Induction of Ethinylestradiol and Levonorgestrel Metabolism by Oxcarbazepine in Healthy Women

Fattore, Cinzia; Cipolla, Giovanna; Gatti, G.; Limido, G; Sturm, Y.; Bernasconi, C; Perucca, Emilio

doi:10.1111/j.1528-1157.1999.tb00779.x

Cited by 149 publications

(72 citation statements)

References 28 publications

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“…The doses used in this study reflect approved dose levels (Lamictal s , 2004; Trileptal s , 2004) or those used in previous drug-interaction studies (Fattore et al, 1999;Hulsman et al, 1995); however, they do not necessarily reflect actual clinical practice, particularly in epilepsy, where higher doses are often prescribed. While the current findings are restricted to the doses studied, it is unlikely that the metabolism and excretion of higher doses will greatly differ.…”

Section: Discussionmentioning

confidence: 99%

Lack of Pharmacokinetic Interaction between Oxcarbazepine and Lamotrigine

Theis

Sidhu

Palmer

et al. 2005

Neuropsychopharmacol

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Epilepsy and bipolar disorder are commonly treated by combination drug therapy, such as lamotrigine and oxcarbazepine. To ensure the safety of this combination, information on pharmacokinetics and tolerability must be available. The objective of study was to evaluate the pharmacokinetics and tolerability of coadministered lamotrigine and oxcarbazepine in healthy subjects. This randomized, single-blind, parallel-group study comprised three cohorts: lamotrigine (200 mg daily) plus oxcarbazepine (600 mg twice daily), lamotrigine (200 mg daily) plus placebo, and oxcarbazepine (600 mg twice daily) plus placebo. Serial blood samples were collected at steady state to determine serum concentrations of lamotrigine and plasma concentrations of oxcarbazepine and its active metabolite 10-monohydroxy metabolite (MHD). Pharmacokinetic parameters were determined by noncompartmental methods. Tolerability was monitored through adverse event reports, clinical laboratory results, vital signs, and electrocardiograms. A total of 47 male volunteers received study drugs. At steady state, lamotrigine AUC and C max were not significantly affected by oxcarbazepine cotherapy, nor were MHD AUC (0)(1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) and C max significantly affected by lamotrigine cotherapy. The most common adverse events, headache, dizziness, nausea, and somnolence, occurred more frequently during lamotrigine and oxcarbazepine combination therapy than during the monotherapy. No significant changes in clinical laboratory parameters, vital signs, or electrocardiograms were reported. In conclusion, the combination of lamotrigine and oxcarbazepine does not require dose adjustments based on pharmacokinetic data. However, it is important to recognize that the combination therapy was associated with more frequent adverse events.

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Section: Discussionmentioning

confidence: 99%

Lack of Pharmacokinetic Interaction between Oxcarbazepine and Lamotrigine

Theis

Sidhu

Palmer

et al. 2005

Neuropsychopharmacol

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“…Newer AEDs, including topiramate (TPM), felbamate (FBM), and oxcarbazepine (OCBZ), are less potent inducers of CYP, but they also may interfere with the metabolism of OCs, thereby altering plasma concentrations of the contraceptive steroids and potentially decreasing their efficacy (8)(9)(10)(11)(12). A third group of AEDs, which includes gabapentin (GBP) and vigabatrin (VGB), is not metabolized in the liver and appears to be devoid of significant CYP enzyme-inducing or -inhibiting properties (13,14), in particular with contraceptive steroids (15,16).…”

mentioning

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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“…With OXC, the reported decrease in the AUC of ethinylestradiol was 47%. 22 No statistically significant difference was found between t max values for levonorgestrel and ethinylestradiol after administration of ESL.…”

Section: Drug Interactionsmentioning

confidence: 83%

“…In a published study with OXC, the reported decrease in the AUC of levonorgestrel was 47%. 22 In the ESL study, mean C max ethinylestradiol decreased 20% (PE: 0.80; 90% CI: 0.79 -0.95) and AUC 0 -24 decreased 32% (PE: 0.76; 90% CI: 0.68 -0.86) after administration of ESL. With OXC, the reported decrease in the AUC of ethinylestradiol was 47%.…”

Section: Drug Interactionsmentioning

confidence: 88%

“…24 The mostly likely explanation is that the decrease in plasma ethinylestradiol and levonorgestrel was due to induction of the CYP3A4 isoenzymes involved in their oxidation. 22 Although the decrease in the extent of exposure to levonorgestrel and ethinylestradiol after ESL was approximately half that reported with OXC, 22 it may be concluded that concomitant administration of ESL and hormonal contraceptives can render these contraceptives less effective.…”

Section: Drug Interactionsmentioning

confidence: 97%

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Eslicarbazepine Acetate (BIA 2-093)

2007

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Summary: Eslicarbazepine acetate (ESL) [(S)-(Ϫ)-10-acetoxy-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide], formerly known as BIA 2-093, is a novel central nervous system (CNS)-active compound with anticonvulsant activity. It behaves as a voltage-gated sodium channel (VGSC) blocker and is currently under clinical development for the treatment of epilepsy and bipolar disorder. ESL shares with carbamazepine and oxcarbazepine the dibenzazepine nucleus bearing the 5-carboxamide substitute, but is structurally different at the 10,11-position. This molecular variation results in differences in metabolism, preventing the formation of toxic epoxide metabolites such as carbamazepine-10,11 epoxide. In pharmacokinetic studies in humans, ESL was rapidly and extensively metabolized to eslicarbazepine (S-licarbazepine), which is responsible for pharmacological activity. ESL has been tested in patients with refractory partial-onset seizures and was found to be efficacious and well tolerated. Monotherapy studies in adult epileptic patients and add-on studies in epileptic children are in the planning process. The efficacy and safety data appear to be very promising considering the refractory nature of the epileptic population enrolled in studies to date. Results of ongoing phase III studies in adult epileptic patients are expected to be available in 2007 and are required to define the position of ESL in the therapy of patients with epilepsy.

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Induction of Ethinylestradiol and Levonorgestrel Metabolism by Oxcarbazepine in Healthy Women

Cited by 149 publications

References 28 publications

Lack of Pharmacokinetic Interaction between Oxcarbazepine and Lamotrigine

Lack of Pharmacokinetic Interaction between Oxcarbazepine and Lamotrigine

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

Eslicarbazepine Acetate (BIA 2-093)

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