Multicenter Double‐Blind, Randomized, Placebo‐Controlled Trial of Levetiracetam as Add‐On Therapy in Patients with Refractory Partial Seizures

Shorvon, Simon; Löwenthal, A.; Janz, Diéter; Bielen, E; Loiseau, P

doi:10.1111/j.1528-1157.2000.tb00323.x

Cited by 427 publications

(428 citation statements)

References 10 publications

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“…This finding supports the notion that LEV does not induce CYP 3A4, the isozyme responsible for contraceptive steroid hydroxylation. Although the study was performed with the recommended starting dose of LEV, other controlled clinical trials have indicated that LEV at doses Յ3,000 mg daily did not alter the plasma concentrations of any concomitantly administered AEDs (19)(20)(21).…”

Section: Discussionmentioning

confidence: 99%

Levetiracetam Does Not Alter the Pharmacokinetics of an Oral Contraceptive in Healthy Women

Ragueneau‐Majlessi

Levy

Janik³

2002

Epilepsia

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Summary:Purpose: This study was designed to evaluate whether levetiracetam, a novel antiepileptic drug (AED), influences the pharmacokinetics of steroid oral contraceptives.Methods: During a run-in phase, 18 healthy female patients received an oral contraceptive containing ethinyl estradiol, 0.03 mg, and levonorgestrel, 0.15 mg, for the first 21 days of two consecutive menstrual cycles. In a subsequent double-blind, randomized, two-way crossover treatment phase, subjects received either levetiracetam, 500 mg, or placebo twice daily concomitant with the oral contraceptive. Plasma concentrations of ethinyl estradiol and levonorgestrel were measured on days 14 and 15 of the two treatment periods for the evaluation of the 24-h kinetic parameters, and an additional sample was collected on day 21 to determine the trough plasma concentrations. Serum progesterone and luteinizing hormone (LH) levels were determined on days 13, 14, 15, and 21 of each cycle of the treatment phase.Results: The plasma concentration-time curves and pharmacokinetic parameters of ethinyl estradiol and levonorgestrel were not statistically different during concomitant treatment with either levetiracetam or placebo. The ratios of the logtransformed geometric mean areas under the plasma concentration-time curves (AUCs), maximal (C max ) and minimal (C min ) plasma concentrations, and trough concentrations on day 21 (C 21 ) ranged from 99.12 to 99.96% for ethinyl estradiol and from 97.13 to 99.41% for levonorgestrel. The 90% confidence intervals of these ratios were well within the 80 to 125% acceptance range for lack of interaction. Serum progesterone and LH concentrations were fairly constant during the run-in and treatment phases and remained markedly below their respective physiologic levels. Safety and menstrual-bleeding patterns were comparable during levetiracetam and placebo administration.Conclusions: Levetiracetam does not affect the pharmacokinetics of an oral contraceptive containing ethinyl estradiol and levonorgestrel, and on the basis of serum progesterone and LH levels, it does not affect the contraceptive efficacy.

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Section: Discussionmentioning

confidence: 99%

Levetiracetam Does Not Alter the Pharmacokinetics of an Oral Contraceptive in Healthy Women

Ragueneau‐Majlessi

Levy

Janik³

2002

Epilepsia

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“…Furthermore, in vitro assays using human liver fractions and specific marker activities have shown that LEV does not inhibit the most common drug-metabolizing enzymes, including CYPs (1A2, 2A6, 2C9, 2C19, 2D6, 2E1, 3A4), UGTs, and epoxide hydrolase (13). The low potential of LEV for drug interactions was noted in several clinical trials in which LEV was administered to patients with refractory seizures who were receiving other AEDs, including CBZ, LTG, PHT, VPA, PB, gabapentin (GBP), and primidone (PRM (14)(15)(16). Although these were not specifically druginteraction studies, LEV appeared to have no significant effect on the serum concentrations of other AEDs.…”

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confidence: 99%

Levetiracetam, a New Antiepileptic Agent: Lack of In Vitro and In Vivo Pharmacokinetic Interaction with Valproic Acid

2003

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Summary:Purpose: The novel antiepileptic drug (AED) levetiracetam (LEV; Keppra) has a wide therapeutic index and pharmacokinetic characteristics predicting limited druginteraction potential. It is indicated as an add-on treatment in patients with epilepsy, and thus coadministration with valproic acid (VPA) is likely. These studies were performed to determine whether coadministration of LEV with VPA might result in pharmacokinetic interactions.Methods: In vitro assays were performed to characterize the transformation of LEV into its main in vivo metabolite UCB L057. The reaction was examined for its sensitivity to clinically relevant concentrations of VPA. An open-label, one-way, onesequence crossover clinical trial was conducted in 16 healthy volunteers to assess further the possibility of any relevant pharmacokinetic interaction. Results:Human whole blood and, to a lesser extent, human liver homogenates were demonstrated to hydrolyze LEV to UCB L057, its main metabolite. The reaction possibly involves type-B esterases and is not affected by 1 mM VPA (i.e., 166 g/ml). Pharmacokinetic parameters of a single dose of LEV (1,500 mg) coadministered with steady-state concentrations of VPA (8 days of 500 mg, b.i.d.) did not differ significantly from the pharmacokinetics of LEV administered alone [area under the curve (AUC) of 397 and 400 g/h/ml, respectively]. Furthermore, LEV did not affect the steady-state pharmacokinetics of VPA.Conclusions: These findings suggest the absence of a pharmacokinetic interaction between VPA and LEV during shortterm administration, and suggest that dose adjustment is not required when these two drugs are given together.

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“…Its exact mechanism of action is unknown. Common side effects include somnolence, fatigue, and dizziness (1)(2)(3)(4)(5)(6). Adverse behavioral effects include agitation, hostility, anxiety, apathy, emotional lability, and depersonalization.…”

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confidence: 99%

Levetiracetam Efficacy in Refractory Partial‐onset Seizures, Especially after Failed Epilepsy Surgery

Motamedi

Nguyen²,

Zaatreh³

et al. 2003

Epilepsia

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Summary:Purpose: We conducted a retrospective study to evaluate the efficacy of levetiracetam as adjunctive therapy in patients with localization-related epilepsy, and specifically in the subset of patients for whom epilepsy surgery failed.Methods: Eighty-two patients with uncontrolled partial-onset seizures treated with levetiracetam were identified; epilepsy surgery had failed for 21 (25.6%; group I), and 61 (74.4%) had no prior surgery (group II). Group I and group II patients were comparable in age (mean, 40.7 vs. 41.5 years) and age at seizure onset (mean, 14.4 vs. 18.2 years). Patients who had Ն50% reduction in seizure frequency were considered responders; the remaining patients were considered nonresponders.Results: In patients (group I) for whom surgery had failed, responder rate was 76.1% (16 of 21), including 10 (47.6%) patients who became seizure free. In nonsurgical patients (group II), responder rate was 34.3% (21 of 61), including nine (14.7%) patients who became seizure free. In group I, 11 (91.6%) of 12 temporal resection patients were responders, of whom eight were seizure free; of the remaining nine operated (extratemporal) patients, five (55.5%) were responders, and two were seizure free. In three responders, all in group I, a severe, delayed psychotic syndrome developed 4 to 9 months after levetiracetam introduction, leading to its discontinuation.Conclusions: These findings suggest that adjunctive levetiracetam therapy should be considered early after failed epilepsy surgery, especially after temporal resection, and may have implications for its use before surgical intervention. Patients should be under close psychiatric observation in this clinical setting.

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Multicenter Double‐Blind, Randomized, Placebo‐Controlled Trial of Levetiracetam as Add‐On Therapy in Patients with Refractory Partial Seizures

Cited by 427 publications

References 10 publications

Levetiracetam Does Not Alter the Pharmacokinetics of an Oral Contraceptive in Healthy Women

Levetiracetam Does Not Alter the Pharmacokinetics of an Oral Contraceptive in Healthy Women

Levetiracetam, a New Antiepileptic Agent: Lack of In Vitro and In Vivo Pharmacokinetic Interaction with Valproic Acid

Levetiracetam Efficacy in Refractory Partial‐onset Seizures, Especially after Failed Epilepsy Surgery

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