By Jeffrey T. Jensen, MD, MPH

Leon Speroff Professor and Vice Chair for Research, Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland

Dr. Jensen reports he is a consultant for Teva Pharmaceuticals, Microchips, and Evofem; and is a consultant for and receives grant-/research support from Bayer Healthcare, Merck, Agile Pharm, Population Council, AbbVie, ContraMed, and FHI360; and receives grant/research support from HRA Pharma and Medicines360.

SYNOPSIS: An international study found that continued use of an etonogestrel contraceptive implant for up to five years, two years longer than the current labeling approval, did not increase the risk of pregnancy.

SOURCE: Ali M, Akin A, Bahamondes L, et al. Extended use up to 5 years of the etonogestrel-releasing subdermal contraceptive implant: Comparison to levonorgestrel-releasing subdermal implant. Hum Reprod 2016;31:2491-2498.

Regulatory approval of the etonogestrel (ENG) contraceptive implant supports use of this highly effective reversible contraception for up to three years, but pharmacokinetic data demonstrate stable ENG levels up to five years. Since cost and inconvenience to women could be reduced by extending the recommended duration of use, the World Health Organization (WHO) sponsored this study to evaluate the safety and efficacy of ENG implant use for up to five years.

The study population represents a subset of women originally enrolled in a multicenter international study designed to evaluate the clinical performance of the three-year single-rod ENG implant and the five-year, two-rod levonorgestrel (LNG)-releasing implant over three years. In the original study, women were randomized in an open label fashion to receive either implant (ENG = 1,003, LNG = 1,005), and the authors also included a separate cohort of copper intrauterine device (IUD) users (n = 974) for comparative purposes (nonhormonal controls).1 The overall clinical performance of the two implants over three years was similar. Both implants had a three-year cumulative pregnancy rate of 0.4/100 woman-years (WY) of use compared with 5.7/100 WY among users of the copper IUD.

To obtain data in support of extended use, the investigators invited subjects to consent to two additional years of participation, which represented off-label use for the ENG implant group only. A subset of 390 ENG, 522 LNG, and 416 IUD participants agreed. Of these, 204 ENG, 330 LNG, and 256 IUD users completed the full five years of use of their respective methods.

No pregnancies occurred in either of the implant groups during year 4 or 5, compared with three additional pregnancies in the copper IUD control group, yielding five-year cumulative Kaplan-Meier pregnancy rates of 0.6/100 WY (95% confidence interval [CI], 0.2-1.8) for the ENG implant, 0.8/100 WY (CI, 0.2-1.8) for LNG, and 4.1/100 WY (CI, 2.5-6.5) for the copper IUD. As previously reported during the initial three years of follow-up, ENG implant users reported more bleeding complaints than LNG, but this association was significantly increased only for heavy bleeding (12% vs. 9%; relative risk, 1.32; CI, 1.01-1.73) during years 4 and 5. Clinicians rated removal of the single-rod ENG system as significantly easier and faster.

The authors concluded that the results support extended use of the ENG implant for up to five years, and recommended that the WHO adopt this policy in family planning programs.

COMMENTARY

The widespread use of highly effective long-acting reversible (LARC) methods of contraception has been a game changer in the United States. The increased use of LARCs correlates with a drop in teen pregnancy and unintended pregnancy that began to 2008.2,3 These user-friendly “forgettable” methods have high continuation rates and extremely low method failure. Any strategy that makes obtaining or continuing a LARC method easier should result in a hefty return on investment.

Worldwide, access remains one of the great barriers to LARC use. Both IUDs and implants require a skilled healthcare provider for placement and removal. Since all LARC methods have an approved duration of use, replacement is required for continuation of the method after expiration. Our most highly effective LARC method, the ENG implant, is approved for three years of use. Since many women find the placement and/or removal of implants unpleasant, extending this duration could increase the acceptability of the method. Increasing the duration of use also would greatly reduce costs associated with long-term implant use.

Substantial evidence now exists to support extending the duration of use. Circulating ENG prevents ovulation as the primary mechanism of implant action, with 90 pg/mL considered sufficient for suppression.4 According to the full prescribing information for Nexplanon, mean levels of ENG decline from around 1,200 pg/mL in the first two weeks after placement, to 202 pg/mL at 12 months, 164 pg/mL at 24 months, and 138 pg/mL at 36 months of use. However, using the cohort of implant users enrolled in the CHOICE study, McNicholas et al reported median (range) ENG levels of 188.8 (CI, 63.8-802.6) pg/mL and 177.0 (CI, 67.9-470.5) pg/mL at the end of three and four years of use, with no effect of body mass index on drug levels.5 Similar to the results reported by the WHO group, no pregnancies have occurred among implant users in the CHOICE studies who consented to continue the method beyond three years, although this study remains in progress.

Once a product receives regulatory approval, pharmaceutical companies have little incentive to change the label unless this would result in increased sales or new evidence of risks require additional information. I suspect that strategies designed to encourage individuals to use a current product longer rather than buy a new one are not taught in business schools. Although a five-year LNG two-rod implant exists in most of the world outside of the United States, the world cost of the system is similar to the ENG implant, and there is no interest in introducing the LNG product to the U.S. market. Thus, we should not expect to see an application from Merck to change the labeling for Nexplanon. However, if such an application were to be filled, the FDA would require data on at least 200 women using the product for the new interval. The results of the Ali study satisfy this requirement.

The results of our recent election threaten to undermine the gains in contraception coverage achieved due to the Affordable Care Act. If so, many women using a LARC method in the United States may find difficulty accessing a new device at the scheduled replacement interval. The literature now provides strong and convincing evidence to recommend that women using the ENG implant continue use of the same device for up to five years. This may help some survive until the next election.

REFERENCES

  1. Bahamondes L, Brache V, Meirik O, et al. A 3-year multicentre randomized controlled trial of etonogestrel- and levonorgestrel-releasing contraceptive implants, with non-randomized matched copper-intrauterine device controls. Hum Reprod 2015;30:2527-2538.
  2. Kavanaugh ML, Jerman J, Finer LB. Changes in use of long-acting reversible contraceptive methods among U.S. women, 2009–2012. Obstet Gynecol 2015;126:917-927.
  3. Finer LB, Zolna MR. Declines in unintended pregnancy in the United States, 2008-2011. N Engl J Med 2016;374:843-852.
  4. Diaz S, Pavez M, Moo-Young AJ, et al. Clinical trial with 3-keto-desogestrel subdermal implants. Contraception 1991;44:393-408.
  5. McNicholas C, Maddipati R, Zhao Q, et al. Use of the etonogestrel implant and levonorgestrel intrauterine device beyond the U.S. Food and Drug Administration-approved duration. Obstet Gynecol 2015;125:599-604.