Additional progestogens are often used in some countries to stop prolonged bleeding in etonogestrel implant users, although no evidence currently supports this practice.

To evaluate the efficacy and safety of oral norethisterone acetate, also known as norethindrone acetate, at a dose of 10 mg/day for prolonged bleeding associated with etonogestrel implant use.

IMPLANET is a randomized, controlled, blinded, multicenter trial conducted in Brazil. It included etonogestrel implant users aged 18 to 40 years who had been using the implant for at least 40 days and had experienced uterine bleeding for a minimum of 7 consecutive days at enrollment. Participants had no prior diagnosis of abnormal uterine bleeding and underwent a standardized evaluation to exclude a secondary cause for the current prolonged bleeding episode. Participants were block-randomized to receive 10 mg of oral norethisterone acetate or placebo daily until they experienced no bleeding for 2 consecutive days or completed 30 consecutive days of treatment, whichever occurred first. Participants could repeat treatment up to 3 times over 210 days. Participants reported bleeding via daily messages. The primary outcome was the proportion of participants who achieved bleeding cessation after using up to 7 consecutive pills. Secondary outcomes included the proportion of participants who achieved bleeding cessation after using up to 14 pills, treatment days required to stop the first bleeding episode, time to bleeding recurrence after the first treatment, bleeding-free days within the first 30 days, treatment failure (continued bleeding after 30 days of pill use), bleeding days and bleeding-free days after the first 30 days, and safety outcomes. Exploratory outcomes included study participation time and premature discontinuation. A sample size of 86 participants provided 80% power to detect a 30% in bleeding cessation rates after using a maximum of 7 pills. The modified intention-to-treat analysis included participants who received at least one dose of the randomized treatment and had a negative chlamydia/gonorrhea screen postrandomization. We used Chi-square and Wilcoxon tests for comparisons. The primary outcome was additionally analyzed using a multiple log-binomial regression to adjust for baseline imbalances (age, employment status, and marital status), with adjusted risk difference and 95% confidence intervals.

Between September 2020 and May 2023, 114 participants were enrolled, 99 were randomized, and 90 (45 per group) were included in the modified intention-to-treat. Baseline characteristics were similar except for age, employment, and marital status. The norethisterone acetate group had a significantly higher percentage of participants who achieved bleeding cessation after using up to 7 pills than the placebo group (86.7% vs 48.9%, P < .001), even after adjusting for baseline imbalances (adjusted risk difference, 35.6% [95% confidence interval, 17.1%–54.0%], P < .001). Bleeding cessation using up to 14 pills was higher (91.1% vs 64.4%; P =.002) and treatment failure was lower (2.2% vs 17.8%; P =.03) in the norethisterone acetate group than in the placebo group, with fewer median treatment days to stop bleeding in the norethisterone acetate group (3.0 vs 5.0 days; P =.01). Compared to placebo, the norethisterone acetate group had a shorter time to bleeding recurrence (5.0 vs 10.5 days; P =.008), more bleeding-free days in the first 30 days (21.0 vs 13.0 days; P =.007), longer trial participation (159.9 vs 127.2 days; P < .001), and a lower discontinuation rate (33.3%; P =.09).

Short-term use of 10 mg/day norethisterone acetate effectively and safely stopped prolonged bleeding in etonogestrel implant users. However, it does not prevent bleeding recurrence.