Pharmacotherapeutic group: progestagens. ATC-classification: G03AC08.
Pharmacology: Pharmacodynamics: The Implanon NXT implant is a non-biodegradable, radiopaque, etonogestrel-containing implant for subdermal use, preloaded in a sterile, innovative, disposable applicator. Etonogestrel is the biologically active metabolite of desogestrel, a progestagen widely used in OCs. It is structurally derived from 19-nortestosterone and binds with high affinity to progesterone receptors in the target organs. The contraceptive effect of etonogestrel is primarily achieved by inhibition of ovulation. Ovulations were not observed in the first two years of use of the implant and only rarely in the third year. Besides inhibition of ovulation, etonogestrel also causes changes in the cervical mucus, which hinders the passage of spermatozoa. Clinical trials were conducted in women between 18 and 40 years. Although no direct comparison was made, the contraceptive efficacy appeared to be at least comparable to that known for combined OCs (over 99%). The high degree of protection against pregnancy is obtained, amongst other reasons, because the contraceptive action of Implanon NXT is not dependent on adherence to a daily, weekly, or monthly dosing regimen by the woman herself. The contraceptive action of etonogestrel is reversible, which is apparent from the rapid return of the normal menstrual cycle after removal of the implant. Although etonogestrel inhibits ovulation, ovarian activity is not completely suppressed. Mean estradiol concentrations remain above the level seen in the early-follicular phase. In a two-year study, in which the bone mineral density in 44 users has been compared with that in a control group of 29 IUD-users no adverse effects on bone mass have been observed. No clinically relevant effects on lipid metabolism have been observed. The use of progestagen-containing contraceptives may have an effect on insulin resistance and glucose tolerance. Clinical trials further indicate that users of Implanon NXT often have a less painful menstrual bleeding (dysmenorrhea).
Implant insertion and removal characteristics: In a clinical trial, Implanon NXT was inserted in 301 women. The mean insertion time (from the removal of the protection cap of the applicator until retraction of the needle from the arm) was 27.9 seconds (standard deviation (SD)=29.3, n=291). After insertion, 300 out of 301 (99.7%) Implanon NXT implants were palpable. The single, non-palpable implant was not inserted according to the instructions. For 293 of the 301 subjects, data on palpability was gathered before removal. The implant was palpable for all 293 subjects with data on palpability. For four subjects, palpability was not assessed and another four subjects were lost to follow-up before removal.
In two clinical trials with Implanon NXT implants, a total of 116 subjects underwent two-dimensional x-ray assessments at (after) insertion and/or (before) removal. For 101 out of 103 (98.1%) subjects for whom x-ray assessments were performed at insertion and before removal, Implanon NXT implants were clearly visible; for two subjects the implants were not clearly visible after insertion but were clearly visible before removal. The implants of the 13 subjects with x-ray assessment only at insertion (n=12) or only before removal (n=1) were all clearly visible.
Pharmacokinetics: Absorption: After the insertion of the implant, etonogestrel is rapidly absorbed into the circulation. Ovulation-inhibiting concentrations are reached within 1 day. Maximum serum concentrations (between 472 and 1270 pg/ml) are reached within 1 to 13 days. The release rate of the implant decreases with time. As a result serum concentrations decline rapidly over the first few months. By the end of the first year a mean concentration of approximately 200 pg/ml (range 150-261 pg/ml) is measured, which slowly decreases to 156 pg/ml (range 111-202 pg/ml) by the end of the third year. The variations observed in serum concentrations can be partly attributed to differences in body weight.
Distribution: Etonogestrel is for 95.5-99% bound to serum proteins, predominantly to albumin and to a lesser extent to sex hormone binding globulin. The central and total volume of distribution are 27 l and 220 l, respectively, and hardly change during the use of Implanon NXT.
Metabolism: Etonogestrel undergoes hydroxylation and reduction. Metabolites are conjugated to sulfates and glucuronides. Animal studies show that enterohepatic circulation probably does not contribute to the progestagenic activity of etonogestrel.
Elimination: After intravenous administration of etonogestrel, the mean elimination half-life is approximately 25 hours and the serum clearance is approximately 7.5 l/hour. Both clearance and elimination-half-life remain constant during the treatment period. The excretion of etonogestrel and its metabolites, either as free steroids or as conjugates, is with urine and feces (ratio 1.5:1). After insertion in lactating women, etonogestrel is excreted in breast milk with a milk/serum ratio of 0.44-0.50 during the first four months. In lactating women, the mean transfer of etonogestrel to the infant is approximately 0.2% of the estimated absolute maternal etonogestrel daily dose (2.2% when values are normalized per kg body weight). Concentrations show a gradual and statistically significant decrease over the time.
Toxicology: Preclinical safety data: Toxicological studies did not reveal any effects other than those, which can be explained on the basis of the hormonal properties of etonogestrel, regardless of the route of administration.