(205) Co-Administration of Oxycodone and CYP3A4-Inhibiting Calcium Channel Blockers and Opioid Overdose: Real-World Evidence from Population-based Claims Data in the United States, 2000-2020.

Background: Medications inhibiting cytochrome P450 (CYP) 3A4 liver enzyme increase oxycodone plasma concentration. However, the clinical implications of this pharmacokinetic drug-drug interaction (DDI) are unknown.

Objectives: To compare the risk of opioid overdose with co-administration of oxycodone and CYP3A4-inhibiting calcium channel blockers (CCBs), verapamil or diltiazem, vs. non-inhibiting CCB (amlodipine).

Methods: Using four US pharmacy and medical claims databases (2000-2020), we constructed two cohorts of adults who (1) initiated oxycodone while treated with CCBs (i.e., oxycodone initiation cohort), or (2) initiated CCBs while treated with oxycodone (i.e., CCB initiation cohort). In each cohort, patients were assigned to CYP3A4-inhibiting or non-inhibiting CCB based on treatment at the index date (initiation of 2nd treatment). Baseline covariates were measured in the 180-days up to and including the index date and were balanced using propensity score (PS) matching weights. In primary analyses, follow-up for the outcome (emergency room visit or hospitalization due to opioid overdose) was 365 days, so long as patients were alive, insured, and on both oxycodone and index CCB therapy. Secondary analyses included a 60-day intention-to-treat (ITT) approach and alternative outcome definitions. Absolute rates were expressed as incidence rates (IR) per 1000 person-years (PY). Adjusted hazard ratios (HR) and 95% confidence intervals (CI) were estimated using weighted Cox proportional hazards models, stratified by database.

Results: The oxycodone initiation cohort included 2,111,085 oxycodone initiators on verapamil or diltiazem and 630,209 initiators on amlodipine. In the weighted sample, 282 outcomes in the CYP3A4-inhibiting CCB (N = 555,056; IR = 6.71 per 1000 PY) and 300 in the amlodipine group (N = 552,211; IR = 7.23 per 1000 PY) yielded a HR of 0.93 (CI: 0.81, 1.06) in the primary analysis. The ITT analysis produced a HR of 0.92 (CI: 0.81, 1.04). The CCB initiation cohort included 432,864 verapamil/diltiazem and 87,455 amlodipine initiators while on oxycodone therapy. In the weighted sample, 149 outcomes in the CYP3A4-inhibiting CCB (N = 71,886; IR = 12.69 per 1000 PY) and 181 in the amlodipine group (N = 71,334; IR = 14.69 per 1000 PY) resulted in a HR of 0.85 (CI: 0.71, 1.03). The ITT analysis estimated an HR of 0.98 (CI: 0.81, 1.18). Results were consistent across alternative outcome definitions.

Conclusions: In this study, the risk of an emergency room visit or hospitalization for opioid overdose during the co-administration of oxycodone and CCBs was low. There was no evidence that CYP3A4-inhibiting CCBs increased opioid overdose risk compared with non-inhibiting CCBs.