(P-265) Detecting Tizanidine and cyp1a2 Inhibitor Interaction Signals Using the Food and Drug Administration’s Adverse Event Reporting System

Background: Tizanidine is a muscle relaxant drug with pain relieving properties. It is primarily cleared from the body through metabolism facilitated by CYP1A2 enzyme. Drugs that inhibit CYP1A2 might reduce tizanidine clearance, thereby increasing the risk of tizanidine toxicity, which can lead to severe decrease in blood pressure, bradycardia, and syncope.

Objectives: To identify drug-drug interaction (DDI) safety signals involving tizanidine and CYP1A2 inhibitors in the United States Food and Drug Administration Adverse Event Reporting System (FAERS) database.

Methods:

Design: observational analytical study. The FAERS database was searched from the first quarter of 2004 through the third quarter of 2020 for reports associated with tizanidine and at least one known CYP1A2 inhibitor, where the report indicated that tizanidine was the primary suspect, secondary suspect, or an interacting drug. Reports were required to include at least one of the following outcomes based on MedDRA Preferred Term: hypotension, drop blood pressure, and bradycardia. A reporting odds ratio (ROR) and 95% CI were calculated as a measure of disproportionality. We defined that a DDI signal was present when the lower bound of the 95% CI ≥ 2.0 and there were more than 5 reports mentioning both tizanidine and CYP1A2 inhibitors. FAERS processing and statistical analyses were performed in SQL using the open source AEOLUS database.

Results: For the reports containing tizanidine and ciprofloxacin mentioning hypotension (n=34), the ROR was 28.1 (19.2-41.2); for reports containing tizanidine and ciprofloxacin mentioning bradycardia (n= 5), the ROR was 13.5 (5.5-32.9). For reports containing tizanidine and fluvoxamine mentioning hypotension (n= 5), the ROR was 36.9 (13.1-103.4). Other CYP1A2 inhibitors analyzed were ethinyl estradiol, mexiletine, zafirlukast, vemurafenib, zileuton and rofecoxib (before it was removed from the market); there were fewer than 5 cases involving these drugs with any of the outcomes of interest.

Conclusions: The concomitant use of tizanidine with either ciprofloxacin or fluvoxamine should be avoided as it could lead to severe cardiovascular side effects. No signal of potential harm for exposure with other CYP1A2 inhibitors using the FAERS data was found.