Description
Indications
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Pharmacology
The exact mechanisms by which topiramate exerts pharmacological actions on seizures and migraines are currently not fully characterized. Several properties of this drug, however, are likely to contribute to its therapeutic effects. Topiramate has been observed to exert actions on voltage-dependent sodium channels, GABA receptors, and glutamate receptors.
Topiramate stimulates GABA-A receptor activity at brain non-benzodiazepine receptor sites and reduces glutamate activity at both AMPA and kainate receptors. Normally, GABA-A receptors are inhibitory and glutaminergic receptors are stimulatory for neuronal activity. By increasing GABA activity and inhibiting glutamate activity, topiramate blocks neuronal excitability, preventing seizures and migraines. Additionally, it blocks the voltage-dependent sodium channels, further blocking seizure activity. Topiramate has been shown to inhibit various carbonic anhydrase isozymes, but the clinical significance of this is unknown at this time.
Dosage & Administration
- Adults and children over 16 years: Titration should begin at 25 mg nightly for 1 week. The dosage should then be increased at 1- or 2-week intervals by increments of 25 or 59 mg/day, administered in two divided doses. The recommended initial target dose for topiramate monotherapy in adults with newly diagnosed epilepsy is 100 mg/day and the maximum recommended daily dose is 400 mg.
- Children aged 6-16 years: Treatment of children aged 6 years and above should begin at 0.5 to 1 mg/kg nightly for the first week. The dosage should then be increased at 1- or 2-week intervals by increments of 0.5 to 1 mg/kg/day, administered in two divided doses. The recommended initial target dose range for topiramate monotherapy in children with newly diagnosed epilepsy aged 6 years and above is 3 to 6 mg/kg/day. Higher doses have been tolerated and rarely doses up to 16 mg/kg/day have been given.
Epilepsy: Adjunctive therapy:
- Adults and children over 16 years: The minimal effective dose as adjunctive therapy is 200 mg per day. The usual total daily dose is 200 mg to 400 mg in two divided doses. Some patients may require doses up to 800 mg per day, which is the maximum recommended dose.
- Children aged 2-16 years: The recommended total daily dose of Topiramate as adjunctive therapy is approximately 5 to 9 mg/kg/day in two divided doses. Titration should begin at 25 mg nightly for the first week. The dosage should then be increased at 1- or 2-week intervals by increments of 1 to 3 mg/kg/day (administered in two divided doses), to achieve optimal clinical response. Dose titration should be guided by clinical outcome. Daily doses up to 30 mg/kg/day have been studied and were generally well tolerated.
Migraine:
- Adults and children over 16 years: Titration should begin at 25 mg nightly for 1-week. The dosage should then be increased in increments of 25 mg/day administered at 1-week intervals. The recommended total daily dose of topiramate as treatment for the prophylaxis of migraine headache is 100 mg/day administered in two divided doses. Some patients may experience a benefit at a total daily dose of 50 mg/day.
- Children: Topiramate in migraine prophylaxis has not been studied in children under 16 years.
Interaction
CNS Depressants: Topiramate should be used with caution if used in combination with alcohol and other CNS depressants.
Oral Contraceptives: In an interaction study with a combined oral contraceptive, Topiramate increased plasma clearance of the oestrogenic component significantly. Consequently, and bearing in mind the potential risk of teratogenicity, patients should receive a preparation containing not less than 50 μg of oestrogen or use some alternative non-hormonal method of contraception. Patients taking oral contraceptives should be asked to report any change in their bleeding patterns.
Lithium: In patients with bipolar disorder, 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 (26% for AUC) following Topiramate doses of up to 600 mg/day. Lithium levels should be monitored when co-administered with Topiramate.
Hydrochlorothiazide (HCTZ): The steady-state pharmacokinetics of HCTZ were not significantly influenced by the concomitant administration of Topiramate. Clinical laboratory results indicated decreases in serum potassium after Topiramate or HCTZ administration, which were greater when HCTZ and Topiramate were administered in combination.
Metformin: Topiramate did not affect metformin tmax. The clinical significance of the effect of topiramate on metformin pharmacokinetics is unclear. Oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect of metformin on topiramate pharmacokinetics is unclear. When Topiramate is added or withdrawn in patients on metformin therapy, careful attention should be given to the routine monitoring for adequate control of their diabetic disease state.
Pioglitazone: When Topiramate is added to pioglitazone therapy or pioglitazone is added to Topiramate therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.
Glibenclamide: The steady-state pharmacokinetics of Topiramate were unaffected by concomitant administration of glibenclamide. When Topiramate is added to glibenclamide therapy or glibenclamide is added to Topiramate therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.
Others: Topiramate, when used concomitantly with other agents predisposing to nephrolithiasis, may increase the risk of nephrolithiasis. While using Topiramate, agents like these should be avoided since they may create a physiological environment that increases the risk of renal stone formation. The interaction with benzodiazepines has not been studied.
Valproic Acid: Concomitant administration of Topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. An association of hyperammonemia with Topiramate monotherapy or concomitant treatment with other anti epileptics has not been established.
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