Post hoc analysis of pooled safety data from eleven Phase 3 clinical trials to identify potential pharmacodynamic drug interactions between tapentadol and SSRIs/SNRIs

Objectives: Tapentadol extended-release (ER) oral tablets prescribing information warns there have been reports of serotonin syndrome with concurrent use of tapentadol and serotonergic drugs.  We analyzed pooled safety data from 11 randomized, double-blind, placebo-controlled trials to identify other potential pharmacodynamic drug interactions associated with concomitant use of tapentadol and selective serotonin reuptake inhibitor (SSRI) or serotonin norepinephrine reuptake inhibitor (SNRI).

Methods: Safety populations were pooled from 7 studies investigating oral immediate-release tapentadol vs. placebo over 3-10 days for acute pain and 4 studies of tapentadol ER vs. placebo over 15 weeks for chronic pain.  All 11 studies permitted SSRIs if dose was stable at baseline and during study. SNRIs were prohibited, but some subjects deviated from protocol and took SNRI.  Across studies, 3269 subjects received tapentadol; 1901 received placebo.  Adverse event (AE) incidences were compared for tapentadol vs. placebo using data from only subjects who took SSRI (n=310), SNRI (n=31), or both (n=4).  Thus, all subjects analyzed (N=345) were taking fluoxetine, paroxetine, fluvoxamine, sertraline, citalopram, escitalopram, venlafaxine, or duloxetine at baseline.  Since SSRIs/SNRIs have an established AE profile, this analysis enabled comparison of AEs reported for Tapentadol+SSRI/SNRI (N=208) vs. Placebo+SSRI/SNRI (N=137) to assess if adding tapentadol (vs. adding placebo) to SSRI or SNRI therapy changed the profile.

Results: Incidences of nausea, vomiting, dry mouth, dizziness, somnolence, pruritis, hyperhidrosis, and hot flush were significantly higher (P<0.05) for Tapentadol+SSRI/SNRI vs. Placebo+SSRI/SNRI, but were similar to incidences listed in tapentadol labeling.  Other AEs occurred at numerically higher rates for Tapentadol+SSRI/SNRI vs. Placebo+SSRI/SNRI, but most were also expected for tapentadol alone.  Unexpected AEs with rates >2% for Tapentadol+SSRI/SNRI were pharyngolaryngeal pain (p=0.045), abdominal pain (ns), and myalgia (ns).

Conclusion: This post hoc analysis of pooled clinical trial data did not identify new clinically relevant adverse drug interactions associated with adding tapentadol to SSRI/SNRI therapy.