Adherence to a flexible extended regimen for oral hormonal contraception provided in blister packaging compared with an adherence-supporting digital tablet dispenser: historical comparison of data from two clinical studies.

BACKGROUND: The Clyk™ digital pill dispenser helps ensure correct and consistent administration of a flexible extended regimen of the combined oral contraceptive, ethinylestradiol (EE) 20 µg/drospirenone 3 mg (EE/drospirenone ; YAZ(®) Flex Flex), guiding users through the intake cycle and 4-day pill break and providing visible and acoustic daily reminders when pill intake is due. A study showed that the audible alarm function of the dispenser could help reduce the number of missed pills, but it lacked an appropriate "non-dispenser" group for a meaningful assessment of the impact of the dispenser on adherence. This study indirectly assessed the overall effect of the digital dispenser on adherence by comparing data from a treatment with standard blister packaging. MATERIALS AND METHODS: One-year adherence data were compared from two similarly designed, Phase III, open-label, randomized trials of EE/drospirenoneFlex. In study 1, women used diary cards to record adherence with EE/drospirenoneFlex dispensed in blister packs (n=640), and in study 2 the dispenser was used with the alarm activated (n=250) or deactivated (n=248) in addition to using diary cards. RESULTS: A mean (±SD) of 4.3 (±4.24) missed pills over 1 year were recorded in diary cards among women who dispensed their pills from the blister packages (study 1) compared with 1.0 (±2.4) recorded by the alarm-activated dispenser (study 2). In study 2, a mean of 1.9 (±4.2) missed pills were reported in the diaries over 1 year compared with 4.4 (±9.1) from automatic recording by the dispenser (both arms of study 2), indicating underreporting of missed pills in diary cards vs the digital dispenser. Adjusting for this rate of underreporting, an estimated mean of ten pills were missed over 1 year by women using EE/drospirenoneFlex in blister packs, or ten times more than with the digital dispenser with activated acoustic alarm. CONCLUSION: The digital dispenser helps reduce the number of missed pills and increases adherence.

Adherence with ethinylestradiol 20 µg/drospirenone 3 mg in a flexible extended regimen supported by the use of a digital tablet dispenser with or without acoustic alarm: an open-label, randomized, multicenter study.

OBJECTIVE: To evaluate the effect of a digital dispenser's acoustic alarm function on adherence to ethinylestradiol (EE) 20 µg/drospirenone 3 mg in a flexible extended regimen (EE/drospirenoneFlex) among women in five European countries (France, Germany, Italy, Spain, UK) seeking oral contraception. STUDY DESIGN: Randomized, parallel-group open-label study. METHODS: Women aged 18-35 years received EE/drospirenoneFlex administered in a regimen with cycle lengths of their choice with the aid of a digital pill dispenser over 1 year. In group A (N=250), the dispenser's acoustic alarm was activated (ie, acoustic alarm + visual reminder). In group B (N=249), the acoustic alarm was deactivated (ie, visual reminder only). In addition, the women recorded pill intake daily in diary cards. The primary efficacy variable was the mean delay of daily pill release after the dispenser reminded the woman to take a pill (reference time). Secondary efficacy variables included number of missed pills, contraceptive efficacy, bleeding pattern, tolerability, and user satisfaction. RESULTS: Dispenser data showed a mean (standard deviation [SD]) daily delay in pill release of 88 (126) minutes in group A vs 178 (140) minutes in group B (P<0.0001). Median (lower quartile, Q1; upper quartile, Q3) number of missed pills was 0 (0; 1) in group A vs 4 (1; 9) in group B (P<0.0001). Diary card results revealed similar trends; however, underreporting of missed pills was evident in both groups. No pregnancies were reported during 424 women-years of exposure. Across the two groups, the mean (SD) EE/drospirenoneFlex cycle length was 51.0 (31.8) days with strong regional differences, and the mean (SD) number of bleeding/spotting days was 50.4 (33.0) days. EE/drospirenoneFlex was well tolerated, and 80% of women were satisfied with treatment. CONCLUSION: The dispenser's activated acoustic alarm improved adherence with daily tablet intake of EE/drospirenoneFlex, reducing missed pills. EE/drospirenoneFlex provided effective contraception and a good tolerability profile.

Contraceptive efficacy and tolerability of ethinylestradiol 20 µg/drospirenone 3 mg in a flexible extended regimen: an open-label, multicentre, randomised, controlled study.

BACKGROUND: The contraceptive efficacy and tolerability of a new flexible extended regimen of ethinylestradiol (EE) 20 µg/drospirenone (DRSP) 3 mg to extend the menstrual cycle and enable management of intracyclic (breakthrough) bleeding (flexible(MIB)) was investigated and the bleeding pattern compared with a conventional 28-day regimen and a fixed extended 124-day regimen. STUDY DESIGN: This Phase III, 2-year, multicentre, open-label study randomly (4:1:1) allocated women (aged 18-35 years) to the following regimens: flexible(MIB) (24-120 days' active hormonal intake with 4-day tablet-free intervals); conventional (24 days' active hormonal intake followed by a 4-day hormone-free interval); or fixed extended (120 days' uninterrupted active hormonal intake followed by a 4-day tablet-free interval). Primary outcomes included the number of bleeding/spotting days during Year 1 (all regimens) and the number of observed unintended pregnancies over 2 years (flexible(MIB) only). RESULTS: Results were analysed in 1067 women (full analysis set). The mean number of bleeding/spotting days was lower with the flexible(MIB) vs the conventional regimen [41.0±29.1 (95% CI 38.8-43.3) vs 65.8±27.0 (95% CI 62.2-69.4) days, p<0.0001; treatment difference -24.8 (95% CI -29.2 to -20.3) days]. The corresponding value for the fixed extended regimen was 60.9±51.1 (95% CI 53.9-67.9) days. The Pearl Index for the flexible(MIB) regimen was 0.64 (95% CI 0.28-1.26). All regimens had comparable tolerability profiles. CONCLUSIONS: EE 20 µg/DRSP 3 mg administered as a flexible extended regimen with MIB is effective, well tolerated and is associated with statistically significantly fewer bleeding/spotting days and fewer withdrawal bleeding episodes vs EE/DRSP in a conventional 28-day regimen. The flexible(MIB) also provided statistically significantly fewer spotting days vs EE/DRSP in a fixed extended 124-day regimen (post hoc evaluation). The flexible(MIB) regimen allows women to extend their menstrual cycle and manage their intracyclic (breakthrough) bleeding.

Long-term tolerability of ethinylestradiol 20 µg/drospirenone 3 mg in a flexible extended regimen: results from a randomised, controlled, multicentre study.

BACKGROUND: This study was designed to assess the long-term safety and tolerability of a new flexible extended regimen of ethinylestradiol (EE) 20 µg/drospirenone (DRSP) 3 mg, which allows management of intracyclic (breakthrough) bleeding [flexible management of intracyclic (breakthrough) bleeding (MIB)], in comparison to conventional 28-day and fixed extended regimens. STUDY DESIGN: In this Phase III, multicentre, open-label study, women (aged 18-35 years) were randomised to EE/DRSP in the following regimens: flexible(MIB) (24-120 days' active hormonal intake followed by a 4-day tablet-free interval), conventional 28-day (24 days' active hormonal intake followed by a 4-day hormone-free interval) or fixed extended (120 days' uninterrupted active hormonal intake followed by a 4-day tablet-free interval) during a 1-year comparative phase. Thereafter, women entered a 1-year safety extension phase in which the majority received the flexible(MIB) regimen. Safety/tolerability outcomes were measured over 2 years. A separate analysis of certain safety parameters (endometrial, hormonal, lipid, haemostatic and metabolic variables) was conducted at two of the study centres. RESULTS: Results were analysed in 1067 and 783 women in the comparative and safety extension phases. Overall, 56.3% of women experienced ≥1 adverse event (AE) in the safety extension phase. Serious AEs occurred in 3.0%, 1.4% and 3.3% of women receiving the flexible(MIB), conventional and fixed extended regimens, respectively. No unexpected endometrial, hormonal, lipid, haemostatic or metabolic findings occurred with any of the three regimens. CONCLUSIONS: EE/DRSP in a flexible extended regimen with management of intracyclic (breakthrough) bleeding is well-tolerated and, when administered for up to 2 years, has a good safety profile comparable to other estrogen/progestogen oral contraceptives.

Efficacy of ethinylestradiol 20 µg/drospirenone 3 mg in a flexible extended regimen in women with moderate-to-severe primary dysmenorrhoea: an open-label, multicentre, randomised, controlled study.

OBJECTIVES: The aim of this Phase III, multicentre, open-label, randomised study was to compare the efficacy and safety of ethinylestradiol (EE)/drospirenone (DRSP) in a new flexible extended regimen that allowed the management of intracyclic (breakthrough) bleeding (MIB) with that of EE/DRSP in a conventional 28-day regimen in women with moderate-to-severe primary dysmenorrhoea. METHODS: Women (aged 18-40 years) with moderate-to-severe primary dysmenorrhoea-related pain received a flexible extended regimen with MIB (flexible(MIB); minimum 24, maximum 120 days of continuous tablet intake for a flexible number of cycles to reach a treatment duration of at least 140 days with 4-day breaks between cycles) or a conventional 28-day regimen (24 active and four placebo tablets for five cycles) of EE/DRSP. The primary outcome was the number of days with dysmenorrhoeic pain over 140 days. Secondary outcomes included other dysmenorrhoea-related pain outcomes, bleeding profile, satisfaction and safety. RESULTS: Overall, 223 patients received study medication. There were significantly fewer days with dysmenorrhoeic pain with the flexible(MIB) regimen than the conventional regimen (difference -4.2 days, 95% CI -6.5 to -2.0; p=0.0003), as well as considerably fewer days with at least moderate dysmenorrhoeic pain (difference -2.5 days, 95% CI -3.7 to -1.3), dysmenorrhoeic pain that interfered with daily activities (difference -2.2 days, 95% CI -4.2 to -0.1) and pelvic pain (difference -3.4 days, 95% CI -5.9 to -0.9). Adverse events were similar with both regimens. CONCLUSIONS: Compared with the conventional regimen, the flexible extended regimen of EE/DRSP with MIB was associated with a significantly greater reduction in days with dysmenorrhoeic pain in women with moderate-to-severe primary dysmenorrhoea. The flexible(MIB) regimen was also associated with greater improvements in dysmenorrhea according to the Clinical Global Impression rating scale and was generally well tolerated.

Bleeding profile of a flexible extended regimen of ethinylestradiol/drospirenone in US women: an open-label, three-arm, active-controlled, multicenter study.

BACKGROUND: Unscheduled bleeding may affect satisfaction and compliance with extended oral contraceptive (OC) regimens. The bleeding patterns of two variants of a flexible dosing regimen designed to manage intracyclic bleeding problems during extended cycles were compared with that of a conventional OC regimen. STUDY DESIGN: This was a 1-year, open-label, active-controlled, Phase 3 study conducted in the USA. Healthy women (18-45 years) received an ethinylestradiol (EE) 20 mcg/drospirenone 3 mg OC in two flexible extended regimens or in a conventional 24/4 (i.e., 28-day) regimen. The primary regimen [management of intracyclic bleeding (flexible(MIB)) regimen] was an extended dosing regimen that required subjects to initiate 4-day tablet-free intervals after 3 days of breakthrough bleeding/spotting. An alternative extended regimen [active period control (flexible(APC)) regimen] allowed subjects to initiate a 4-day tablet-free interval irrespective of the occurrence of bleeding. Bleeding profiles were compared between treatments. Efficacy and safety outcomes were also assessed. RESULTS: The full analysis set comprised 1864 women (flexible(MIB), N=1406; flexible(APC), N=232; conventional 24/4, N=226). Over 1 year, subjects in the flexible(MIB) group experienced significantly fewer (mean±SD, 40±30) bleeding/spotting days than those in the conventional 24/4 group (52±35). The corresponding value in the flexible(APC) group was 47±33 days. The pregnancy rate in the flexible(MIB) group was 1.65 per 100 woman-years (95% confidence interval, 0.96-2.65). All three regimens were well tolerated. CONCLUSION: A flexible(MIB) dosing regimen of EE 20 mcg/drospirenone 3 mg is associated with good contraceptive efficacy and fewer bleeding/spotting days than the conventional 24/4 regimen.

Male hormonal contraception: a double-blind, placebo-controlled study.

BACKGROUND: This study was performed to assess spermatogenesis suppression and safety of a new combination of an etonogestrel (ENG) implant combined with testosterone undecanoate (TU) injections for male contraception. This is the first large placebo-controlled study for male hormonal contraception. DESIGN AND STUDY SUBJECTS: In this double-blind, multicenter study, we randomly assigned 354 healthy men to receive either a low- or high-release ENG implant sc combined with im TU injections (750 mg every 10 or 12 wk or 1000 mg every 12 wk) or placebo implant and injections. Treatment duration was 42 or 44 wk and posttreatment follow-up at least 24 wk. RESULTS: Overall, spermatogenesis was suppressed to 1 million/ml or less at wk 16 in 89% of men, with approximately 94% in two high-release ENG groups. Suppression was maintained up to the end of the treatment period in 91% of men. For all men who completed the treatment period, 3% never achieved 1 million/ml or less. Median recovery time to a sperm concentration above 20 million/ml was 15 wk (mean 17 wk, 95% confidence interval 16-18 wk). Treatment was well tolerated. As compared with the placebo group, more men in the active treatment groups reported adverse events such as weight gain, mood changes, acne, sweating, or libido change. For both spermatogenesis suppression and safety, differences were small between the active treatment groups. CONCLUSIONS: The combination of an ENG implant with TU injections is a well-tolerated male hormonal method, providing effective and reversible suppression of spermatogenesis. Although the results are good, there is still room for improvement, possibly by adjusting the dose regimen or changing the mode of application.