Safety, pharmacokinetics, and preliminary pharmacodynamics of 1% and 3% diclofenac vaginal hydrogel for the treatment of primary dysmenorrhea: a randomized, placebo controlled trial

Abstract

Objective: To describe the safety and pharmacokinetics (PK) of a novel 1% and 3% diclofenac vaginal hydrogel among healthy premenopausal women with symptomatic primary dysmenorrhea. Preliminary efficacy was an exploratory objective. Methods: A Phase 1, randomized, double-blind, placebo-controlled, clinical trial was conducted. Safety was measured by treatment emergent adverse events (TEAEs) after both a single and three daily vaginal doses. Vaginal fluid and plasma PK of diclofenac were measured after a single dose. Participants recorded daily dysmenorrhea associated pain (DAP) scores in a control cycle and during treatment with the three daily doses of study product, and recorded use of rescue pain medications and non-pharmacologic pain-relieving measures. Results: Vaginal diclofenac 1% and 3% was well tolerated, with no significant difference in the frequency or severity of TEAEs compared to placebo vaginal hydrogel (p values > 0.13). Median maximum plasma diclofenac concentrations were 36.4 ng/mL and 57.6 ng/mL for the 1% and 3% dose, respectively, and were mostly below the limit of quantification by 48 h post single dose. Median vaginal fluid diclofenac concentrations peaked at 2 h for the 1% formulation (1105 µg/mL) and 8 h for the 3% formulation (4415 µg/mL). Participants in the 1% diclofenac group had non-significant reductions in DAP scores post-treatment, but sample size and variability of DAP scores limited statistical comparisons of this exploratory endpoint. Conclusion: The safety and PK data support further development of vaginal diclofenac hydrogel (DARE-PDM1) for the treatment of primary dysmenorrhea. Clinical Trial Registration: NCT05752526