Effective management of endometriosis over the longer term is an important objective. The painful symptoms and impairment in quality of life associated with endometriosis may persist or deteriorate in the absence of effective treatment. Recurrence is frequent even after successful surgery, while there are only limited trial data to confirm the efficacy and safety of long-term treatment for many medications used in endometriosis.
Dienogest has been investigated as a long-term treatment of endometriosis in two large trials performed in Europe and Japan, which included assessments of efficacy, change in quality of life, safety, and tolerability.
Women who completed the 12-week placebo-controlled study in Europe54
were offered the opportunity to enter an open-label extension study of dienogest for up to 53 additional weeks, providing an overall treatment period of up to 65 weeks.62
Notably, of the 188 women completing the placebo-controlled study, a large proportion (n = 168, 89%) consented to enter the long-term extension study. The intensity of pain showed significant, sustained improvements during the long-term study, in addition to the improvements associated with dienogest during the placebo-controlled phase. Mean visual analog scores decreased from 56.9 mm at baseline of the placebo-controlled study to 34.1 mm at baseline of the long-term study, to 11.5 mm at the end of the 53 additional weeks of treatment (). During a 24-week treatment-free period following the long-term study, visual analog scores increased only moderately, suggesting that dienogest induces a beneficial effect that may persist after treatment cessation. Short Form 36 Health Survey scores during the treatment-free period indicated minimal changes in physical or mental indices of quality of life over six months after cessation of dienogest.
Figure 2 Change in visual analog scale (VAS) score during the placebo-controlled (A) and the extension (B) studies.54,62
During the long-term study, laboratory parameters, vital signs, and body weight remained stable or underwent minimal changes. Adverse effects considered potentially treatment-related developed in 16.1% of women, including breast discomfort (4.2%), nausea (3.0%), and irritability (2.4%). The maximal intensity of treatment-related adverse events was mild or moderate in 92.5% of cases. In agreement with trends observed in the 12- and 24-week studies, the intensity and frequency of bleeding reduced progressively over the course of the long-term study. During post-treatment follow-up, bleeding returned to normal intensity and cyclic patterns resumed within 4–6 weeks. Treatment compliance during the long-term study was high (98%) and discontinuation rates due to adverse events or lack of efficacy were both low (2.4% and 0.6%, respectively).
The results of this long-term study performed in Europe are supported by a 52-week, nonrandomized trial of dienogest 2 mg daily conducted in Japan on 135 women with confirmed endometriosis.63
Global improvement was measured by change in the severity of five subjective symptoms (lower abdominal pain, lumbago, dyschezia, dyspareunia, and pain on vaginal examination) and two objective findings (induration involving pouch of Douglas and uterine mobility). Moderate or marked global improvement was recorded in 72.5% of patients after 24 weeks and in 90.6% after 52 weeks of dienogest treatment (). Changes in visual analog score for lower abdominal pain and lumbago decreased progressively, while the proportion of patients demonstrating a reduction in cyst size >25% was 85% at 52 weeks. Quality of life assessments using the Short Form 36 Health Survey score indicated improvements in bodily pain by 23.57 and 27.37 points (on a 100-point scale) at 24 and 52 weeks, respectively, compared with baseline. Patient satisfaction with dienogest at the end of treatment was high, with 88.9% of women responding that they were “certainly willing” or “would prefer” to use dienogest again.
Figure 3 Increase over time in the proportion of cases assessed as “marked or moderate” for global improvement, overall improvement of subjective symptoms during non-menstruation, and overall improvement of objective findings.58
The most commonly reported treatment-related adverse event was metrorrhagia (71.9%), followed by headaches (18.5%) and constipation (10.4%). None of the treatment-related adverse events was rated as serious. Metrorrhagia resolved in 96 of the 97 affected patients either during the study or within two months of study cessation. The frequency of bleeding lessened as treatment progressed, so that 40.5% of women were experiencing no bleeding by 49–52 weeks. Resumption of menses was confirmed in all women at the end of the study. The discontinuation rate due to treatment-related adverse events was 5.2%. Lumbar bone mineral density decreased by 1.7 ± 2.2% between baseline and week 52, with the greatest change in the first 24 weeks. The authors noted that this bone mineral density change may be considered mild and not significantly greater than that observed in untreated women of similar age. No biochemical markers of bone metabolism indicated changes outside the normal reference range.
Recently, a small open-label, nonrandomized study performed in Japan has investigated continued dienogest 2 mg/day for 12 months (n = 33 women) in comparison with sequential treatment including GnRH agonist (leuprorelin acetate or buserelin acetate) for 4–6 months followed by dienogest 1 mg/day for 12 months (n = 38).65
Continued dienogest significantly reduced the mean visual analog scores for dysmenorrhea, nonmenstrual pelvic pain, and dyspareunia at six and 12 months, equivalent to the score reductions achieved with GnRH agonist followed by dienogest. For approximately 40% of women in the sequential treatment group, the dienogest dose was increased from 1 mg to 1.5–2 mg/day to optimize bleeding control. Consistent with other studies, uterine bleeding was significantly reduced in the second compared with the first six months of dienogest treatment. The divergence in dienogest dose hinders the interpretation of bleeding rates across the treatment groups. The authors concluded that dienogest represents a practical and efficient long-term therapy in patients who respond to GnRH agonist therapy. The data may be interpreted also to indicate that continued long-term dienogest is as effective for pain relief as a GnRH agonist followed by dienogest therapy.