Dose: 400 mg PO once daily.

    Children and Adolescents 10 to 17 years

    50 mg PO once daily for 1 week, initially. Titrate dose by 50 mg/day weekly for 3 weeks, then 100 mg/day weekly for 2 weeks. Usual Dose: 400 mg PO once daily.

    Children 6 to 9 years weighing more than 38 kg

    25 mg PO once daily in the evening for 1 week, initially. Titrate dose by 25 mg/day weekly for 1 week, then 25 to 50 mg/day weekly as tolerated. Usual Dose: 250 to 400 mg PO once daily.

    Children 6 to 9 years weighing 32 to 38 kg

    25 mg PO once daily in the evening for 1 week, initially. Titrate dose by 25 mg/day weekly for 1 week, then 25 to 50 mg/day weekly as tolerated. Usual Dose: 250 to 350 mg PO once daily.

    Children 6 to 9 years weighing 23 to 31 kg

    25 mg PO once daily in the evening for 1 week, initially. Titrate dose by 25 mg/day weekly for 1 week, then 25 to 50 mg/day weekly as tolerated. Usual Dose: 200 to 350 mg PO once daily.

    Children 6 to 9 years weighing 12 to 22 kg

    25 mg PO once daily in the evening for 1 week, initially. Titrate dose by 25 mg/day weekly for 1 week, then 25 to 50 mg/day weekly as tolerated. Usual Dose: 200 to 300 mg PO once daily.

    Children 6 to 9 years weighing 11 kg or less

    25 mg PO once daily in the evening for 1 week, initially. Titrate dose by 25 mg/day weekly for 1 week, then 25 to 50 mg/day weekly as tolerated. Usual Dose: 150 to 250 mg PO once daily.

    Oral dosage (extended-release, Qudexy XR)
    Adults

    50 mg PO once daily for 1 week, initially. Titrate dose by 50 mg/day weekly for 3 weeks, then 100 mg/day weekly for 2 weeks. Usual Dose: 400 mg PO once daily.

    Children and Adolescents 10 to 17 years

    50 mg PO once daily for 1 week, initially. Titrate dose by 50 mg/day weekly for 3 weeks, then 100 mg/day weekly for 2 weeks. Usual Dose: 400 mg PO once daily.

    Children 2 to 9 years weighing more than 38 kg

    25 mg PO once daily in the evening for 1 week, initially. Titrate dose by 25 mg/day weekly for 1 week, then 25 to 50 mg/day weekly as tolerated. Usual Dose: 250 to 400 mg PO once daily.

    Children 2 to 9 years weighing 32 to 38 kg

    25 mg PO once daily in the evening for 1 week, initially. Titrate dose by 25 mg/day weekly for 1 week, then 25 to 50 mg/day weekly as tolerated. Usual Dose: 250 to 350 mg PO once daily.

    Children 2 to 9 years weighing 23 to 31 kg

    25 mg PO once daily in the evening for 1 week, initially. Titrate dose by 25 mg/day weekly for 1 week, then 25 to 50 mg/day weekly as tolerated. Usual Dose: 200 to 350 mg PO once daily.

    Children 2 to 9 years weighing 12 to 22 kg

    25 mg PO once daily in the evening for 1 week, initially. Titrate dose by 25 mg/day weekly for 1 week, then 25 to 50 mg/day weekly as tolerated. Usual Dose: 200 to 300 mg PO once daily.

    Children 2 to 9 years weighing 11 kg or less

    25 mg PO once daily in the evening for 1 week, initially. Titrate dose by 25 mg/day weekly for 1 week, then 25 to 50 mg/day weekly as tolerated. Usual Dose: 150 to 250 mg PO once daily.

    For adjunctive treatment of partial seizures.
    Oral dosage (immediate-release)
    Adults

    25 mg PO once or twice daily for 1 week, initially. Titrate dose by 25 to 50 mg/day weekly. Usual Dose: 100 to 200 mg PO twice daily. Doses above 400 mg/day have not been shown to improve response.

    Adolescents 17 years

    25 mg PO once or twice daily for 1 week, initially. Titrate dose by 25 to 50 mg/day weekly. Usual Dose: 100 to 200 mg PO twice daily. Doses above 400 mg/day have not been shown to improve response.

    Children and Adolescents 2 to 16 years

    1 to 3 mg/kg/day PO once daily (Max: 25 mg/day) in the evening, initially. Titrate dose by 1 to 3 mg/kg/day every 1 to 2 weeks in 2 divided doses. Usual Dose: 5 to 9 mg/kg/day. Max: 400 mg/day.

    Infants† and Children 1 to 2 years†

    Limited data available; further study needed. A target dose of 3 to 25 mg/kg/day PO (divided and given every twice daily) has been safely used in infants and young children with refractory partial seizures ; however, efficacy data is lacking. Case reports have described topiramate efficacy at a dose range of 2.5 to 6 mg/kg/day PO in infants with refractory partial seizures; the maximum dose used in these reports was 7.7 mg/kg/day. However, in a double-blind, placebo-controlled, parallel-group, multicenter study of infants and young children (n = 149; mean age: 12 months; range: 1 to 24 months) topiramate was not effective as adjuvant treatment for refractory partial seizures. Patients in the study were started at a dose of 3 mg/kg/day PO (divided and given twice daily) and titrated every 3 days, as tolerated, to a target dose of 5, 15, or 25 mg/kg/day. At 25 mg/kg/day, there was no difference (p = 0.97) in median percentage reduction from baseline in daily seizure rate compared to placebo (20.4% topiramate vs. 13.1% placebo). In addition, the percentages of treatment responders in the topiramate groups (27% in the 5 mg/kg/day group, 38% in the 15 mg/kg/day group, and 44% in the 25 mg/kg/day group) were not different from placebo (36%) (p > 0.4 for all groups compared to placebo).

    Neonates†

    Limited data available. In a retrospective review, adjunctive topiramate at a dose of 3 or 10 mg/kg/day administered via nasogastric tube controlled or reduced seizure activity (including generalized tonic, partial tonic, and partial clonic) in 4 of 6 term neonates who were considered refractory to phenobarbital or phenobarbital and phenytoin therapy. Maintenance therapy was initiated at 10 mg/kg/day in 5 children and 3 mg/kg/day in 1 patient. At follow-up 5 to 11.5 months later, 5 of 6 patients were seizure free.

    Oral dosage (extended-release, Trokendi XR)
    Adults

    25 to 50 mg PO once daily for 1 week, initially. Titrate dose by 25 to 50 mg/day weekly. Usual Dose: 200 to 400 mg PO once daily. Doses above 400 mg/day have not been shown to improve response.

    Adolescents 17 years

    25 to 50 mg PO once daily for 1 week, initially. Titrate dose by 25 to 50 mg/day weekly. Usual Dose: 200 to 400 mg PO once daily. Doses above 400 mg/day have not been shown to improve response.

    Children and Adolescents 6 to 16 years

    1 to 3 mg/kg/day PO once daily (Max: 25 mg/day) in the evening, initially. Titrate dose by 1 to 3 mg/kg/day every 1 to 2 weeks. Usual Dose: 5 to 9 mg/kg/day. Max: 400 mg/day.

    Oral dosage (extended-release, Qudexy XR)
    Adults

    25 to 50 mg PO once daily for 1 week, initially. Titrate dose by 25 to 50 mg/day weekly. Usual Dose: 200 to 400 mg PO once daily. Doses above 400 mg/day have not been shown to improve response.

    Adolescents 17 years

    25 to 50 mg PO once daily for 1 week, initially. Titrate dose by 25 to 50 mg/day weekly. Usual Dose: 200 to 400 mg PO once daily. Doses above 400 mg/day have not been shown to improve response.

    Children and Adolescents 2 to 16 years

    1 to 3 mg/kg/day PO once daily (Max: 25 mg/day) in the evening, initially. Titrate dose by 1 to 3 mg/kg/day every 1 to 2 weeks. Usual Dose: 5 to 9 mg/kg/day. Max: 400 mg/day.

    For the treatment of primary generalized tonic-clonic seizures (monotherapy or adjunctive therapy).
    For monotherapy treatment of primary generalized tonic-clonic seizures.
    Oral dosage (immediate-release)
    Adults

    25 mg PO twice daily for 1 week, initially. Titrate dose by 50 mg/day weekly for 3 weeks, then by 100 mg/day weekly for 2 weeks. Usual Dose: 200 mg PO twice daily.

    Children and Adolescents 10 to 17 years

    25 mg PO twice daily for 1 week, initially. Titrate dose by 50 mg/day weekly for 3 weeks, then by 100 mg/day weekly for 2 weeks. Usual Dose: 200 mg PO twice daily.

    Children 2 to 9 years weighing more than 38 kg

    25 mg PO once daily in the evening for 1 week, initially. Titrate dose by 25 mg/day weekly for 1 week, then by 25 to 50 mg/day weekly as tolerated. Usual Dose: 125 to 200 mg PO twice daily.

    Children 2 to 9 years weighing 32 to 38 kg

    25 mg PO once daily in the evening for 1 week, initially. Titrate dose by 25 mg/day weekly for 1 week, then by 25 to 50 mg/day weekly as tolerated. Usual Dose: 125 to 175 mg PO twice daily.

    Children 2 to 9 years weighing 23 to 31 kg

    25 mg PO once daily in the evening for 1 week, initially. Titrate dose by 25 mg/day weekly for 1 week, then by 25 to 50 mg/day weekly as tolerated. Usual Dose: 100 to 175 mg PO twice daily.

    Children 2 to 9 years weighing 12 to 22 kg

    25 mg PO once daily in the evening for 1 week, initially. Titrate dose by 25 mg/day weekly for 1 week, then by 25 to 50 mg/day weekly as tolerated. Usual Dose: 100 to 150 mg PO twice daily.

    Children 2 to 9 years weighing 11 kg or less

    25 mg PO once daily in the evening for 1 week, initially. Titrate dose by 25 mg/day weekly for 1 week, then by 25 to 50 mg/day weekly as tolerated. Usual Dose: 75 to 125 mg PO twice daily.

    Oral dosage (extended-release, Trokendi XR)
    Adults

    50 mg PO once daily for 1 week, initially. Titrate dose by 50 mg/day weekly for 3 weeks, then 100 mg/day weekly for 2 weeks. Usual Dose: 400 mg PO once daily.

    Children and Adolescents 10 to 17 years

    50 mg PO once daily for 1 week, initially. Titrate dose by 50 mg/day weekly for 3 weeks, then 100 mg/day weekly for 2 weeks. Usual Dose: 400 mg PO once daily.

    Children 6 to 9 years weighing more than 38 kg

    25 mg PO once daily in the evening for 1 week, initially. Titrate dose by 25 mg/day weekly for 1 week, then 25 to 50 mg/day weekly as tolerated. Usual Dose: 250 to 400 mg PO once daily.

    Children 6 to 9 years weighing 32 to 38 kg

    25 mg PO once daily in the evening for 1 week, initially. Titrate dose by 25 mg/day weekly for 1 week, then 25 to 50 mg/day weekly as tolerated. Usual Dose: 250 to 350 mg PO once daily.

    Children 6 to 9 years weighing 23 to 31 kg

    25 mg PO once daily in the evening for 1 week, initially. Titrate dose by 25 mg/day weekly for 1 week, then 25 to 50 mg/day weekly as tolerated. Usual Dose: 200 to 350 mg PO once daily.

    Children 6 to 9 years weighing 12 to 22 kg

    25 mg PO once daily in the evening for 1 week, initially. Titrate dose by 25 mg/day weekly for 1 week, then 25 to 50 mg/day weekly as tolerated. Usual Dose: 200 to 300 mg PO once daily.

    Children 6 to 9 years weighing 11 kg or less

    25 mg PO once daily in the evening for 1 week, initially. Titrate dose by 25 mg/day weekly for 1 week, then 25 to 50 mg/day weekly as tolerated. Usual Dose: 150 to 250 mg PO once daily.

    Oral dosage (extended-release, Qudexy XR)
    Adults

    50 mg PO once daily for 1 week, initially. Titrate dose by 50 mg/day weekly for 3 weeks, then 100 mg/day weekly for 2 weeks. Usual Dose: 400 mg PO once daily.

    Children and Adolescents 10 to 17 years

    50 mg PO once daily for 1 week, initially. Titrate dose by 50 mg/day weekly for 3 weeks, then 100 mg/day weekly for 2 weeks. Usual Dose: 400 mg PO once daily.

    Children 2 to 9 years weighing more than 38 kg

    25 mg PO once daily in the evening for 1 week, initially. Titrate dose by 25 mg/day weekly for 1 week, then 25 to 50 mg/day weekly as tolerated. Usual Dose: 250 to 400 mg PO once daily.

    Children 2 to 9 years weighing 32 to 38 kg

    25 mg PO once daily in the evening for 1 week, initially. Titrate dose by 25 mg/day weekly for 1 week, then 25 to 50 mg/day weekly as tolerated. Usual Dose: 250 to 350 mg PO once daily.

    Children 2 to 9 years weighing 23 to 31 kg

    25 mg PO once daily in the evening for 1 week, initially. Titrate dose by 25 mg/day weekly for 1 week, then 25 to 50 mg/day weekly as tolerated. Usual Dose: 200 to 350 mg PO once daily.

    Children 2 to 9 years weighing 12 to 22 kg

    25 mg PO once daily in the evening for 1 week, initially. Titrate dose by 25 mg/day weekly for 1 week, then 25 to 50 mg/day weekly as tolerated. Usual Dose: 200 to 300 mg PO once daily.

    Children 2 to 9 years weighing 11 kg or less

    25 mg PO once daily in the evening for 1 week, initially. Titrate dose by 25 mg/day weekly for 1 week, then 25 to 50 mg/day weekly as tolerated. Usual Dose: 150 to 250 mg PO once daily.

    For adjunctive treatment of primary generalized tonic-clonic seizures.
    Oral dosage (immediate-release)
    Adults

    25 mg PO once or twice daily for 1 week, initially. Titrate dose by 25 to 50 mg/day weekly. Usual Dose: 200 mg PO twice daily.

    Adolescents 17 years

    25 mg PO once or twice daily for 1 week, initially. Titrate dose by 25 to 50 mg/day weekly. Usual Dose: 200 mg PO twice daily.

    Children and Adolescents 2 to 16 years

    1 to 3 mg/kg/day PO once daily (Max: 25 mg/day) in the evening, initially. Titrate dose by 1 to 3 mg/kg/day every 1 to 2 weeks in 2 divided doses. Usual Dose: 5 to 9 mg/kg/day. Max: 400 mg/day.

    Infants† and Children younger than 2 years†

    Limited data available, particularly for tonic-clonic seizures; further study needed. A target dose of 3 to 25 mg/kg/day PO (divided and given every twice daily) has been safely used in infants and young children with refractory partial seizures ; however, efficacy data is lacking. Case reports have described topiramate efficacy at a dose range of 2.5 to 6 mg/kg/day PO in infants with refractory partial seizures; the maximum dose used in these reports was 7.7 mg/kg/day. However, in a double-blind, placebo-controlled, parallel-group, multicenter study of infants and young children (n = 149; mean age: 12 months; range: 1 to 24 months) topiramate was not effective as adjuvant treatment for refractory partial seizures. Patients in the study were started at a dose of 3 mg/kg/day PO (divided and given twice daily) and titrated every 3 days, as tolerated, to a target dose of 5, 15, or 25 mg/kg/day. At 25 mg/kg/day, there was no difference (p = 0.97) in median percentage reduction from baseline in daily seizure rate compared to placebo (20.4% topiramate vs. 13.1% placebo). In addition, the percentages of treatment responders in the topiramate groups (27% in the 5 mg/kg/day group, 38% in the 15 mg/kg/day group, and 44% in the 25 mg/kg/day group) were not different from placebo (36%) (p > 0.4 for all groups compared to placebo).

    Neonates†

    Limited data available. In a retrospective review, adjunctive topiramate at a dose of 3 or 10 mg/kg/day administered via nasogastric tube controlled or reduced seizure activity (including generalized tonic, partial tonic, and partial clonic) in 4 of 6 term neonates who were considered refractory to phenobarbital or phenobarbital and phenytoin therapy. Maintenance therapy was initiated at 10 mg/kg/day in 5 children and 3 mg/kg/day in 1 patient. At follow-up 5 to 11.5 months later, 5 of 6 patients were seizure free.

    Oral dosage (extended-release, Trokendi XR)
    Adults

    25 to 50 mg PO once daily for 1 week, initially. Titrate dose by 25 to 50 mg/day weekly. Usual Dose: 400 mg PO once daily.

    Adolescents 17 years

    25 to 50 mg PO once daily for 1 week, initially. Titrate dose by 25 to 50 mg/day weekly. Usual Dose: 400 mg PO once daily.

    Children and Adolescents 6 to 16 years

    1 to 3 mg/kg/day PO once daily (Max: 25 mg/day) in the evening, initially. Titrate dose by 1 to 3 mg/kg/day every 1 to 2 weeks. Usual Dose: 5 to 9 mg/kg/day. Max: 400 mg/day.

    Oral dosage (extended-release, Qudexy XR)
    Adults

    25 to 50 mg PO once daily for 1 week, initially. Titrate dose by 25 to 50 mg/day weekly. Usual Dose: 400 mg PO once daily.

    Adolescents 17 years

    25 to 50 mg PO once daily for 1 week, initially. Titrate dose by 25 to 50 mg/day weekly. Usual Dose: 400 mg PO once daily.

    Children and Adolescents 2 to 16 years

    1 to 3 mg/kg/day PO once daily (Max: 25 mg/day) in the evening, initially. Titrate dose by 1 to 3 mg/kg/day every 1 to 2 weeks. Usual Dose: 5 to 9 mg/kg/day. Max: 400 mg/day.

    For the adjunctive treatment of Lennox-Gastaut syndrome.
    NOTE: Topiramate is designated an orphan drug by the FDA for Lennox-Gastaut.
    Oral dosage (immediate-release)
    Adults

    25 mg PO once or twice daily for 1 week, initially. Titrate dose by 25 to 50 mg/day weekly. Usual Dose: 100 to 200 mg PO twice daily.

    Adolescents 17 years

    25 mg PO once or twice daily for 1 week, initially. Titrate dose by 25 to 50 mg/day weekly. Usual Dose: 100 to 200 mg PO twice daily.

    Children and Adolescents 2 to 16 years

    1 to 3 mg/kg/day PO once daily (Max: 25 mg/day) in the evening, initially. Titrate dose by 1 to 3 mg/kg/day every 1 to 2 weeks in 2 divided doses. Usual Dose: 5 to 9 mg/kg/day. Max: 400 mg/day.

    Oral dosage (extended-release, Trokendi XR)
    Adults

    25 to 50 mg PO once daily for 1 week, initially. Titrate dose by 25 to 50 mg/day weekly. Usual Dose: 200 to 400 mg PO once daily.

    Adolescents 17 years

    25 to 50 mg PO once daily for 1 week, initially. Titrate dose by 25 to 50 mg/day weekly. Usual Dose: 200 to 400 mg PO once daily.

    Children and Adolescents 6 to 16 years

    1 to 3 mg/kg/day PO once daily (Max: 25 mg/day) in the evening, initially. Titrate dose by 1 to 3 mg/kg/day every 1 to 2 weeks. Usual Dose: 5 to 9 mg/kg/day. Max: 400 mg/day.

    Oral dosage (extended-release, Qudexy XR)
    Adults

    25 to 50 mg PO once daily for 1 week, initially. Titrate dose by 25 to 50 mg/day weekly. Usual Dose: 200 to 400 mg PO once daily.

    Adolescents 17 years

    25 to 50 mg PO once daily for 1 week, initially. Titrate dose by 25 to 50 mg/day weekly. Usual Dose: 200 to 400 mg PO once daily.

    Children and Adolescents 2 to 16 years

    1 to 3 mg/kg/day PO once daily (Max: 25 mg/day) in the evening, initially. Titrate dose by 1 to 3 mg/kg/day every 1 to 2 weeks. Usual Dose: 5 to 9 mg/kg/day. Max: 400 mg/day.

    For migraine prophylaxis.
    Oral dosage (immediate-release)
    Adults

    25 mg PO every evening for 1 week, then 25 mg PO twice daily for 1 week, then 25 mg PO every morning and 50 mg PO every evening for 1 week, and then 50 mg PO twice daily. Adjust dose and titration according to clinical outcome; use longer intervals between dose adjustments if needed. Guidelines classify topiramate as having established efficacy for migraine prophylaxis.[57981] [64551]

    Children and Adolescents 12 to 17 years

    25 mg PO every evening for 1 week, then 25 mg PO twice daily for 1 week, then 25 mg PO every morning and 50 mg PO every evening for 1 week, and then 50 mg PO twice daily. Adjust dose and titration according to clinical outcome; use longer intervals between dose adjustments if needed. Pediatric patients receiving topiramate are probably more likely than those receiving placebo to have a decrease in headache frequency.[64586]

    Children 6 to 11 years†

    12.5 to 25 mg PO once daily in the evening, initially. Titrate dose gradually every 1 to 2 weeks. Usual Dose: 2 to 3 mg/kg/day or 50 mg PO twice daily.[42981] [55920] [55921] [55923] Some patients respond to doses as low as 25 mg/day.[55920] Max: 200 mg/day.[55921] Pediatric patients receiving topiramate are probably more likely than those receiving placebo to have a decrease in headache frequency.[64586]

    Oral dosage (extended-release)
    Adults

    25 mg PO once daily for 1 week, then 50 mg PO once daily for 1 week, then 75 mg PO once daily for 1 week, and then 100 mg PO once daily. Adjust dose and titration according to clinical outcome; use longer intervals between dose adjustments if needed.[56847] [55675] Guidelines classify topiramate as having established efficacy for migraine prophylaxis.[57981] [64551]

    Children and Adolescents 12 to 17 years

    25 mg PO once daily for 1 week, then 50 mg PO once daily for 1 week, then 75 mg PO once daily for 1 week, and then 100 mg PO once daily. Adjust dose and titration according to clinical outcome; use longer intervals between dose adjustments if needed. Pediatric patients receiving topiramate are probably more likely than those receiving placebo to have a decrease in headache frequency.[64586]

    For the adjunctive treatment of refractory infantile spasms† associated with West syndrome.
    Oral dosage (immediate-release)
    Children

    25 mg PO once daily, initially. Titrate dose by 25 mg every 2 to 3 days until spasms are controlled or up to a maximum dose of 24 mg/kg/day in divided doses.

    For the treatment of alcohol dependence†.
    Oral dosage (immediate-release)
    Adults

    25 mg PO once daily, initially. Titrate dose according to response and tolerability. Max: 300 mg/day in divided doses. Guidelines suggest topiramate for patients with moderate to severe alcohol use disorder who have a goal of reducing alcohol consumption or achieving abstinence, prefer topiramate or are intolerant to or have not responded to naltrexone and acamprosate, and have no contraindications to the use of topiramate.  

    For the adjunctive treatment of bulimia nervosa†.
    Oral dosage (immediate-release)
    Adults

    25 mg PO once daily, initially. Titrate dose gradually. Dose range: 25 to 400 mg/day in divided doses.

    For the treatment of cocaine dependence†.
    Oral dosage (immediate-release)
    Adults

    25 mg PO once or twice daily for 1 week, initially. Titrate dose by 25 to 50 mg/day weekly. Usual dose: 100 to 150 mg PO twice daily. Guidelines suggest topiramate as a possible treatment option, as treatment options are limited and some evidence suggests a potential benefit.

    For long-term prophylaxis of short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT)†.
    Oral dosage (immediate-release)
    Adults

    12.5 to 25 mg PO once daily, initially. Titrate dose to 25 to 75 mg PO twice daily as tolerated. Higher doses of 150 to 400 mg PO twice daily have also been efficacious.

    For the treatment of binge-eating disorder† (BED).
    Oral dosage (immediate-release)
    Adults

    25 mg PO once daily for 1 week, initially. Titrate dose by 25 to 50 mg/day weekly for 4 weeks, then may titrate by up to 100 mg/day weekly. Usual Dose: 200 to 300 mg/day in 2 divided doses. Usual Max: 400 mg/day (up to 600 mg/day).

    For the treatment of Tourette's syndrome† or chronic tic disorders†.
    Oral dosage (immediate-release)
    Adults

    25 mg PO once or twice daily, initially. Titrate dose according to response and tolerability. Usual dose: 50 to 200 mg/day in divided doses. Doses more than 200 mg/day are poorly tolerated. Topiramate is possibly more likely than placebo to reduce tic severity in patients with Tourette's syndrome or chronic tic disorders and may be useful in patients with mild but troublesome tics and inadequate response or intolerance to other treatments.

    Children and Adolescents 7 to 17 years

    25 mg PO once daily, initially. Titrate dose according to response and tolerability. Usual dose: 25 to 200 mg/day in divided doses.  Doses more than 200 mg/day are poorly tolerated. Topiramate is possibly more likely than placebo to reduce tic severity in patients with Tourette's syndrome or chronic tic disorders and may be useful in patients with mild but troublesome tics and inadequate response or intolerance to other treatments.

    For neuroprotection in neonates with hypoxic-ischemic encephalopathy†.
    Oral dosage (immediate-release)
    Neonates

    Limited data; optimal dose and efficacy have not been established. Topiramate 5 mg/kg via naso- or orogastric tube once, then 3 to 5 mg/kg/day for 2 to 5 days has been used in trials with mixed outcomes; a higher dosage of 10 mg/kg/day for 3 days has also been used in a small pilot study. Topiramate 5 mg/kg once, then 3 mg/kg/day for 5 days reduced seizure activity and mortality in a randomized, controlled, double-blind trial of neonates also receiving therapeutic hypothermia (n = 110); however, these results did not reach statistical significance when compared to placebo. Topiramate achieved therapeutic serum concentrations (5 to 20 mg/L) in 36.9% and 75.5% of patients at 24 and 48 hours, respectively. Topiramate 5 mg/kg on day 1 then either 3 mg/kg/day (n = 11) or 5 mg/kg/day (n = 16) on days 2 and 3 was used in a safety study in combination with hypothermia. There was no statistically significant difference in short-term outcomes, survival rate at discharge, or incidence of cerebral lesions on MRI. Long-term effects on cognitive function were not assessed. Additionally, no significant differences were seen in the combined frequency of mortality and severe neurological disability in a small pilot trial (n = 44) comparing topiramate 10 mg/kg/dose for 3 days plus moderate hypothermia vs. hypothermia alone. Average topiramate serum concentrations were 6.5 to 7 mg/L after the first dose and increased to 12 to 13 mg/L after the third dose.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    400 mg/day PO for epilepsy; 100 mg/day PO for migraine prophylaxis.

    Geriatric

    400 mg/day PO for epilepsy; 100 mg/day PO for migraine prophylaxis.

    Adolescents

    17 years: 400 mg/day PO for epilepsy; 100 mg/day PO for migraine prophylaxis.
    13 to 16 years: 400 mg/day PO (monotherapy) or 9 mg/kg/day PO (adjunct therapy) for epilepsy; 100 mg/day PO for migraine prophylaxis.

    Children

    12 years: 400 mg/day PO (monotherapy) or 9 mg/kg/day PO (adjunct therapy) for epilepsy; 100 mg/day PO for migraine prophylaxis.
    10 to 11 years: 400 mg/day PO (monotherapy) or 9 mg/kg/day PO (adjunct therapy) for epilepsy.
    2 to 9 years weighing more than 38 kg: 400 mg/day PO (monotherapy) or 9 mg/kg/day PO (adjunct therapy) for epilepsy.
    2 to 9 years weighing 23 to 38 kg: 350 mg/day PO (monotherapy) or 9 mg/kg/day PO (adjunct therapy) for epilepsy.
    2 to 9 years weighing 12 to 22 kg: 300 mg/day PO (monotherapy) or 9 mg/kg/day PO (adjunct therapy) for epilepsy.
    2 to 9 years weighing 11 kg or less: 250 mg/day PO (monotherapy) or 9 mg/kg/day PO (adjunct therapy) for epilepsy.
    Younger than 2 years: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; however, clearance may be reduced.

    Renal Impairment

    Patients with renal impairment may require a longer time than patients with normal renal function to reach steady-state with each topiramate dosage adjustment.
    CrCl 70 mL/minute or more: No dosage adjustment needed.
    CrCl less than 70 mL/minute: In adults, reduce the topiramate dose to one-half of the usual dose.
    In pediatric patients, adjustment to the usual mg/kg dosage may be required, but should be individualized since clearance rates are higher in the pediatric population than in adults. Some experts recommend administering one-half of the usual dose for pediatric patients with a GFR 10 to 50 mL/minute/1.73 m2 and one-quarter of the usual dose for pediatric patients with a GFR less than 10 mL/minute/1.73 m2.
     
    Intermittent hemodialysis
    During the hemodialysis session, adult patients clear topiramate at a rate that is 4 to 6 times greater than an adult person with normal renal function. A supplemental dose of topiramate may be required during or post-hemodialysis in some patients. Dosage adjustments should be based on duration of dialysis period, clearance rate of the dialysis system being used, and the effective renal clearance of topiramate in the patient to be dialyzed.

    ADMINISTRATION

    For storage information, see specific product information within the How Supplied section.
    Hazardous Drugs Classification
    NIOSH 2016 List: Group 3
    NIOSH (Draft) 2020 List: Table 2
    Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
    Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Eye/face and respiratory protection may be needed during preparation and administration.

    Oral Administration

    May administer without regard to meals.

    Oral Solid Formulations

    Tablets
    Do not break the tablets due to bitter taste.
    Sprinkle capsules
    Swallow whole. Alternatively, sprinkle the contents of the capsule on a small amount of soft food (e.g., applesauce, custard, ice cream, oatmeal, pudding, yogurt). Prepare entire dose and swallow immediately after preparation. Do not chew. Drink fluids to ensure entire dose is swallowed. Do not store any drug/food mixture for use at a later time.
    Additionally, the capsule contents may be administered via nasogastric (NG) tube; use an adequate amount of fluid to wash the full dose down the tube.
    Trokendi XR extended-release capsules
    Swallow whole and intact. Do not sprinkle on food, chew, or crush.
    Extended-release capsules are not recommended for children younger than 6 years, as they must be swallowed whole and intact.
    Qudexy XR extended-release capsules
    Swallow whole or sprinkle contents of the capsule on a small amount (teaspoon) of soft food. Prepare entire dose and swallow immediately after preparation. Do not chew or crush. Do not store any drug/food mixture for use at a later time.

    Oral Liquid Formulations

    Oral solution (25 mg/mL)
    Administer using a calibrated measuring device.
    Storage: Discard unused medication 30 days after opening the bottle.

    Extemporaneous Compounding-Oral

    Topiramate 20 mg/mL Oral Suspension
    NOTE: A 25 mg/mL oral solution is commercially available. ASHP recommends topiramate 20 mg/mL as the compounded oral liquid standard concentration; however, this recommendation was made prior to commercial availability of a 25 mg/mL oral solution.
    Measure out 2,000 mg of topiramate tablets or powder. If tablets are used, pulverized them to a fine powder.
    Mix the powder with about 10 mL of Ora-Plus to form a smooth, uniform paste.
    Geometrically incorporate 40 mL of Ora-Plus and mix well.
    Add Ora-Sweet in a sufficient quantity for a final volume of 100 mL and mix well.
    Shake well prior to administration.
    Storage: Store in a tight, light-resistant container at controlled room temperature or in the refrigerator for up to 90 days.

    STORAGE

    EPRONTIA:
    - Avoid excessive heat (above 104 degrees F)
    - Product should be used within 2 months after opening
    - Protect from freezing
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Qudexy XR:
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in a cool, dry place
    - Store in original container
    Topamax:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Topamax Sprinkle:
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Topiragen :
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Trokendi XR:
    - Protect from light
    - Protect from moisture
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    - Store in a dry place

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Topiramate is contraindicated for use in any patient hypersensitive to the drug or any of the product components. Serious and potentially fatal exfoliative dermatologic reactions have been reported in post-marketing experience with topiramate.[28378] [55675] Cross-sensitivity between antibiotic sulfonamides and nonantibiotic sulfonamides, such as topiramate, is controversial.[56047] Antibiotic sulfonamides contain an amine linked to a benzene ring (arylamine moiety), attached directly to the sulfonamide structure; this arylamine attached to the sulfonamide structure is believed to be the central pathogenesis of hypersensitivity reactions.[56047] [56048] Although topiramate is a simple sulfonamide, the sulfonamide structure is not directly connected to a ring structure, and it lacks an arylamine moiety.[56047] [56049] Some experts believe apparent cross-reactivity represents multiple concurrent and unlinked drug hypersensitivities in predisposed patients.[32382] [56048] Although cross-reactivity with sulfonamide antibiotics appears unlikely, precaution or complete avoidance of nonantibiotic sulfonamides in individuals whose previous reaction was serious and/or life-threatening or in those with multiple drug hypersensitivities may be prudent.[32382] [56047] [56048] [56049]

    Depression, suicidal ideation

    Monitor all patients beginning treatment with antiepileptic drugs (AEDs) or currently receiving topiramate closely for emerging or worsening depression or suicidal ideation. Advise patients and caregivers of the increased risk of suicidal thoughts and behaviors and to immediately report the emergence of new or worsening of depression, suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior. AEDs should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with an increased risk of suicidal thoughts and behavior. If suicidal thoughts and behavior emerge during treatment, consider whether the emergence of these symptoms in any patient may be related to the illness being treated. There is an increased risk of suicidal ideation and behavior in patients receiving AEDs to treat epilepsy, psychiatric disorders, or other conditions (e.g., migraine, neuropathic pain). The primary analysis consisted of 199 placebo-controlled clinical studies with a total of 27,863 patients in drug treatment groups and 16,029 patients in placebo groups (5 years of age and older). There were 4 completed suicides among patients in drug treatment groups versus none in the placebo groups. Patients receiving AEDs had approximately twice the risk of suicidal behavior or ideation as patients receiving placebo (0.43% vs. 0.24%, respectively; RR 1.8, 95% CI: 1.2 to 2.7). The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions; however, the absolute risk differences were similar in trials for epilepsy and psychiatric indications. Age was not a determining factor. The increased risk of suicidal ideation and behavior was observed between 1 and 24 weeks after therapy initiation. However, a longer duration of therapy should not preclude the possibility of an association to the drug since most studies included in the analysis did not continue beyond 24 weeks.[28378] [55675] [56847]

    Abrupt discontinuation

    In patients with or without a history of seizures or epilepsy, withdraw topiramate gradually to minimize the potential for seizures or increased seizure frequency.  In situations where abrupt discontinuation of topiramate is medically required, appropriate monitoring is recommended.[28378] [55675] [56847]

    Diarrhea, metabolic acidosis, pulmonary disease, status epilepticus

    Extended-release topiramate is contraindicated in patients with metabolic acidosis who are taking concomitant metformin. Topiramate can cause hyperchloremic, non-anion gap metabolic acidosis. Conditions or therapies that predispose patients to acidosis, such as kidney disease, severe pulmonary disease, status epilepticus, diarrhea, ketogenic diet, or certain drugs, may be additive to the bicarbonate lowering effects of topiramate. Measurement of baseline and periodic serum bicarbonate during topiramate treatment is recommended. If metabolic acidosis develops and persists, consider reducing the dose or discontinuing topiramate (using dose tapering). If the decision is made to continue patients on topiramate in the face of persistent acidosis, consider alkali treatment. Also, the concomitant use of topiramate with any other drug producing metabolic acidosis, or potentially in patients on a ketogenic diet, may create a physiological environment that increases the risk of kidney stone formation, and should therefore be avoided.[28378] [55675] [56847]

    Ethanol ingestion, ethanol intoxication

    Trokendi XR is contraindicated with recent ethanol ingestion or ethanol intoxication (i.e., within 6 hours before and 6 hours after use). In the presence of alcohol, the pattern of topiramate release from Trokendi XR is significantly altered. As a result, plasma concentrations of topiramate may be markedly higher soon after dosing and subtherapeutic later in the day.[55675]

    Ambient temperature increase, children, infants, neonates

    Closely monitor patients (especially neonates, infants, and children) treated with topiramate for evidence of decreased sweating and increased body temperature, especially in hot weather. Use caution when topiramate is given with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, other carbonic anhydrase inhibitors and drugs with anticholinergic activity. Oligohidrosis, infrequently resulting in hospitalization, has been reported in association with topiramate use. Some of the cases were reported after exposure to an ambient temperature increase. The majority of these reports have been in pediatric patients. Monitor growth carefully in pediatric patients receiving prolonged treatment with topiramate. Topiramate is associated with negative effects on growth (weight, height, and height velocity) in pediatric patients 6 to 15 years. Significant decreases in bone mineral density (lumbar spine and total body less head) were also reported in this population. Decreases in bone mineral density correlated with decreased serum bicarbonate (reflective of metabolic acidosis), suggesting that metabolic acidosis is at least a partial factor contributing to decreased bone mineral density.

    Mitochondrial disease

    Hyperammonemia with and without encephalopathy has been observed in patients who were taking topiramate. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity (mitochondrial disease) may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, topiramate treatment or an interaction of concomitant topiramate-based product and valproic acid treatment may exacerbate existing defects or unmask deficiencies in susceptible persons. In patients who develop unexplained lethargy, vomiting, or changes in mental status associated with any topiramate treatment, consider hyperammonemic encephalopathy and measure an ammonia concentration.[28378] [55986] [56847]

    Geriatric

    According to the Beers Criteria, anticonvulsants are considered potentially inappropriate medications (PIMs) in geriatric patients with a history of falls or fractures and should be avoided in these patient populations, except for treating seizure and mood disorders, since anticonvulsants can produce ataxia, impaired psychomotor function, syncope, and additional falls. If topiramate must be used, consider reducing the use of other CNS-active medications that increase the risk of falls and fractures and implement strategies to reduce fall risk.[63923] The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities; the use of any anticonvulsant for any condition should be based on confirmation of the condition and its potential cause(s). Determine effectiveness and tolerability by evaluating symptoms, and use these as the basis for dosage adjustment for most patients. Therapeutic drug monitoring is not required or available for most anticonvulsants. Serum medication concentrations (when available) may assist in identifying toxicity. Monitor the treated patient for drug efficacy and side effects. Anticonvulsants can cause a variety of side effects; some adverse reactions can increase the risk of falls. When an anticonvulsant is being used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt periodic tapering of the medication or provide documentation of medical necessity as outlined in the OBRA guidelines.[60742]

    Autoimmune disease, diabetes mellitus, dialysis, hypertension, renal disease, renal failure, renal impairment

    Topiramate dosage adjustment is necessary for patients with renal impairment. Before dosing, obtain an estimated creatinine clearance in patients at high risk for renal disease (e.g., older patients, or those with diabetes mellitus, hypertension, or autoimmune disease). In patients with renal insufficiency, a reduction in the topiramate dose is needed. In patients with renal failure receiving dialysis, a supplemental topiramate dose may be required; topiramate is removed by hemodialysis at a rate greater than in patients with normal renal function. Also, conditions that predispose patients to acidosis, such as renal disease, may be additive to the bicarbonate lowering effects of topiramate. Measurement of baseline and periodic serum bicarbonate during topiramate treatment is recommended. If metabolic acidosis develops and persists, consider reducing the dose or discontinuing topiramate (using dose tapering). If the decision is made to continue patients on topiramate in the face of persistent acidosis, consider alkali treatment.

    Serious rash

    Serious rash (Stevens-Johnson syndrome [SJS] and toxic epidermal necrolysis [TEN]) has been reported in patients receiving topiramate. Discontinue topiramate at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, do not resume topiramate use and consider alternative therapy. Inform patients about the signs of serious skin reactions.[28378]

    Anticoagulant therapy, thrombocytopenia

    Topiramate is associated with an increased risk of bleeding. In patients with serious bleeding events, conditions that increased the risk for bleeding were often present, or patients were often taking drugs that cause thrombocytopenia (other antiepileptic drugs) or affect platelet function or coagulation (e.g., aspirin, nonsteroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, or warfarin or other anticoagulant therapy).[28378] [55675] [56847]

    Driving or operating machinery

    Warn patients about the potential for somnolence, dizziness, confusion, difficulty concentrating, or visual effects, and advise patients against driving or operating machinery until they have gained sufficient experience on topiramate to gauge whether it adversely affects their mental performance, motor performance, and/or vision.[28378] [55675] [56847]

    Labor, pregnancy

    Topiramate can cause fetal harm when administered to a pregnant woman. Consider the benefits and risks of topiramate in women of childbearing potential, particularly when it is being considered for conditions not usually associated with permanent injury or death. Counsel women of childbearing potential regarding the potential risk to the fetus from topiramate exposure, and consider alternative therapeutic options in women who are planning a pregnancy. Data from pregnancy registries indicate infants exposed to topiramate during pregnancy have an increased risk for cleft lip and/or cleft palate. The prevalence of oral clefts among topiramate-exposed infants was 1.4% compared to 0.3% in infants exposed to another antiepileptic drug (AED), and 0.11% in infants with mothers without epilepsy or AED exposure. The relative risk of oral clefts in topiramate-exposed pregnancies was 12.5 (95% CI 5.9 to 26.37) compared to untreated women.[28378] [55675] Oral clefts develop in the first trimester before many women know that they are pregnant.[43569] Data from pregnancy registries indicate infants exposed to topiramate during pregnancy have an increased risk for being small for gestational age (SGA), defined as a birth weight below the tenth percentile. SGA has been seen at all doses and appears to be dose-dependent. SGA occurs more frequently in infants of women who received higher topiramate doses or continued topiramate use until later in pregnancy (i.e., third trimester). According to registry data, the prevalence of SGA was 19.7% to 25% in topiramate-exposed infants compared to 7.9% in infants exposed to a reference AED, and 5.4% to 9% in infants with mothers without epilepsy or AED exposure. Excluding oral clefts, no other specific patterns of major congential malformations were observed based on data from pregnancy registries. The prevalence of major congenital malformations among topiramate-exposed infants was 4.1% compared to 1.8% in infants exposed to another AED, and 1.1% in infants with mothers without epilepsy or AED exposure. Registry data and findings from other studies suggest that combination therapy with AEDs may increase the risk of teratogenic effects compared to monotherapy with an AED. Structural malformations such as craniofacial defects and reduced fetal weight occurred in the offspring of multiple animal species during studies of topiramate. Topiramate can cause metabolic acidosis which, when occurring during pregnancy, has been associated with decreased fetal growth, decreased fetal oxygenation, fetal death, and may impact the ability of the fetus to tolerate labor. Monitor women taking topiramate during pregnancy for metabolic acidosis and treat as in the nonpregnant state. Monitor newborns of mothers treated with topiramate for metabolic acidosis after birth. Limited data indicate topiramate may be associated with pre-term labor and premature delivery. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to topiramate; information about the registry can be obtained at www.aedpregnancyregistry.org or by calling 1-888-233-2334.[28378] [55675]

    Breast-feeding

    Topiramate is excreted in human breast milk. Diarrhea and somnolence have been observed in breast-fed infants whose mothers received topiramate. The effects of topiramate on milk production are unknown. Consider the developmental and health benefits from breast-feeding along with the mother's clinical need for topiramate and any potential adverse effects on the breast-fed infant from topiramate or the underlying maternal condition.[55675] Data from 5 breast-feeding infants has shown topiramate plasma concentrations of 10% to 20% of the maternal plasma concentration.[28378] Based on breast milk concentrations from 3 women taking 150 to 200 mg topiramate daily, it was estimated that a breast-fed infant (assuming a milk intake of 150 mL/kg/day) would receive approximately 0.1 to 0.7 mg/kg/day or 3% to 23% of the maternal weight-adjusted dose.[46385]

    Contraception requirements, reproductive risk

    Topiramate is associated with reproductive risk. Discuss contraception requirements with the patient. Women of childbearing age who are not planning a pregnancy should use effective contraception because of the fetal risks of oral clefts and being small for gestational age.

    ADVERSE REACTIONS

    Severe

    visual impairment / Early / 1.0-3.0
    hearing loss / Delayed / 1.0-2.0
    seizures / Delayed / 1.0-1.0
    thrombosis / Delayed / 0.1-1.0
    pulmonary embolism / Delayed / 0.1-1.0
    oliguria / Early / 0.1-1.0
    bradycardia / Rapid / 0-1.0
    AV block / Early / 0.1-1.0
    pancytopenia / Delayed / 0-0.1
    acute cerebellar syndrome / Early / 1.0
    bronchospasm / Rapid / 1.0
    suicidal ideation / Delayed / Incidence not known
    ocular hypertension / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    pemphigus / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known

    Moderate

    hyperammonemia / Delayed / 0-26.0
    memory impairment / Delayed / 0-11.0
    nystagmus / Delayed / 10.0-10.0
    depression / Delayed / 0-9.0
    hyperthyroidism / Delayed / 0-8.0
    hypophosphatemia / Delayed / 0-6.0
    bleeding / Early / 0.2-4.5
    involuntary movements / Delayed / 0-4.0
    ataxia / Delayed / 3.0-4.0
    confusion / Early / 0-4.0
    blurred vision / Early / 2.0-4.0
    urinary incontinence / Early / 1.0-4.0
    gastritis / Delayed / 0-3.0
    anemia / Delayed / 1.0-3.0
    dyspnea / Early / 1.0-3.0
    cystitis / Delayed / 1.0-3.0
    nephrolithiasis / Delayed / 0-3.0
    vaginal bleeding / Delayed / 0-3.0
    ejaculation dysfunction / Delayed / 0-3.0
    hypertonia / Delayed / 0-3.0
    aphasia / Delayed / 2.0-2.0
    dysarthria / Delayed / 0-2.0
    leukopenia / Delayed / 1.0-2.0
    secondary malignancy / Delayed / 0-2.0
    hematuria / Delayed / 0-2.0
    hot flashes / Early / 1.0-2.0
    edema / Delayed / 1.0-2.0
    hypertension / Early / 0-2.0
    dysphonia / Delayed / 0.1-1.0
    hyperesthesia / Delayed / 0.1-1.0
    EEG changes / Delayed / 0.1-1.0
    peripheral neuropathy / Delayed / 0.1-1.0
    scotomata / Delayed / 0.1-1.0
    delirium / Early / 0.1-1.0
    euphoria / Early / 0.1-1.0
    esophagitis / Delayed / 0.1-1.0
    dysphagia / Delayed / 0-1.0
    melena / Delayed / 0.1-1.0
    glossitis / Early / 0-1.0
    stomatitis / Delayed / 0.1-1.0
    fecal incontinence / Early / 0-1.0
    gingival hyperplasia / Delayed / 0-1.0
    hemorrhoids / Delayed / 0.1-1.0
    thrombocytosis / Delayed / 0.1-1.0
    eosinophilia / Delayed / 0.1-1.0
    thrombocytopenia / Delayed / 0-1.0
    hematoma / Early / 0-1.0
    lymphadenopathy / Delayed / 0.1-1.0
    lymphopenia / Delayed / 0.1-1.0
    photophobia / Early / 0.1-1.0
    urinary retention / Early / 0.1-1.0
    orthostatic hypotension / Delayed / 0.1-1.0
    peripheral vasodilation / Rapid / 0.1-1.0
    hypotension / Rapid / 0.1-1.0
    angina / Early / 0.1-1.0
    dyskinesia / Delayed / 0.1-1.0
    dystonic reaction / Delayed / 0.1-1.0
    hypocalcemia / Delayed / 0.1-1.0
    dehydration / Delayed / 0.1-1.0
    hypoglycemia / Early / 1.0-1.0
    hyperglycemia / Delayed / 0.1-1.0
    hyperlipidemia / Delayed / 0.1-1.0
    diabetes mellitus / Delayed / 0.1-1.0
    phlebitis / Rapid / 0.1-1.0
    mania / Early / 0-0.1
    lymphocytosis / Delayed / 0-0.1
    polycythemia / Delayed / 0-0.1
    iritis / Delayed / 0-0.1
    hyponatremia / Delayed / 0-0.1
    hypernatremia / Delayed / 0-0.1
    migraine / Early / 1.0
    psychosis / Early / 1.0
    hallucinations / Early / 1.0
    constipation / Delayed / 1.0
    conjunctivitis / Delayed / 1.0
    candidiasis / Delayed / 1.0
    impotence (erectile dysfunction) / Delayed / 1.0
    chest pain (unspecified) / Early / 1.0
    encephalopathy / Delayed / Incidence not known
    hyperemia / Delayed / Incidence not known
    myopia / Delayed / Incidence not known
    bullous rash / Early / Incidence not known
    hyperthermia / Delayed / Incidence not known

    Mild

    paresthesias / Delayed / 2.0-51.0
    fatigue / Early / 7.0-19.0
    weight loss / Delayed / 6.0-17.0
    drowsiness / Early / 2.0-15.0
    dysgeusia / Early / 2.0-15.0
    abdominal pain / Early / 6.0-15.0
    anorexia / Delayed / 4.0-15.0
    infection / Delayed / 1.0-15.0
    dizziness / Early / 0-14.0
    nausea / Early / 0-14.0
    fever / Early / 1.0-12.0
    diplopia / Early / 10.0-10.0
    sinusitis / Delayed / 1.0-10.0
    insomnia / Early / 0-9.0
    diarrhea / Early / 2.0-9.0
    hypoesthesia / Delayed / 4.0-8.0
    anxiety / Delayed / 0-8.0
    psychomotor impairment / Early / 0-8.0
    emotional lability / Early / 0-8.0
    purpura / Delayed / 0-8.0
    epistaxis / Delayed / 0-8.0
    laryngitis / Delayed / 0-8.0
    cough / Delayed / 2.0-7.0
    hypersalivation / Early / 0-6.0
    pharyngitis / Delayed / 2.0-6.0
    asthenia / Delayed / 0-6.0
    hyperkinesis / Delayed / 5.0-5.0
    dyspepsia / Early / 3.0-5.0
    xerostomia / Early / 1.0-5.0
    rhinitis / Early / 1.0-5.0
    flushing / Rapid / 0-5.0
    rash / Early / 1.0-4.0
    alopecia / Delayed / 1.0-4.0
    pruritus / Rapid / 1.0-4.0
    vertigo / Early / 0-3.0
    libido decrease / Delayed / 0-3.0
    vomiting / Early / 0-3.0
    increased urinary frequency / Early / 0-3.0
    acne vulgaris / Delayed / 2.0-3.0
    hyporeflexia / Delayed / 0-2.0
    irritability / Delayed / 2.0-2.0
    agitation / Early / 1.0-2.0
    hypertrichosis / Delayed / 2.0-2.0
    menorrhagia / Delayed / 1.0-2.0
    amenorrhea / Delayed / 2.0-2.0
    leukorrhea / Delayed / 2.0-2.0
    polydipsia / Early / 1.0-2.0
    tinnitus / Delayed / 0-2.0
    ptosis / Delayed / 0.1-1.0
    paranoia / Early / 0.1-1.0
    appetite stimulation / Delayed / 0-1.0
    weight gain / Delayed / 0-1.0
    flatulence / Early / 0-1.0
    gingivitis / Delayed / 0-1.0
    xerophthalmia / Early / 0.1-1.0
    lacrimation / Early / 1.0-1.0
    pallor / Early / 0-1.0
    polyuria / Early / 0.1-1.0
    nocturia / Early / 0-1.0
    seborrhea / Delayed / 1.0-1.0
    skin discoloration / Delayed / 1.0-1.0
    hyperhidrosis / Delayed / 0-1.0
    drug-induced body odor / Delayed / 0-1.0
    breast discharge / Delayed / 0.1-1.0
    parosmia / Delayed / 0.1-1.0
    libido increase / Delayed / 0-0.1
    mydriasis / Early / 0-0.1
    tremor / Early / 1.0
    headache / Early / 1.0
    gastroesophageal reflux / Delayed / 1.0
    ocular pain / Early / 1.0
    menstrual irregularity / Delayed / 1.0
    syncope / Early / 1.0
    hypothermia / Delayed / Incidence not known
    ecchymosis / Delayed / Incidence not known
    oligohidrosis / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Moderate) Caution is warranted when dolutegravir is administered with topiramate as there is a potential for decreased dolutegravir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Dolutegravir is partially metabolized by this isoenzyme.
    Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Monitor for increased CNS effects if topiramate is coadministered with diphenhydramine. Although not specifically studied, coadministration of CNS depressant drugs with topiramate may potentiate CNS depression, such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with topiramate can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If topiramate is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Topiramate is a weak inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Monitor for increased CNS effects if topiramate is coadministered with doxylamine. Although not specifically studied, coadministration of CNS depressant drugs with topiramate may potentiate CNS depression, such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents.
    Acetaminophen; Diphenhydramine: (Moderate) Monitor for increased CNS effects if topiramate is coadministered with diphenhydramine. Although not specifically studied, coadministration of CNS depressant drugs with topiramate may potentiate CNS depression, such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents.
    Acetaminophen; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with topiramate is necessary; consider increasing the dose of hydrocodone as needed. If topiramate is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and topiramate is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Acetaminophen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with topiramate is necessary; consider increasing the dose of oxycodone as needed. If topiramate is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and topiramate is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Aliskiren; Amlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as topiramate, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide. (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as topiramate, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide.
    Alogliptin; Metformin: (Moderate) Consider more frequent monitoring of patients receiving metformin and concomitant topiramate due to increased risk for lactic acidosis. Carbonic anhydrase inhibitors, such as topiramate, frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. In healthy volunteers, metformin Cmax and AUC increased by 17% and 25%, respectively, when topiramate was added, and oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect on the pharmacokinetics of metformin or topiramate are not known.
    Alogliptin; Pioglitazone: (Moderate) A decrease in the exposures of pioglitazone and its active metabolites were observed in a clinical trial during concurrent use of topiramate. The clinical significance is unknown; however, results of routine blood glucose monitoring should be carefully followed during coadministration of pioglitazone and topiramate to ensure adequate glucose control.
    Alprazolam: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines.
    Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide.
    Amitriptyline: (Moderate) Monitor for unusual drowsiness or excess sedation and for increased amitriptyline-related adverse events during concomitant topiramate use. Concomitant use resulted in an increase in amitriptyline exposure by 12% and may increase the risk for additive CNS depression.
    Amlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as topiramate, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Atorvastatin: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as topiramate, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Benazepril: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as topiramate, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Celecoxib: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as topiramate, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Olmesartan: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as topiramate, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Valsartan: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as topiramate, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide. (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as topiramate, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amphetamines: (Moderate) Monitor for amphetamine-related adverse events if coadministered with topiramate. Concurrent use may increase amphetamine concentrations, resulting in potentiation of the action of amphetamines.
    Anticholinergics: (Moderate) Monitor for decreased sweating and increased body temperature, especially in hot weather, during concomitant use of topiramate and other drugs that predispose persons to heat-related disorders, such as anticholinergic medications. Concomitant use increases the risk for oligohidrosis and hyperthermia.
    Anxiolytics; Sedatives; and Hypnotics: (Moderate) Although not specifically studied, coadministration of CNS depressant drugs (e.g., anxiolytics, sedatives, and hypnotics) with topiramate may potentiate CNS depression such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents. Monitor for increased CNS effects if coadministering.
    Apixaban: (Moderate) Concurrent use of topiramate and anticoagulants, such as apixaban, may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if topiramate and aprepitant, fosaprepitant are used concurrently and monitor for a possible decrease in the efficacy of aprepitant for several days after administration of a multi-day aprepitant regimen. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer; aprepitant is a CYP3A4 substrate. When a single dose of aprepitant (375 mg, or 3 times the maximum recommended dose) was administered on day 9 of a 14-day rifampin regimen (a strong CYP3A4 inducer), the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased by 3-fold. The manufacturer of aprepitant recommends avoidance of administration with strong CYP3A4 inducers, but does not provide guidance for weak-to-moderate inducers. After administration, fosaprepitant is rapidly converted to aprepitant and shares the same drug interactions.
    Aripiprazole: (Moderate) Monitor for unusal drowsiness and excessive sedation during concomitant aripiprazole and topiramate use due to the risk for additive CNS depression.
    Aspirin, ASA; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with topiramate is necessary; consider increasing the dose of oxycodone as needed. If topiramate is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and topiramate is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Atazanavir: (Moderate) Caution is warranted when atazanavir is administered with topiramate as there is a potential for decreased concentrations of atazanavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Atazanavir is a substrate of CYP3A4.
    Atazanavir; Cobicistat: (Moderate) Caution is warranted when atazanavir is administered with topiramate as there is a potential for decreased concentrations of atazanavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Atazanavir is a substrate of CYP3A4. (Moderate) Caution is warranted when cobicistat is administered with topiramate as there is a potential for decreased concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Cobicistat is a substrate of CYP3A4.
    Atovaquone; Proguanil: (Minor) Proguanil is metabolized to cycloguanil by CYP2C19. Potential interactions between proguanil or cycloguanil and other drugs that are CYP2C19 inhibitors are unknown. Use caution when combining atovaquone; proguanil with CYP2C19 inhibitors, such as topiramate.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Carbonic anhydrase inhibiting drugs, such as topiramate (a weak carbonic anhydrase inhibitor) can alkalinize the urine, thereby decreasing the effectiveness of methenamine by inhibiting the conversion of methenamine to formaldehyde.
    Barbiturates: (Moderate) Although topiramate is not extensively metabolized (70% renally eliminated), an interaction with barbiturates via hepatic isoenzyme activity is possible. In patients receiving either phenobarbital or primidone in combination with topiramate, there was a < 10% change in phenobarbital or primidone plasma concentrations; the effects on topiramate plasma concentrations were not evaluated. Barbiturates may cause additive sedation or other CNS depressive effects when used concurrently with topiramate. When topiramate is combined with phentermine for the treatment of obesity, a greater risk of CNS depression exists. Concurrent use of topiramate and drugs that cause thrombocytopenia, such as the barbiturates, may also increase the risk of bleeding; monitor patients appropriately.
    Belzutifan: (Moderate) Monitor for anemia and hypoxia if concomitant use of topiramate with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and topiramate is a CYP2C19 inhibitor.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide.
    Benzodiazepines: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Carbonic anhydrase inhibiting drugs, such as topiramate (a weak carbonic anhydrase inhibitor) can alkalinize the urine, thereby decreasing the effectiveness of methenamine by inhibiting the conversion of methenamine to formaldehyde.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide.
    Brexpiprazole: (Moderate) Because brexpiprazole is partially metabolized by CYP3A4, concurrent use of CYP3A4 inducers such as topiramate may result in decreased plasma concentrations of brexpiprazole. If these agents are used in combination, the patient should be carefully monitored for a decrease in brexpiprazole efficacy. An increase in brexpiprazole dosage may be clinically warranted in some patients. Similar precautions apply to combination products containing topiramate such as phentermine; topiramate.
    Bumetanide: (Moderate) Monitor potassium concentration before and during concomitant topiramate and loop diuretic use due to risk for additive hypokalemia. Topiramate can increase the risk of hypokalemia through its inhibition of carbonic anhydrase activity and concomitant use with loop diuretics may further potentiate potassium-wasting.
    Bupivacaine; Lidocaine: (Moderate) Concomitant use of systemic lidocaine and topiramate may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; topiramate induces CYP3A4.
    Cabotegravir; Rilpivirine: (Moderate) Close clinical monitoring is advised when administering topiramate with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Topiramate is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Canagliflozin; Metformin: (Moderate) Consider more frequent monitoring of patients receiving metformin and concomitant topiramate due to increased risk for lactic acidosis. Carbonic anhydrase inhibitors, such as topiramate, frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. In healthy volunteers, metformin Cmax and AUC increased by 17% and 25%, respectively, when topiramate was added, and oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect on the pharmacokinetics of metformin or topiramate are not known.
    Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide.
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide.
    Carbamazepine: (Moderate) A topiramate dosage adjustment may be needed during concomitant carbamazepine use. Concomitant administration of topiramate with carbamazepine resulted in a clinically significant decrease (40%) in plasma topiramate concentrations.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Monitor for increased CNS effects if topiramate is coadministered with diphenhydramine. Although not specifically studied, coadministration of CNS depressant drugs with topiramate may potentiate CNS depression, such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents.
    Carbonic anhydrase inhibitors: (Major) Avoid concurrent use of acetazolamide or methazolamide with topiramate. Topiramate is a weak carbonic anhydrase inhibitor. Concomitant use of topiramate with acetazolamide or methazolamide may create a physiological environment that increases the risk of renal stone formation associated with topiramate use. Additionally, through an additive effect, the use of topiramate with agents that may increase the risk for heat-related disorders (acetazolamide and methazolamide), may lead to oligohidrosis, hyperthermia and heat stroke.
    Cariprazine: (Major) Cariprazine and its active metabolites are extensively metabolized by CYP3A4. Concurrent use of cariprazine with CYP3A4 inducers, such as topiramate, has not been evaluated and is not recommended because the net effect on active drug and metabolites is unclear.
    Celecoxib; Tramadol: (Moderate) Reserve concomitant prescribing of opioids and other CNS depressants, such as topiramate, for use in patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
    Chlordiazepoxide: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines.
    Chlordiazepoxide; Amitriptyline: (Moderate) Monitor for unusual drowsiness or excess sedation and for increased amitriptyline-related adverse events during concomitant topiramate use. Concomitant use resulted in an increase in amitriptyline exposure by 12% and may increase the risk for additive CNS depression. (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines.
    Chlordiazepoxide; Clidinium: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines.
    Chlorothiazide: (Moderate) Topiramate is a carbonic anhydrase inhibitor. Concurrent use of topiramate with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Monitor baseline and periodic potassium concentrations during coadministration.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with topiramate can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If topiramate is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Topiramate is a weak inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Chlorpheniramine; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with topiramate is necessary; consider increasing the dose of hydrocodone as needed. If topiramate is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and topiramate is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Chlorpromazine: (Moderate) Monitor for unusual drowsiness and excess sedation during coadministration of phenothiazines and topiramate due to the risk for additive CNS depression.
    Cilostazol: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as cilostazol may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation. In addition, cilostazol is metabolized by the cytochrome P450 CYP2C19 hepatic isoenzyme and may interact with medications that are inhibitors of CYP2C19, including topiramate.
    Citalopram: (Moderate) Limit the dose of citalopram to 20 mg/day if coadministered with topiramate. Concurrent use may increase citalopram exposure increasing the risk of QT prolongation. Citalopram is a sensitive CYP2C19 substrate; topiramate is a weak inhibitor of CYP2C19.
    Clomipramine: (Moderate) Monitor for unusual drowsiness or excess sedation during concomitant clomipramine and topiramate use due to the risk for additive CNS depression.
    Clonazepam: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines.
    Clorazepate: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines.
    Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with topiramate as there is a potential for decreased concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Cobicistat is a substrate of CYP3A4.
    Cobimetinib: (Moderate) If concurrent use of cobimetinib and topiramate is necessary, use caution and monitor for decreased efficacy of cobimetinib. Cobimetinib is a CYP3A substrate in vitro, and topiramate is a weak inducer of CYP3A. The manufacturer of cobimetinib recommends avoiding coadministration of cobimetinib with moderate or strong CYP3A inducers based on simulations demonstrating that cobimetinib exposure would decrease by 73% or 83% when coadministered with a moderate or strong CYP3A inducer, respectively. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inducers.
    Codeine; Phenylephrine; Promethazine: (Moderate) Monitor for unusual drowsiness and excess sedation during coadministration of phenothiazines and topiramate due to the risk for additive CNS depression.
    Codeine; Promethazine: (Moderate) Monitor for unusual drowsiness and excess sedation during coadministration of phenothiazines and topiramate due to the risk for additive CNS depression.
    Conjugated Estrogens; Medroxyprogesterone: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Dapagliflozin; Metformin: (Moderate) Consider more frequent monitoring of patients receiving metformin and concomitant topiramate due to increased risk for lactic acidosis. Carbonic anhydrase inhibitors, such as topiramate, frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. In healthy volunteers, metformin Cmax and AUC increased by 17% and 25%, respectively, when topiramate was added, and oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect on the pharmacokinetics of metformin or topiramate are not known.
    Dapsone: (Minor) The metabolism of dapsone may be accelerated when administered concurrently with topiramate, a known inducer of CYP3A4. Coadministration is expected to decrease the plasma concentration of dapsone and increase the formation of dapsone hydroxylamine (a metabolite associated with hemolysis). If these drugs must be administered together, closely monitor for a reduction in dapsone efficacy and signs of hemolytic anemia.
    Darunavir: (Moderate) Caution is warranted when darunavir is administered with topiramate as there is a potential for decreased concentrations of darunavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Darunavir is a substrate of CYP3A4.
    Darunavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with topiramate as there is a potential for decreased concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Cobicistat is a substrate of CYP3A4. (Moderate) Caution is warranted when darunavir is administered with topiramate as there is a potential for decreased concentrations of darunavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Darunavir is a substrate of CYP3A4.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Caution is warranted when cobicistat is administered with topiramate as there is a potential for decreased concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Cobicistat is a substrate of CYP3A4. (Moderate) Caution is warranted when darunavir is administered with topiramate as there is a potential for decreased concentrations of darunavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Darunavir is a substrate of CYP3A4.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of topiramate with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in decreased concentrations of dasabuvir, paritaprevir, and ritonavir. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Ritonavir, paritaprevir, and dasabuvir (minor) are all metabolized by this enzyme. Caution and close monitoring are advised if these drugs are administered together. (Moderate) Concurrent administration of topiramate with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in decreased concentrations of dasabuvir, paritaprevir, and ritonavir. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Ritonavir, paritaprevir, and dasabuvir (minor) are all metabolized by this enzyme. Caution and close monitoring are advised if these drugs are administered together. (Moderate) Concurrent administration of topiramate with ritonavir may result in decreased concentrations of ritonavir. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Ritonavir is metabolized by this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Delavirdine: (Moderate) Delavirdine is a potent inhibitor of cytochrome P450 2C9 and might decrease topiramate metabolism leading to increased topiramate serum concentrations and a risk of adverse reactions.
    Desipramine: (Moderate) Monitor for unusual drowsiness or excess sedation during concomitant desipramine and topiramate use due to the risk for additive CNS depression.
    Desogestrel; Ethinyl Estradiol: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Monitor for increased CNS effects if topiramate is coadministered with diphenhydramine. Although not specifically studied, coadministration of CNS depressant drugs with topiramate may potentiate CNS depression, such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents.
    Diazepam: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines.
    Dichlorphenamide: (Moderate) Use dichlorphenamide and topiramate, another carbonic anhydrase inhibitor, together with caution as both drugs can cause metabolic acidosis. Concurrent use may increase the severity of metabolic acidosis. Measure sodium bicarbonate concentrations at baseline and periodically during dichlorphenamide treatment. If metabolic acidosis occurs or persists, consider reducing the dose or discontinuing dichlorphenamide therapy.
    Dienogest; Estradiol valerate: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Digoxin: (Moderate) Serum digoxin AUC was decreased by 12% when coadministered with topiramate. Although the clinical relevance has not been determined, the clinician should be aware that serum digoxin concentrations may be affected when digoxin and topiramate are used concomitantly.
    Diltiazem: (Moderate) Monitor for loss of diltiazem efficacy and an increase in topiramate-related adverse events during coadministration. Concomitant use of diltiazem (240 mg) with topiramate (150 mg/day) resulted in a 10% decrease in Cmax and a 25% decrease in diltiazem AUC, a 27% decrease in Cmax and an 18% decrease in desacetyl diltiazem AUC, and no effect on N-desmethyl diltiazem. Co-administration of topiramate with diltiazem resulted in a 16% increase in Cmax and a 19% increase in AUC of topiramate.
    Diphenhydramine: (Moderate) Monitor for increased CNS effects if topiramate is coadministered with diphenhydramine. Although not specifically studied, coadministration of CNS depressant drugs with topiramate may potentiate CNS depression, such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents.
    Diphenhydramine; Ibuprofen: (Moderate) Monitor for increased CNS effects if topiramate is coadministered with diphenhydramine. Although not specifically studied, coadministration of CNS depressant drugs with topiramate may potentiate CNS depression, such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents.
    Diphenhydramine; Naproxen: (Moderate) Monitor for increased CNS effects if topiramate is coadministered with diphenhydramine. Although not specifically studied, coadministration of CNS depressant drugs with topiramate may potentiate CNS depression, such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents.
    Diphenhydramine; Phenylephrine: (Moderate) Monitor for increased CNS effects if topiramate is coadministered with diphenhydramine. Although not specifically studied, coadministration of CNS depressant drugs with topiramate may potentiate CNS depression, such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents.
    Dolutegravir: (Moderate) Caution is warranted when dolutegravir is administered with topiramate as there is a potential for decreased dolutegravir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Dolutegravir is partially metabolized by this isoenzyme.
    Dolutegravir; Lamivudine: (Moderate) Caution is warranted when dolutegravir is administered with topiramate as there is a potential for decreased dolutegravir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Dolutegravir is partially metabolized by this isoenzyme.
    Dolutegravir; Rilpivirine: (Moderate) Caution is warranted when dolutegravir is administered with topiramate as there is a potential for decreased dolutegravir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Dolutegravir is partially metabolized by this isoenzyme. (Moderate) Close clinical monitoring is advised when administering topiramate with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Topiramate is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Doravirine: (Minor) Concurrent administration of doravirine and topiramate may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; topiramate is a weak CYP3A4 inducer.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Minor) Concurrent administration of doravirine and topiramate may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; topiramate is a weak CYP3A4 inducer.
    Doxepin: (Moderate) Monitor for unusual drowsiness or excess sedation during concomitant doxepin and topiramate use due to the risk for additive CNS depression.
    Doxorubicin Liposomal: (Major) Topiramate is a mild CYP3A4 inducer; doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of topiramate and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Doxorubicin: (Major) Topiramate is a mild CYP3A4 inducer; doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of topiramate and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Doxylamine: (Moderate) Monitor for increased CNS effects if topiramate is coadministered with doxylamine. Although not specifically studied, coadministration of CNS depressant drugs with topiramate may potentiate CNS depression, such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents.
    Doxylamine; Pyridoxine: (Moderate) Monitor for increased CNS effects if topiramate is coadministered with doxylamine. Although not specifically studied, coadministration of CNS depressant drugs with topiramate may potentiate CNS depression, such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents.
    Dronabinol: (Moderate) Use caution if coadministration of dronabinol with topiramate is necessary, and monitor for a decrease in the efficacy of dronabinol. Dronabinol is a CYP2C9 and 3A4 substrate; topiramate is a weak inducer of CYP3A4. Concomitant use may result in decreased plasma concentrations of dronabinol.
    Dronedarone: (Major) The concomitant use of dronedarone and CYP3A4 inducers should be avoided. Dronedarone is metabolized by CYP3A. Topiramate induces CYP3A4. Coadministration of CYP3A4 inducers, such as topiramate, with dronedarone may result in reduced plasma concentration and subsequent reduced effectiveness of dronedarone therapy.
    Droperidol: (Major) Although not specifically studied, coadministration of CNS depressant drugs with topiramate may potentiate CNS depression such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents. Monitor for increased CNS effects if coadministering.
    Drospirenone: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Drospirenone; Estetrol: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Drospirenone; Estradiol: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Drospirenone; Ethinyl Estradiol: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Elagolix; Estradiol; Norethindrone acetate: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Elbasvir; Grazoprevir: (Moderate) Caution is advised when administering elbasvir with topiramate. Topiramate is a mild CYP3A inducer, while elbasvir is a substrate of CYP3A. Use of these drugs together may decrease the plasma concentrations of elbasvir and could result in decreased virologic response. (Moderate) Caution is advised when administering elbasvir; grazoprevir with topiramate. Topiramate is a mild CYP3A inducer, while grazoprevir is a substrate of CYP3A. Use of these drugs together may decrease the plasma concentrations of grazoprevir and could result in decreased virologic response.
    Elvitegravir: (Moderate) Caution is warranted when elvitegravir is administered with topiramate as there is a potential for decreased elvitegravir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Elvitegravir is a CYP3A4 substrate.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is warranted when cobicistat is administered with topiramate as there is a potential for decreased concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Cobicistat is a substrate of CYP3A4. (Moderate) Caution is warranted when elvitegravir is administered with topiramate as there is a potential for decreased elvitegravir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Elvitegravir is a CYP3A4 substrate.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is warranted when cobicistat is administered with topiramate as there is a potential for decreased concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Cobicistat is a substrate of CYP3A4. (Moderate) Caution is warranted when elvitegravir is administered with topiramate as there is a potential for decreased elvitegravir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Elvitegravir is a CYP3A4 substrate.
    Empagliflozin; Linagliptin: (Major) Inducers of CYP3A4 (e.g., topiramate) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended.
    Empagliflozin; Linagliptin; Metformin: (Major) Inducers of CYP3A4 (e.g., topiramate) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended. (Moderate) Consider more frequent monitoring of patients receiving metformin and concomitant topiramate due to increased risk for lactic acidosis. Carbonic anhydrase inhibitors, such as topiramate, frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. In healthy volunteers, metformin Cmax and AUC increased by 17% and 25%, respectively, when topiramate was added, and oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect on the pharmacokinetics of metformin or topiramate are not known.
    Empagliflozin; Metformin: (Moderate) Consider more frequent monitoring of patients receiving metformin and concomitant topiramate due to increased risk for lactic acidosis. Carbonic anhydrase inhibitors, such as topiramate, frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. In healthy volunteers, metformin Cmax and AUC increased by 17% and 25%, respectively, when topiramate was added, and oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect on the pharmacokinetics of metformin or topiramate are not known.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Close clinical monitoring is advised when administering topiramate with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Topiramate is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Close clinical monitoring is advised when administering topiramate with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Topiramate is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide.
    Ertugliflozin; Metformin: (Moderate) Consider more frequent monitoring of patients receiving metformin and concomitant topiramate due to increased risk for lactic acidosis. Carbonic anhydrase inhibitors, such as topiramate, frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. In healthy volunteers, metformin Cmax and AUC increased by 17% and 25%, respectively, when topiramate was added, and oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect on the pharmacokinetics of metformin or topiramate are not known.
    Estazolam: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines.
    Estradiol Cypionate; Medroxyprogesterone: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Estradiol; Levonorgestrel: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Estradiol; Norethindrone: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Estradiol; Norgestimate: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Estradiol; Progesterone: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Estrogens affected by CYP3A inducers: (Major) Women taking both estrogens and topiramate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed topiramate, especially for patients receiving topiramate doses greater than 200 mg per day. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of topiramate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on topiramate, with dose adjustments made based on clinical efficacy. Concurrent administration may increase estrogen elimination.
    Ethacrynic Acid: (Moderate) Monitor potassium concentration before and during concomitant topiramate and loop diuretic use due to risk for additive hypokalemia. Topiramate can increase the risk of hypokalemia through its inhibition of carbonic anhydrase activity and concomitant use with loop diuretics may further potentiate potassium-wasting.
    Ethanol: (Major) Advise patients to avoid alcohol consumption while taking topiramate. Topiramate is a CNS depressant. Concomitant administration of topiramate with alcohol can result in significant CNS depression. Trokendi XR is contraindicated with recent alcohol use (i.e., within 6 hours before and 6 hours after use). In the presence of alcohol, the pattern of topiramate release from Trokendi XR is significantly altered. As a result, plasma concentrations of topiramate may be markedly higher soon after dosing and subtherapeutic later in the day. (Major) Avoid alcohol with topiramate. Topiramate is a CNS depressant. Concomitant administration of topiramate with alcohol can result in significant CNS depression. Trokendi XR is contraindicated with recent alcohol use (i.e., within 6 hours before and 6 hours after use). In the presence of alcohol, the pattern of topiramate release from Trokendi XR is significantly altered. As a result, plasma concentrations of topiramate may be markedly higher soon after dosing and subtherapeutic later in the day.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Ethinyl Estradiol; Norelgestromin: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Ethinyl Estradiol; Norgestrel: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Ethynodiol Diacetate; Ethinyl Estradiol: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Etonogestrel: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Etonogestrel; Ethinyl Estradiol: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Fentanyl: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of topiramate is necessary. If topiramate is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like topiramate with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
    Flibanserin: (Major) The concomitant use of flibanserin with CYP3A4 inducers significantly decreases flibanserin exposure compared to the use of flibanserin alone. Therefore, concurrent use of flibanserin and CYP3A4 inducers, such as topiramate is not recommended.
    Fluphenazine: (Moderate) Monitor for unusual drowsiness and excess sedation during coadministration of phenothiazines and topiramate due to the risk for additive CNS depression.
    Flurazepam: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide.
    Furosemide: (Moderate) Monitor potassium concentration before and during concomitant topiramate and loop diuretic use due to risk for additive hypokalemia. Topiramate can increase the risk of hypokalemia through its inhibition of carbonic anhydrase activity and concomitant use with loop diuretics may further potentiate potassium-wasting.
    Gefitinib: (Moderate) Monitor for clinical response of gefitinib if used concomitantly with topiramate. Gefitinib is metabolized significantly by CYP3A4 and topiramate is a weak CYP3A4 inducer; coadministration may increase gefitinib metabolism and decrease gefitinib concentrations. This also applies to combination products containing topiramate, such as phentermine; topiramate. While the manufacturer has provided no guidance regarding the use of gefitinib with mild or moderate CYP3A4 inducers, administration of a single 500 mg gefitinib dose with a concurrent strong CYP3A4 inducer (rifampin) resulted in reduced mean AUC of gefitinib by 83%.
    Glipizide; Metformin: (Moderate) Consider more frequent monitoring of patients receiving metformin and concomitant topiramate due to increased risk for lactic acidosis. Carbonic anhydrase inhibitors, such as topiramate, frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. In healthy volunteers, metformin Cmax and AUC increased by 17% and 25%, respectively, when topiramate was added, and oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect on the pharmacokinetics of metformin or topiramate are not known.
    Glyburide: (Minor) Coadministration of glyburide with topiramate may decrease systemic exposure to glyburide. A pharmacokinetic drug interaction study evaluated the combination of topiramate and glyburide. Reductions in AUC and Cmax were noted for glyburide and the active metabolites.
    Glyburide; Metformin: (Moderate) Consider more frequent monitoring of patients receiving metformin and concomitant topiramate due to increased risk for lactic acidosis. Carbonic anhydrase inhibitors, such as topiramate, frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. In healthy volunteers, metformin Cmax and AUC increased by 17% and 25%, respectively, when topiramate was added, and oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect on the pharmacokinetics of metformin or topiramate are not known. (Minor) Coadministration of glyburide with topiramate may decrease systemic exposure to glyburide. A pharmacokinetic drug interaction study evaluated the combination of topiramate and glyburide. Reductions in AUC and Cmax were noted for glyburide and the active metabolites.
    Guaifenesin; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with topiramate is necessary; consider increasing the dose of hydrocodone as needed. If topiramate is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and topiramate is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with topiramate is necessary; consider increasing the dose of hydrocodone as needed. If topiramate is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and topiramate is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Homatropine; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with topiramate is necessary; consider increasing the dose of hydrocodone as needed. If topiramate is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and topiramate is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Hydantoins: (Moderate) A dosage adjustment may be needed during coadministration of topiramate and hydantoins, closely monitor patients appropriately for increased adverse effects or altered clinical response to therapy. Serum phenytoin concentration may be needed for optimal dosage adjustments. Hydantoins have been shown to reduce topiramate serum concentrations.Topiramate may increase phenytoin concentrations through its inhibitory effects on CYP2C19. In some patients receiving phenytoin concurrently with topiramate, plasma concentrations of phenytoin were increased by 25% and topiramate plasma concentrations were decreased by 48%. These patients were generally receiving dosage regimens of phenytoin twice-daily. Other patients experienced a change of less than 10% in phenytoin plasma concentrations. A similar reaction would be expected with fosphenytoin.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide.
    Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide.
    Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with topiramate is necessary; consider increasing the dose of hydrocodone as needed. If topiramate is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and topiramate is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Hydrocodone; Ibuprofen: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with topiramate is necessary; consider increasing the dose of hydrocodone as needed. If topiramate is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and topiramate is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Hydrocodone; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with topiramate is necessary; consider increasing the dose of hydrocodone as needed. If topiramate is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and topiramate is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Hydroxychloroquine: (Moderate) Monitor persons with epilepsy for seizure activity during concomitant topiramate and hydroxychloroquine use. Hydroxychloroquine can lower the seizure threshold; therefore, the activity of antiepileptic drugs may be impaired with concomitant use.
    Hydroxyzine: (Moderate) Monitor for increased CNS effects if topiramate is coadministered with hydroxyzine. Although not specifically studied, coadministration of CNS depressant drugs with topiramate may potentiate CNS depression, such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) Carbonic anhydrase inhibiting drugs, such as topiramate (a weak carbonic anhydrase inhibitor) can alkalinize the urine, thereby decreasing the effectiveness of methenamine by inhibiting the conversion of methenamine to formaldehyde.
    Ibuprofen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with topiramate is necessary; consider increasing the dose of oxycodone as needed. If topiramate is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and topiramate is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Imatinib: (Moderate) Imatinib is a potent inhibitors of cytochrome P450 2C9 and might decrease topiramate metabolism leading to increased topiramate serum concentrations and a risk of adverse reactions.
    Imipramine: (Moderate) Monitor for unusual drowsiness or excess sedation during concomitant imipramine and topiramate use due to the risk for additive CNS depression.
    Irbesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide.
    Isavuconazonium: (Moderate) Caution and close monitoring are warranted when isavuconazonium is administered with topiramate as there is a potential for decreased concentrations of isavuconazonium. Decreased isavuconazonium concentrations may lead to a reduction of antifungal efficacy and the potential for treatment failure. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate of this enzyme.
    Lacosamide: (Moderate) Use lacosamide with caution in patients taking concomitant medications that affect cardiac conduction including those that prolong PR interval, such as sodium channel blocking anticonvulsants (e.g., topiramate), because of the risk of AV block, bradycardia, or ventricular tachyarrhythmia. If use together is necessary, obtain an ECG prior to lacosamide initiation and after treatment has been titrated to steady-state. In addition, monitor patients receiving lacosamide via the intravenous route closely.
    Lamotrigine: (Moderate) Monitor for loss of topiramate efficacy and/or an increase in topiramate-related adverse events during coadministration. Coadministration has resulted in both a 13% decrease and 15% increase in topiramate concentrations.
    Leuprolide; Norethindrone: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Levamlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as topiramate, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Levonorgestrel: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Levonorgestrel; Ethinyl Estradiol: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Lidocaine: (Moderate) Concomitant use of systemic lidocaine and topiramate may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; topiramate induces CYP3A4.
    Lidocaine; Epinephrine: (Moderate) Concomitant use of systemic lidocaine and topiramate may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; topiramate induces CYP3A4.
    Lidocaine; Prilocaine: (Moderate) Concomitant use of systemic lidocaine and topiramate may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; topiramate induces CYP3A4.
    Linagliptin: (Major) Inducers of CYP3A4 (e.g., topiramate) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended.
    Linagliptin; Metformin: (Major) Inducers of CYP3A4 (e.g., topiramate) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended. (Moderate) Consider more frequent monitoring of patients receiving metformin and concomitant topiramate due to increased risk for lactic acidosis. Carbonic anhydrase inhibitors, such as topiramate, frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. In healthy volunteers, metformin Cmax and AUC increased by 17% and 25%, respectively, when topiramate was added, and oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect on the pharmacokinetics of metformin or topiramate are not known.
    Lisinopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide.
    Lithium: (Moderate) Monitor serum lithium concentrations during concomitant high-dose topiramate use. Lithium concentrations were unaffected during treatment with topiramate 200 mg/day; however, there was an observed increase in systemic exposure of lithium (26%) after topiramate doses up to 600 mg/day.
    Loop diuretics: (Moderate) Monitor potassium concentration before and during concomitant topiramate and loop diuretic use due to risk for additive hypokalemia. Topiramate can increase the risk of hypokalemia through its inhibition of carbonic anhydrase activity and concomitant use with loop diuretics may further potentiate potassium-wasting.
    Lopinavir; Ritonavir: (Moderate) Concurrent administration of topiramate with ritonavir may result in decreased concentrations of ritonavir. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Ritonavir is metabolized by this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Lorazepam: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines.
    Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide.
    Lumateperone: (Major) Avoid coadministration of lumateperone and topiramate as concurrent use may decrease lumateperone exposure which may reduce efficacy. Lumateperone is a CYP3A4 substrate; topiramate is a weak CYP3A4 inducer.
    Lurasidone: (Moderate) Because lurasidone is primarily metabolized by CYP3A4, decreased plasma concentrations of lurasidone may theoretically occur when the drug is co-administered with inducers of CYP3A4 such as topiramate.
    Maprotiline: (Moderate) Maprotiline, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when maprotiline is used concurrently. Because of the lowering of seizure threshold, an alternative antidepressant may be a more optimal choice for patients taking drugs for epilepsy.
    Maraviroc: (Minor) Use caution if coadministration of maraviroc with topiramate is necessary, due to a possible decrease in maraviroc exposure. Maraviroc is a CYP3A substrate and topiramate is a CYP3A4 inducer. Monitor for a decrease in maraviroc efficacy with concomitant use.
    Medroxyprogesterone: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Mefloquine: (Moderate) Topiramate induces CYP3A4 and may increase the metabolism of mefloquine if coadministered. Use may reduce the clinical efficacy of mefloquine, increasing the risk of Plasmodium falciparum resistance during treatment of malaria. Coadministration of mefloquine and anticonvulsants may also result in lower than expected anticonvulsant concentrations and loss of seizure control. Monitoring of drug concentrations (if therapeutic monitoring is advised for the anticonvulsant) is recommended. When topiramate is used for other conditions, monitor for clinical efficacy. Mefloquine may additionally cause CNS side effects that may cause seizures or alter moods or behaviors.
    Meperidine; Promethazine: (Moderate) Monitor for unusual drowsiness and excess sedation during coadministration of phenothiazines and topiramate due to the risk for additive CNS depression.
    Mestranol; Norethindrone: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Metformin: (Moderate) Consider more frequent monitoring of patients receiving metformin and concomitant topiramate due to increased risk for lactic acidosis. Carbonic anhydrase inhibitors, such as topiramate, frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. In healthy volunteers, metformin Cmax and AUC increased by 17% and 25%, respectively, when topiramate was added, and oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect on the pharmacokinetics of metformin or topiramate are not known.
    Metformin; Repaglinide: (Moderate) Consider more frequent monitoring of patients receiving metformin and concomitant topiramate due to increased risk for lactic acidosis. Carbonic anhydrase inhibitors, such as topiramate, frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. In healthy volunteers, metformin Cmax and AUC increased by 17% and 25%, respectively, when topiramate was added, and oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect on the pharmacokinetics of metformin or topiramate are not known.
    Metformin; Rosiglitazone: (Moderate) Consider more frequent monitoring of patients receiving metformin and concomitant topiramate due to increased risk for lactic acidosis. Carbonic anhydrase inhibitors, such as topiramate, frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. In healthy volunteers, metformin Cmax and AUC increased by 17% and 25%, respectively, when topiramate was added, and oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect on the pharmacokinetics of metformin or topiramate are not known.
    Metformin; Saxagliptin: (Moderate) Consider more frequent monitoring of patients receiving metformin and concomitant topiramate due to increased risk for lactic acidosis. Carbonic anhydrase inhibitors, such as topiramate, frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. In healthy volunteers, metformin Cmax and AUC increased by 17% and 25%, respectively, when topiramate was added, and oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect on the pharmacokinetics of metformin or topiramate are not known.
    Metformin; Sitagliptin: (Moderate) Consider more frequent monitoring of patients receiving metformin and concomitant topiramate due to increased risk for lactic acidosis. Carbonic anhydrase inhibitors, such as topiramate, frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. In healthy volunteers, metformin Cmax and AUC increased by 17% and 25%, respectively, when topiramate was added, and oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect on the pharmacokinetics of metformin or topiramate are not known.
    Methenamine: (Moderate) Carbonic anhydrase inhibiting drugs, such as topiramate (a weak carbonic anhydrase inhibitor) can alkalinize the urine, thereby decreasing the effectiveness of methenamine by inhibiting the conversion of methenamine to formaldehyde.
    Methenamine; Sodium Acid Phosphate: (Moderate) Carbonic anhydrase inhibiting drugs, such as topiramate (a weak carbonic anhydrase inhibitor) can alkalinize the urine, thereby decreasing the effectiveness of methenamine by inhibiting the conversion of methenamine to formaldehyde.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Moderate) Carbonic anhydrase inhibiting drugs, such as topiramate (a weak carbonic anhydrase inhibitor) can alkalinize the urine, thereby decreasing the effectiveness of methenamine by inhibiting the conversion of methenamine to formaldehyde.
    Methenamine; Sodium Salicylate: (Moderate) Carbonic anhydrase inhibiting drugs, such as topiramate (a weak carbonic anhydrase inhibitor) can alkalinize the urine, thereby decreasing the effectiveness of methenamine by inhibiting the conversion of methenamine to formaldehyde.
    Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide.
    Midazolam: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines.
    Molindone: (Moderate) Consistent with the pharmacology of molindone, additive effects may occur with other CNS active drugs such as anticonvulsants. In addition, seizures have been reported during the use of molindone, which is of particular significance in patients with a seizure disorder receiving anticonvulsants. Adequate dosages of anticonvulsants should be continued when molindone is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either molindone or the anticonvulsant.
    Nanoparticle Albumin-Bound Sirolimus: (Moderate) Monitor for loss of efficacy of sirolimus during coadministration of topiramate; a sirolimus dose adjustment may be necessary. Monitor sirolimus serum concentrations as appropriate. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; topiramate is a weak CYP3A inducer.
    Nirmatrelvir; Ritonavir: (Moderate) Concurrent administration of topiramate with ritonavir may result in decreased concentrations of ritonavir. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Ritonavir is metabolized by this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Nisoldipine: (Major) Avoid coadministration of nisoldipine with topiramate due to decreased plasma concentrations of nisoldipine. Alternative antihypertensive therapy should be considered. Nisoldipine is a CYP3A4 substrate and topiramate is a weak CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer lowered nisoldipine plasma concentrations to undetectable levels.
    Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Norethindrone: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Norethindrone; Ethinyl Estradiol: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Norgestimate; Ethinyl Estradiol: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Norgestrel: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Nortriptyline: (Moderate) Monitor for unusual drowsiness or excess sedation during concomitant nortriptyline and topiramate use due to the risk for additive CNS depression.
    Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide. (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as topiramate, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Olmesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of topiramate with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in decreased concentrations of dasabuvir, paritaprevir, and ritonavir. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Ritonavir, paritaprevir, and dasabuvir (minor) are all metabolized by this enzyme. Caution and close monitoring are advised if these drugs are administered together. (Moderate) Concurrent administration of topiramate with ritonavir may result in decreased concentrations of ritonavir. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Ritonavir is metabolized by this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Oxazepam: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines.
    Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with topiramate is necessary; consider increasing the dose of oxycodone as needed. If topiramate is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and topiramate is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Pazopanib: (Moderate) Coadministration of pazopanib and topiramate may cause a decrease in systemic concentrations of pazopanib. Use caution when administering these drugs concomitantly. Pazopanib is a substrate for CYP3A4. Topiramate in a weak CYP3A4 inducer.
    Perampanel: (Moderate) During clinical trials, co-administration of topiramate and perampanel to patients led to a 20% decrease in the AUC of perampanel compared to patients not taking enzyme-inducing antiepileptic drugs. Topiramate is an inducer of CYP3A4, while perampanel is a substrate of this enzyme. Patients taking topiramate who begin treatment with perampanel should be closely monitored for adverse effects and receive a higher initial dose of perampanel. Addition or withdrawal of enzyme-inducing antiepileptic drugs may require a perampanel dose adjustment.
    Perindopril; Amlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as topiramate, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Perphenazine: (Moderate) Monitor for unusual drowsiness and excess sedation during coadministration of phenothiazines and topiramate due to the risk for additive CNS depression.
    Perphenazine; Amitriptyline: (Moderate) Monitor for unusual drowsiness and excess sedation during coadministration of phenothiazines and topiramate due to the risk for additive CNS depression. (Moderate) Monitor for unusual drowsiness or excess sedation and for increased amitriptyline-related adverse events during concomitant topiramate use. Concomitant use resulted in an increase in amitriptyline exposure by 12% and may increase the risk for additive CNS depression.
    Phenothiazines: (Moderate) Monitor for unusual drowsiness and excess sedation during coadministration of phenothiazines and topiramate due to the risk for additive CNS depression.
    Pioglitazone: (Moderate) A decrease in the exposures of pioglitazone and its active metabolites were observed in a clinical trial during concurrent use of topiramate. The clinical significance is unknown; however, results of routine blood glucose monitoring should be carefully followed during coadministration of pioglitazone and topiramate to ensure adequate glucose control.
    Pioglitazone; Glimepiride: (Moderate) A decrease in the exposures of pioglitazone and its active metabolites were observed in a clinical trial during concurrent use of topiramate. The clinical significance is unknown; however, results of routine blood glucose monitoring should be carefully followed during coadministration of pioglitazone and topiramate to ensure adequate glucose control.
    Pioglitazone; Metformin: (Moderate) A decrease in the exposures of pioglitazone and its active metabolites were observed in a clinical trial during concurrent use of topiramate. The clinical significance is unknown; however, results of routine blood glucose monitoring should be carefully followed during coadministration of pioglitazone and topiramate to ensure adequate glucose control. (Moderate) Consider more frequent monitoring of patients receiving metformin and concomitant topiramate due to increased risk for lactic acidosis. Carbonic anhydrase inhibitors, such as topiramate, frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. In healthy volunteers, metformin Cmax and AUC increased by 17% and 25%, respectively, when topiramate was added, and oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect on the pharmacokinetics of metformin or topiramate are not known.
    Pregabalin: (Moderate) Monitor for respiratory depression and sedation during concomitant topiramate and pregabalin use; consider starting pregabalin at a low dose. Concomitant use increases the risk for additive CNS depression.
    Probenecid: (Minor) Probenecid may increase the renal clearance of topiramate resulting in lower topiramate concentrations. Although not evaluated in humans, animal studies using probenecid along with topiramate showed a significant increase in renal clearance of topiramate. This suggests that topiramate may undergo renal tubular reabsorption. Probenecid may block renal tubular reabsorption of topiramate, thus increasing the renal clearance of the drug.
    Probenecid; Colchicine: (Minor) Probenecid may increase the renal clearance of topiramate resulting in lower topiramate concentrations. Although not evaluated in humans, animal studies using probenecid along with topiramate showed a significant increase in renal clearance of topiramate. This suggests that topiramate may undergo renal tubular reabsorption. Probenecid may block renal tubular reabsorption of topiramate, thus increasing the renal clearance of the drug.
    Prochlorperazine: (Moderate) Monitor for unusual drowsiness and excess sedation during coadministration of phenothiazines and topiramate due to the risk for additive CNS depression.
    Progesterone: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Progestins: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Promethazine: (Moderate) Monitor for unusual drowsiness and excess sedation during coadministration of phenothiazines and topiramate due to the risk for additive CNS depression.
    Promethazine; Dextromethorphan: (Moderate) Monitor for unusual drowsiness and excess sedation during coadministration of phenothiazines and topiramate due to the risk for additive CNS depression.
    Promethazine; Phenylephrine: (Moderate) Monitor for unusual drowsiness and excess sedation during coadministration of phenothiazines and topiramate due to the risk for additive CNS depression.
    Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide.
    Protriptyline: (Moderate) Monitor for unusual drowsiness or excess sedation during concomitant protriptyline and topiramate use due to the risk for additive CNS depression.
    Quazepam: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines.
    Quinapril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide.
    Ramelteon: (Major) Although not specifically studied, coadministration of CNS depressant drugs with topiramate may potentiate CNS depression such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents. Monitor for increased CNS effects if coadministering.
    Relugolix; Estradiol; Norethindrone acetate: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Remimazolam: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines.
    Rilpivirine: (Moderate) Close clinical monitoring is advised when administering topiramate with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Topiramate is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Ritonavir: (Moderate) Concurrent administration of topiramate with ritonavir may result in decreased concentrations of ritonavir. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Ritonavir is metabolized by this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Romidepsin: (Moderate) Romidepsin is a substrate for CYP3A4. Coadministration of a CYP3A4 inducer, like topiramate, may decrease systemic concentrations of romidepsin. Use caution when concomitant administration of these agents is necessary.
    Segesterone Acetate; Ethinyl Estradiol: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Simeprevir: (Major) Avoid concurrent use of simeprevir and topiramate. Induction of CYP3A4 by topiramate may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
    Sirolimus: (Moderate) Monitor for loss of efficacy of sirolimus during coadministration of topiramate; a sirolimus dose adjustment may be necessary. Monitor sirolimus serum concentrations as appropriate. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; topiramate is a weak CYP3A inducer.
    Sofosbuvir; Velpatasvir: (Major) Use caution when administering velpatasvir with topiramate. Taking these drugs together may decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a CYP3A4 substrate; topiramate is a weak inducer of CYP3A4.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Use caution when administering velpatasvir with topiramate. Taking these drugs together may decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a CYP3A4 substrate; topiramate is a weak inducer of CYP3A4.
    Solifenacin: (Moderate) Through an additive effect, the use of topiramate with agents that may increase the risk for heat related disorders, such as solifenacin, may lead to oligohidrosis, hyperthermia, and/or heat stroke.
    Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide.
    Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if topiramate must be administered. Monitor for reduced efficacy of sufentanil injection and signs of opioid withdrawal if coadministration with topiramate is necessary; consider increasing the dose of sufentanil injection as needed. If topiramate is discontinued, consider a dose reduction of sufentanil injection and frequently monitor for signs or respiratory depression and sedation. Sufentanil is a CYP3A4 substrate and topiramate is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease sufentanil concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Telithromycin: (Moderate) Caution is warranted when topiramate is administered with telithromycin as there is a potential for decreased telithromycin concentrations and loss of efficacy. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Telithromycin is a substrate of CYP3A4.
    Telmisartan; Amlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as topiramate, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Telmisartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide.
    Temazepam: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines.
    Terbinafine: (Moderate) Caution is advised when administering terbinafine with topiramate. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may alter the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP2C19 and CYP3A4; topiramate is an inducer of CYP3A4 and an inhibitor of CYP2C19. Monitor patients for adverse reactions and breakthrough fungal infections if these drugs are coadministered.
    Thiethylperazine: (Moderate) Monitor for unusual drowsiness and excess sedation during coadministration of phenothiazines and topiramate due to the risk for additive CNS depression.
    Thioridazine: (Moderate) Monitor for unusual drowsiness and excess sedation during coadministration of phenothiazines and topiramate due to the risk for additive CNS depression.
    Tolterodine: (Moderate) Through an additive effect, the use of topiramate (a weak carbonic anhydrase inhibitor) with agents that may increase the risk for heat-related disorders, such as antimuscarinics, may lead to oligohidrosis, hyperthermia and/or heat stroke.
    Torsemide: (Moderate) Monitor potassium concentration before and during concomitant topiramate and loop diuretic use due to risk for additive hypokalemia. Topiramate can increase the risk of hypokalemia through its inhibition of carbonic anhydrase activity and concomitant use with loop diuretics may further potentiate potassium-wasting.
    Tramadol: (Moderate) Reserve concomitant prescribing of opioids and other CNS depressants, such as topiramate, for use in patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
    Tramadol; Acetaminophen: (Moderate) Reserve concomitant prescribing of opioids and other CNS depressants, such as topiramate, for use in patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
    Triamterene; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide.
    Triazolam: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines.
    Trifluoperazine: (Moderate) Monitor for unusual drowsiness and excess sedation during coadministration of phenothiazines and topiramate due to the risk for additive CNS depression.
    Trimipramine: (Moderate) Monitor for unusual drowsiness or excess sedation during concomitant trimipramine and topiramate use due to the risk for additive CNS depression.
    Trospium: (Moderate) Oligohidrosis and hyperthermia have been reported in post-marketing experience with topiramate. Use caution when topiramate is prescribed with agents known to predispose patients to similar heat-related disorders such as trospium.
    Ulipristal: (Major) Avoid administration of ulipristal with drugs that induce CYP3A4. Ulipristal is a substrate of CYP3A4 and topiramate is a mild CYP3A4 inducer. Concomitant use may decrease the plasma concentration and effectiveness of ulipristal.
    Valproic Acid, Divalproex Sodium: (Moderate) Concomitant administration of topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. In addition, concomitant administration of topiramate and valproic acid has been associated with hypothermia with or without hyperammonemia in patients who have tolerated either drug alone. Assessment of blood ammonia levels may be advisable in patients presenting with symptoms of hypothermia. Concurrent use of topiramate and drugs that cause thrombocytopenia, such as valproic acid, may also increase the risk of bleeding; monitor patients appropriately. In several case reports, children with localized epilepsy have presented with somnolence, seizure exacerbation, behavioral alteration, decline in speech and cognitive abilities, and ataxia while being treated with a combination of valproate and topiramate. Previously, the children tolerated valproic acid with other antiepileptic drugs. Children presented with elevated serum ammonia, normal or elevated LFTs, and generalized slowing of EEG background activity during encephalopathy, which promptly reverted to normal along with clinical improvement following withdrawal of valproate. The possible mechanism is topiramate-induced aggravation of all the known complications of valproic acid monotherapy; it is not due to a pharmacokinetic interaction. This condition is reversible with cessation of either valproic acid or topiramate.
    Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide.
    Vemurafenib: (Major) Concomitant use of vemurafenib and topiramate may result in decreased concentrations of vemurafenib. Vemurafenib is a CYP3A4 substrate and topiramate is a weak CYP3A4 inducer. Use caution and monitor patients for therapeutic effects.
    Vorapaxar: (Moderate) Use caution during concurrent use of vorapaxar and topiramate. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with topiramate, a mild inducer of CYP3A4 in vitro. In addition, concurrent use of topiramate and drugs that affect platelet function such as platelet inhibitors may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (23%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with topiramate is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy; increased bleeding is also possible with the combination. Topiramate is a weak CYP3A4 inducer and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
    Zonisamide: (Moderate) Monitor for the appearance or worsening of metabolic acidosis if zonisamide is given concomitantly with topiramate. Concomitant use of zonisamide with another carbonic anhydrase inhibitor, like topiramate, may increase the severity of metabolic acidosis and may also increase the risks of hyperammonemia, encephalopathy, and kidney stone formation. Monitor serum ammonia concentrations if signs or symptoms of encephalopathy occur. Hyperammonemia resulting from zonisamide resolves when zonisamide is discontinued and may resolve or decrease in severity with a decrease of the daily dose.

    PREGNANCY AND LACTATION

    Pregnancy

    Topiramate can cause fetal harm when administered to a pregnant woman. Consider the benefits and risks of topiramate in women of childbearing potential, particularly when it is being considered for conditions not usually associated with permanent injury or death. Counsel women of childbearing potential regarding the potential risk to the fetus from topiramate exposure, and consider alternative therapeutic options in women who are planning a pregnancy. Data from pregnancy registries indicate infants exposed to topiramate during pregnancy have an increased risk for cleft lip and/or cleft palate. The prevalence of oral clefts among topiramate-exposed infants was 1.4% compared to 0.3% in infants exposed to another antiepileptic drug (AED), and 0.11% in infants with mothers without epilepsy or AED exposure. The relative risk of oral clefts in topiramate-exposed pregnancies was 12.5 (95% CI 5.9 to 26.37) compared to untreated women.[28378] [55675] Oral clefts develop in the first trimester before many women know that they are pregnant.[43569] Data from pregnancy registries indicate infants exposed to topiramate during pregnancy have an increased risk for being small for gestational age (SGA), defined as a birth weight below the tenth percentile. SGA has been seen at all doses and appears to be dose-dependent. SGA occurs more frequently in infants of women who received higher topiramate doses or continued topiramate use until later in pregnancy (i.e., third trimester). According to registry data, the prevalence of SGA was 19.7% to 25% in topiramate-exposed infants compared to 7.9% in infants exposed to a reference AED, and 5.4% to 9% in infants with mothers without epilepsy or AED exposure. Excluding oral clefts, no other specific patterns of major congential malformations were observed based on data from pregnancy registries. The prevalence of major congenital malformations among topiramate-exposed infants was 4.1% compared to 1.8% in infants exposed to another AED, and 1.1% in infants with mothers without epilepsy or AED exposure. Registry data and findings from other studies suggest that combination therapy with AEDs may increase the risk of teratogenic effects compared to monotherapy with an AED. Structural malformations such as craniofacial defects and reduced fetal weight occurred in the offspring of multiple animal species during studies of topiramate. Topiramate can cause metabolic acidosis which, when occurring during pregnancy, has been associated with decreased fetal growth, decreased fetal oxygenation, fetal death, and may impact the ability of the fetus to tolerate labor. Monitor women taking topiramate during pregnancy for metabolic acidosis and treat as in the nonpregnant state. Monitor newborns of mothers treated with topiramate for metabolic acidosis after birth. Limited data indicate topiramate may be associated with pre-term labor and premature delivery. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to topiramate; information about the registry can be obtained at www.aedpregnancyregistry.org or by calling 1-888-233-2334.[28378] [55675]

    MECHANISM OF ACTION

    The exact mechanism of topiramate's anticonvulsant and migraine prophylaxis effects is unknown. It appears that topiramate may block the spread of seizures rather than raise the seizure threshold like other AEDs. The drug appears to have several mechanisms of action. First, topiramate reduces the duration of abnormal discharges and the number of action potentials within each discharge. This is probably secondary to its ability to block voltage-sensitive sodium channels. Second, topiramate enhances the activity of the inhibitory neurotransmitter gamma-aminobutyrate (GABA) at GABA-A receptors by increasing the frequency at which GABA activates GABA-A receptors. Third, topiramate inhibits excitatory transmission by antagonizing some types of glutamate receptors. Specifically, topiramate antagonizes the ability of kainate to activate the kainate/AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid; non-NMDA) subtype of excitatory amino acid (glutamate) receptor. There is no apparent effect on the activity of N-methyl-D-aspartate (NMDA) at the NMDA receptor subtype. Topiramate is also a weak carbonic anhydrase inhibitor (isozymes II and IV); however, while this action can cause a risk for metabolic acidosis, this mechanism does not appear to be involved in the anticonvulsant action of the drug.
     
    In addition to its efficacy in epilepsy and migraine prophylaxis, topiramate has also demonstrated neuroprotective effects against hypoxic-ischemic brain damage in both in vitro and animal models. The cerebral damage of hypoxic-ischemic encephalopathy occurs in part due to an increased release of excitatory neurotransmitters, including glutamate. Glutamate activates AMPA receptors, depolarizes the cell, and promotes the removal of the voltage-sensitive magnesium block on NMDA receptors. This, in turn, promotes the entry of calcium into the cell, stimulating a series of reactions that lead to cell necrosis and apoptosis. The neuroprotective properties of topiramate appear to be primarily related to its inhibition of the kainate/AMPA subtype of glutamate receptors. In addition, blockade of sodium channels, high-voltage calcium currents, carbonic anhydrase isoenzymes, and mitochondrial permeability transition pore (MPTP) may also contribute to its neuroprotective effects.

    PHARMACOKINETICS

    Topiramate is administered orally. Protein binding ranges from 15% to 41% to over the concentration range of 0.5 to 250 mcg/mL. It is not metabolized to a great extent. Six metabolites have been identified and are formed via hydroxylation, hydrolysis, and glucuronidation. None of these metabolites constitutes more than 5% of an administered dose. About 70% of an administered dose is eliminated unchanged in the urine. Topiramate undergoes renal tubular reabsorption. Oral plasma clearance (CL/F) is approximately 20 to 30 mL/minute in adults after oral administration. Steady-state concentrations are reached in 4 and 5 days with immediate-release formulations and extended-release capsules (Qudexy XR), respectively, in adult patients with normal renal function. The mean plasma elimination half-life is 21 hours after single or multiple doses of immediate-release tablets or capsules. The mean effective half-life of extended-release capsules (Qudexy XR) is about 56 hours. The mean elimination half-life of topiramate was approximately 31 hours after repeat administration of extended-release capsules (Trokendi XR).
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP2C19, CYP3A4
    In vitro studies indicate that topiramate may induce CYP3A4 (weak inducer) and inhibit CYP2C19 (weak inhibitor). Topiramate does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, CYP3A4/5 isozymes. Some hepatic enzyme-inducing antiepileptic drugs (i.e., phenytoin, carbamazepine) have been shown to reduce topiramate serum concentrations by 40% to 48%.

    Oral Route

    Topiramate is absorbed rapidly with peak plasma concentrations occurring approximately 2 hours after oral administration of a 400 mg immediate-release tablet and approximately 0.5 hours after oral solution administration under fasting conditions. Peak plasma concentrations of topiramate extended-release capsules are reached approximately 20 hours after a 200 mg dose of Qudexy XR and approximately 24 hours after a 200 mg dose of Trokendi XR. The sprinkle formulation is bioequivalent to the immediate-release tablet formulation and, therefore, may be substituted as a therapeutic equivalent. The relative bioavailability from the tablets is about 80% compared to a topiramate solution. At steady-state, the plasma exposure of topiramate from extended-release capsules (Trokendi XR and Qudexy XR) administered once-daily were shown to be bioequivalent to the immediate-release tablet administered twice-daily. Overall, the impact of food-intake on topiramate pharmacokinetics is not expected to be clinically significant. Bioavailability of topiramate immediate-release tablets and capsules is not affected by coadministration with food. Oral administration of topiramate oral solution with a high-fat and high calorie meal did not affect topiramate AUC, but lowered the Cmax by 28% and delayed the Tmax by 5 hours. Compared to the fasted state, administration of a single dose of topiramate extended-release capsules (Trokendi XR) with a high-fat meal increased the Cmax of topiramate by 37% and decreased Tmax to approximately 8 hours. AUC was not affected. The effect of food on Cmax is expected to be significantly reduced after repeat administrations. Tmax was delayed by approximately 4 hours after administration of a single dose of topiramate extended-release capsules (Qudexy XR) with a high-fat meal. Bioavailability (AUC and Cmax) were not affected.