Ischemic and Thrombotic Events Associated with Concomitant Xa-inhibiting Direct Oral Anticoagulants and Antiepileptic Drugs: Analysis of the FDA Adverse Event Reporting System (FAERS)

Perlman, Amichai; Wanounou, Maor; Goldstein, Rachel; Cohen, Lotan Choshen; Singer, Daniel E.; Muszkat, Mordechai

doi:10.1007/s40263-019-00677-5

Cited by 28 publications

(33 citation statements)

References 21 publications

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“…Whether these potential interactions may have a clinically relevant significance is largely unknown. In a recent analysis of adverse event reports submitted to Food and Drug Present study GLORIA AF [24] ORBIT AF [25] GAR-FIELD AF [26] Age Administration (FDA) Adverse Event Reporting System, the risk of ischaemic and thromboembolic events in patients concomitantly treated with factor Xa-inhibitors, mainly apixaban and rivaroxaban, and enzyme-inducing AEDs, was higher than in those treated with other antiepileptic drugs [29]. In addition, in a retrospective study, DOAC concentrations were lower than expected in patients treated with carbamazepine, phenobarbital and phenytoin (50% of patients below the 5th percentile) [30].…”

Section: Discussionmentioning

confidence: 99%

Concomitant Use of Direct Oral Anticoagulants and Antiepileptic Drugs: A Prospective Cohort Study in Patients with Atrial Fibrillation

et al. 2020

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Section: Discussionmentioning

confidence: 99%

Concomitant Use of Direct Oral Anticoagulants and Antiepileptic Drugs: A Prospective Cohort Study in Patients with Atrial Fibrillation

et al. 2020

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“…carbamazepine, phenytoin) and the anti‐HIV drugs efavirenz and nevirapine. Although no pharmacokinetic studies are currently available, data from the Food and Drug Administration Adverse Event Reporting System indicate a significant increase of anticoagulant treatment failures when DOACs are combined with enzyme‐inducing antiepileptic agents 23 and several case reports also describe treatment failure in combination of rivaroxaban with these agents 8,24–27 . In a retrospective study evaluating the management of the interaction between DOACs and enzyme inducing drugs, strategies included stopping the inducer, increasing the dose of the DOAC or exchanging the DOAC 56 .…”

Section: Discussionmentioning

confidence: 99%

“…While previous reports indicate that drug–drug interactions occur when rivaroxaban is combined with strong inducers, 5–8,22–27 there are currently no clinical data available regarding the effect of a combined CYP3A4 and P‐gp inducing H. perforatum extract on the pharmacokinetics and pharmacodynamics of rivaroxaban administered in the absence of other substances. The aim of the present study was to investigate the influence of hyperforin‐containing H. perforatum extract on the pharmacokinetics (plasma concentration) and pharmacodynamics (factor Xa activity) of rivaroxaban.…”

Section: Introductionmentioning

confidence: 99%

Effects of Hypericum perforatum (St John's wort) on the pharmacokinetics and pharmacodynamics of rivaroxaban in humans

Scholz

Liakoni

Hammann

et al. 2020

Brit J Clinical Pharma

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Aims To investigate the influence of a cytochrome P450 CYP3A4 and efflux transporter P‐glycoprotein (P‐gp) inducing Hypericum perforatum extract on the pharmacokinetics and pharmacodynamics of rivaroxaban. Methods Open‐label, nonrandomized, sequential treatment interaction study. Following CYP3A4 and P‐gp phenotyping using low‐dose midazolam and fexofenadine, 12 healthy volunteers received a single oral dose of 20 mg rivaroxaban and rivaroxaban plasma concentrations and inhibition of the activated coagulation factor X (factor Xa) activity were measured prior to and up to 48 h postdosing. The procedures were repeated after 2 weeks’ treatment with the H. perforatum extract. Results The geometric mean ratios for the area under the concentration–time curve and Cmax of rivaroxaban after/before induction with the H. perforatum extract were 0.76 (90% confidence interval [CI] 0.70, 0.82) and 0.86 (90% CI 0.76, 0.97), respectively. Inhibition of factor Xa activity was reduced with a geometric mean area under the effect–time curve ratio after/before induction of 0.80 (90% CI 0.71, 0.89). No clinically significant differences were found regarding Tmax (median 1.5 vs 1 h, P = .26) and terminal elimination half‐life (mean 10.6 vs 10.8 h, P = .93) of rivaroxaban. The H. perforatum extract significantly induced CYP3A4 and P‐gp activity, as evidenced by phenotyping. Conclusion The CYP3A4/P‐gp inducing H. perforatum extract caused a decrease of rivaroxaban exposure with a proportional decrease of the pharmacodynamic effect. Although the data do not justify a contraindication for the combination or a systematic adjustment of rivaroxaban dosage, avoidance of the combination or laboratory monitoring should be considered in patients taking hyperforin‐containing H. perforatum extracts with rivaroxaban.

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“…More than 50% of DOAC serum concentrations were less than the fifth percentile observed in phase III trials. 73 Cases of DOAC treatment failure involving thrombotic events have been reported in patients taking combined P-gp and concomitant weak, 74 moderate, 75 and strong CYP3A4 inducers. [76][77][78][79][80][81] The majority of these reports are with antiepileptic agents.…”

Section: Considerations For Doac Induction Interactionsmentioning

confidence: 99%

“…[76][77][78][79][80][81] The majority of these reports are with antiepileptic agents. 73 Cases of anticoagulant failure have not been reported with dexamethasone. Reasons for this are speculative and include less significant CYP and/or P-gp induction, infrequent concurrent use, or short course dexamethasone exposure limiting full induction potential.…”

Section: Considerations For Doac Induction Interactionsmentioning

confidence: 99%

Potential Dexamethasone–Direct Oral Anticoagulant Drug Interaction: Is This a Concern in COVID?

et al. 2021

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Objective To evaluate the literature on a potential dexamethasone–direct oral anticoagulant (DOAC) drug interaction and provide management considerations with COVID hypercoagulability. Data Sources A search of EMBASE, PubMed, and Google Scholar (January 1990 to May 2021), limited to the English language, using applicable search terms resulted in 137 articles, with 21 relevant articles included. Regulatory agency and clinical guidance documents were also reviewed. Study Selection and Data Extraction Included articles describe in vitro or in vivo animal or human data for dexamethasone induction of cytochrome P450 (CYP) 3A4 or P-glycoprotein (P-gp). Data Synthesis Dexamethasone has the potential to interact with the DOACs via CYP3A4 and/or P-gp induction. Only apixaban and rivaroxaban have CYP3A4 metabolism. Dexamethasone can increase CYP3A4 activity by up to 70% and reduce the area under the concentration-time curve (AUC) of CYP3A4 substrates by >40%, which is consistent with criteria for a weak CYP inducer. In rodents, dexamethasone P-gp induction is associated with AUC reductions of 20% to 50%. Human data are lacking. Relevance to Patient Care and Clinical Practice Severe COVID-19 infection is associated with hypercoagulability. Although heparins are the preferred anticoagulants for hospitalized COVID-19 patients, DOACs are being utilized. Dexamethasone is recommended for hospitalized COVID-19 patients requiring supplemental oxygen. The concurrent use of dexamethasone and apixaban or rivaroxaban in such patients carries the potential for reduced anticoagulant effect during a state of heightened thrombotic risk. Conclusions Concurrent use of dexamethasone and apixaban or rivaroxaban in hospitalized COVID-19 patients with laboratory evidence of COVID coagulopathy should be avoided until higher-quality data are available.

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Ischemic and Thrombotic Events Associated with Concomitant Xa-inhibiting Direct Oral Anticoagulants and Antiepileptic Drugs: Analysis of the FDA Adverse Event Reporting System (FAERS)

Cited by 28 publications

References 21 publications

Concomitant Use of Direct Oral Anticoagulants and Antiepileptic Drugs: A Prospective Cohort Study in Patients with Atrial Fibrillation

Concomitant Use of Direct Oral Anticoagulants and Antiepileptic Drugs: A Prospective Cohort Study in Patients with Atrial Fibrillation

Effects of Hypericum perforatum (St John's wort) on the pharmacokinetics and pharmacodynamics of rivaroxaban in humans

Potential Dexamethasone–Direct Oral Anticoagulant Drug Interaction: Is This a Concern in COVID?

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