Objective
To investigate the efficacy, safety, removal characteristics, and x-ray visibility of Nexplanon, a radiopaque etonogestrel contraceptive implant combined with a next-generation applicator.
Study Design
A 3-year, nocomparative, multicenter study in women aged 18–40 years at 23 clinical sites.
Results
Of 301 women who had an implant inserted, none became pregnant while the implant was in situ. Serious adverse events were reported in 16 of 301 (5.3%) women; none were judged as drug related. Fibrosis around the implant was the most common removal complication (4.4%). The implant was visible on X-ray and palpable before removal with a mean removal time of 2 minutes.
Conclusion
Nexplanon showed high contraceptive efficacy, palpability before removal, short removal times, and few removal complications. Nexplanon provides clinicians with a long-term hormonal contraceptive method with a safety and efficacy profile comparable to Implanon, radiopacity, and a new applicator.
Implanon (Merck & Co., Whitehouse Station, NJ) is a highly effective progestogen-only contraceptive implant. After subdermal insertion in the woman’s upper arm, the implant steadily releases etonogestrel, which provides contraceptive coverage for up to 3 years. When the implant is inserted correctly with the preloaded applicator, it is easily located by palpation. However, when the manufacturer’s instructions for insertion are not followed accurately, the implant may be difficult to locate by palpation and may require referral to a specialist center for implant detection by ultrasound or magnetic resonance imaging and/or removal by an experienced clinician.
To facilitate in situ localization of the implant, a radiopaque implant was recently developed, which is identical in dimensions and hormone content to the original Implanon implant but can be detected by 2-dimensional x-ray imaging in addition to palpation, ultrasound, and/or magnetic resonance imaging. Furthermore, a next-generation applicator (NGA) for inserting the radiopaque implant has been developed to facilitate subdermal insertion of the implant using 1 hand ( Figure 1 ). The original applicator typically required the clinician to use 2 hands, which could sometimes make implant insertion less easy. Together, this product is named Nexplanon (Merck & Co.) or Implanon NXT.
The results of an interim analysis, in which the insertion characteristics of Nexplanon and clinician satisfaction with implant insertion using the NGA were investigated, have been reported previously. In the interim analysis, almost all clinicians were satisfied or very satisfied with the NGA from the first insertion onward, and all clinicians were either satisfied or very satisfied after 12 insertions. Clinicians cited ease of use, 1-handed action, and fast insertion time as advantages of the NGA. Of the 2.0% of cases in which the insertion was considered to be difficult, the reasons were difficulty in puncturing the skin and/or subdermal sliding of the needle, or because it was one of the first insertions.
Here, we report on the outcomes of this study after 3 years, including contraceptive efficacy, safety and removal characteristics, and assessment of x-ray visibility of Nexplanon.
Materials and Methods
Study design and study population
As described previously this was a 3-year, open-label, noncomparative, multicenter study conducted in Australia, Germany, France, the United Kingdom, Norway, and Sweden from April 2007 to October 2010. In total, 23 clinicians participated in the study (1 per clinical study site). Before the first insertion, all clinicians attended a training session, during which they received an instruction leaflet, viewed a video, and were required to perform 2 successful insertions on a training arm. Implant insertions were performed according to the labeling instructions of Nexplanon.
Women who were included in this study had to meet the following inclusion criteria: aged between 18–40 years at the time of screening; a body mass index (BMI) ≥18 and ≤35 kg/m 2 ; and regular menstrual cycles of 24 to 35 days. Written informed consent was obtained from all women. Women were excluded when they had any contraindication for the use of Implanon, hypertension, or had used hepatic enzyme-inducing medications in the previous 2 months that could affect the bioavailability of steroids. Women were also excluded if they experienced one of the following conditions during a previous pregnancy or during previous use of sex steroids: jaundice and/or severe pruritus related to cholestasis, gallstone formation, porphyria, systemic lupus erythematosus, hemolytic uremic syndrome, Sydenham’s chorea, herpes gestationis, or otosclerosis-related hearing loss.
The study consisted of a screening period, a 3-year treatment period starting on the day of implant insertion and ending on the day of implant removal, and a 3-month follow-up period. Clinic visits occurred at screening, implant insertion, months 3, 6, 9, 12, 18, 24, 30, and 36 (implant removal or earlier in cases of premature discontinuation).
A posttreatment assessment was scheduled at 3 (±1) months after implant removal, which could be carried out by telephone or by e-mail.
Contraceptive efficacy
Contraceptive efficacy was based on the occurrence of pregnancies with an estimated conception date within the treatment period. To exclude pregnancy, a urine test was performed directly before the implant insertion, at each clinic visit, and at implant removal. A pregnancy test was also indicated in case of suspicion of pregnancy outside the scheduled visits.
Safety
Safety was assessed by the reporting of (serious) adverse events ([S]AEs), examination of the implant site at all in-treatment visits, general physical and gynecologic examinations at screening and end-of-treatment, complications at insertion (as previously reported) and removal, and vital signs assessments. All clinically relevant findings during implant site, physical and gynecologic examinations were to be reported as (S)AEs.
A drug-related AE was defined as an AE that was “definitely,” “probably,” or “possibly” related to the contraceptive implant as judged by the investigator. An AE defined as unrelated to the implant was one that was considered “unlikely” or “not related” by the investigator. In addition, the investigator had to report for every AE the relationship to the applicator as “yes” or “no.”
Removal
Clinicians completed a questionnaire on removal characteristics after every implant removal. If complications occurred during removal, the clinician could choose among the prespecified categories of “larger incision required,” “multiple removal attempts required,” and “presence of fibrotic tissue around the implant,” or to specify another complication; multiple categories were allowed. Removal complications were reported as AEs based on the judgement of the clinician. The removal time was defined as time from making the incision until placing the butterfly closure. Removal times between removals with or without fibrotic tissue around the implant were compared by using the nonparametric Wilcoxon rank sum test with Hodges-Lehmann estimate for the difference in removal times.
X-ray
The first 50 women undergoing the insertion were to be scheduled for 2-dimensional x-ray imaging after insertion and before implant removal. Subsequently, x-ray imaging was only performed for women for whom the implant was not palpable.
Statistical analysis
Summary statistics for continuous variables included mean, median, standard deviation (SD), minimum and maximum. Frequency counts and percentages were calculated for categorical variables. Summary statistics and frequency tables per assessment were based on the number of subjects with nonmissing measurement values. All analyses were performed using SAS 9.1.3 (SAS Institute, Inc., Cary, NC) on a Windows XP system (Microsoft Corporation, Seattle, WA).
The trial size of 300 women was chosen so that the upper limit of the 1-sided 95% confidence interval (CI) for the population incidence of safety issues related to the applicator was equal to 1%, if no occurrences were observed.
Ethical approval
The trial protocol and amendments were approved by the independent ethics committee of each trial center and the study was conducted in compliance with the current revisions of the Declaration of Helsinki, the International Conference on Harmonization guideline, and Good Clinical Practice.
Results
Study population
The mean (SD) age of the women in this study was 28.2 (6.7) years. The mean BMI was 23.8 (3.7) kg/m 2 ranging from 16.9 to 35.2 kg/m 2 . The majority of the women were white (95.3%) ( Table 1 ). Of the 301 women who had an implant inserted, 156 of 301 (52%) completed the 3-year treatment period, whereas 145 of 301 (48%) discontinued from the study prematurely ( Figure 2 ). The cumulative Kaplan-Meier discontinuation rates after 1- and 2-years of treatment were 19% and 38%, respectively. Overall, 106 of 301 (35%) women discontinued because of an AE, most frequently because of bleeding irregularities (58/301 [19.3%]), and to a lesser extent because of weight gain (14/301 [4.7%]), acne (12/301 [4.0%]), or altered mood (10/301 [3.3%]). One woman discontinued after 2 weeks of treatment because of implant expulsion, which was the result of an incorrect intra cutaneous insertion of the implant instead of sub cutaneous insertion. Other reasons for discontinuation included pregnancy wish (18/301 [6.0%]), moving to another city/country (8/301 [2.7%]), and lost to follow-up (4/301 [1.3%]).
| Demographic | Nexplanon (n = 301) |
|---|---|
| Age, y | |
| Mean (standard deviation) | 28.2 (6.7) |
| Median (min–max) | 27.0 (18–40) |
| Age (y), n (%) | |
| 18–20 | 43 (14.3) |
| 21–25 | 79 (26.2) |
| 26–30 | 64 (21.3) |
| 31–35 | 54 (17.9) |
| 36–40 | 61 (20.3) |
| Race, n (%) | |
| White | 287 (95.3) |
| Asian | 8 (2.7) |
| Black or African American | 2 (0.7) |
| Other | 4 (1.3) |
| Body mass index, kg/m 2 | |
| Mean (standard deviation) | 23.8 (3.7) |
| Median (min–max) | 23.2 (16.9–35.2) |
| Parity | |
| 0 | 156 (51.8) |
| 1 | 50 (16.6) |
| 2 | 66 (21.9) |
| ≥3 | 29 (9.6) |
| Breastfeeding | |
| Yes | 16 (5.3) |
| No | 285 (94.7) |
Contraceptive efficacy
No woman became pregnant while the implant was in situ, up to and including 14 days after implant removal, resulting in an estimated overall Pearl Index of 0.0 (95% CI, 0.0–0.56). The total extent of exposure was 655.0 women-years. Five women became pregnant 21 or more days after implant removal. Three of these 5 women discontinued treatment prematurely because of pregnancy wish.
Safety
Of the 301 women who had an implant inserted, 272 (90.4%) had 1 or more AEs during the 3-year treatment period. The AEs that were most frequently reported were vaginal hemorrhage (85/301 [28.2%], which includes different vaginal bleeding related AEs as specified in Table 2 ), headache (56/301 [18.6%]), metrorrhagia (53/301 [17.6%]), acne (39/301 [13%]), and weight gain (35/301 [11.6%]) ( Table 2 ). The mean (SD) weight increase at month 36 (n = 146) and at the last in-treatment assessment (n = 300) compared with baseline was 1.4 (5.2) kg and 1.3 (5.4 kg), respectively.
| Variable | n = 301 | ||
|---|---|---|---|
| Related, n (%) | Not related, n (%) | Total, n (%) | |
| Infections and infestations | |||
| Influenza | 0 (0.0) | 19 (6.3) | 19 (6.3) |
| Nasopharyngitis | 0 (0.0) | 32 (10.6) | 32 (10.6) |
| Upper respiratory tract infection | 0 (0.0) | 20 (6.6) | 20 (6.6) |
| Urinary tract infection | 0 (0.0) | 20 (6.6) | 20 (6.6) |
| Vulvovaginal candidiasis | 2 (0.7) | 17 (5.6) | 19 (6.3) |
| Nervous system disorders | |||
| Headache | 27 (9.0) | 29 (9.6) | 56 (18.6) |
| Skin and subcutaneous system disorders | |||
| Acne | 37 (12.3) | 2 (0.7) | 39 (13.0) |
| Reproductive system and breast disorders | |||
| Amenorrhea | 18 (6.0) | 3 (1.0) | 21 (7.0) |
| Dysmenorrhea | 11 (3.7) | 5 (1.7) | 16 (5.3) |
| Menorrhagia | 30 (10.0) | 1 (0.3) | 31 (10.3) |
| Metrorrhagia | 52 (17.3) | 1 (0.3) | 53 (17.6) |
| Vaginal hemorrhage b | 83 (27.6) | 2 (0.7) | 85 (28.2) |
| General disorders and administration site conditions | |||
| Implant site hematoma | 7 (2.3) | 9 (3.0) | 16 (5.3) |
| Implant site pain | 12 (4.0) | 6 (2.0) | 18 (6.0) |
| Investigations | |||
| Weight gain | 33 (11.0) | 2 (0.7) | 35 (11.6) |
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