Return to ovulation after Sayana Press is injected every 4 months for one year: Empirical and pharmacokinetic/pharmacodynamic modeling results

Abstract

Objective: To characterize return to ovulation after injecting Sayana Press (104 mg/0.65 mL medroxyprogesterone acetate [MPA] in the Uniject device) every 4 months for 1 year of treatment.

Study design: We followed a subset of women for return to ovulation in a trial that demonstrated Sayana Press remains highly effective when the subcutaneous reinjection interval is extended from 3 to 4 months. We measured serum progesterone in weeks 38 to 42 and 46 to 50 after a final (third) injection and used a concentration ≥4.7 ng/mL as a surrogate for ovulation. We also performed pharmacokinetic and pharmacodynamic modeling to predict differences in MPA accumulation and return to ovulation had - contrary to fact - injections been given every 3 months.

Results: Ten of 19 women (53%; 95% confidence interval: 29-76) ovulated within 50 weeks of their last injection. We predicted that typical 12-month trough MPA concentrations are 34% lower (0.46 vs 0.69 ng/mL) and the median time from last dose to ovulation is 1.1 months shorter (13.1 vs 14.2 months) when injections are given every four months for 1 year.

Conclusion: Extending the Sayana Press reinjection interval from 3 to 4 months leads to less drug accumulation, without a noticeable loss in efficacy. Although the Sayana Press patient leaflet specifies that over 80% of women desiring pregnancy will conceive within a year of stopping the method (independent of treatment duration), our empirical and modeling results indicate women should anticipate waiting a year or more for fertility to return after repeat dosing, with a somewhat shorter delay were the reinjection interval extended to four months.

Implications: Providers should counsel women regarding the distinct possibility that return to fertility will take a year or longer following repeat use of Sayana Press. Extending the dosing interval from 3 to 4 months would result in approximately a 1-month shorter delay, without any appreciable reduction in contraceptive efficacy.

Keywords: Depo-subQ provera; Medroxyprogesterone acetate; Pharmacodynamics; Pharmacokinetics.

Fig. 1

Observed and predicted medroxyprogesterone acetate (MPA) concentrations and the probability of ovulation following subcutaneous injection of Depo-SC. Data are from 92 women who received injections in the abdomen or thigh at months 0, 4, and 8, including 20 followed for return to ovulation after the 12-month treatment period, in a study conducted between 2017 and 2020 . Injection times are denoted by red arrows and months since last injection are in parentheses above the x-axis. Empirical results include cumulative proportions ovulating 10 and 12 months after last injection (purple diamonds, 95% CIs); observed MPA levels (open circles); and medians of observed levels (black diamonds). Filled circles at study month 19 are empirical Bayes estimates of MPA levels among women who discontinued or ovulated in the tenth month after their last injection. Model predictions are for a population of women with a median weight of 66 kg, and include median MPA levels (blue, with 95% CIs); a 90% prediction interval for individual MPA levels (gray band); and the cumulative probability of ovulation at the end of treatment (solid purple, 95% CIs). The model predicts 44% of women ovulate within 12 months of their final injection, and a median time to ovulation of 13.1 months since last injection.

Fig. 2

External validity of model used to predict medroxyprogesterone acetate (MPA) concentrations and the probability of ovulation following subcutaneous injection of Depo-SC. Model fit to sparse MPA data in a study of Depo-SC injected every 4 months was used to predict MPA levels and the cumulative probability of ovulation in a hypothetical population of women who receive two injections at 3-month intervals . Injection times are denoted by red arrows and months since last injection in parentheses above the x-axis. Model predictions include median MPA levels (blue, 95% CIs); a 90% prediction interval for individual MPA levels (gray band); and the cumulative probability of ovulation after treatment (solid purple, 95% CIs). Predictions are compared to results of a phase 1 trial of this 2-dose regimen, including cumulative proportions ovulating by 12, 15, and 18 months after last injection (purple diamonds, 95% CIs); observed MPA levels (open circles); medians of 3- and 6-month trough levels (black diamonds); and MPA levels below the limit of quantification (filled circles). The model predicts that 46% of women ovulate within 12 months of their final injection, versus 44% observed in the trial [10,11].