Kristina Gemzell-Danielsson1, Regine Sitruk-Ware2, Mitchell D Creinin3, Michael Thomas4, Kurt T Barnhart5, George Creasy2, Heather Sussman2, Mohcine Alami2, Anne E Burke6, Edith Weisberg7, Ian Fraser8, Marie-José Miranda9, Melissa Gilliam10, James Liu11, Bruce R Carr12, Marlena Plagianos2, Kevin Roberts2, Diana Blithe13. 1. Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden. Electronic address: kristina.gemzell@ki.se. 2. Center for Biomedical Research, Population Council, New York, NY, USA. 3. Department of Obstetrics and Gynecology, University of California, Davis, Sacramento, CA, USA. 4. Department of Obstetrics and Gynecology, University of Cincinnati, Cincinnati, OH, USA. 5. Department of Obstetrics and Gynecology, Perelman School of medicine, University of Pennsylvania, Philadelphia, PA, USA. 6. Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Bayview Medical Center, Baltimore, MD, USA. 7. Family Planning NSW, and University of Sydney, Sydney, Australia. 8. University of New South Wales; Family Planning NSW, and University of Sydney, Sydney, Australia. 9. Instituto Chileno de Medicina Reproductiva (ICMER), Santiago, Chile. 10. Department of Obstetrics, Gynecology and Pediatrics, University of Chicago, Chicago, IL, USA. 11. Department of Obstetrics and Gynecology, Case Western Reserve University, Cleveland, OH, USA. 12. UT Southwestern University, Dallas, TX, USA. 13. Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA.
Abstract
OBJECTIVES: To evaluate safety outcomes from clinical studies of a 12-month contraceptive vaginal system (CVS) releasing an average of segesterone acetate (SA) 150 mcg and ethinyl estradiol (EE) 13 mcg daily. STUDY DESIGN: We integrated clinical safety data from nine studies in which women used the CVS for 21 consecutive days and removed it for 7 days of each 28-day cycle. Four studies used the final manufactured CVS, including a 1-year pharmacokinetic study, two 1-year phase 3 trials and a second-year treatment extension study. We assessed safety by evaluating adverse events women reported in a daily diary. We also included data from focused safety studies evaluating endometrial biopsies, vaginal microbiology and liver proteins from one of the phase 3 studies. RESULTS: The combined studies included 3052 women; 2308 women [mean age 26.7±5.1 years; mean body mass index (BMI) 24.1±3.7 kg/m2] received the final manufactured CVS, of whom 999 (43.3%) completed 13 cycles of use. Women using the final CVS most commonly reported adverse events of headache (n=601, 26%), nausea (n=420, 18%), vaginal discharge/vulvovaginal mycotic infection (n=242, 10%) and abdominal pain (n=225, 10%). Few (<1.5%) women discontinued for these complaints. Four (0.2%) women experienced venous thromboembolism (VTE), three of whom had risk factors for thrombosis [Factor V Leiden mutation (n=1); BMI>29 kg/m2 (n=2)]. During 21,482 treatment cycles in the phase 3 studies evaluable for expulsion, women reported partial expulsions in 4259 (19.5%) cycles and complete expulsions in 1509 (7%) cycles, most frequently in the initial cycle [499/2050 (24.3%) and 190/2050 (9.3%), respectively]. Safety-focused studies revealed no safety concerns. CONCLUSION: The 1-year SA/EE CVS has an acceptable safety profile. Additional studies are warranted in obese women at higher risk of VTE. IMPLICATIONS: This 1-year contraceptive vaginal system represents a new long-term, user-controlled and procedure-free option with a safety profile similar to other combination hormonal contraceptives. The same precautions currently used for combination hormonal contraceptive prescriptions apply to this new contraceptive vaginal system.
OBJECTIVES: To evaluate safety outcomes from clinical studies of a 12-month contraceptive vaginal system (CVS) releasing an average of segesterone acetate (SA) 150 mcg and ethinyl estradiol (EE) 13 mcg daily. STUDY DESIGN: We integrated clinical safety data from nine studies in which women used the CVS for 21 consecutive days and removed it for 7 days of each 28-day cycle. Four studies used the final manufactured CVS, including a 1-year pharmacokinetic study, two 1-year phase 3 trials and a second-year treatment extension study. We assessed safety by evaluating adverse events women reported in a daily diary. We also included data from focused safety studies evaluating endometrial biopsies, vaginal microbiology and liver proteins from one of the phase 3 studies. RESULTS: The combined studies included 3052 women; 2308 women [mean age 26.7±5.1 years; mean body mass index (BMI) 24.1±3.7 kg/m2] received the final manufactured CVS, of whom 999 (43.3%) completed 13 cycles of use. Women using the final CVS most commonly reported adverse events of headache (n=601, 26%), nausea (n=420, 18%), vaginal discharge/vulvovaginal mycotic infection (n=242, 10%) and abdominal pain (n=225, 10%). Few (<1.5%) women discontinued for these complaints. Four (0.2%) women experienced venous thromboembolism (VTE), three of whom had risk factors for thrombosis [Factor V Leiden mutation (n=1); BMI>29 kg/m2 (n=2)]. During 21,482 treatment cycles in the phase 3 studies evaluable for expulsion, women reported partial expulsions in 4259 (19.5%) cycles and complete expulsions in 1509 (7%) cycles, most frequently in the initial cycle [499/2050 (24.3%) and 190/2050 (9.3%), respectively]. Safety-focused studies revealed no safety concerns. CONCLUSION: The 1-year SA/EE CVS has an acceptable safety profile. Additional studies are warranted in obesewomen at higher risk of VTE. IMPLICATIONS: This 1-year contraceptive vaginal system represents a new long-term, user-controlled and procedure-free option with a safety profile similar to other combination hormonal contraceptives. The same precautions currently used for combination hormonal contraceptive prescriptions apply to this new contraceptive vaginal system.
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