Ospemifene for the treatment of vulvar and vaginal atrophy: A meta-analysis of randomized trials. Part II: Evaluation of tolerability and safety

Objective: To evaluate the tolerability and safety of ospemifene in treating dyspareunia associated with post-menopausal vulvo- vaginal atrophy (VVA). Methods: The literature was searched through to 31 July 2018 to identify randomized controlled trials comparing ospemifene 60 mg against placebo for the treatment of VVA. Two groups of outcomes were selected: 1) side-effects, including hot flushes, urinary tract infection (UTI), headache, deep venous thrombosis (DVT), coronary heart disease (CHD), cardiovascular event (CVE), discontinuation due to side-effects, serious adverse event (SAE); 2) Safety, in relation to endometrial thickness, vaginal bleeding, breast tenderness, breast and endometrial cancer. A random-effects model was used in the meta-analysis. Study quality and bias risk were assessed with the Cochrane tool. Results: In the group of patients treated with ospemifene, there was a slightly higher rate of hot flushes (OR:2.36, 95% CI 1.26-4.42; p = 0.007) and UTI (OR:1.97, 95% CI 1.23-3.14, p = 0.005) at 12 weeks of treatment, but no differences were noted after 52 weeks. The incidence of headaches, DVT, CHD, CVE, discontinuation of treatment, and SAES was not significantly different between groups. Ospemifene treatment was statistically associated with a greater endometrial thickness in women with an intact uterus both at 12 weeks (SMD: 0.40, (95% CI 0.17 to 0.63, p < 0.0005) and at 52 weeks (SMD: 0.62, 95% CI 0.23-1.01, p = 0.002); however, this increase was not clinically relevant. The incidence of vaginal bleeding, endometrial cancer, breast tenderness, breast and endometrial cancer was not significantly different between groups. Conclusions: This meta-analysis suggests that ospemifene treatment is well tolerated and presents a good safety profile. Long-term safety studies with larger samples, which include patients at high risk, are warranted.