One-year endometrial safety evaluation of a continuous combined transdermal matrix patch delivering low-dose estradiol-norethisterone acetate in postmenopausal women.
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.
Samsioe
Göran
G
Department of Obstetrics and Gynaecology, Lund University Hospital, Lund, Sweden. goran.samsioe@med.lu.se
Dvorak
Vladimir
V
Genazzani
Andrea R
AR
Hamann
Bernd
B
Heikkinen
Jorma
J
Mueck
Alfred O
AO
Suzin
Jacek
J
Kawakami
Fernando T
FT
Ferreira
Alberto
A
Sun
Dongming
D
Arguinzoniz
Miguel
M
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
D004958:Estradiol; D009640:Norethindrone