Topical sildenafil cream associated with lower systemic exposure vs oral sildenafil

A phase 1 study found that investigational topical sildenafil cream 3.6% was associated with lower systemic exposure compared with the oral dosing referent in healthy men, according to findings published in Sexual Medicine.¹

The investigators also reported that all treatment-emergent adverse events (TEAEs) with topically applied sildenafil were mild.

“These phase 1 findings provide important clinical evidence regarding the potential safety and pharmacokinetic profile of topical sildenafil cream in men,” said David Friend, PhD, Chief Scientific Officer of Daré Bioscience, in a news release on the results.² “The substantially lower systemic exposure observed with topical administration is consistent with the rationale for localized delivery of sildenafil and supports continued development of our investigational sildenafil cream, 3.6% as a potential differentiated approach for arousal concerns.”

Trial design and findings

The open-label, randomized, parallel-group phase 1 study enrolled 62 healthy men. Participants were randomly assigned 1:1:1:1:1 to receive either 36 mg of sildenafil in 1 g of cream or 71 mg in 2 g of cream, each administered with or without male condom use, or a 50-mg oral sildenafil dose. Blood samples and orthostatic vital signs were collected before dosing and for up to 32 hours after administration.

The primary objectives were to characterize systemic pharmacokinetics and assess safety. The investigators measured plasma concentrations of sildenafil and its active metabolite, N-desmethyl sildenafil.

Fourteen TEAEs were reported, and all were characterized as mild. Seven events occurred after oral sildenafil administration, including 4 reports of headache and 2 of flushing. The study reported no serious or severe adverse events, deaths, or discontinuations attributable to TEAEs.

Mean maximum plasma concentrations (Cmax) ranged from 969 to 1274 pg/mL across the topical groups, compared with 238,000 pg/mL following oral sildenafil. Relative bioavailability of sildenafil after topical administration ranged from 2.55% to 3.20% compared with the oral reference dose. Pharmacokinetic findings were similar when the cream was used with or without a condom.

At the 36-mg topical dose, the mean Cmax was approximately 187-fold lower than that observed with 50 mg of oral sildenafil. Measures of systemic exposure were approximately 35-fold lower for AUC_last and 32-fold lower for AUC_inf at the 36-mg topical dose compared with oral administration.

The investigators also reported less-than-dose-proportional increases in Cmax and systemic exposure when the topical sildenafil dose was doubled from 36 mg to 71 mg.

Development in female sexual health

Sildenafil cream has also been investigated in premenopausal women with female sexual arousal disorder (FSAD). A phase 2b randomized, placebo-controlled study (NCT04948151) evaluated sildenafil cream 3.6% in premenopausal women with FSAD.Published analyses from that program have examined both preliminary efficacy and safety, including TEAEs among participants and their sexual partners.^3,4

In the phase 2b safety analysis, 99 participants received sildenafil cream and 94 received placebo during the 12-week double-blind dosing period. TEAEs were reported by 29 participants in the sildenafil arm and 28 participants in the placebo arm; all events were mild or moderate, and application-site discomfort was the most common treatment-related event.

Data from a phase 1 study of sildenafil cream in premenopausal women with FSAD were also recently published in Menopause. According to the authors, the results were consistent with findings from the phase 2b study.⁵

The phase 1 study of sildenafil cream in men further characterizes the behavior of the 3.6% formulation and the localized drug-delivery approach.

“We are a women’s health company, and that remains at the center of everything we do. One of Daré Bioscience’s core strengths is our ability to apply sophisticated formulation and drug-delivery science to well-understood active ingredients in ways designed to address important gaps in care,” said Sabrina Martucci Johnson, President and CEO of Daré Bioscience, in the news release.² “These peer-reviewed results are exciting because they demonstrate the potential power of that approach. Topical dosing is targeted and has been shown to result in substantially lower systemic exposure than an oral dose of sildenafil. This study in men provided additional clinical insight into our proprietary topical sildenafil cream formulation and expanded the evidence supporting its differentiated delivery profile. We believe that knowledge ultimately strengthens the scientific foundation of our work in women’s sexual health while also supporting the broader potential of Daré Bioscience’s formulation.”

REFERENCES

1. Cornell K, Johnson I, Thurman A, Friend D. An open-label, single-dose, randomized, parallel-group study of the safety and relative bioavailability of topical sildenafil cream vs oral sildenafil in healthy male adults. Sex Med. 2026;14(6):qfag083. doi:10.1093/sexmed/qfag083

2. Daré Bioscience announces peer-reviewed publication of phase 1 sildenafil cream study in men demonstrating substantially lower systemic exposure versus oral sildenafil. News release. Daré Bioscience, Inc. September 14, 2026. Accessed September 15, 2026. https://www.globenewswire.com/news-release/2026/09/14/3361123/30757/en/dar%c3%a9-bioscience-announces-peer-reviewed-publication-of-phase-1-sildenafil-cream-study-in-men-demonstrating-substantially-lower-systemic-exposure-versus-oral-sildenafil.html

3. Johnson I, Thurman AR, Cornell KA, et al. Preliminary efficacy of topical sildenafil cream for the treatment of female sexual arousal disorder: A randomized controlled trial. Obstet Gynecol. 2024;144(2):144-152. doi:10.1097/AOG.0000000000005648

4. Thurman AR, Johnson I, Cornell KA, et al. Safety of topical sildenafil cream, 3.6% in a randomized, placebo-controlled trial for the treatment of female sexual arousal disorder. J Sex Med. 2024;21(9):793-799. doi:10.1093/jsxmed/qdae089

5. Cornell K, Johnson I, Thurman A, Friend D. A phase 1, open-label, within-participant dose-escalation study to evaluate the safety and pharmacokinetics of topical sildenafil cream in healthy postmenopausal women. Menopause. 2026. doi:10.1097/GME.0000000000002879