title: One-year endometrial safety evaluation of a continuous combined transdermal matrix patch delivering low-dose estradiol-norethisterone acetate in postmenopausal women.
abstract: OBJECTIVE
  To evaluate the safety and endometrial protection of low-dose transdermal estradiol (E2)/norethisterone acetate (NETA) patches (Estalis 25/125) in terms of post-treatment incidence of endometrial hyperplasia/cancer after 1 year of treatment in postmenopausal women with intact uteri.
  
  
  METHODS
  Patients were randomized to receive either transdermal E2/NETA (delivering daily doses of E2 25 microg and NETA 125 microg; applied every 3-4 days) or oral E2/NETA (E2 1mg and NETA 0.5 mg; given daily) in this open-label study. The primary variable was the incidence of endometrial hyperplasia/cancer based on endometrial biopsies; secondary variables included vaginal bleeding/spotting patterns, patch adhesion, safety and tolerability.
  
  
  RESULTS
  Six hundred and seventy-seven patients were randomized (507 in the transdermal group and 169 in the oral group; one did not receive study drug) and >80% completed the study. There were no cases of endometrial hyperplasia or cancer in either group and the upper limit of the one-sided 95% confidence interval in the transdermal group was 0.85%. Over time, both treatments were associated with a decreasing frequency of spotting/bleeding days. The overall incidence of adverse events (AEs) was comparable in both groups, and the majority was mild-to-moderate in intensity. Breast tenderness was the most frequently reported AE (transdermal 19.9% versus oral 28.4%). AEs related to the gastrointestinal system were more frequent with oral E2/NETA, and episodes of spotting and bleeding were more frequent with transdermal E2/NETA. Local skin tolerability of the transdermal matrix system was good.
  
  
  CONCLUSIONS
  Transdermal E2/NETA (25 and 125 microg) provided adequate endometrial protection in postmenopausal women when evaluated according to CPMP/CHMP criteria, achieved a high rate of amenorrhea, and was well tolerated.
authors.affiliation: Department of Obstetrics and Gynaecology, Lund University Hospital, Lund, Sweden. goran.samsioe@med.lu.se
authors.forename: Göran
authors.initials: G
authors.lastname: Samsioe
authors.forename: Vladimir
authors.initials: V
authors.lastname: Dvorak
authors.forename: Andrea R
authors.initials: AR
authors.lastname: Genazzani
authors.forename: Bernd
authors.initials: B
authors.lastname: Hamann
authors.forename: Jorma
authors.initials: J
authors.lastname: Heikkinen
authors.forename: Alfred O
authors.initials: AO
authors.lastname: Mueck
authors.forename: Jacek
authors.initials: J
authors.lastname: Suzin
authors.forename: Fernando T
authors.initials: FT
authors.lastname: Kawakami
authors.forename: Alberto
authors.initials: A
authors.lastname: Ferreira
authors.forename: Dongming
authors.initials: D
authors.lastname: Sun
authors.forename: Miguel
authors.initials: M
authors.lastname: Arguinzoniz
mesh_terms: D000279:Administration, Cutaneous; D000368:Aged; D004359:Drug Therapy, Combination; D004717:Endometrium / Q000187:drug effects / Q000473:pathology; D004958:Estradiol / Q000008:administration & dosage* / Q000009:adverse effects; D015914:Estrogen Replacement Therapy; D005260:Female; D019584:Hot Flashes / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008875:Middle Aged; D009640:Norethindrone / Q000008:administration & dosage* / Q000009:adverse effects; D017698:Postmenopause; D016896:Treatment Outcome
chemical_list: D004958:Estradiol; D009640:Norethindrone