The edition · Clinical Pharmacology
Enzyme-inducing antiseizure drugs left DOAC levels subtherapeutic, and doubling the dose did not always rescue them
A scoping review of antiseizure drug and DOAC interactions, PPIs that blur CYP2C19 genotype in escitalopram users, a reappraisal of the fezolinetant neoplasm signal, and a recall of compounded tirzepatide and semaglutide.
The edition in brief
A scoping review of 30 clinical reports found that enzyme-inducing antiseizure medications (carbamazepine, phenobarbital, primidone, oxcarbazepine) consistently lowered rivaroxaban and apixaban concentrations, with serious thrombotic failures; doubling the DOAC dose did not prevent events in several cases. Data for levetiracetam and valproate were sparse and inconsistent. A Norwegian therapeutic drug monitoring study of 2,818 CYP2C19-genotyped escitalopram users found that proton pump inhibitor co-medication narrowed the metabolic gap between ultrarapid and poor metabolisers from 4.5-fold to 2.8-fold with pantoprazole and 1.8-fold with omeprazole or esomeprazole, a phenoconversion effect that weakens genotype-based prescribing. A Drug Safety analysis argues that the dose-related, non-significant neoplasm imbalance in the fezolinetant phase 3 programme (RR 6.6, 95% CI 0.9 to 51.3) was dismissed on weak mechanistic grounds and calls for structured surveillance. The FDA lists Class II recalls of compounded tirzepatide and semaglutide products for lack of sterility assurance. The pearl covers checking for enzyme inducers before any DOAC.
PPIs narrowed the CYP2C19 genotype effect on escitalopram metabolism, omeprazole most of all
When interpreting a CYP2C19 genotype for escitalopram, check for PPI co-prescription; PPIs, particularly omeprazole or esomeprazole, can blunt the difference between fast and slow metabolisers.
A reappraisal argues the fezolinetant neoplasm signal was dismissed too readily
When prescribing fezolinetant, record the indication, note any personal or family cancer history, and report new neoplasms through pharmacovigilance channels.
FDA lists Class II recalls of compounded tirzepatide and semaglutide for sterility concerns
Ask patients on incretin injections whether their product is compounded, and favour approved, licensed products.
Check for enzyme inducers before starting any DOAC
Before prescribing a DOAC, check for strong CYP3A4 and P-glycoprotein inducers; if one is essential, consider warfarin with INR monitoring instead.
Enzyme-inducing antiseizure drugs left DOAC levels subtherapeutic, with clinical failures despite dose increases
Avoid combining a DOAC with carbamazepine, phenobarbital, primidone or similar inducers; if both are unavoidable, consider switching the antiseizure drug or using warfarin, and measure DOAC levels where available.
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