Endometrial safety, overall safety and tolerability of transdermal continuous combined hormone replacement therapy over 96 weeks: a randomized open-label study.

OBJECTIVES: To establish whether transdermal continuous hormone replacement therapy (HRT) with estrogen/progestogen provides adequate long-term endometrial protection in postmenopausal women over a period of 96 weeks. METHODS: This multicenter, randomized, open-label, parallel-group study evaluated the endometrial effects and overall safety and tolerability of a transdermal matrix patch delivering estradiol (E2) 50 microg/day and norethisterone acetate (NETA) 140 microg/day (Estalis; patches applied twice weekly without intermediate breaks) and a once-daily oral comparator (Kliogest; one tablet containing E2 2 mg/NETA 1 mg) in postmenopausal women. A total of 406 women with an intact uterus, aged 44-69 years, were randomized in the 48-week core phase of the study, and 239 continued into the 48-week extension phase. Subjects were randomized in the ratio 3 : 1 to transdermal or oral E2/NETA treatment. RESULTS: No cases of endometrial hyperplasia or endometrial cancer were reported with either treatment during the core or extension phase. Both treatments were generally well tolerated, with most adverse events (>90%) being mild to moderate, although minor differences in the tolerability profile were observed between treatments. CONCLUSIONS: Continuous combined transdermal HRT with E2/NETA shows no evidence of an increased endometrial hyperplasia or endometrial cancer risk over a 96-week period.

Efficacy, tolerability and safety of darifenacin, an M(3) selective receptor antagonist: an investigation of warning time in patients with OAB.

This double-blind, randomised placebo-controlled, multicentre study evaluated the efficacy, tolerability and safety of 12 weeks' treatment with controlled release darifenacin 15 mg once daily (qd), in 445 patients with overactive bladder (OAB). The primary endpoint was warning time (time from first sensation of urgency to voiding), and secondary endpoints included urge incontinence episodes and volume voided. Darifenacin treatment resulted in numerical increases in warning time, but these were not significant compared with placebo -- highlighting difficulties in assessing this parameter. Significant improvements were seen with darifenacin vs. placebo in urge incontinence episodes/week, volume voided and quality of life (QoL). Darifenacin was associated with increases in urgency-free time (UFT; time between any void to the next urgency event) vs. placebo. Treatment was well tolerated; the most commonly reported adverse events were the typical antimuscarinic effects of dry mouth and constipation, both infrequently leading to discontinuation. This study demonstrated the difficulty in measuring warning time, due in part to its subjective nature; the authors believe further investigation is warranted to allow urgency to be better defined. Further investigation of UFT is required to determine its role in evaluating urgency. The study confirmed that darifenacin 15 mg qd is an effective and well-tolerated treatment for OAB, which improves QoL.