Systematic literature review and meta-analysis of lotilaner 0.25% and tea tree oil for Demodex blepharitis

Introduction Demodex blepharitis (DB) is a common, often underdiagnosed inflammatory eyelid disease caused by Demodex mite infestation. Currently, the only FDA-approved treatment for DB is lotilaner ophthalmic solution, 0.25%. Off-label therapies, including tea tree oil or terpinen-4-ol (collectively referred to as TTO) products, have also been used; however, supporting evidence is inconsistent. This systematic literature review and meta-analysis evaluated the treatment effects and quality of evidence for lotilaner ophthalmic solution, 0.25% and TTO products in patients with DB. Methods MEDLINE, EMBASE, Cochrane CENTRAL, ClinicalTrials.gov, and ICTRP were searched from inception through July 10, 2025, to identify randomized controlled trials of lotilaner 0.25% or TTO. Results Nine randomized controlled trials were included, with four evaluating lotilaner 0.25% versus vehicle and five evaluating TTO versus sham, comprising a total of 1,513 patients. Compared with vehicle, lotilaner 0.25% produced significantly lower mite density (mean difference -1.29 mites/lash at both 2–4 and 6–8 weeks; p<0.0001) and significantly higher odds of mite eradication (OR 4.70 at 2–4 weeks; OR 9.60 at 6–8 weeks), collarette reduction to 0–2 collarettes (OR 8.39 and 9.67), and erythema cure at 6–8 weeks (OR 3.91; all p<0.0001). TTO did not demonstrate a statistically significant difference versus sham for mite density or mite eradication at either timepoint. Discussion These findings demonstrate a consistent, statistically significant benefit of lotilaner 0.25% across assessed outcomes compared with vehicle, supporting lotilaner 0.25% as an effective pharmacological treatment for DB. In contrast, randomized TTO studies were heterogeneous in product concentration, dosing regimen, and sham comparators and did not demonstrate a statistically significant effect on mite density or mite eradication versus sham comparators.