Forms of Interaction: (For purposes of this section, a no effect dose is defined as a ≤15% change.)
Effects of TOPAMAX on Other AEDs: The addition of TOPAMAX to other AEDs (phenytoin, carbamazepine, valproic acid, phenobarbital, primidone) has no effect on their steady-state plasma concentrations, except in the occasional patient, where the addition of TOPAMAX to phenytoin may result in an increase of plasma concentrations of phenytoin. This is possibly due to inhibition of a specific enzyme polymorphic isoform (CYP2C19). Consequently, any patient on phenytoin showing clinical signs or symptoms of toxicity should have phenytoin levels monitored.
A pharmacokinetic interaction study of patients with epilepsy indicated the addition of topiramate to lamotrigine had no effect on steady state plasma concentration of lamotrigine at topiramate doses of 100 to 400 mg/day. In addition, there was no change in steady state plasma concentration of topiramate during or after removal of lamotrigine treatment (mean dose of 327 mg/day).
Effects of Other AEDs on TOPAMAX: Phenytoin and carbamazepine decrease the plasma concentration of TOPAMAX. The addition or withdrawal of phenytoin or carbamazepine to TOPAMAX therapy may require an adjustment in dosage of the latter. This should be done by titrating to clinical effect. The addition or withdrawal of valproic acid does not produce clinically significant changes in plasma concentrations of TOPAMAX and, therefore, does not warrant dosage adjustment of TOPAMAX. The results of these interactions are summarized as follows: See Table 10.
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Other Drug Interactions: Digoxin: In a single-dose study, serum digoxin area under plasma concentration curve (AUC) decreased 12% due to concomitant administration of TOPAMAX. The clinical relevance of this observation has not been established. When TOPAMAX is added or withdrawn in patients on digoxin therapy, careful attention should be given to the routine monitoring of serum digoxin.
Central nervous system (CNS) Depressants: Concomitant administration of TOPAMAX and alcohol or other CNS depressant drugs has not been evaluated in clinical studies. It is recommended that TOPAMAX not be used concomitantly with alcohol or other CNS depressant drugs.
Oral Contraceptives: In a pharmacokinetic interaction study in healthy volunteers with a concomitantly administered combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 mcg ethinyl estradiol (EE), TOPAMAX given in the absence of other medications at doses of 50 to 200 mg/day was not associated with statistically significant changes in mean exposure (AUC) to either component of the oral contraceptive. In another study, exposure to EE was statistically significantly decreased at doses of 200, 400, and 800 mg/day (18%, 21%, and 30%, respectively) when given as adjunctive therapy in patients taking valproic acid. In both studies, TOPAMAX (50 mg/day to 800 mg/day) did not significantly affect exposure to NET. Although there was a dose dependent decrease in EE exposure for doses between 200-800 mg/day, there was no significant dose dependent change in EE exposure for doses of 50-200 mg/day. The clinical significance of the changes observed is not known. The possibility of decreased contraceptive efficacy and increased breakthrough bleeding should be considered in patients taking combination oral contraceptive products with TOPAMAX. Patients taking estrogen containing contraceptives should be asked to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding.
Lithium: In healthy volunteers, there was an observed reduction (18% for AUC) in systemic exposure for lithium during concomitant administration with topiramate 200 mg/day. 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.
Risperidone: Drug-drug interaction studies conducted under single and multiple dose conditions in healthy volunteers and patients with bipolar disorder yielded similar results. When administered concomitantly with topiramate at escalating doses of 100, 250 and 400 mg/day there was a reduction in risperidone (administered at doses ranging from 1 to 6 mg/day) systemic exposure (16% and 33% for steady-state AUC at the 250 and 400 mg/day doses, respectively). Minimal alterations in the pharmacokinetics of the total active moiety (risperidone plus 9-hydroxyrisperidone) and no alterations for 9-hydroxyrisperidone were observed. There were no clinically significant changes in the systemic exposure of the risperidone total active moiety or of topiramate, therefore this interaction is not likely to be of clinical significance.
Hydrochlorothiazide (HCTZ): A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of HCTZ (25 mg every 24 h) and topiramate (96 mg q12h) when administered alone and concomitantly. The results of this study indicate that topiramate Cmax increased by 27% and AUC increased by 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The addition of HCTZ to topiramate therapy may require an adjustment of the topiramate dose. 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: A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of metformin and topiramate in plasma when metformin was given alone and when metformin and topiramate were given simultaneously. The results of this study indicated that metformin mean Cmax and mean AUC0-12h increased by 18% and 25%, respectively, while mean CL/F decreased 20% when metformin was co-administered with topiramate. 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 extent of change in the clearance is unknown. The clinical significance of the effect of metformin on topiramate pharmacokinetics is unclear. When TOPAMAX 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: A drug-drug interaction study conducted in healthy volunteers evaluated the steadystate pharmacokinetics of topiramate and pioglitazone when administered alone and concomitantly. A 15% decrease in the AUCΤ,ss of pioglitazone with no alteration in Cmax,ss was observed. This finding was not statistically significant. In addition, a 13% and 16% decrease in Cmax,ss and AUCΤ,ss respectively, of the active hydroxy-metabolite was noted as well as a 60% decrease in Cmax,ss and AUCΤ,ss of the active ketometabolite. The clinical significance of these findings is not known. When TOPAMAX is added to pioglitazone therapy or pioglitazone is added to TOPAMAX therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.
Glyburide: A drug-drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state pharmacokinetics of glyburide (5 mg/day) alone and concomitantly with topiramate (150 mg/day). There was a 25% reduction in glyburide AUC24 during topiramate administration. Systemic exposure of the active metabolites, 4-trans-hydroxy-glyburide (M1) and 3-cis-hydroxyglyburide (M2), were also reduced by 13% and 15%, respectively. The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide. When topiramate is added to glyburide therapy or glyburide is added to topiramate therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.
Other forms of interactions: Agents predisposing to nephrolithiasis: TOPAMAX, when used concomitantly with other agents predisposing to nephrolithiasis, may increase the risk of nephrolithiasis. While using TOPAMAX, agents like these should be avoided since they may create a physiological environment that increases the risk of renal stone formation.
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. In most cases, symptoms and signs abated with discontinuation of either drug. This adverse event is not due to a pharmacokinetic interaction. An association of hyperammonemia with topiramate monotherapy or concomitant treatment with other AEDs has not been established.
Hypothermia, defined as an unintentional drop in body core temperature to < 35°C, has been reported in association with concomitant use of topiramate and valproic acid (VPA) both in conjunction with hyperammonemia and in the absence of hyperammonemia. This adverse event in patients using concomitant topiramate and valproate can occur after starting topiramate treatment or after increasing the daily dose of topiramate.
Additional Pharmacokinetic Drug Interaction Studies: Clinical studies have been conducted to assess the potential pharmacokinetic drug interaction between topiramate and other agents. The changes in Cmax or AUC as a result of the interactions are summarized in Table 11. The second column (concomitant drug concentration) describes what happens to the concentration of the concomitant drug listed in the first column when topiramate is added. The third column (topiramate concentration) describes how the coadministration of a drug listed in the first column modifies the concentration of topiramate. See Table 11.
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