pms-Topiramate

pms-Topiramate Drug Interactions

topiramate

Manufacturer:

Pharmascience

Distributor:

T-BOMA
Full Prescribing Info
Drug Interactions
Drug-Drug Interactions: In all of the following studies, except where noted, the maximum topiramate dose administered was 200 mg/day.
Antiepileptic Drugs (AEDs): Potential interactions between topiramate and standard AEDs were measured in controlled clinical pharmacokinetic studies in patients with epilepsy. The effects of these interactions on plasma concentrations are summarized in Table 18. (See Table 18.)

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Effects of Topiramate on Other AEDs: The addition of topiramate 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 topiramate to phenytoin may result in an increase of plasma concentrations of phenytoin.
The effect of topiramate on the steady-state pharmacokinetics of phenytoin may be related to the frequency of phenytoin dosing. A slight increase in steady-state phenytoin plasma concentrations was observed, primarily in patients receiving phenytoin in two divided doses. The slight increase may be due to the saturable nature of phenytoin pharmacokinetics and inhibition of phenytoin metabolism CYP2C19.
The addition of topiramate therapy to phenytoin should be guided by clinical outcome. In general, as evidenced in clinical trials, patients do not require dose adjustments. However, any patient on phenytoin showing clinical signs or symptoms of toxicity should have phenytoin levels monitored. The effects of these interactions on plasma concentrations are summarized in Table 18.
Effects of Other AEDs on pms-TOPIRAMATE: Phenytoin and Carbamazepine: Phenytoin and carbamazepine decrease the plasma concentration of topiramate. The addition or withdrawal of phenytoin and/or carbamazepine during adjunctive therapy with topiramate may require adjustment of the dose of topiramate. This should be done by titrating to clinical effect.
Valproic Acid: The addition or withdrawal of valproic acid does not produce clinically significant changes in plasma concentrations of topiramate, and therefore, does not warrant dosage adjustment of topiramate. The effects of these interactions on plasma concentrations are summarized in Table 18.
Rare post-marketing reports of encephalopathy with or without hyperammonemia have been received for patients treated with topiramate alone or in combination with valproic acid or other antiepileptic medications. The majority of the cases reported concomitant administration of topiramate and valproic acid. This adverse reaction is not the consequence of a pharmacokinetic interaction between topiramate and VPA. Caution is advised when polytherapy is necessary (see Endocrine and Metabolism: Hyperammonemia and Encephalopathy under Precautions; Post-Market Adverse Drug Reactions under Adverse Reactions).
Concomitant administration of topiramate with valproic acid has also been associated with hypothermia (with and without hyperammonemia) in patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported (see Endocrine and Metabolism: Hypothermia with Concomitant Valproic Acid (VPA) Use under Precautions).
Other Drug Interactions: Digoxin: In a single-dose study, serum digoxin AUC decreased 12% due to concomitant topiramate administration (200 mg/day). Multiple-dose studies have not been performed. When pms-TOPIRAMATE is added or withdrawn in patients on digoxin therapy, careful attention should be given to the routine monitoring of serum digoxin.
CNS Depressants: Concomitant administration of topiramate and alcohol or other CNS depressant drugs has not been evaluated in clinical studies. It is recommended that pms-TOPIRAMATE not be used concomitantly with alcohol or other CNS depressant drugs.
Oral Contraceptives: Topiramate (50 - 200 mg/day) in Healthy Volunteers: In a pharmacokinetic interaction study in healthy volunteers, subjects were stratified into obese vs. non-obese (n = 12 vs. n = 12) with both groups concomitantly administered a combination oral contraceptive product containing 1 mg norethindrone plus 35 mcg ethinyl estradiol and topiramate (50 to 200 mg/day) given in the absence of other medications. For the ethinyl estradiol component, both obese and non-obese volunteers showed a decrease in mean AUC and Cmax at 200 mg/day (-10.7% and -9.4% vs. -15.2% and -11.3%, respectively) that were not statistically significant. Changes in individual subjects ranged from decreases of approximately 35% to 90% in five individuals to increases of approximately 35% to 60% in three individuals. At the 50 and 100 mg/day topiramate doses, similar changes in mean Cmax and AUC were observed for non-obese volunteers. The clinical significance of these changes is unknown. For the norethindrone component, only the non-obese group showed a decrease (-11.8%). In view of the dose-dependent decreases seen in the ethinyl estradiol component in epileptic patients receiving topiramate as adjunctive therapy (see Topiramate as Adjunctive Therapy with Valproic Acid in Epileptic Patients as follows), and the fact that the recommended dose is up to 400 mg/day, there may be greater decreases seen at doses above 200 mg/day as monotherapy.
Topiramate as Adjunctive Therapy with Valproic Acid in Epileptic Patients: In a pharmacokinetic interaction study, epileptic patients received topiramate as adjunctive therapy with valproic acid and a combination oral contraceptive product containing norethindrone (1 mg) plus ethinyl estradiol (35 mcg). In this study, topiramate did not significantly affect the oral clearance of norethindrone. The serum levels of the estrogenic component decreased by 18%, 21% and 30% at daily doses of 200, 400 and 800 mg of topiramate, respectively. There are minimal clinical data regarding interaction of valproic acid and oral contraceptives.
In view of both of the previously mentioned study findings, the efficacy of low-dose (e.g., 20 mcg) oral contraceptives may be reduced in both the monotherapy and adjunctive therapy situation with topiramate. For topiramate doses up to 200 mg/day, which includes the recommended dose for migraine prophylaxis of 100 mg/day, the mean reduction in norethindrone and ethinyl estradiol exposure from topiramate treatment is not significant, although marked changes in individual patients are possible. In the treatment of epilepsy at doses greater than 200 mg/day, significant dose-dependent decreases in ethinyl estradiol exposure are expected. Patients on topiramate doses greater than 200 mg/day who are taking oral contraceptives should receive a preparation containing not less than 30 mcg of estrogen.
The possibility of decreased contraceptive efficacy and increased breakthrough bleeding should be considered in patients taking combination oral contraceptive products with topiramate. 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.
Hydrochlorothiazide (HCTZ): A parallel-arm drug-drug interaction study conducted in healthy volunteers (12 males, 11 females) evaluated the steady-state pharmacokinetics of the diuretic HCTZ (25 mg every 24 hours) and topiramate (96 mg every 12 hours) when administered alone and concomitantly. The results of this study indicate that mean topiramate Cmax increased by 27% and mean AUC increased by 29% when HCTZ was added to topiramate. The clinical significance of this statistically significant change is unknown. Thus, the concomitant use of topiramate and HCTZ may require a downward adjustment of the topiramate dose. The steady-state pharmacokinetics of HCTZ were not significantly influenced by the concomitant administration of topiramate. In addition, greater decreases in serum potassium were seen with concomitant treatment than with either drug alone, both in terms of percentage of patients with a serum potassium measurement of < 3.6 mEq/L at the end of each treatment period [61% (14/23) with concomitant treatment vs. 27% (3/11) with topiramate alone vs. 25% (3/12) with HCTZ alone] and in mean change from baseline (approximately -0.60 mEq/L for concomitant treatment vs. -0.25 mEq/L for topiramate alone vs. -0.12 mEq/L for HCTZ alone). One of the subjects who had hypokalemia with concomitant treatment also had an abnormal ECG (non-specific ST-T wave changes), which may have been related to the decrease in plasma potassium levels. See also Endocrine and Metabolism: Decreases in Serum Potassium with Concomitant Treatment with Hydrochlorothiazide (HCTZ) under Precautions.
Metformin: A drug-drug interaction study conducted in 18 healthy volunteers, ages 18 - 37, evaluated the steady-state pharmacokinetics of metformin and topiramate in plasma when metformin (500 mg b.i.d.) was given alone and when metformin and topiramate (50, 75 and 100 mg) were given simultaneously for six consecutive days. 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 coadministered with topiramate (up-titrated to 100 mg b.i.d.). Topiramate did not affect metformin Tmax. The effects of higher doses of topiramate (> 100 mg b.i.d.) on metformin are unknown. 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 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.
Glyburide: A drug-drug interaction study conducted in 28 patients with type 2 diabetes, ages 38 - 68 years and BMIs 25 - 40 kg/m2, evaluated the steady-state pharmacokinetics of glyburide and topiramate in plasma when glyburide (5 mg/day) was given alone and when glyburide and topiramate (150 mg/day) were given concomitantly for 48 consecutive days. Glyburide systemic exposure was statistically significantly reduced when combined with topiramate such that mean Cmax and mean AUC24 decreased by 22% and 25%, respectively, while mean CL/F increased by 21%. Systemic exposure of the active metabolites, 4-trans-hydroxyglyburide and 3-cis-hydroxyglyburide, was also statistically significantly reduced by 13% and 15%, respectively. The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide. The clinical significance of the effect of glyburide on topiramate pharmacokinetics is unclear. Mild to moderate declines in serum bicarbonate without metabolic acidosis were associated with the addition of topiramate (see Endocrine and Metabolism: Metabolic Acidosis under Precautions). The effects of higher doses of topiramate (> 150 mg/day) on glyburide are unknown. 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.
Pioglitazone: A drug-drug interaction study conducted in healthy volunteers (26 males, 26 females) evaluated the steady-state pharmacokinetics of topiramate and the antidiabetic agent, pioglitazone, when administered alone and concomitantly. The pharmacokinetic parameters of topiramate were not affected; mean pioglitazone AUC decreased by 15%, and mean Cmax increased non-significantly by 10%, but with individual subjects showing large increases and three of the four highest values recorded by males. In addition, each of the active hydroxy-metabolite and the active keto-metabolite showed mean decreases in Cmax and AUC (approximately 15% for the hydroxy-metabolite and 60% for the keto-metabolite). The clinical significance of these findings is not known. When pms-TOPIRAMATE is added to pioglitazone therapy or pioglitazone is added to pms-TOPIRAMATE therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.
Lithium: Healthy Volunteers: A drug-drug interaction study conducted in twelve healthy volunteers, ages 20 - 40 years, evaluated the steady-state pharmacokinetics of lithium in plasma when lithium (300 mg q8h) was administered for 14 days and topiramate (up-titrated to 100 mg q12h) was given concomitantly for the last six days. Based on the data analysis of twelve subjects, systemic exposure of lithium was statistically significantly reduced in the presence of topiramate such that Cmax and AUC0-8h decreased by 20% and 18%, respectively, while mean CL/F and CLR increased by 36% and 12%, respectively. One subject did not have measurable trough lithium concentrations on Day 14, potentially indicating missed dose administration. By excluding this subject from the analyses, systemic exposure of lithium was slightly reduced in the presence of topiramate (12% for Cmax, 10% for AUC0-8h) while mean CL/F and CLR increased by 11% and 16%, respectively. The clinical significance of the effect of topiramate on lithium pharmacokinetics is unclear. The effects of higher doses of topiramate (> 200 mg/day) on the pharmacokinetics of lithium are unknown.
Patients with Bipolar Disorder: A drug-drug interaction study conducted in 31 patients with various types of bipolar disorder, ages 20 - 60 years, evaluated the steady-state pharmacokinetics of lithium and topiramate when administered concomitantly. Subjects were randomized to receive either low doses of topiramate of up to 200 mg/day or high doses of topiramate of up to 600 mg/day. Pharmacokinetic profiles for lithium were obtained following one week and three weeks of continuous lithium dosing. The pharmacokinetics of lithium were unaffected during treatment with topiramate at doses of up to 200 mg/day, and were unaffected by short-term treatment with topiramate (one week) at doses up to 600 mg/day. Following treatment with topiramate at doses of up to 600 mg/day for three weeks, there was an observed statistically significant increase in systemic exposure of lithium (about 27% for both Cmax and AUC). Topiramate exposure for both the low and high dose groups was similar following one week and three weeks of continuous treatment in the presence of lithium. The effects of higher doses of topiramate (> 600 mg/day) on lithium have not been studied and are unknown. Lithium levels should be monitored when coadministered with topiramate and dose adjustments for lithium should be based on both lithium levels and clinical outcome for the patient.
Risperidone: Healthy Volunteers: A drug-drug interaction study was conducted in 12 healthy volunteers (6 males, 6 females), ages 28 - 40 years, with single-dose administration of risperidone (2 mg) and multiple doses of topiramate (titrated up to 200 mg/day). In the presence of topiramate, systemic exposure of the total active moiety (risperidone + 9-hydroxyrisperidone) was reduced such that mean AUC0-∞ was 11% lower and mean Cmax was statistically significantly (18%) lower. In the presence of topiramate, systemic exposure of risperidone was statistically significantly reduced such that mean Cmax and AUC0-∞ were 29% and 23% lower, respectively. The pharmacokinetics of 9-hydroxyrisperidone were unaffected. The effects of a single dose (2 mg/day) of risperidone on the pharmacokinetics of multiple doses of topiramate have not been studied. Therefore, patients receiving risperidone in combination with topiramate should be closely monitored for clinical response to risperidone.
Patients with Bipolar Disorder: A drug-drug interaction study conducted in 52 patients with various types of bipolar disorder (24 males, 28 females), ages 19 - 56 years, evaluated the steady-state pharmacokinetics of risperidone and topiramate when administered concomitantly. Eligible subjects were stabilized on a risperidone dose of 1 - 6 mg/day for two to three weeks. Topiramate was then titrated up to escalating doses of 100, 250 and 400 mg/day along with risperidone for up to six weeks. Risperidone was then tapered and discontinued over four weeks while maintaining topiramate (up to 400 mg/day). There was a statistically significant reduction in risperidone systemic exposure (16% and 33% for AUC12 and 13% and 34% for Cmax at the 250 and 400 mg/day doses, respectively). Minimal alterations were observed in the pharmacokinetics of the total active moiety (risperidone plus 9-hydroxyrisperidone) and 9-hydroxyrisperidone. Topiramate systemic exposure was slightly reduced (12.5% for mean Cmax and 11% for mean AUC12) in the presence of risperidone, which achieved statistical significance. There were no clinically significant changes in the systemic exposure of the risperidone total active moiety or of topiramate. The effects of higher doses of topiramate (> 400 mg/day) are unknown. Patients with bipolar disorder receiving risperidone in combination with topiramate should be closely monitored for clinical response to risperidone.
Haloperidol: The pharmacokinetics of a single dose of the antipsychotic haloperidol (5 mg) were not affected following multiple dosing of topiramate (200 mg/day) in 13 healthy adults (6 males, 7 females).
Venlafaxine: A drug-drug interaction study was conducted in 26 healthy volunteers (16 males/10 females, ages 18 - 40 years, BMI ranging from 25 to 30 kg/m2) to evaluate the interaction between venlafaxine and topiramate. Subjects received single 150-mg doses of extended release venlafaxine and multiple doses of topiramate titrated up to 150 mg/day. The single-dose pharmacokinetics of venlafaxine were unaffected by treatment with topiramate. While the Cmax, AUC and CL/F of the active metabolite, O-desmethylvenlafaxine were unaffected, the renal clearance of the active metabolite was increased by 53% during treatment with topiramate. These observed increases in urinary excretion of O-desmethylvenlafaxine during treatment with topiramate did not affect systemic exposure. The steady-state pharmacokinetics of topiramate were unaffected by repeated daily-dose administration of venlafaxine for five days. The effects of higher doses of topiramate (> 150 mg/day) on the pharmacokinetics of venlafaxine and higher doses of venlafaxine up to the maximum dose of 375 mg/day on the pharmacokinetics of topiramate are unknown.
Amitriptyline: There was a 12% increase in both AUC and Cmax for the tricyclic antidepressant amitriptyline (25 mg/day) in 18 normal subjects (9 males, 9 females) receiving 200 mg/day of topiramate. Individual subjects experienced large changes in amitriptyline concentration, either up or down, in the presence of topiramate; any adjustments in amitriptyline dose should be made according to patients' clinical response and not on the basis of plasma levels.
Pizotifen: Multiple dosing of topiramate (200 mg/day) in 19 healthy volunteers (12 males, 7 females) had little effect on the pharmacokinetics of the antihistamine pizotifen following daily 1.5 mg doses. There was a mean 12% and 15% decrease respectively in topiramate Cmax and AUC in the volunteers (12 males and 7 females) receiving 200 mg/day topiramate and 1.5 mg/day pizotifen. This is not considered to be clinically significant.
Dihydroergotamine: Multiple dosing of topiramate (200 mg/day) in 24 healthy volunteers (12 males, 12 females) had little effect on the pharmacokinetics of a 1 mg subcutaneous dose of dihydroergotamine, and a 1 mg subcutaneous dose of dihydroergotamine similarly had little effect on the pharmacokinetics of a 200 mg/day dose of topiramate.
Sumatriptan: Multiple dosing of topiramate (200 mg/day) in 24 healthy volunteers (14 males, 10 females) had little effect on the pharmacokinetics of single doses of the anti-migraine medication sumatriptan, either orally (100 mg) or subcutaneously (6 mg).
Propranolol: Multiple dosing of topiramate (100, then 200 mg/day) in 34 healthy volunteers (17 males, 17 females) had little effect on the pharmacokinetics of propranolol following daily 160 mg doses. There was a 17% increase in Cmax of the metabolite 4-OH propranolol at 100 mg/day topiramate. Propranolol doses of 80, then 160, mg/day in 39 volunteers (27 males, 12 females) had a dose-dependent effect on exposure to topiramate (200 mg/day), reaching approximately a 9% and 16% increase for Cmax and a 9% and 17% increase for AUC at 80 and 160 mg/day propranolol, respectively.
Diltiazem: A drug-drug interaction study was conducted in 28 healthy volunteers (13 males/15 females, ages 18 - 45 years and BMIs 25 - 35 kg/m2) to evaluate the interaction between topiramate and diltiazem. Eligible subjects received single 240-mg doses of extended-release diltiazem and multiple doses of topiramate titrated to 150 mg/day. Systemic exposure of diltiazem was statistically significantly reduced during topiramate treatment, where Cmax and AUC were 10% and 25% lower, respectively, following single-dose administration. There was an increase in diltiazem CL/F by approximately 30%. Systemic exposure of the active metabolite, desacetyl diltiazem, was statistically significantly reduced during treatment with topiramate where Cmax and AUC36 were 27% and 18% lower, respectively. The single-dose pharmacokinetics of the active metabolite, N-demethyl-diltiazem, were unaffected by topiramate. Following repeated daily-dose administration of diltiazem for five days, steady-state systemic exposure of topiramate was greater during treatment with diltiazem, where Cmax and AUC12 were approximately 17% and 20% higher, respectively, and CL/F was 16% lower. The effects of higher doses of topiramate (> 150 mg/day) on the pharmacokinetics of diltiazem or its metabolites have not been studied. Overall, the clinical significance of these observations is unclear.
Vitamin K-antagonist Anticoagulant Medications: Decreased Prothrombin Time/International Normalized Ratio (PT/INR) responses have been reported following concomitant administration of topiramate with vitamin K-antagonist anticoagulant medications. Closely monitor INR during concomitant administration of topiramate therapy with vitamin K-antagonist anticoagulant medications.
Flunarizine: Patients with Migraine - Effects of topiramate on the pharmacokinetics of flunarizine: The dose of flunarizine used in this study is one-half of the recommended daily dose. A drug-drug interaction study that was conducted in 47 patients with a history migraine (13 males, 34 females, ages 20 - 53 years), evaluated the steady-state pharmacokinetics of flunarizine when topiramate was administered concomitantly. Subjects were taking flunarizine for at least four weeks before study start. One subgroup was administered only flunarizine (5 mg every 24h) for 81 days, and, a second subgroup received flunarizine (5 mg every 24h) for 81 days and topiramate (up-titrated to 50 mg/day and then to 100 mg/day) from Day 4 to a.m. dose on Day 82 concomitantly.
Mean Cmax of flunarizine decreased by 22% with concomitant administration of topiramate at 50 mg/day. During concomitant treatment with topiramate at 100 mg/day, Cmax estimates returned to those observed during treatment with flunarizine alone. Mean AUC0-24 for flunarizine was similar with concomitant administration of topiramate at 50 mg/day and 16% higher with topiramate at 100 mg/day compared to treatment with flunarizine alone. Mean CL/F of flunarizine was unaffected by treatment with topiramate. Systemic exposure of topiramate (Cmax and AUC0-12) doubled with increasing topiramate dose from 50 mg/day to 100 mg/day. Mean CL/F was similar during both dose periods and was consistent with previously observed estimates in healthy volunteers. These alterations are unlikely to be of clinical significance. However, there are no data on the effects of higher doses of topiramate on flunarizine levels. There is also no information on the interaction of topiramate and flunarizine in patients with history of seizure or epilepsy.
Agents Predisposing to Nephrolithiasis: pms-TOPIRAMATE, when used concomitantly with other agents predisposing to nephrolithiasis, such as carbonic anhydrase inhibitors (e.g., acetazolamide), may increase the risk of nephrolithiasis. While using pms-TOPIRAMATE, agents like these should be avoided since they may create a physiological environment that increases the risk of renal stone formation (see Renal: Kidney Stones under Precautions).
Drug-Food Interactions: There was no clinically significant effect of food on the bioavailability of topiramate.
Drug-Herb Interactions: Interactions with herbal products have not been established.
Drug-Laboratory Interactions: There are no known interactions of topiramate with commonly used laboratory tests.
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