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  • CLASSES

    Anticonvulsants, Miscellaneous
    Other Anti-migraine Drugs

    DEA CLASS

    Rx

    DESCRIPTION

    Oral anticonvulsant; weak carbonic anhydrase inhibitor
    Used for partial and generalized seizures, Lennox-Gastaut, refractory seizures, and migraine prophylaxis
    Close monitoring for emerging or worsening suicidal thoughts/behavior or depression recommended

    COMMON BRAND NAMES

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

    HOW SUPPLIED

    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 adjuvant therapy).
    For monotherapy.
    Oral dosage (oral tablets or sprinkle capsules)
    Adults, Adolescents, and Children 10 years and older

    Initially, 50 mg/day PO administered in 2 divided doses. Increase the daily dose by 50 mg once per week during weeks 2, 3, and 4. Increase the daily dose by 100 mg once per week during weeks 5 and 6; administer total daily dose in 2 divided doses. The recommended final dose, 400 mg per day PO in 2 divided doses, is achieved during week 6. Approximately 58% of patients randomized to 400 mg per day achieved this maximal dose in the monotherapy controlled trial; the mean dose achieved in the trial was 275 mg per day.

    Children 2 to 9 years weighing more than 38 kg

    Initially, 25 mg PO once daily in the evening. If tolerated, may increase the dosage to 25 mg PO twice daily during week 2 of therapy. Thereafter, the dosage may be increased by 25 to 50 mg/day increments at weekly intervals to achieve optimal clinical response; attempt to titrate to the minimum maintenance dose of 125 mg PO twice daily by week 5 to 7 of therapy. If seizure control is not achieved, the dosage may be further increased by 25 to 50 mg/day increments at weekly intervals. Max: 200 mg PO twice daily.

    Children 2 to 9 years weighing 32 to 38 kg

    Initially, 25 mg PO once daily in the evening. If tolerated, may increase the dosage to 25 mg PO twice daily during week 2 of therapy. Thereafter, the dosage may be increased by 25 to 50 mg/day increments at weekly intervals to achieve optimal clinical response; attempt to titrate to the minimum maintenance dose of 125 mg PO twice daily by week 5 to 7 of therapy. If seizure control is not achieved, the dosage may be further increased by 25 to 50 mg/day increments at weekly intervals. Max: 175 mg PO twice daily.

    Children 2 to 9 years weighing 23 to 31 kg

    Initially, 25 mg PO once daily in the evening. If tolerated, may increase the dosage to 25 mg PO twice daily during week 2 of therapy. Thereafter, the dosage may be increased by 25 to 50 mg/day increments at weekly intervals to achieve optimal clinical response; attempt to titrate to the minimum maintenance dose of 100 mg PO twice daily by week 5 to 7 of therapy. If seizure control is not achieved, the dosage may be further increased by 25 to 50 mg/day increments at weekly intervals. Max: 175 mg PO twice daily.

    Children 2 to 9 years weighing 12 to 22 kg

    Initially, 25 mg PO once daily in the evening. If tolerated, may increase the dosage to 25 mg PO twice daily during week 2 of therapy. Thereafter, the dosage may be increased by 25 to 50 mg/day increments at weekly intervals to achieve optimal clinical response; attempt to titrate to the minimum maintenance dose of 100 mg PO twice daily by week 5 to 7 of therapy. If seizure control is not achieved, the dosage may be further increased by 25 to 50 mg/day increments at weekly intervals. Max: 150 mg PO twice daily.

    Children 2 to 9 years weighing 11 kg or less

    Initially, 25 mg PO once daily in the evening. If tolerated, may increase the dosage to 25 mg PO twice daily during week 2 of therapy. Thereafter, the dosage may be increased by 25 to 50 mg/day increments at weekly intervals to achieve optimal clinical response; attempt to titrate to the minimum maintenance dose of 75 mg PO twice daily by week 5 to 7 of therapy. If seizure control is not achieved, the dosage may be further increased by 25 to 50 mg/day increments at weekly intervals. Max: 125 mg PO twice daily.

    Oral dosage (Trokendi XR extended-release capsules)
    Adults, Adolescents, and Children 10 years and older

    Initially, 50 mg PO once daily. Increase the daily dose by 50 mg once per week during weeks 2, 3, and 4. Increase the daily dose by 100 mg once per week during weeks 5 and 6. The recommended final dose, 400 mg PO once daily, is achieved during week 6.

    Children 6 to 9 years weighing more than 38 kg

    Initially, 25 mg PO once daily in the evening. If tolerated, may increase the dosage to 50 mg PO once daily during week 2 of therapy. Thereafter, the dosage may be increased by 25 to 50 mg/day increments at weekly intervals to achieve optimal clinical response; attempt to titrate to the minimum maintenance dose of 250 mg PO once daily by week 5 to 7 of therapy. If seizure control is not achieved, the dosage may be further increased by 25 to 50 mg/day increments at weekly intervals. Max: 400 mg PO once daily.

    Children 6 to 9 years weighing 32 to 38 kg

    Initially, 25 mg PO once daily in the evening. If tolerated, may increase the dosage to 50 mg PO once daily during week 2 of therapy. Thereafter, the dosage may be increased by 25 to 50 mg/day increments at weekly intervals to achieve optimal clinical response; attempt to titrate to the minimum maintenance dose of 250 mg PO once daily by week 5 to 7 of therapy. If seizure control is not achieved, the dosage may be further increased by 25 to 50 mg/day increments at weekly intervals. Max: 350 mg PO once daily.

    Children 6 to 9 years weighing 23 to 31 kg

    Initially, 25 mg PO once daily in the evening. If tolerated, may increase the dosage to 50 mg PO once daily during week 2 of therapy. Thereafter, the dosage may be increased by 25 to 50 mg/day increments at weekly intervals to achieve optimal clinical response; attempt to titrate to the minimum maintenance dose of 200 mg PO once daily by week 5 to 7 of therapy. If seizure control is not achieved, the dosage may be further increased by 25 to 50 mg/day increments at weekly intervals. Max: 350 mg PO once daily.

    Children 6 to 9 years weighing 12 to 22 kg

    Initially, 25 mg PO once daily in the evening. If tolerated, may increase the dosage to 50 mg PO once daily during week 2 of therapy. Thereafter, the dosage may be increased by 25 to 50 mg/day increments at weekly intervals to achieve optimal clinical response; attempt to titrate to the minimum maintenance dose of 200 mg PO once daily by week 5 to 7 of therapy. If seizure control is not achieved, the dosage may be further increased by 25 to 50 mg/day increments at weekly intervals. Max: 300 mg PO once daily.

    Children 6 to 9 years weighing 11 kg or less

    Initially, 25 mg PO once daily in the evening. If tolerated, may increase the dosage to 50 mg PO once daily during week 2 of therapy. Thereafter, the dosage may be increased by 25 to 50 mg/day increments at weekly intervals to achieve optimal clinical response; attempt to titrate to the minimum maintenance dose of 150 mg PO once daily by week 5 to 7 of therapy. If seizure control is not achieved, the dosage may be further increased by 25 to 50 mg/day increments at weekly intervals. Max: 250 mg PO once daily.

    Oral dosage (Qudexy XR extended-release capsules)
    Adults, Adolescents, and Children 10 years and older

    Initially, 50 mg PO once daily. Increase the daily dose by 50 mg once per week during weeks 2, 3, and 4. Increase the daily dose by 100 mg once per week during weeks 5 and 6. The recommended final dose, 400 mg PO once daily, is achieved during week 6.

    Children 2 to 9 years weighing more than 38 kg

    Initially, 25 mg PO once daily in the evening. If tolerated, may increase the dosage to 50 mg PO once daily during week 2 of therapy. Thereafter, the dosage may be increased by 25 to 50 mg/day increments at weekly intervals to achieve optimal clinical response; attempt to titrate to the minimum maintenance dose of 250 mg PO once daily by week 5 to 7 of therapy. If seizure control is not achieved, the dosage may be further increased by 25 to 50 mg/day increments at weekly intervals. Max: 400 mg PO once daily.

    Children 2 to 9 years weighing 32 to 38 kg

    Initially, 25 mg PO once daily in the evening. If tolerated, may increase the dosage to 50 mg PO once daily during week 2 of therapy. Thereafter, the dosage may be increased by 25 to 50 mg/day increments at weekly intervals to achieve optimal clinical response; attempt to titrate to the minimum maintenance dose of 250 mg PO once daily by week 5 to 7 of therapy. If seizure control is not achieved, the dosage may be further increased by 25 to 50 mg/day increments at weekly intervals. Max: 350 mg PO once daily.

    Children 2 to 9 years weighing 23 to 31 kg

    Initially, 25 mg PO once daily in the evening. If tolerated, may increase the dosage to 50 mg PO once daily during week 2 of therapy. Thereafter, the dosage may be increased by 25 to 50 mg/day increments at weekly intervals to achieve optimal clinical response; attempt to titrate to the minimum maintenance dose of 200 mg PO once daily by week 5 to 7 of therapy. If seizure control is not achieved, the dosage may be further increased by 25 to 50 mg/day increments at weekly intervals. Max: 350 mg PO once daily.

    Children 2 to 9 years weighing 12 to 22 kg

    Initially, 25 mg PO once daily in the evening. If tolerated, may increase the dosage to 50 mg PO once daily during week 2 of therapy. Thereafter, the dosage may be increased by 25 to 50 mg/day increments at weekly intervals to achieve optimal clinical response; attempt to titrate to the minimum maintenance dose of 200 mg PO once daily by week 5 to 7 of therapy. If seizure control is not achieved, the dosage may be further increased by 25 to 50 mg/day increments at weekly intervals. Max: 300 mg PO once daily.

    Children 2 to 9 years weighing 11 kg or less

    Initially, 25 mg PO once daily in the evening. If tolerated, may increase the dosage to 50 mg PO once daily during week 2 of therapy. Thereafter, the dosage may be increased by 25 to 50 mg/day increments at weekly intervals to achieve optimal clinical response; attempt to titrate to the minimum maintenance dose of 150 mg PO once daily by week 5 to 7 of therapy. If seizure control is not achieved, the dosage may be further increased by 25 to 50 mg/day increments at weekly intervals. Max: 250 mg PO once daily.

    For adjunctive therapy.
    Oral dosage (oral tablets or sprinkle capsules)
    Adults and Adolescents 17 years and older

    Initially, 25 to 50 mg/day PO; doses more than 25 mg/day should be divided and given twice daily. If tolerated, the dosage may be increased by 25 to 50 mg/day increments at weekly intervals to achieve optimal clinical response. The recommended maintenance dose is 200 to 400 mg/day (divided and given twice daily); doses above 400 mg/day have not been shown to improve responses. Doses more than 1,600 mg/day have not been studied.

    Children and Adolescents 2 to 16 years

    Initially, 1 to 3 mg/kg/day (Max: 25 mg/day) PO once daily in the evening. If tolerated, may increase the dosage by 1 to 3 mg/kg/day increments every 1 to 2 weeks to achieve optimal clinical response; doses should be divided and given twice daily. The recommended maintenance dose is 5 to 9 mg/kg/day. A retrospective and prospective review of 41 children (mean age: 6.3 years; age range: 0.4 to 12 years) on topiramate therapy reported mean doses of adjuvant topiramate ranging from 7 to 14 mg/kg/day. Children 5 years and younger receiving a concurrent enzyme-inducing antiepileptic agent required the largest mean dose.

    Infants† and Children younger than 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 (Trokendi XR extended-release capsules)
    Adults and Adolescents 17 years and older

    Initially, 25 to 50 mg/day PO once daily. If tolerated, the dosage may be increased by 25 to 50 mg/day increments at weekly intervals to achieve optimal clinical response. The recommended maintenance dose is 200 to 400 mg/day; doses above 400 mg/day have not been shown to improve responses. Doses more than 1,600 mg/day have not been studied.

    Children and Adolescents 6 to 16 years

    Initially, 1 to 3 mg/kg/day (Max: 25 mg/day) PO once daily in the evening. If tolerated, may increase the dosage by 1 to 3 mg/kg/day increments every 1 to 2 weeks to achieve optimal clinical response. The recommended maintenance dose is 5 to 9 mg/kg/day.

    Oral dosage (Qudexy XR extended-release capsules)
    Adults and Adolescents 17 years and older

    Initially, 25 to 50 mg/day PO once daily. If tolerated, the dosage may be increased by 25 to 50 mg/day increments at weekly intervals to achieve optimal clinical response. The recommended maintenance dose is 200 to 400 mg/day; doses above 400 mg/day have not been shown to improve responses. Doses more than 1,600 mg/day have not been studied.

    Children and Adolescents 2 to 16 years

    Initially, 1 to 3 mg/kg/day (Max: 25 mg/day) PO once daily in the evening. If tolerated, may increase the dosage by 1 to 3 mg/kg/day increments every 1 to 2 weeks to achieve optimal clinical response. The recommended maintenance dose is 5 to 9 mg/kg/day.

    For the treatment of primary generalized tonic-clonic seizures (monotherapy or adjuvant therapy).
    For monotherapy.
    Oral dosage (oral tablets or sprinkle capsules)
    Adults, Adolescents, and Children 10 years and older

    Initially, 50 mg per day PO administered in 2 divided doses. Increase the daily dose by 50 mg once per week during weeks 2, 3, and 4. Increase the daily dose by 100 mg once per week during weeks 5 and 6; administer total daily dose in 2 divided doses. The recommended final dose, 400 mg per day PO in 2 divided doses, is achieved during week 6. Approximately 58% of patients randomized to 400 mg per day achieved this maximal dose in the monotherapy controlled trial; the mean dose achieved in the trial was 275 mg per day.

    Children 2 to 9 years weighing more than 38 kg

    Initially, 25 mg PO once daily in the evening. If tolerated, may increase the dosage to 25 mg PO twice daily during week 2 of therapy. Thereafter, the dosage may be increased by 25 to 50 mg/day increments at weekly intervals to achieve optimal clinical response; attempt to titrate to the minimum maintenance dose of 125 mg PO twice daily by week 5 to 7 of therapy. If seizure control is not achieved, the dosage may be further increased by 25 to 50 mg/day increments at weekly intervals. Max: 200 mg PO twice daily.

    Children 2 to 9 years weighing 32 to 38 kg

    Initially, 25 mg PO once daily in the evening. If tolerated, may increase the dosage to 25 mg PO twice daily during week 2 of therapy. Thereafter, the dosage may be increased by 25 to 50 mg/day increments at weekly intervals to achieve optimal clinical response; attempt to titrate to the minimum maintenance dose of 125 mg PO twice daily by week 5 to 7 of therapy. If seizure control is not achieved, the dosage may be further increased by 25 to 50 mg/day increments at weekly intervals. Max: 175 mg PO twice daily.

    Children 2 to 9 years weighing 23 to 31 kg

    Initially, 25 mg PO once daily in the evening. If tolerated, may increase the dosage to 25 mg PO twice daily during week 2 of therapy. Thereafter, the dosage may be increased by 25 to 50 mg/day increments at weekly intervals to achieve optimal clinical response; attempt to titrate to the minimum maintenance dose of 100 mg PO twice daily by week 5 to 7 of therapy. If seizure control is not achieved, the dosage may be further increased by 25 to 50 mg/day increments at weekly intervals. Max: 175 mg PO twice daily.

    Children 2 to 9 years weighing 12 to 22 kg

    Initially, 25 mg PO once daily in the evening. If tolerated, may increase the dosage to 25 mg PO twice daily during week 2 of therapy. Thereafter, the dosage may be increased by 25 to 50 mg/day increments at weekly intervals to achieve optimal clinical response; attempt to titrate to the minimum maintenance dose of 100 mg PO twice daily by week 5 to 7 of therapy. If seizure control is not achieved, the dosage may be further increased by 25 to 50 mg/day increments at weekly intervals. Max: 150 mg PO twice daily.

    Children 2 to 9 years weighing 11 kg or less

    Initially, 25 mg PO once daily in the evening. If tolerated, may increase the dosage to 25 mg PO twice daily during week 2 of therapy. Thereafter, the dosage may be increased by 25 to 50 mg/day increments at weekly intervals to achieve optimal clinical response; attempt to titrate to the minimum maintenance dose of 75 mg PO twice daily by week 5 to 7 of therapy. If seizure control is not achieved, the dosage may be further increased by 25 to 50 mg/day increments at weekly intervals. Max: 125 mg PO twice daily.

    Oral dosage (Trokendi XR extended-release capsules)
    Adults, Adolescents, and Children 10 years and older

    Initially, 50 mg PO once daily. Increase the daily dose by 50 mg once per week during weeks 2, 3, and 4. Increase the daily dose by 100 mg once per week during weeks 5 and 6. The recommended final dose, 400 mg PO once daily, is achieved during week 6.

    Children 6 to 9 years weighing more than 38 kg

    Initially, 25 mg PO once daily in the evening. If tolerated, may increase the dosage to 50 mg PO once daily during week 2 of therapy. Thereafter, the dosage may be increased by 25 to 50 mg/day increments at weekly intervals to achieve optimal clinical response; attempt to titrate to the minimum maintenance dose of 250 mg PO once daily by week 5 to 7 of therapy. If seizure control is not achieved, the dosage may be further increased by 25 to 50 mg/day increments at weekly intervals. Max: 400 mg PO once daily.

    Children 6 to 9 years weighing 32 to 38 kg

    Initially, 25 mg PO once daily in the evening. If tolerated, may increase the dosage to 50 mg PO once daily during week 2 of therapy. Thereafter, the dosage may be increased by 25 to 50 mg/day increments at weekly intervals to achieve optimal clinical response; attempt to titrate to the minimum maintenance dose of 250 mg PO once daily by week 5 to 7 of therapy. If seizure control is not achieved, the dosage may be further increased by 25 to 50 mg/day increments at weekly intervals. Max: 350 mg PO once daily.

    Children 6 to 9 years weighing 23 to 31 kg

    Initially, 25 mg PO once daily in the evening. If tolerated, may increase the dosage to 50 mg PO once daily during week 2 of therapy. Thereafter, the dosage may be increased by 25 to 50 mg/day increments at weekly intervals to achieve optimal clinical response; attempt to titrate to the minimum maintenance dose of 200 mg PO once daily by week 5 to 7 of therapy. If seizure control is not achieved, the dosage may be further increased by 25 to 50 mg/day increments at weekly intervals. Max: 350 mg PO once daily.

    Children 6 to 9 years weighing 12 to 22 kg

    Initially, 25 mg PO once daily in the evening. If tolerated, may increase the dosage to 50 mg PO once daily during week 2 of therapy. Thereafter, the dosage may be increased by 25 to 50 mg/day increments at weekly intervals to achieve optimal clinical response; attempt to titrate to the minimum maintenance dose of 200 mg PO once daily by week 5 to 7 of therapy. If seizure control is not achieved, the dosage may be further increased by 25 to 50 mg/day increments at weekly intervals. Max: 300 mg PO once daily.

    Children 6 to 9 years weighing 11 kg or less

    Initially, 25 mg PO once daily in the evening. If tolerated, may increase the dosage to 50 mg PO once daily during week 2 of therapy. Thereafter, the dosage may be increased by 25 to 50 mg/day increments at weekly intervals to achieve optimal clinical response; attempt to titrate to the minimum maintenance dose of 150 mg PO once daily by week 5 to 7 of therapy. If seizure control is not achieved, the dosage may be further increased by 25 to 50 mg/day increments at weekly intervals. Max: 250 mg PO once daily.

    Oral dosage (Qudexy XR extended-release capsules)
    Adults, Adolescents, and Children 10 years and older

    Initially, 50 mg PO once daily. Increase the daily dose by 50 mg once per week during weeks 2, 3, and 4. Increase the daily dose by 100 mg once per week during weeks 5 and 6. The recommended final dose, 400 mg PO once daily, is achieved during week 6.

    Children 2 to 9 years weighing more than 38 kg

    Initially, 25 mg PO once daily in the evening. If tolerated, may increase the dosage to 50 mg PO once daily during week 2 of therapy. Thereafter, the dosage may be increased by 25 to 50 mg/day increments at weekly intervals to achieve optimal clinical response; attempt to titrate to the minimum maintenance dose of 250 mg PO once daily by week 5 to 7 of therapy. If seizure control is not achieved, the dosage may be further increased by 25 to 50 mg/day increments at weekly intervals. Max: 400 mg PO once daily.

    Children 2 to 9 years weighing 32 to 38 kg

    Initially, 25 mg PO once daily in the evening. If tolerated, may increase the dosage to 50 mg PO once daily during week 2 of therapy. Thereafter, the dosage may be increased by 25 to 50 mg/day increments at weekly intervals to achieve optimal clinical response; attempt to titrate to the minimum maintenance dose of 250 mg PO once daily by week 5 to 7 of therapy. If seizure control is not achieved, the dosage may be further increased by 25 to 50 mg/day increments at weekly intervals. Max: 350 mg PO once daily.

    Children 2 to 9 years weighing 23 to 31 kg

    Initially, 25 mg PO once daily in the evening. If tolerated, may increase the dosage to 50 mg PO once daily during week 2 of therapy. Thereafter, the dosage may be increased by 25 to 50 mg/day increments at weekly intervals to achieve optimal clinical response; attempt to titrate to the minimum maintenance dose of 200 mg PO once daily by week 5 to 7 of therapy. If seizure control is not achieved, the dosage may be further increased by 25 to 50 mg/day increments at weekly intervals. Max: 350 mg PO once daily.

    Children 2 to 9 years weighing 12 to 22 kg

    Initially, 25 mg PO once daily in the evening. If tolerated, may increase the dosage to 50 mg PO once daily during week 2 of therapy. Thereafter, the dosage may be increased by 25 to 50 mg/day increments at weekly intervals to achieve optimal clinical response; attempt to titrate to the minimum maintenance dose of 200 mg PO once daily by week 5 to 7 of therapy. If seizure control is not achieved, the dosage may be further increased by 25 to 50 mg/day increments at weekly intervals. Max: 300 mg PO once daily.

    Children 2 to 9 years weighing 11 kg or less

    Initially, 25 mg PO once daily in the evening. If tolerated, may increase the dosage to 50 mg PO once daily during week 2 of therapy. Thereafter, the dosage may be increased by 25 to 50 mg/day increments at weekly intervals to achieve optimal clinical response; attempt to titrate to the minimum maintenance dose of 150 mg PO once daily by week 5 to 7 of therapy. If seizure control is not achieved, the dosage may be further increased by 25 to 50 mg/day increments at weekly intervals. Max: 250 mg PO once daily.

    For adjunctive therapy.
    Oral dosage (oral tablets or sprinkle capsules)
    Adults and Adolescents 17 years and older

    Initially, 25 to 50 mg/day PO; doses more than 25 mg/day should be divided and given twice daily. If tolerated, the dosage may be increased by 25 to 50 mg/day increments at weekly intervals to achieve optimal clinical response. During clinical trials, the optimum dose was reached at the end of 8 weeks. The recommended maintenance dose is 400 mg/day (divided and given twice daily); doses above 400 mg/day have not been shown to improve responses. Doses more than 1,600 mg/day have not been studied.

    Children and Adolescents 2 to 16 years

    Initially, 1 to 3 mg/kg/day (Max: 25 mg/day) PO once daily in the evening. If tolerated, may increase the dosage slowly to 6 mg/kg/day PO by the end of 8 weeks; doses should be divided and given twice daily. Do not titrate by more than 1 to 3 mg/kg/day every 1 to 2 weeks. Max dose: 9 mg/kg/day. A retrospective and prospective review of 41 children (mean age: 6.3 years; age range: 0.4 to 12 years) on topiramate therapy reported mean doses of adjuvant topiramate ranging from 7 to 14 mg/kg/day. Children 5 years and younger receiving a concurrent enzyme-inducing antiepileptic agent required the largest mean dose.

    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 (Trokendi XR extended-release capsules)
    Adults and Adolescents 17 years and older

    Initially, 25 to 50 mg/day PO once daily. If tolerated, the dosage may be increased by 25 to 50 mg/day increments at weekly intervals to achieve optimal clinical response. During clinical trials, the optimum dose was reached at the end of 8 weeks. The recommended maintenance dose is 400 mg/day; doses above 400 mg/day have not been shown to improve responses. Doses more than 1,600 mg/day have not been studied.

    Children and Adolescents 6 to 16 years

    Initially, 1 to 3 mg/kg/day (Max: 25 mg/day) PO once daily in the evening. If tolerated, may increase the dosage slowly to 6 mg/kg/day PO by the end of 8 weeks. Do not titrate by more than 1 to 3 mg/kg/day every 1 to 2 weeks. Max dose: 9 mg/kg/day.

    Oral dosage (Qudexy XR extended-release capsules)
    Adults and Adolescents 17 years and older

    Initially, 25 to 50 mg/day PO once daily. If tolerated, the dosage may be increased by 25 to 50 mg/day increments at weekly intervals to achieve optimal clinical response. During clinical trials, the optimum dose was reached at the end of 8 weeks. The recommended maintenance dose is 400 mg/day; doses above 400 mg/day have not been shown to improve responses. Doses more than 1,600 mg/day have not been studied.

    Children and Adolescents 2 to 16 years

    Initially, 1 to 3 mg/kg/day (Max: 25 mg/day) PO once daily in the evening. If tolerated, may increase the dosage slowly to 6 mg/kg/day PO by the end of 8 weeks. Do not titrate by more than 1 to 3 mg/kg/day every 1 to 2 weeks. Max dose: 9 mg/kg/day.

    For the adjuvant treatment of Lennox-Gastaut syndrome.
    NOTE: Topiramate is designated an orphan drug by the FDA for Lennox-Gastaut.
    Oral dosage (oral tablets or sprinkle capsules)
    Adults and Adolescents 17 years and older

    Initially, 25 to 50 mg/day PO; doses more than 25 mg/day should be divided and given twice daily. If tolerated, the dosage may be increased by 25 to 50 mg/day increments at weekly intervals to achieve optimal clinical response. The recommended maintenance dose is 200 to 400 mg/day (divided and given twice daily); doses above 400 mg/day have not been shown to improve responses. Doses more than 1,600 mg/day have not been studied.

    Children and Adolescents 2 to 16 years

    Initially, 1 to 3 mg/kg/day (Max: 25 mg/day) PO once daily in the evening. If tolerated, may increase the dosage by 1 to 3 mg/kg/day increments every 1 to 2 weeks to achieve optimal clinical response; doses should be divided and given twice daily. The recommended maintenance dose is 5 to 9 mg/kg/day. A retrospective and prospective review of 41 children (mean age: 6.3 years; age range: 0.4 to 12 years) on topiramate therapy reported mean doses of adjuvant topiramate ranging from 7 to 14 mg/kg/day. Children 5 years and younger receiving a concurrent enzyme-inducing antiepileptic agent required the largest mean dose.

    Oral dosage (Trokendi XR extended-release capsules)
    Adults and Adolescents 17 years and older

    Initially, 25 to 50 mg PO once daily. If tolerated, the dosage may be increased by 25 to 50 mg/day increments at weekly intervals to achieve optimal clinical response. The recommended maintenance dose is 200 to 400 mg/day; doses above 400 mg/day have not been shown to improve responses. Doses more than 1,600 mg/day have not been studied.

    Children and Adolescents 6 to 16 years

    Initially, 1 to 3 mg/kg/day (Max: 25 mg/day) PO once daily in the evening. If tolerated, may increase the dosage by 1 to 3 mg/kg/day increments every 1 to 2 weeks to achieve optimal clinical response. The recommended maintenance dose is 5 to 9 mg/kg/day.

    Oral dosage (Qudexy XR extended-release capsules)
    Adults and Adolescents 17 years and older

    Initially, 25 to 50 mg PO once daily. If tolerated, the dosage may be increased by 25 to 50 mg/day increments at weekly intervals to achieve optimal clinical response. The recommended maintenance dose is 200 to 400 mg/day; doses above 400 mg/day have not been shown to improve responses. Doses more than 1,600 mg/day have not been studied.

    Children and Adolescents 2 to 16 years

    Initially, 1 to 3 mg/kg/day (Max: 25 mg/day) PO once daily in the evening. If tolerated, may increase the dosage by 1 to 3 mg/kg/day increments every 1 to 2 weeks to achieve optimal clinical response. The recommended maintenance dose is 5 to 9 mg/kg/day.

    For migraine prophylaxis.
    NOTE: The usefulness of topiramate in the treatment of acute migraine has not been evaluated.
    Oral dosage (immediate-release products)
    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, which is the target dose. Adjust dose and titration according to clinical outcome; longer intervals between dose adjustments can be used if needed. Clinical practice guidelines classify topiramate as having established efficacy for migraine prophylaxis.

    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, which is the target dose. Adjust dose and titration according to clinical outcome; longer intervals between dose adjustments can be used if needed. Clinical practice guidelines do not make recommendations regarding migraine prophylaxis with topiramate due to insufficient evidence.

    Oral dosage (extended-release capsules)
    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, which is the target dose. Adjust dose and titration according to clinical outcome; longer intervals between dose adjustments can be used if needed. Clinical practice guidelines classify topiramate as having established efficacy for migraine prophylaxis.

    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, which is the target dose. Adjust dose and titration according to clinical outcome; longer intervals between dose adjustments can be used if needed. Clinical practice guidelines do not make recommendations regarding migraine prophylaxis with topiramate due to insufficient evidence.

    For the adjunctive treatment of other refractory epilepsy syndromes (e.g., atonic seizures†, atypical absence seizures†, myoclonic seizures†).
    Oral dosage
    Adults and Adolescents 17 years of age and older

    Data are limited. A suggested initial dose is 50 mg PO once daily. Then, titrate dose slowly by increments of 50 mg/week up to a target dose of 100 to 300 mg PO 3 times daily.

    Children and Adolescents 2 years to 16 years of age

    Based on limited clinical trials, initially 0.5 to 1 mg/kg/dose (Max: 25 mg for initial titration) PO once daily for 7 days, followed by weekly dosage increases of 0.5 to 1 mg/kg/day PO. It appears that the minimally effective target dose of topiramate as add-on therapy in children with refractory epilepsy is 3 to 6 mg/kg/day PO, given in divided doses. However, doses of up to 24 mg/kg/day PO have been used in some patients.

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

    One pilot study has used an initial dosage of 25 mg PO once daily added to current anti-epileptic drug regimens. Dosage was increased by 25 mg PO every 2 to 3 days until spasms were controlled, or a maximum dosage of 24 mg/kg/day PO given in divided doses was achieved. The frequency of infantile spasms was reduced by half in 80% of the children treated; 45% became spasm free. Over half of the treated children were able to achieve monotherapy with topiramate after slow reduction of their other anti-epileptic medications.

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

    Initially, 25 mg/day PO (usually given at bedtime), then titrate slowly. Max: 300 mg/day PO in divided doses has been used. Several randomized outpatient controlled trials have shown improvements in measures of alcohol use, such as the length of time to relapse or reduction in daily alcohol intake. As with other treatments, dropout rates for treatment are high, and medication should be used as a part of a comprehensive management program that includes psychosocial support and treatment. More data are needed to establish a role for topiramate in treating alcohol dependence.

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

    In one randomized, double-blind placebo-controlled trial, adult women (n = 60) treated with topiramate (titrated to 250 mg/day PO) experienced a reduction in binge or purge episodes when compared to placebo (greater than 50% reduction, p < 0.001) during the 10-week trial. The evidence available is considered of relatively low-quality compared to data available for other treatments; experts stress the need for quality data and that side effects of treatment (e.g., paresthesias) may be problematic.

    For the treatment of painful diabetic neuropathy†.
    Oral dosage (immediate-release tablets)
    Adults

    Future studies will determine if topiramate has a role for treating painful diabetic neuropathy. In clinical trials, patients received 25 mg PO once daily at bedtime for 1 week. The daily dosage was titrated by 25 mg during weeks 2 through 4; by 50 mg during weeks 5 and 6; and by 100 mg during weeks 7 and 8 up to the maximum tolerated dose, not to exceed 400 mg/day PO (e.g., 200 mg PO twice daily). Due to insufficient evidence of efficacy from this study and other available data, the American Academy of Neurology guidelines do not support or refute the use of topiramate for the treatment of painful diabetic neuropathy.

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

    The American Psychiatric Association Practice Guidelines list topiramate as a possible treatment option, as treatment options are limited and some evidence suggests a potential benefit. Topiramate is commonly initiated at 25 mg/day to 50 mg/day PO and the daily dose increased by 25 mg/week to 50 mg/week to a range of 200 mg/day to 300 mg/day in divided doses. The optimal dose range has not been established, and study results are conflicting. One study yielded positive results, with a higher proportion of cocaine nonuse (abstinent) days and urinary cocaine free weeks observed with use of topiramate vs. placebo , while other studies have not found topiramate to be more effective than placebo. In one small placebo-controlled trial (n = 40) of patients with low cocaine withdrawal symptom severity, patients randomized to topiramate (titrated to 200 mg/day by week 8) were more likely after week 8 to be cocaine-abstinent than placebo-treated patients as measured by twice weekly qualitative urine benzoylecgonine tests (UBTs). Continuous 3-week abstinence and Clinical Global Impression scale improvements were higher for topiramate than placebo (59% vs. 26%, and 71% vs. 32%, respectively). Topiramate-treated patients showed improvement in drug use problems and employment problems as measured by Addiction Severity Index (ASI) composite scores.

    For use as an adjunct agent in the maintenance treatment of bipolar disorder†.
    Oral dosage (immediate-release)
    Adults

    According to the Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines, there is level 3 evidence for use of topiramate as a third-line adjunct agent in the maintenance treatment of bipolar disorder; however, topiramate is not recommended as monotherapy for acute mania and is not recommended as monotherapy in the maintenance treatment of bipolar disorder. An effective dose range has not been established. If use of topiramate is necessary, it is advisable to initiate treatment with a low dose (e.g., 25 to 50 mg/day PO), and increase the daily dose in increments of 25 to 50 mg based on clinical response and tolerability.

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

    Case reports suggest a starting dose of 12.5 to 25 mg PO once daily titrating to 25 to 75 mg PO twice daily as tolerated may be effective. Higher doses of 150 to 400 mg PO twice daily have also been efficacious.

    †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.

    Oral Administration

    Topiramate may be given orally without regard to meals.
     

    Oral Solid Formulations

    Tablets: Because of the bitter taste, the tablets should not be broken.
    Sprinkle capsules: Swallow whole. Alternatively, the contents of the capsules may be sprinkled on a small amount of soft food (e.g., applesauce, custard, ice cream, oatmeal, pudding, or yogurt) for administration. Prepare entire dose and swallow immediately after preparation. Do not chew. Drink fluids to ensure entire dose is swallowed. Do not store any sprinkle/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. Because the extended release capsules must be swallowed whole and cannot be sprinkled on food, crushed or chewed, they are not recommended for children less than 6 years.
    Qudexy XR extended-release capsules: May be swallowed whole or the contents of the capsule may be sprinkled 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 for use at a later time.

    STORAGE

    Qudexy XR:
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Topamax:
    - Protect from moisture
    - 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 :
    - Protect from moisture
    - 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

    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. Cross-sensitivity between antibiotic sulfonamides and nonantibiotic sulfonamides, such as topiramate, is controversial. 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. Although topiramate is a simple sulfonamide, the sulfonamide structure is not directly connected to a ring structure, and it lacks an arylamine moiety. Some experts believe apparent cross-reactivity represents multiple concurrent and unlinked drug hypersensitivities in predisposed patients. 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.
     
    During pre-marketing evaluation of topiramate, 10 sudden unexplained deaths occurred among a cohort group (2,796 subject years of exposure), correlating to an incidence of 0.0035 deaths per patient year. This incidence exceeded the rate expected from a matched, healthy population; however, it was within the range of estimates for sudden unexplained deaths in patients with epilepsy who were not receiving topiramate.

    Depression, suicidal ideation

    In January 2008, the FDA alerted healthcare professionals of an increased risk of suicidal ideation and behavior in patients receiving anticonvulsants to treat epilepsy, psychiatric disorders, or other conditions (e.g., migraine, neuropathic pain). This alert followed an initial request by the FDA in March 2005 for manufacturers of marketed anticonvulsants to provide data from existing controlled clinical trials for analysis. Prior to this request, preliminary evidence had suggested a possible link between anticonvulsant use and suicidality. 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). There were 4 completed suicides among patients in drug treatment groups versus none in the placebo groups. Patients receiving anticonvulsants 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—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. Data were analyzed from drugs with adequately designed clinical trials including carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide. However, this is considered to be a class effect. All patients beginning treatment with anticonvulsants or currently receiving such treatment should be closely monitored for emerging or worsening depression or suicidal thoughts/behavior. Patients and caregivers should be informed of the increased risk of suicidal thoughts and behaviors and should be advised to immediately report the emergence or worsening of depression, the emergence of suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior. Anticonvulsants should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose.

    Abrupt discontinuation

    Abrupt discontinuation of topiramate therapy should not be undertaken. Topiramate and other antiepileptic drugs should be withdrawn gradually to minimize the potential of increased seizure frequency.

    Nephrolithiasis

    Topiramate should be used cautiously in patients with nephrolithiasis. Carbonic anhydrase inhibitors promote stone formation by reducing urinary citrate excretion and by increasing urinary pH. During clinical trials, 1.3—1.5% of topiramate-treated patients developed kidney stones. This incidence is about 2—4 times that expected in a similar, untreated population and was higher in men. The concomitant use of topiramate with other carbonic anhydrase inhibitors or in patients on a ketogenic diet may create a physiological environment that increases the risk of kidney stone formation, and should therefore be avoided. Patients who are receiving topiramate, especially those who have a history of kidney stones, should be instructed to maintain adequate fluid intake in order to reduce the formation of kidney stones.

    Chronic obstructive pulmonary disease (COPD), dialysis, diarrhea, emphysema, metabolic acidosis, renal disease, renal failure, renal impairment, status asthmaticus, status epilepticus, surgery

    Topiramate should be used cautiously in patients with renal failure or renal impairment because the major route of elimination of unchanged drug and its metabolites is the kidney. Dosage adjustments may be required (see Dosage). Because topiramate clearance is affected by both glomerular filtration rate and renal tubular reabsorption, there may be some patients with renal disease who do not need dosage adjustments based on creatinine clearance alone. In addition, patients receiving hemodialysis may need dose adjustments in relation to their dialysis sessions (see Dosage). Topiramate has been associated with metabolic acidosis in both adults and pediatrics (see Adverse Reactions) and patients with renal disease may be at greater risk for this complication. Other conditions that may predispose patients to acidosis [i.e., diarrhea, ketogenic diet, severe pulmonary disease (chronic obstructive pulmonary disease (COPD), emphysema, status asthmaticus), surgery, status epilepticus or administration with other bicarbonate-lowering drugs] may have an additive risk for this complication. Measurement of baseline and periodic serum bicarbonate is recommended during topiramate therapy. If metabolic acidosis occurs, consider reducing the dose or tapering the patient off of topiramate. Alkali treatment (i.e., oral sodium bicarbonate) should be considered if it is decided that the patient continue topiramate despite metabolic acidosis. Patients undergoing surgery that are being treated with topiramate should have a careful history taken preoperatively. Baseline blood chemistries should be measured before surgery to screen for asymptomatic metabolic acidosis.

    Hepatic disease

    Topiramate should be used with extreme caution in patients with hepatic disease, including cirrhosis. The clearance of topiramate may be decreased in hepatically impaired patients, although the mechanism is not well understood. There have been post-marketing reports of hepatic failure resulting in death.

    Children, growth inhibition, infants, neonates

    Safety and effectiveness of topiramate in neonates, infants and children below the age of 2 years have not been established. Although not FDA approved in this population, a controlled trial in infants and children less than 2 years of age demonstrated that the degree of metabolic acidosis caused by topiramate was notably greater in this population than that observed in trials of older children and adults, and the incidence was greater with higher doses. Related complications (i.e., growth inhibition, osteomalacia) may occur in pediatric patients with chronic metabolic acidosis. Some data in infants and toddlers with intractable partial seizures receiving topiramate showed reductions from baseline in Z SCORES for length, weight, and head circumference compared to age and sex-matched normative data; however, it should be noted that these patients with epilepsy are likely to have different growth rates than healthy infants. Reductions in Z SCORES for length and weight were correlated with the degree of acidosis. Pediatric patients receiving topiramate should be screened for asymptomatic metabolic acidosis prior to surgery. In clinical studies, the incidences of cognitive/neuropsychiatric adverse events in pediatric patients were generally lower than previously observed in adults.

    Driving or operating machinery

    Topiramate commonly causes somnolence, fatigue, dizziness and difficulty with concentration, particularly in the first month of therapy. Patients should be advised to use caution when driving or operating machinery, or performing other tasks that require mental alertness until they are aware of whether topiramate adversely affects their mental and/or motor performance. Clinicians should be aware that cognitive and neuropsychiatric events are among the most common adverse reactions seen with topiramate use. Confusion, psychomotor slowing, difficulties with memory or speech, depression, fatigue and somnolence are examples of the kind of cognitive and neuropsychiatric dose-related adverse events that can occur. Rapid dose titration and higher initial doses were associated with higher incidences of these events. Many of these events contributed to withdrawal from treatment in clinical trials. While cognitive and neuropsychiatric events do not appear to occur as frequently in the pediatric population, difficulty with concentration or attention was reported as the most common reason for discontinuation in pediatric patients in the monotherapy clinical trials (400 mg/day group).

    Closed-angle glaucoma, glaucoma, increased intraocular pressure, ocular disease, visual disturbance

    Use topiramate cautiously in patients with a history of glaucoma and/or ocular disease. A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in adult and pediatric patients receiving topiramate. Symptoms typically occur within 1 month of topiramate initiation and include acute onset visual disturbance and/or ocular pain. Ophthalmologic findings can include myopia, anterior chamber shallowing, ocular hyperemia (redness), increased intraocular pressure, mydriasis, and supraciliary effusion with anterior displacement of the lens and iris, with secondary closed-angle glaucoma. Visual field defects independent of elevated intraocular pressure have also been reported with topiramate. Patients experiencing ocular disturbances should seek immediate medical attention. Consideration should be given to discontinuing topiramate in an effort to reverse ocular symptoms. Other measures in conjunction with discontinuation of topiramate may be helpful. Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss.

    Ambient temperature increase

    Oligohidrosis and hyperthermia have been reported in post-marketing experience with topiramate; heat stroke may occur. All patients, especially children, should be instructed to limit exposure to ambient temperature increase (i.e., elevated environmental temperature) or other temperature extremes that might aggravate temperature regulation. To help prevent oligohidrosis and hyperthermia in patients treated with topiramate, proper hydration is suggested before and during strenuous activity or exposure to warm temperatures. Use caution when topiramate is prescribed with other drugs that predispose patients to heat-related disorders, such as drugs with anticholinergic activity, carbonic anhydrase inhibitors, and zonisamide. Since topiramate exhibits carbonic anhydrase inhibitor activity, use with other carbonic anhydrase inhibitors is not recommended.

    Encephalopathy, females, mitochondrial disease

    Hyperammonemia with and without encephalopathy has been reported with topiramate use and may be dose-related. Females, children under the age of 3 years, and those with inborn errors of metabolism, reduced hepatic mitochondrial activity (mitochondrial disease), or generalized tonic-clonic seizures may be at increased risk. Although hyperammonemia with and without encephalopathy has occurred with topiramate monotherapy, it appears to be more common with adjuvant valproate therapy. Concomitant administration of topiramate and valproate may exacerbate existing metabolic deficits or unmask deficiencies in susceptible persons, and has been associated with hyperammonemia in patients who have tolerated either drug alone. Monitor serum ammonia concentrations in patients who develop unexplained lethargy, vomiting, changes in mental status, or hypothermia. Patients who develop unexplained symptoms of hyperammonemia encephalopathy while receiving antiepileptic therapy should discontinue the afflicting drug and receive prompt treatment for hyperammonemia. In most cases, signs and symptoms abate with discontinuation of either topiramate or valproate.

    Geriatric

    In clinical trials, 3% of patients receiving topiramate were over 60 years of age. No age-related difference in effectiveness, adverse effects, or pharmacokinetics were seen in geriatric versus younger adults. However, the possibility of age-associated renal functional abnormalities should be considered. Because geriatric patients are at increased risk for renal insufficiency, an estimated GFR measurement should be obtained prior to dosing. 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, with the exception of treating seizure and mood disorders, since anticonvulsants can produce ataxia, impaired psychomotor function, syncope, and additional falls. If topiramate must be used, consider reducing use of other CNS-active medications that increase the risk of falls and fractures and implement other strategies to reduce fall risk. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities. According to the OBRA guidelines, some anticonvulsants may be used to treat disorders other than seizures (e.g., bipolar disorder, schizoaffective disorder, chronic neuropathic pain, migraine prevention). The need for indefinite continuation in treating any condition should be based on confirmation of the condition and its potential cause(s). Determining effectiveness and tolerability through evaluation of symptoms should be used to adjust doses. Therapeutic drug monitoring is not required or available for most anticonvulsants. In addition, significant signs and symptoms of toxicity can occur at normal or low serum concentrations, and symptom control for seizures or behavior can occur at subtherapeutic serum concentrations. Obtaining serum medication concentrations may assist in identifying toxicity. High or toxic serum concentrations should become a consideration for dosage adjustments. Anticonvulsants may cause liver dysfunction, blood dyscrasias, and serious skin rashes requiring treatment discontinuation. Anticonvulsants may also cause nausea/vomiting, dizziness, ataxia, somnolence/lethargy, incoordination, blurred or double vision, restlessness, toxic encephalopathy, anorexia, and headaches; these effects can increase the risk for 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 in accordance with OBRA guidelines.

    Autoimmune disease, diabetes mellitus, hypertension

    In patients at high risk for renal insufficiency (e.g., older patients, or those with diabetes mellitus, hypertension, or autoimmune disease), an estimated GFR measurement should be obtained prior to dosing.

    Bleeding, thrombocytopenia

    Topiramate should be used with caution in patients with thrombocytopenia or an increased risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported for topiramate (4.5% adults and 4.4% pediatrics) than for placebo (3% adults and 2.3% pediatrics); serious bleeding events occurred in 0.3% vs. 0.2% of adult patients and 0.4% vs. 0% of pediatric patients for those treated with topiramate and placebo, respectively. Adverse events reported ranged from mild epistaxis, ecchymosis, and increased menstrual bleeding to life-threatening hemorrhage. In those with serious events, risk factors for bleeding were often present, or patients were taking other drugs that cause thrombocytopenia or affect platelet function or coagulation. Patients should be instructed to promptly report any bleeding-related events to their practitioner.

    Labor, pregnancy

    Topiramate can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate infants exposed to topiramate during pregnancy have an increased risk for cleft lip and/or cleft palate and for being small for gestational age (SGA), defined as a birth weight < 10th percentile. 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. Women who are planning a pregnancy should be counseled regarding risks and benefits of topiramate use; alternative therapeutic options should be considered. According to registry data, the prevalence of SGA was 18% to 25% in topiramate-exposed infants compared to 7% in infants exposed to a reference antiepileptic agent (AED) and 5% to 9% in those without antiepileptic drug (AED) exposure. The prevalence of oral clefts was 1.2% compared to 0.39% to 0.46% in infants exposed to another AED. The relative risk of oral clefts in topiramate-exposed pregnancies was 9.6 (95% CI 4 to 23) compared to untreated women. Oral clefts develop in the first trimester before many women know that they are pregnant. Pregnancy registry data also suggest a possible association between the use of topiramate during pregnancy and congenital malformations such as craniofacial defects, hypospadias, and anomalies of various body systems. 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. 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. Women taking topiramate during pregnancy should be monitored for metabolic acidosis and treated as in the nonpregnant state. Newborns of mothers treated with topiramate should be monitored for metabolic acidosis after birth. Topiramate-treated patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. Patients must call 1-888-233-2334 to enroll in the registry. More information can be found at http://www.aedpregnancyregistry.org/.

    Breast-feeding

    Topiramate is excreted in human breast milk. The effects of topiramate on the breast-fed infant 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. Data from 5 breast-feeding infants has shown topiramate plasma concentrations of 10% to 20% of the maternal plasma concentration. 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.

    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
    Stevens-Johnson syndrome / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    pemphigus / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known

    Moderate

    hyperammonemia / Delayed / 0-26.0
    memory impairment / Delayed / 0-11.0
    nystagmus / Delayed / 10.0-11.0
    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
    dysuria / Early / 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
    hyperglycemia / Delayed / 0.1-1.0
    diabetes mellitus / Delayed / 0.1-1.0
    hypocalcemia / Delayed / 0.1-1.0
    dehydration / Delayed / 0.1-1.0
    hyperlipidemia / Delayed / 0.1-1.0
    hypoglycemia / Early / 1.0-1.0
    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
    hypernatremia / Delayed / 0-0.1
    hyponatremia / 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
    myopia / Delayed / Incidence not known
    hyperemia / Delayed / Incidence not known
    crystalluria / 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
    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
    xerosis / Delayed / 0-5.0
    flushing / Rapid / 0-5.0
    rash (unspecified) / 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
    lacrimation / Early / 1.0-1.0
    xerophthalmia / Early / 0.1-1.0
    pallor / Early / 0-1.0
    polyuria / Early / 0.1-1.0
    nocturia / Early / 0-1.0
    seborrhea / Delayed / 1.0-1.0
    drug-induced body odor / Delayed / 0-1.0
    photosensitivity / Delayed / 0.1-1.0
    skin discoloration / Delayed / 1.0-1.0
    urticaria / Rapid / 0.1-1.0
    hyperhidrosis / 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
    melasma / Delayed / 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
    diplopia / Early / 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.
    Abciximab: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates or 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 (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Acetaminophen; Dextromethorphan; Doxylamine: (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.
    Acetaminophen; Diphenhydramine: (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.
    Acetaminophen; Tramadol: (Moderate) Topiramate may contribute to the CNS depression seen with tramadol; tramadol may also decrease the seizure threshold in some patients and thus, potentially, interfere with the ability of anticonvulsants to control seizures.
    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: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree. (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: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree.
    Alogliptin; Metformin: (Major) Concurrent use of topiramate and metformin is contraindicated in patients with metabolic acidosis. Topiramate frequently causes metabolic acidosis, a condition for which the use of metformin is contraindicated. During a drug interaction study evaluating concurrent use of topiramate and metformin in healthy volunteers, the following changes in metformin pharmacokinetics were observed: the mean Cmax was increased by 17%, the mean AUC was increased by 25%, and the oral plasma clearance was decreased by 20%. The oral plasma clearance of topiramate was reduced, but the extent of the change is unknown.
    Alogliptin; Pioglitazone: (Moderate) Reductions in AUC and Cmax have been noted in pioglitazone and the active metabolites when coadministered with topiramate. The clinician may suggest that the patient more frequently monitor blood glucose when these drugs are added or deleted from therapy.
    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. Concurrent use of topiramate and benzodiazepines associated with thrombocytopenia (e.g., clonazepam, lorazepam, and clobazam), may also increase the risk of bleeding; monitor patients appropriately during benzodiazepine therapy.
    Amiloride; Hydrochlorothiazide, HCTZ: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree.
    Aminosalicylate sodium, Aminosalicylic acid: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Amitriptyline: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold. In addition, during concurrent use of topiramate and amitriptyline the Cmax and AUC of amitriptyline were increased by 12%. Dosage adjustments of amitriptyline may be needed based upon tolerability to the regimen during combined use of amitriptyline and topiramate.
    Amitriptyline; 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. Concurrent use of topiramate and benzodiazepines associated with thrombocytopenia (e.g., clonazepam, lorazepam, and clobazam), may also increase the risk of bleeding; monitor patients appropriately during benzodiazepine therapy. (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold. In addition, during concurrent use of topiramate and amitriptyline the Cmax and AUC of amitriptyline were increased by 12%. Dosage adjustments of amitriptyline may be needed based upon tolerability to the regimen during combined use of amitriptyline and topiramate.
    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; Hydrochlorothiazide, HCTZ; Olmesartan: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree. (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; Hydrochlorothiazide, HCTZ; Valsartan: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree. (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; Telmisartan: (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.
    Amoxapine: (Moderate) Amoxapine, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Some anticonvulsants, such as phenobarbital or carbamazepine, may potentially induce the metabolism of amoxapine as well. Monitor patients for side effects or altered responses to drug therapy.
    Amphetamines: (Major) Concurrent use of amphetamines and urinary alkalinizers, such as topiramate, should be avoided. Urinary alkalinizers diminish the urinary excretion of amphetamines by increasing the proportion of non-ionized amphetamines, resulting in increased renal tubular reabsorption of these compounds. The half-life and therapeutic actions of amphetamines will be prolonged in the presence of these drugs. In addition, patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary.
    Anagrelide: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates or 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 (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Anticholinergics: (Moderate) Use caution if carbonic anhydrase inhibitors are administered with anticholinergics and monitor for excessive anticholinergic adverse effects. The use of topiramate with agents that may increase the risk for heat-related disorders, such as anticholinergics, may lead to oligohidrosis, hyperthermia and/or heat stroke.
    Antithrombin III: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) 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.
    Anxiolytics; Sedatives; and Hypnotics: (Major) 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 (e.g., warfarin, enoxaparin, dabigatran) 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.
    Argatroban: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) 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.
    Aripiprazole: (Moderate) Because aripiprazole is partially metabolized by CYP3A4, concurrent use of CYP3A4 inducers such as topiramate may result in decreased plasma concentrations of aripiprazole. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. An increase in aripiprazole dosage may be clinically warranted in some patients. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. There are no dosing recommendations for Aristada during use of a mild to moderate CYP3A4 inducer.
    Aspirin, ASA: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Aspirin, ASA; Carisoprodol: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Aspirin, ASA; Dipyridamole: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation. (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates or 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 (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Aspirin, ASA; Omeprazole: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Aspirin, ASA; Oxycodone: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Aspirin, ASA; Pravastatin: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    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. (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Axitinib: (Moderate) Use caution if coadministration of axitinib with topiramate is necessary, due to the risk of decreased efficacy of axitinib. Axitinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1. Topiramate is a weak CYP3A4 inducer. Coadministration with a strong CYP3A4/5 inducer, rifampin, significantly decreased the plasma exposure of axitinib in healthy volunteers. Topiramate is also a weak CYP2C19 inhibitor, which theoretically could increase exposure to axitinib; however, the effects of topiramate on CYP2C19 are not expected to overcome its effects on CYP3A4, as CYP3A4 is the major route of metabolism for axitinib.
    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.
    Benazepril; Hydrochlorothiazide, HCTZ: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree.
    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. Concurrent use of topiramate and benzodiazepines associated with thrombocytopenia (e.g., clonazepam, lorazepam, and clobazam), may also increase the risk of bleeding; monitor patients appropriately during benzodiazepine therapy.
    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. (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Bismuth Subsalicylate: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree.
    Bivalirudin: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) 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.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering topiramate with boceprevir due to the potential for boceprevir treatment failure. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of topiramate and boceprevir. Topiramate is a weak inducer of the hepatic isoenzyme CYP3A4; boceprevir is a substrate of this isoenzyme. When used in combination, the plasma concentrations of boceprevir may decrease.
    Bosentan: (Moderate) Bosentan is a significant inducer of CYP2C9 hepatic isoenzymes.Theoretically, bosentan can increase the hepatic clearance of topiramate, a potential CYP2C9 substrate.
    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) Topiramate is a carbonic anhydrase inhibitor. Concurrent use of topiramate with non-potassium sparing diuretics (e.g., loop diuretics) may potentiate the potassium-wasting action of these diuretics. Monitor baseline and periodic potassium concentrations during coadministration.
    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.
    Bupropion: (Moderate) Bupropion should not be used by patients with a preexisting seizure disorder because it may lower the seizure threshold. Bupropion may also interact pharmacokinetically with anticonvulsant drugs that induce hepatic microsomal isoenzyme function such as carbamazepine, barbiturates, or phenytoin, as well as fosphenytoin and ethotoin.
    Bupropion; Naltrexone: (Moderate) Bupropion should not be used by patients with a preexisting seizure disorder because it may lower the seizure threshold. Bupropion may also interact pharmacokinetically with anticonvulsant drugs that induce hepatic microsomal isoenzyme function such as carbamazepine, barbiturates, or phenytoin, as well as fosphenytoin and ethotoin.
    Buspirone: (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.
    Cabazitaxel: (Moderate) Cabazitaxel is a CYP3A4 substrate and concomitant use with CYP3A4 inducers such as topiramate may lead to reduced concentrations of cabazitaxel. Caution should be utilized when CYP3A4 inducers are coadministered with cabazitaxel, and alternative therapies with low enzyme induction potential should be considered.
    Canagliflozin; Metformin: (Major) Concurrent use of topiramate and metformin is contraindicated in patients with metabolic acidosis. Topiramate frequently causes metabolic acidosis, a condition for which the use of metformin is contraindicated. During a drug interaction study evaluating concurrent use of topiramate and metformin in healthy volunteers, the following changes in metformin pharmacokinetics were observed: the mean Cmax was increased by 17%, the mean AUC was increased by 25%, and the oral plasma clearance was decreased by 20%. The oral plasma clearance of topiramate was reduced, but the extent of the change is unknown.
    Candesartan; Hydrochlorothiazide, HCTZ: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree.
    Captopril; Hydrochlorothiazide, HCTZ: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree.
    Carbamazepine: (Moderate) Although topiramate is not extensively metabolized (70% renally eliminated), hepatic enzyme inducers. such as carbamazepine, have been shown to reduce topiramate serum concentrations. In patients receiving carbamazepine with topiramate, plasma concentrations of topiramate were decreased by 40% with < 10% change in carbamazepine plasma concentrations. Concurrent use of topiramate and drugs that cause thrombocytopenia, such as carbamazepine and oxcarbazepine, may also increase the risk of bleeding; monitor patients appropriately.
    Carbetapentane; Diphenhydramine; Phenylephrine: (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.
    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: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    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. Concurrent use of topiramate and benzodiazepines associated with thrombocytopenia (e.g., clonazepam, lorazepam, and clobazam), may also increase the risk of bleeding; monitor patients appropriately during benzodiazepine therapy.
    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. Concurrent use of topiramate and benzodiazepines associated with thrombocytopenia (e.g., clonazepam, lorazepam, and clobazam), may also increase the risk of bleeding; monitor patients appropriately during benzodiazepine therapy.
    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.
    Chlorpromazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Choline Salicylate; Magnesium Salicylate: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    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) The plasma concentration of citalopram, a CYP2C19 substrate, may be increased when administered concurrently with topiramate, a CYP2C19 inhibitor. Because citalopram causes dose-dependent QT prolongation, the maximum daily dose should not exceed 20 mg per day in patients receiving CYP2C19 inhibitors. In addition, concurrent use of topiramate and drugs that affect platelet function such as selective serotonin reuptake inhibitors (SSRIs) 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Clomipramine: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold. In addition, during concurrent use of topiramate and amitriptyline the Cmax and AUC of amitriptyline were increased by 12%. Dosage adjustments of amitriptyline may be needed based upon tolerability to the regimen during combined use of amitriptyline and topiramate.
    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. Concurrent use of topiramate and benzodiazepines associated with thrombocytopenia (e.g., clonazepam, lorazepam, and clobazam), may also increase the risk of bleeding; monitor patients appropriately during benzodiazepine therapy.
    Clopidogrel: (Major) Topiramate may reduce the antiplatelet activity of clopidogrel by inhibiting clopidogrel's metabolism to its active metabolite. Use clopidogrel and topiramate together with caution and monitor for reduced efficacy of clopidogrel. Clopidogrel requires hepatic biotransformation via 2 cytochrome dependent oxidative steps; the CYP2C19 isoenzyme is involved in both steps. Topiramate is an inhibitor of CYP2C19.
    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. Concurrent use of topiramate and benzodiazepines associated with thrombocytopenia (e.g., clonazepam, lorazepam, and clobazam), may also increase the risk of bleeding; monitor patients appropriately during benzodiazepine therapy.
    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.
    Cobicistat; Elvitegravir; 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.
    Cobicistat; Elvitegravir; 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.
    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.
    Conjugated Estrogens; Medroxyprogesterone: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. 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. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. 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 may also be needed.
    Dabigatran: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) 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.
    Dapagliflozin; Metformin: (Major) Concurrent use of topiramate and metformin is contraindicated in patients with metabolic acidosis. Topiramate frequently causes metabolic acidosis, a condition for which the use of metformin is contraindicated. During a drug interaction study evaluating concurrent use of topiramate and metformin in healthy volunteers, the following changes in metformin pharmacokinetics were observed: the mean Cmax was increased by 17%, the mean AUC was increased by 25%, and the oral plasma clearance was decreased by 20%. The oral plasma clearance of topiramate was reduced, but the extent of the change is unknown.
    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.
    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) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold. In addition, during concurrent use of topiramate and amitriptyline the Cmax and AUC of amitriptyline were increased by 12%. Dosage adjustments of amitriptyline may be needed based upon tolerability to the regimen during combined use of amitriptyline and topiramate.
    Desirudin: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) 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.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (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.
    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. Concurrent use of topiramate and benzodiazepines associated with thrombocytopenia (e.g., clonazepam, lorazepam, and clobazam), may also increase the risk of bleeding; monitor patients appropriately during benzodiazepine therapy.
    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.
    Diclofenac: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Diclofenac; Misoprostol: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Dienogest; Estradiol valerate: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. 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. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. 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 may also be needed.
    Diflunisal: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    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) Coadministrator topiramate with diltiazem with caution. Concomitant administration 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. Monitor for loss of diltiazem efficacy and or increased adverse events coming from the topiramate component of phentermine;topiramate.
    Diphenhydramine: (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.
    Diphenhydramine; Hydrocodone; Phenylephrine: (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.
    Diphenhydramine; Ibuprofen: (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. (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Diphenhydramine; Naproxen: (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. (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Diphenhydramine; Phenylephrine: (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.
    Dipyridamole: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates or 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 (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    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; 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.
    Doxepin: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold. In addition, during concurrent use of topiramate and amitriptyline the Cmax and AUC of amitriptyline were increased by 12%. Dosage adjustments of amitriptyline may be needed based upon tolerability to the regimen during combined use of amitriptyline and topiramate.
    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: (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.
    Doxylamine; Pyridoxine: (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.
    Dronabinol, THC: (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; Estradiol: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. 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. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. 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 may also be needed.
    Drospirenone; Ethinyl Estradiol: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. 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. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. 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 may also be needed.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. 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. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. 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 may also be needed.
    Edoxaban: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) 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.
    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.
    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; Metformin: (Major) Concurrent use of topiramate and metformin is contraindicated in patients with metabolic acidosis. Topiramate frequently causes metabolic acidosis, a condition for which the use of metformin is contraindicated. During a drug interaction study evaluating concurrent use of topiramate and metformin in healthy volunteers, the following changes in metformin pharmacokinetics were observed: the mean Cmax was increased by 17%, the mean AUC was increased by 25%, and the oral plasma clearance was decreased by 20%. The oral plasma clearance of topiramate was reduced, but the extent of the change is unknown.
    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: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree.
    Eptifibatide: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates or 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 (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Erlotinib: (Major) Avoid the coadministration of erlotinib with topiramate if possible due to the risk of decreased erlotinib efficacy; if concomitant use is unavoidable, the manufacturer recommends increasing the dose of erlotinib by 50 mg increments at 2-week intervals, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Topiramate is a weak CYP3A4 inducer. Coadministration with topiramate decreased the AUC and Cmax of another CYP3A4 substrate, diltiazem, by 25% and 10%, respectively. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with topiramate may also decrease erlotinib exposure.
    Esomeprazole; Naproxen: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    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. Concurrent use of topiramate and benzodiazepines associated with thrombocytopenia (e.g., clonazepam, lorazepam, and clobazam), may also increase the risk of bleeding; monitor patients appropriately during benzodiazepine therapy.
    Estradiol Cypionate; Medroxyprogesterone: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. 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. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. 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 may also be needed.
    Estradiol; Levonorgestrel: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. 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. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. 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 may also be needed.
    Estradiol; Norethindrone: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. 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. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. 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 may also be needed.
    Estradiol; Norgestimate: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. 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. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. 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 may also be needed.
    Estrogens: (Major) Topiramate can increase the clearance of estrogens and compromise the efficacy of estrogens used as hormone replacement therapies or contraceptives. Patients taking oral contraceptives, non-oral combination contraceptives, or progestions for contraception or patients taking estrogens or progestins for hormone replacement therapy should report changes in their bleeding patterns to their prescribers. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of the products may need adjustment; the manufacturer of topiramate recommends that an oral contraceptive containing 50 mcg of ethinyl estradiol be used. Different or additional forms of contraception may also be needed.
    Ethacrynic Acid: (Moderate) Topiramate is a carbonic anhydrase inhibitor. Concurrent use of topiramate with non-potassium sparing diuretics (e.g., loop diuretics) may potentiate the potassium-wasting action of these diuretics. Monitor baseline and periodic potassium concentrations during coadministration.
    Ethanol: (Major) Ethanol consumption is contraindicated within 6 hours prior to and 6 hours after administration of topiramate extended-release capsules. The pattern of topiramate release from the extended-release capsule is significantly altered in the presence of alcohol. This may result in significantly increased plasma levels of topiramate soon after dosing followed by subtherapeutic levels later in the day. Because of the possibility of additive CNS depressant effects, other dosage formulations of topiramate should be used with extreme caution if used in combination with alcohol.
    Ethinyl Estradiol; Desogestrel: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. 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. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. 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 may also be needed.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. 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. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. 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 may also be needed.
    Ethinyl Estradiol; Etonogestrel: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. 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. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. 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 may also be needed.
    Ethinyl Estradiol; Levonorgestrel: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. 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. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. 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 may also be needed.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. 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. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. 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 may also be needed.
    Ethinyl Estradiol; Norelgestromin: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. 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. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. 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 may also be needed.
    Ethinyl Estradiol; Norethindrone Acetate: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. 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. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. 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 may also be needed.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. 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. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. 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 may also be needed.
    Ethinyl Estradiol; Norethindrone: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. 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. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. 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 may also be needed.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. 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. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. 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 may also be needed.
    Ethinyl Estradiol; Norgestimate: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. 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. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. 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 may also be needed.
    Ethinyl Estradiol; Norgestrel: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. 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. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. 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 may also be needed.
    Etodolac: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Etonogestrel: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. 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. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. 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 may also be needed.
    Etoposide, VP-16: (Moderate) Monitor for clinical efficacy of etoposide if used concomitantly with topiramate. Topiramate is a weak inducer of CYP3A4; etoposide, VP-16 is a CYP3A4 substrate. Coadministration of etoposide with a strong CYP3A4 inducer (phenytoin) resulted in increased etoposide clearance and reduced efficacy, as did coadministration with a weak inducer of CYP3A4 and P-glycoprotein (P-gp) (valproic acid).
    Ezogabine: (Moderate) Concurrent use of topiramate and drugs that cause thrombocytopenia such as the anticonvulsant ezogabine, 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.
    Famotidine; Ibuprofen: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Felbamate: (Moderate) Concurrent use of topiramate and drugs that cause thrombocytopenia such as the anticonvulsant felbamate 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Fenoprofen: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    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.
    Fluoxetine: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as selective serotonin reuptake inhibitors (SSRIs) like fluoxetine 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Fluoxetine; Olanzapine: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as selective serotonin reuptake inhibitors (SSRIs) like fluoxetine 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Fluphenazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    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. Concurrent use of topiramate and benzodiazepines associated with thrombocytopenia (e.g., clonazepam, lorazepam, and clobazam), may also increase the risk of bleeding; monitor patients appropriately during benzodiazepine therapy.
    Flurbiprofen: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Fluvoxamine: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as selective serotonin reuptake inhibitors (SSRIs) like fluvoxamine 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Fondaparinux: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) 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.
    Food: (Moderate) Topiramate may influence the pharmacokinetic profile of cannabinoids in Marijuana and may also influence the pharmacodynamic profile. This may result in an altered adverse event profile of one or both drugs. Topiramate is an inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (THC). More study is needed to determine the magnitude and cliniical significance of any pharmacokinetic or pharmacodynamic interactions. Additive drowsiness and CNS depression is possible. Monitor for changes in moods or behaviors, or for other CNS effects.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree.
    Furosemide: (Moderate) Topiramate is a carbonic anhydrase inhibitor. Concurrent use of topiramate with non-potassium sparing diuretics (e.g., loop diuretics) may potentiate the potassium-wasting action of these diuretics. Monitor baseline and periodic potassium concentrations during coadministration.
    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%.
    Glimepiride; Pioglitazone: (Moderate) Reductions in AUC and Cmax have been noted in pioglitazone and the active metabolites when coadministered with topiramate. The clinician may suggest that the patient more frequently monitor blood glucose when these drugs are added or deleted from therapy.
    Glipizide; Metformin: (Major) Concurrent use of topiramate and metformin is contraindicated in patients with metabolic acidosis. Topiramate frequently causes metabolic acidosis, a condition for which the use of metformin is contraindicated. During a drug interaction study evaluating concurrent use of topiramate and metformin in healthy volunteers, the following changes in metformin pharmacokinetics were observed: the mean Cmax was increased by 17%, the mean AUC was increased by 25%, and the oral plasma clearance was decreased by 20%. The oral plasma clearance of topiramate was reduced, but the extent of the change is unknown.
    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: (Major) Concurrent use of topiramate and metformin is contraindicated in patients with metabolic acidosis. Topiramate frequently causes metabolic acidosis, a condition for which the use of metformin is contraindicated. During a drug interaction study evaluating concurrent use of topiramate and metformin in healthy volunteers, the following changes in metformin pharmacokinetics were observed: the mean Cmax was increased by 17%, the mean AUC was increased by 25%, and the oral plasma clearance was decreased by 20%. The oral plasma clearance of topiramate was reduced, but the extent of the change is unknown. (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.
    Heparin: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) 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.
    Hydantoins: (Moderate) Although topiramate is not extensively metabolized (70% renally eliminated), hepatic enzyme inducers, such as 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 < 10% in phenytoin plasma concentrations. A similar reaction would be expected with fosphenytoin or ethotoin. Concurrent use of topiramate and drugs that cause thrombocytopenia, such as the hydantoins, may also increase the risk of bleeding; monitor patients appropriately.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree.
    Hydrochlorothiazide, HCTZ: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree.
    Hydrochlorothiazide, HCTZ; Irbesartan: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree.
    Hydrochlorothiazide, HCTZ; Losartan: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree.
    Hydrochlorothiazide, HCTZ; Moexipril: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree.
    Hydrochlorothiazide, HCTZ; Olmesartan: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree.
    Hydrochlorothiazide, HCTZ; Propranolol: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree.
    Hydrochlorothiazide, HCTZ; Quinapril: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree.
    Hydrochlorothiazide, HCTZ; Spironolactone: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree.
    Hydrochlorothiazide, HCTZ; Telmisartan: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree.
    Hydrochlorothiazide, HCTZ; Triamterene: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree.
    Hydrochlorothiazide, HCTZ; Valsartan: (Major) Concurrent use or topiramate, a carbonic anhydrase inhibitor, with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Additionally, the addition of HCTZ to topiramate therapy may require a reduction in the topiramate dose. Alternatively, the discontinuation of HCTZ therapy may require a dose increase in topiramate. In a pharmacokinetic drug interaction study, the topiramate Cmax and AUC increased by 27% and 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The steady-state pharmacokinetics of HCTZ were not altered to any significant degree.
    Hydrocodone; Ibuprofen: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Hydroxychloroquine: (Moderate) Caution is warranted with the coadministration of hydroxychloroquine and antiepileptic drugs, such as topiramate. Hydroxychloroquine can lower the seizure threshold; therefore, the activity of antiepileptic drugs may be impaired with concomitant use.
    Hydroxyprogesterone: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. 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. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. 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 may also be needed.
    Hydroxyzine: (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.
    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. (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Ibuprofen: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Ibuprofen; Oxycodone: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Ibuprofen; Pseudoephedrine: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    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) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold. In addition, during concurrent use of topiramate and amitriptyline the Cmax and AUC of amitriptyline were increased by 12%. Dosage adjustments of amitriptyline may be needed based upon tolerability to the regimen during combined use of amitriptyline and topiramate.
    Indomethacin: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    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.
    Ivabradine: (Major) Avoid coadministration of ivabradine and topiramate. Ivabradine is primarily metabolized by CYP3A4; topiramte is a weak inducer of CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
    Ivacaftor: (Moderate) Use caution when administering ivacaftor and topiramate concurrently; the clinical impact of this interaction has not yet been determined. Ivacaftor is a CYP3A substrate and topiramate is a weak CYP3A inducer. Administration of ivacaftor with strong CYP3A inducers is not recommended because sub-therapeutic ivacaftor exposure could result; the impact of mild inducers is not known.
    Kava Kava, Piper methysticum: (Major) The German Commission E warns that any substances that act on the CNS, including anticonvulsants, may interact with kava kava. While the interactions can be pharmacodynamic in nature, kava kava has been reported to inhibit many CYP isozymes (i.e., CYP1A2, 2C9, 2C19, 2D6, 3A4, and 4A9/11) and important pharmacokinetic interactions with CNS-active agents that undergo oxidative metabolism via these CYP isozymes are also possible. Persons taking an anticonvulsant should discuss the use of herbal supplements with their health care professional prior to consuming them.
    Ketoprofen: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Ketorolac: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Lamotrigine: (Moderate) Use caution when coadministering lamotrigine and topiramate. Concurrent use of topiramate and drugs that cause thrombocytopenia, such as lamotrigine, may increase the risk of bleeding. In pediatric patients who underwent craniotomy for epilepsy surgery (n = 84), treatment for confirmed or suspected coagulopathy was required in 5 of 7 patients taking a regimen of topiramate and lamotrigine, approximately one-third of the overall study population requiring blood products. Concurrent use may also result in significant CNS depression. Further, co-administration of topiramate and lamotrigine resulted in a 13% decrease in topiramate concentration; however, the clinical significance of this finding is unknown. Plasma concentrations of lamotrigine do not appear to be affected by the combined use of the drugs.
    Lansoprazole; Naproxen: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Lepirudin: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) 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.
    Leuprolide; Norethindrone: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. 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. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. 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 may also be needed.
    Levetiracetam: (Moderate) Concurrent use of topiramate and drugs that cause thrombocytopenia such as the anticonvulsant levetiracetam, 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Levonorgestrel: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. 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. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. 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 may also be needed.
    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.
    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) Concurrent use of topiramate and metformin is contraindicated in patients with metabolic acidosis. Topiramate frequently causes metabolic acidosis, a condition for which the use of metformin is contraindicated. During a drug interaction study evaluating concurrent use of topiramate and metformin in healthy volunteers, the following changes in metformin pharmacokinetics were observed: the mean Cmax was increased by 17%, the mean AUC was increased by 25%, and the oral plasma clearance was decreased by 20%. The oral plasma clearance of topiramate was reduced, but the extent of the change is unknown. (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.
    Lithium: (Moderate) In patients, the pharmacokinetics of lithium were unaffected during treatment with topiramate at doses of 200 mg/day; however, there was an observed increase in systemic exposure of lithium (27% for Cmax and 26% for AUC) following topiramate doses up to 600 mg/day. Lithium levels should be monitored; monitor patients for adequate control of symptoms when phentermine; topiramate is added to lithium therapy.
    Loop diuretics: (Moderate) Topiramate is a carbonic anhydrase inhibitor. Concurrent use of topiramate with non-potassium sparing diuretics (e.g., loop diuretics) may potentiate the potassium-wasting action of these diuretics. Monitor baseline and periodic potassium concentrations during coadministration.
    Loperamide: (Moderate) The plasma concentration and efficacy of loperamide may be reduced when administered concurrently with topiramate. Loperamide is metabolized by the hepatic enzyme CYP3A4; topiramate is a mild inducer of this enzyme.
    Loperamide; Simethicone: (Moderate) The plasma concentration and efficacy of loperamide may be reduced when administered concurrently with topiramate. Loperamide is metabolized by the hepatic enzyme CYP3A4; topiramate is a mild inducer of this enzyme.
    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. Concurrent use of topiramate and benzodiazepines associated with thrombocytopenia (e.g., clonazepam, lorazepam, and clobazam), may also increase the risk of bleeding; monitor patients appropriately during benzodiazepine therapy.
    Low Molecular Weight Heparins: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) 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.
    Lumacaftor; Ivacaftor: (Moderate) Use caution when administering ivacaftor and topiramate concurrently; the clinical impact of this interaction has not yet been determined. Ivacaftor is a CYP3A substrate and topiramate is a weak CYP3A inducer. Administration of ivacaftor with strong CYP3A inducers is not recommended because sub-therapeutic ivacaftor exposure could result; the impact of mild inducers is not known.
    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.
    Magnesium Salicylate: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    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.
    Meclofenamate Sodium: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Medroxyprogesterone: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. 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. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. 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 may also be needed.
    Mefenamic Acid: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Mefloquine: (Moderate) Coadministration of mefloquine and anticonvulsants may result in lower than expected anticonvulsant concentrations and loss of seizure control. Monitoring of the anticonvulsant serum concentration is recommended. Dosage adjustments may be required during and after therapy with mefloquine.
    Megestrol: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. 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. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. 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 may also be needed.
    Meloxicam: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Mesoridazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Mestranol; Norethindrone: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. 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. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. 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 may also be needed.
    Metformin: (Major) Concurrent use of topiramate and metformin is contraindicated in patients with metabolic acidosis. Topiramate frequently causes metabolic acidosis, a condition for which the use of metformin is contraindicated. During a drug interaction study evaluating concurrent use of topiramate and metformin in healthy volunteers, the following changes in metformin pharmacokinetics were observed: the mean Cmax was increased by 17%, the mean AUC was increased by 25%, and the oral plasma clearance was decreased by 20%. The oral plasma clearance of topiramate was reduced, but the extent of the change is unknown.
    Metformin; Pioglitazone: (Major) Concurrent use of topiramate and metformin is contraindicated in patients with metabolic acidosis. Topiramate frequently causes metabolic acidosis, a condition for which the use of metformin is contraindicated. During a drug interaction study evaluating concurrent use of topiramate and metformin in healthy volunteers, the following changes in metformin pharmacokinetics were observed: the mean Cmax was increased by 17%, the mean AUC was increased by 25%, and the oral plasma clearance was decreased by 20%. The oral plasma clearance of topiramate was reduced, but the extent of the change is unknown. (Moderate) Reductions in AUC and Cmax have been noted in pioglitazone and the active metabolites when coadministered with topiramate. The clinician may suggest that the patient more frequently monitor blood glucose when these drugs are added or deleted from therapy.
    Metformin; Repaglinide: (Major) Concurrent use of topiramate and metformin is contraindicated in patients with metabolic acidosis. Topiramate frequently causes metabolic acidosis, a condition for which the use of metformin is contraindicated. During a drug interaction study evaluating concurrent use of topiramate and metformin in healthy volunteers, the following changes in metformin pharmacokinetics were observed: the mean Cmax was increased by 17%, the mean AUC was increased by 25%, and the oral plasma clearance was decreased by 20%. The oral plasma clearance of topiramate was reduced, but the extent of the change is unknown.
    Metformin; Rosiglitazone: (Major) Concurrent use of topiramate and metformin is contraindicated in patients with metabolic acidosis. Topiramate frequently causes metabolic acidosis, a condition for which the use of metformin is contraindicated. During a drug interaction study evaluating concurrent use of topiramate and metformin in healthy volunteers, the following changes in metformin pharmacokinetics were observed: the mean Cmax was increased by 17%, the mean AUC was increased by 25%, and the oral plasma clearance was decreased by 20%. The oral plasma clearance of topiramate was reduced, but the extent of the change is unknown.
    Metformin; Saxagliptin: (Major) Concurrent use of topiramate and metformin is contraindicated in patients with metabolic acidosis. Topiramate frequently causes metabolic acidosis, a condition for which the use of metformin is contraindicated. During a drug interaction study evaluating concurrent use of topiramate and metformin in healthy volunteers, the following changes in metformin pharmacokinetics were observed: the mean Cmax was increased by 17%, the mean AUC was increased by 25%, and the oral plasma clearance was decreased by 20%. The oral plasma clearance of topiramate was reduced, but the extent of the change is unknown.
    Metformin; Sitagliptin: (Major) Concurrent use of topiramate and metformin is contraindicated in patients with metabolic acidosis. Topiramate frequently causes metabolic acidosis, a condition for which the use of metformin is contraindicated. During a drug interaction study evaluating concurrent use of topiramate and metformin in healthy volunteers, the following changes in metformin pharmacokinetics were observed: the mean Cmax was increased by 17%, the mean AUC was increased by 25%, and the oral plasma clearance was decreased by 20%. The oral plasma clearance of topiramate was reduced, but the extent of the change is unknown.
    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.
    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. Concurrent use of topiramate and benzodiazepines associated with thrombocytopenia (e.g., clonazepam, lorazepam, and clobazam), may also increase the risk of bleeding; monitor patients appropriately during benzodiazepine therapy.
    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.
    Nabumetone: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Naproxen: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Naproxen; Pseudoephedrine: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Naproxen; Sumatriptan: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Nintedanib: (Major) Coadministration of nintedanib with CYP3A4 inducers such as topiramate should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy. Topiramate is a mild CYP3A4 inducer and nintedanib is a minor substrate of CYP3A4.
    Nonsteroidal antiinflammatory drugs: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Norethindrone: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. 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. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. 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 may also be needed.
    Norgestrel: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. 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. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. 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 may also be needed.
    Nortriptyline: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold. In addition, during concurrent use of topiramate and amitriptyline the Cmax and AUC of amitriptyline were increased by 12%. Dosage adjustments of amitriptyline may be needed based upon tolerability to the regimen during combined use of amitriptyline and topiramate.
    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.
    Orlistat: (Moderate) Seizures have been reported in patients treated concomitantly with orlistat and anticonvulsants. Patients should be monitored for possible changes in the frequency and/or severity of convulsions. A mechanism for the potential interaction has not been stated.
    Oxaprozin: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    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. Concurrent use of topiramate and benzodiazepines associated with thrombocytopenia (e.g., clonazepam, lorazepam, and clobazam), may also increase the risk of bleeding; monitor patients appropriately during benzodiazepine therapy.
    Oxcarbazepine: (Moderate) Coadministration of carbamazepine has resulted in a clinically significant decrease in topiramate exposure; a topiramate dosage increase may be necessary. Additionally, concurrent use of topiramate and drugs that cause thrombocytopenia, such as carbamazepine, may also increase the risk of bleeding; monitor patients appropriately.
    Paroxetine: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as selective serotonin reuptake inhibitors (SSRIs) like paroxetine 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    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.
    Pemoline: (Major) A reduction in seizure threshold has been reported following concomitant administration of pemoline with anticonvulsant agents. Dosage adjustments of anticonvulsants may be necessary during simultaneous use of these drugs.
    Pentosan: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) 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.
    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) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Perphenazine; Amitriptyline: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added. (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold. In addition, during concurrent use of topiramate and amitriptyline the Cmax and AUC of amitriptyline were increased by 12%. Dosage adjustments of amitriptyline may be needed based upon tolerability to the regimen during combined use of amitriptyline and topiramate.
    Phenothiazines: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Pioglitazone: (Moderate) Reductions in AUC and Cmax have been noted in pioglitazone and the active metabolites when coadministered with topiramate. The clinician may suggest that the patient more frequently monitor blood glucose when these drugs are added or deleted from therapy.
    Piroxicam: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Prasugrel: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates or 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 (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Pregabalin: (Moderate) Concurrent use of topiramate and drugs that cause thrombocytopenia such as the anticonvulsant pregabalin, 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    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.
    Prochlorperazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Progesterone: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. 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. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. 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 may also be needed.
    Progestins: (Major) Topiramate may increase the clearance and compromise the efficacy of progestins used in contraception or hormone replacement therapies. 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. However, pregnancy has been reported in patients who are using hormonal-containing contraceptives and taking hepatic enzyme inducers like topiramate. Patients taking progestin-containing contraceptives or patients taking progestins for hormone replacement therapy (HRT) should report changes in their bleeding patterns to their prescribers. 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 may also be needed.
    Protriptyline: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold. In addition, during concurrent use of topiramate and amitriptyline the Cmax and AUC of amitriptyline were increased by 12%. Dosage adjustments of amitriptyline may be needed based upon tolerability to the regimen during combined use of amitriptyline and topiramate.
    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. Concurrent use of topiramate and benzodiazepines associated with thrombocytopenia (e.g., clonazepam, lorazepam, and clobazam), may also increase the risk of bleeding; monitor patients appropriately during benzodiazepine therapy.
    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.
    Ribociclib: (Moderate) Use caution if coadministration of ribociclib with topiramate is necessary, as the systemic exposure of ribociclib may decrease resulting in decreased efficacy. Ribociclib is extensively metabolized by CYP3A4 and topiramate is a weak CYP3A4 inducer.
    Ribociclib; Letrozole: (Moderate) Use caution if coadministration of ribociclib with topiramate is necessary, as the systemic exposure of ribociclib may decrease resulting in decreased efficacy. Ribociclib is extensively metabolized by CYP3A4 and topiramate is a weak CYP3A4 inducer.
    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.
    Rivaroxaban: (Moderate) Concurrent use of topiramate and anticoagulants 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. However, coadministration of rivaroxaban and topiramate may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Topiramate is a mild inducer of CYP3A4, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs of bleeding or lack of efficacy of rivaroxaban.
    Rofecoxib: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    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.
    Rufinamide: (Moderate) Concurrent use of topiramate and drugs that cause thrombocytopenia such as the anticonvulsant rufinamide, 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 to3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Salicylates: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Salsalate: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Sertraline: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as selective serotonin reuptake inhibitors (SSRIs) like topiramate 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    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.
    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.
    Sulindac: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Tamoxifen: (Major) Topiramate is a CYP3A4 inducer and a weak CYP2C19 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Topiramate may affect the metabolism of tamoxifen to these metabolites; plasma concentrations of tamoxifen its active metabolites have been reduced when coadministered other CYP3A4 inducers. The clinical significance of this interaction is not known. If coadministration is necessary, monitor for tamoxifen efficacy.
    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.
    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. Concurrent use of topiramate and benzodiazepines associated with thrombocytopenia (e.g., clonazepam, lorazepam, and clobazam), may also increase the risk of bleeding; monitor patients appropriately during benzodiazepine therapy.
    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) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Thioridazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Thrombin Inhibitors: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) 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.
    Tiagabine: (Moderate) Concurrent use of topiramate and drugs that cause thrombocytopenia such as the anticonvulsant tiagabine, 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Ticagrelor: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates or 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 (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Ticlopidine: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates or 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 (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Tirofiban: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates or 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 (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Tolmetin: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    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.
    Tolvaptan: (Major) Tolvaptan is metabolized by CYP3A4. Topiramate is an inducer of CYP3A4. Coadministration may result in reduced plasma concentration and subsequent reduced effectiveness of tolvaptan therapy and should be avoided. If coadministration is unavoidable, an increase in the tolvaptan dose may be necessary and patients should be monitored for decreased effectiveness of tolvaptan.
    Torsemide: (Moderate) Topiramate is a carbonic anhydrase inhibitor. Concurrent use of topiramate with non-potassium sparing diuretics (e.g., loop diuretics) may potentiate the potassium-wasting action of these diuretics. Monitor baseline and periodic potassium concentrations during coadministration.
    Tramadol: (Moderate) Topiramate may contribute to the CNS depression seen with tramadol; tramadol may also decrease the seizure threshold in some patients and thus, potentially, interfere with the ability of anticonvulsants to control seizures.
    Trazodone: (Moderate) Trazodone can lower the seizure threshold of anticonvulsants, although the overall risk is low at therapeutic doses. Patients may require increased concentrations of anticonvulsants to achieve equivalent effects if trazodone is added.
    Tretinoin, ATRA: (Moderate) Topiramate may increase the CYP450 metabolism of tretinoin, ATRA, potentially resulting in decreased plasma concentrations of tretinoin, ATRA. Monitor for decreased clinical effects of tretinoin, ATRA while receiving concomitant therapy.
    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. Concurrent use of topiramate and benzodiazepines associated with thrombocytopenia (e.g., clonazepam, lorazepam, and clobazam), may also increase the risk of bleeding; monitor patients appropriately during benzodiazepine therapy.
    Tricyclic antidepressants: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold. In addition, during concurrent use of topiramate and amitriptyline the Cmax and AUC of amitriptyline were increased by 12%. Dosage adjustments of amitriptyline may be needed based upon tolerability to the regimen during combined use of amitriptyline and topiramate.
    Trifluoperazine: (Moderate) The phenothiazines, when used concomitantly with anticonvulsants, can lower the seizure threshold. Adequate dosages of anticonvulsants should be continued when a phenothiazine is added.
    Trimipramine: (Moderate) Tricyclic antidepressants, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold. In addition, during concurrent use of topiramate and amitriptyline the Cmax and AUC of amitriptyline were increased by 12%. Dosage adjustments of amitriptyline may be needed based upon tolerability to the regimen during combined use of amitriptyline and topiramate.
    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: (Moderate) Ulipristal is a substrate of CYP3A4 and topiramate is a CYP3A4 inducer. Concomitant use may decrease the plasma concentration and effectiveness of ulipristal.
    Valdecoxib: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as NSAIDs 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 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Valproic Acid, Divalproex Sodium: (Major) 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.
    Vandetanib: (Moderate) Use caution if coadministration of vandetanib with topiramate is necessary. Topiramate is a weak inducer of CYP3A4 in vitro. In a crossover study (n = 12), coadministration of vandetanib with a strong CYP3A4 inducer, rifampicin, decreased the mean AUC of vandetanib by 40% (90% CI, 56% to 63%); a clinically meaningful change in the mean vandetanib Cmax was not observed. However, the AUC and Cmax of the active metabolite, N-desmethyl-vandetanib, increased by 266% and 414%, respectively. It is not clear if topiramate would reduce vandetanib exposure or increase metabolite exposure to a clinically relevant degree.
    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) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) 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.
    Zonisamide: (Moderate) Monitor for evidence of metabolic acidosis, kidney stones, heat intolerance, decreased sweating or increased body temperature and bleeding if coadministration of topiramate and zonisamide is necessary. Because both topiramate and zonisamide are carbonic anhydrase inhibitors, concurrent use may increase the severity of metabolic acidosis and increase the risk of kidney stone formation. In addition, zonisamide may cause decreased sweating, elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as topiramate. Zonisamide has also been associated with thrombocytopenia; concurrent use with topiramate may increase the risk of bleeding.

    PREGNANCY AND LACTATION

    Pregnancy

    Topiramate is excreted in human breast milk. The effects of topiramate on the breast-fed infant 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. Data from 5 breast-feeding infants has shown topiramate plasma concentrations of 10% to 20% of the maternal plasma concentration. 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.

    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. Topiramate's actions involve several mechanisms. 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, 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 human plasma proteins 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. 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. The mean plasma elimination half-life is 21 hours following single or multiple doses. Steady-state concentrations are reached in 4 to 8 days in adult patients with normal renal function.
     
    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). 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 dose. Peak plasma concentrations of topiramate are reached approximately 24 hours after a 200 mg dose of extended-release capsules. The relative bioavailability from the tablets is about 80% compared to topiramate solution. Bioavailability is not affected by coadministration with food. Oral sprinkle capsules of topiramate are bioequivalent to the tablets. At steady state, topiramate extended-release capsules administered once-daily were shown to be bioequivalent to the immediate-release tablet administered twice-daily.