Initial monotherapy and adjunct in partial-onset or primary generalized tonic-clonic seizures. Adjunct in Lennox-Gastaut syndrome.
A seizure is an abnormal and unregulated electrical discharge occurring in the brain. This leads to a transient interruption in brain function, manifested by reduced alertness, abnormal sensations, and focal involuntary movements or convulsions. Several types of seizures exist, with common types including tonic-clonic seizures and partial onset seizures.
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.
ORAL Adjunct for seizures associated w/ the Lennox-gastaut syndrome: Adult:lnitially, 25 mg at night for 1 wk, thereafter increase in steps of 25-50 mg at intervals of 1-2 wk until effective dose is achieved. Doses >25 mg/day should be taken in 2 divided doses. Usual dose: 200-400 mg daily. Max: 800 mg daily. Child: 2-1 6 yr: initially, 25 mg nightly for the 1st wk increased at intervals of 1-2 wk by increments of 1-3 mg/kg daily according to response. Daily doses of >25 mg should be taken in 2 divided doses. Usual dose: 5-9 mg/kg daily. Max: 30 mg/kg/day. Epilepsy: Adult: Monotherapy: Initially, 25 mg at night for 1 wk, thereafter increase in steps of 25-50 mg at intervals of 1-2 wk. Doses >25 mg/day should be taken in 2 divided doses. Usual dose: 100-400 mg daily. Max: 400 mg daily. Adjunctive treatment: Initially, 25 mg at night for 1 wk, thereafter increase in steps of 25-50 mg at intervals of 1-2 wk until effective dose is achieved. Doses >25 mg/day should be taken in 2 divided doses. Usual dose: 200-400 mg daily. Max: 800 mg daily. Child:1 0-16 yr Initially. 0.5-1 mg/kg at night for the 1st wk, increased at intervals of 1-2 wk by increments of 0.5 to 1 mg/ kg daily. Usual dose: 3-6 mg/kg daily. Daily doses >25 mg should be taken in 2 divided doses. Max: 16 mg/kg/day. Prophylaxis of migraine: Adult: >16 yr: Initially 25 mg daily at night for 1 wk, increased in steps of 25-mg at wkly intervals. Usual dose: 50-100 mg daily in 2 divided doses. Daily doses >25 mg should be taken in 2 divided doses.
The addition of topiramate to other antiepileptic drugs (phenytoin, carbamazepine, valproic add, phenobarbitai, primidone) has no clinically significant effect on their steady-state plasma concentrations, except in some patients where the addition of topiramate to phenytoin may result in an increase of plasma concentrations of phenytoin.
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.
Lactation is contraindicated. Renal or hepatic impairment, pregnancy. May impair ability to drive or operate machinery. Maintain adequate hydration to reduce the risk of renal calculi esp in predisposed patients. Measure serum bicarbonate at baseline & periodically during treatment. Avoid abrupt withdrawal: decrease dose by 100 mg daily at wkly intervals. Seek immediate medical attention if blurred vision or eye pain. Monitor closely for decreased sweating & increased body temperature, esp in hot weather. Ensure proper hydration before & during activities or exposure to warm temperatures.
Confusion, dizziness, drowsiness, generalised slowing of mental & physical activity, difficulty w/ concentrations, ataxia, paresthesia, anorexia, wt loss, abnormal vision, metabolic acidosis, mood or mental changes, behavioural disturbances, depression, fatigue, agitation, nervousness, anxiety, oligohidrosis, hyperthermia & hyperammonaemic encephalopathy.
Both studies showed an increased risk of oral clefts in infants exposed to topiramate during the first trimester compared to infants not exposed to antiepileptic medicines. Previous studies have shown a potential association between oral clefts and the use of topiramate during pregnancy. Limited information indicates that maternal doses of topiramate up to 200 mg daily produce relatively low levels in infant serum. Monitor the infant for diarrhea, drowsiness, irritability, adequate weight gain, and developmental milestones, especially in younger, exclusively breastfed infants and when using combinations of anticonvulsant or psychotropic drugs.
Topiramate overdose can result in severe metabolic acidosis. In acute topiramate overdose, if the ingestion is recent, the stomach should be emptied immediately by lavage or by induction of emesis. Activated charcoal has been shown to adsorb topiramate in vitro. Treatment should be appropriately supportive. Haemodialysis has been shown to be an effective means of removing topiramate from the body. The patient should be well hydrated.
Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.
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