Safety and tolerability of dienogest in endometriosis: pooled analysis from the European clinical study program

Abstract

BackgroundIn four randomized, controlled, European trials, dienogest 2 mg once daily demonstrated significant efficacy for lesion reduction and reduction in pain intensity in endometriosis. We describe a pooled analysis of the safety and tolerability data from these trials to confirm and further characterize the safety profile of dienogest in the treatment of endometriosis.MethodsAll 332 women treated with dienogest 2 mg who participated in the four clinical trials were included in the pooled analyses for safety assessments, including adverse events, laboratory tests, vital signs, body weight, and bleeding patterns. Safety variables were analyzed using descriptive statistics.ResultsPooled analyses of this large patient population confirmed that dienogest 2 mg is well tolerated, with a favorable safety profile extending over a period up to 65 weeks in women with endometriosis. The most common adverse drug reactions were headache, breast discomfort, depressed mood, and acne, each occurring in <10% of women. All these adverse events were generally of mild-to-moderate intensity and associated with low discontinuation rates. The bleeding pattern associated with dienogest 2 mg was well tolerated, and only two women (0.6%) reported bleeding events as the primary reason for premature discontinuation. Laboratory and vital sign assessments indicated no safety concerns for dienogest. Estradiol levels were maintained within the low-physiological range, in support of previous evidence indicating that dienogest 2 mg demonstrates therapeutic efficacy without inducing estradiol deficiency.ConclusionIn this pooled analysis of 332 women with endometriosis, dienogest was well tolerated with a favorable safety profile extending over a period of up to 65 weeks. There is a paucity of randomized trial evidence to support the use of many treatments in endometriosis. These pooled analyses from four clinical trials of dienogest 2 mg represent a contribution to evidence-based medicine in endometriosis, providing outcomes of potential relevance to daily practice.

Long‐term dienogest administration in patients with symptomatic adenomyosis

“…Previous studies reported a slight hypoestrogenic effect of dienogest after 52 or 65 weeks of treatment . Our result was consistent with that of the previous reports, and we showed that dienogest is tolerable for long‐term use.…”

“…Our result was consistent with that of the previous reports, and we showed that dienogest is tolerable for long‐term use. Estradiol levels in dienogest treatment, unlike those in GnRH agonist treatment, were maintained with low physiologic range and without inducing hypoestrogenic effects, thereby indicating that dienogest is tolerable and preferable for long‐term use.…”

“…Only one study on the long‐term dienogest use for uterine adenomyosis has been conducted, although some studies reported on long‐term dienogest use and its effects on endometriosis . Moreover, no study that describes dienogest use for >2 years has been reported.…”

Endometriosis: where are we and where are we going?

“…Of the progestins, the 19-nortestosterone derivatives are less androgenic and offer better side effect profiles (Angioni et al 2014). In a RCT, dienogest significantly decreases endometriosis-related pain similar to gonadotropin releasing hormone agonists (GnRHa), both as initial and post-operative therapy, without the negative side effect profile of GnRHa (Angioni et al 2014, Andres Mde et al 2015, Granese et al 2015, Strowitzki et al 2015). Levonorgestrel, delivered through an intrauterine system after conservative surgery, significantly decreases dysmenorrhea, dyspareunia, and non-cyclic pelvic pain compared to expectant management in a RCT of 55 patients (Tanmahasamut et al 2012, Imai et al 2014).…”

Use of dienogest in endometriosis: a narrative literature review and expert commentary

“…In a pooled analysis of four clinical trials, dienogest 2 mg was well tolerated, with a favorable safety profile extending for up to 65 weeks. The most commonly reported adverse events were headache, breast discomfort, depressed mood, and acne, each occurring in <10% of patients, which were generally mild to moderate in intensity and associated with low discontinuation rates 41 . Administration of dienogest for up to 5 years has also demonstrated a favorable safety and tolerability profile [29][30][31][32][33][34] .…”