Etonogestrel

Did You Know?

• Efavirenz, an inducer of CYP3A4, appears to decrease etonogestrel levels and increase rates of undesired pregnancy among implant users.
• Etonogestrel is also known as 11-methylene-17α-ethynyl-18-methyl-19-nortestosterone.
• The failure rate of etonogestrel implants is 0.05% for both perfect and typical use.

Side effects

Irregular bleeding and spotting are common, with many women experiencing unpredictable, prolonged, frequent, or infrequent bleeding; some develop amenorrhea. While these patterns are not dangerous, they are the most frequent reason for discontinuing the implant. After removal, bleeding patterns typically return to previous norms. Insertion complications include minor bruising, skin irritation, or pain, and rare events such as infection or expulsion.

A serious complication is failure to insert the rod, which an Australian study linked to 84 pregnancies. The rod may rarely migrate within the arm, making removal difficult; correct subdermal insertion over the triceps muscle reduces this risk. Very rare reports describe implants reaching the lung via the pulmonary artery. Some women experience slight weight gain, though studies lack control groups; the average increase was less than 5 pounds over 2 years.

Ovarian cysts occur in a small portion of users and usually resolve without treatment. If pregnancy occurs, implant removal is recommended, but no evidence suggests harm to the fetus. Acne is self-reported and listed by the FDA, but a study found that most users with pre-existing acne reported improvement, and only 16% of those without prior acne developed it.

Device description

Nexplanon and Implanon consist of a single rod made of ethylene vinylacetate copolymer, 4 cm long and 2 mm in diameter, containing 68 mg of etonogestrel. Peak serum concentrations reach 781–894 pg/mL in the first few weeks, declining to 192–261 pg/mL after one year, 154–194 pg/mL after two years, and 156–177 pg/mL after three years, maintaining ovulation suppression. The implant was originally FDA-approved for 3 years and is now approved for 5 years.

Insertion must be performed by an experienced clinician; the arm is cleaned and a local anesthetic applied, then a needle-like applicator places the rod subdermally on the inner side of the arm posterior to the groove between the biceps and triceps muscles. Average insertion time is 0.5 to 1 minute. A bandage is kept on for 24 hours. Serious complications such as infection occur in less than 1% of patients. If inserted outside the first five days of menstruation, a backup method is recommended for one week.

Pharmacology

The primary mechanism of action of etonogestrel implants is inhibition of ovulation, which was not observed in studies during the first two years and only rarely in the third year, with no pregnancies. A secondary mechanism is increased cervical mucus viscosity that impedes sperm penetration. Hormonal contraceptives also affect the endometrium, but no scientific evidence indicates that prevention of implantation results from their use. Etonogestrel is a progestogen and agonist of the progesterone receptor, with less androgenic activity than levonorgestrel and norethisterone; it does not decrease sex hormone-binding globulin levels.

It binds to the glucocorticoid receptor with about 14% of the affinity of dexamethasone and has very weak glucocorticoid activity. It has no estrogenic or antimineralocorticoid activity. Some inhibition of 5α-reductase and hepatic cytochrome P450 enzymes has been observed in vitro. Bioavailability is 100% when given as a subcutaneous implant or vaginal ring.

Steady-state levels are achieved within one week. The volume of distribution is 201 L, and plasma protein binding is at least 98%. It is metabolized in the liver by CYP3A4, and its elimination half-life is about 25 to 29 hours.

History

The concept of subdermal contraceptive implants began after silicone was discovered in the 1940s and found to be biocompatible. In 1964, Folkman and Long published the first study showing that a rod could deliver drugs, and in 1966 Dziuk and Cook suggested rods could suit contraception. The Population Council developed Norplant (six rods) and Jadelle (two rods). In 1990, De Nijs patented a co-axial extrusion technique using ethylene vinylacetate copolymers and 3-keto-desogestrel (etonogestrel) for long-acting contraceptive devices, leading to Implanon, Nexplanon, and NuvaRing.

Single rods were less visible and used etonogestrel to reduce side effects. Desogestrel, a prodrug of etonogestrel, was introduced in 1981. Norplant was used internationally from 1983 and marketed in the United States and United Kingdom in 1993, but was taken off the US market in 2002 due to removal complications. Jadelle was FDA-approved but never marketed in the US.

Etonogestrel was introduced as Implanon in Indonesia in 1998, then in the United Kingdom, and approved in the US in 2006. Nexplanon replaced Implanon by 2012, featuring a changed inserter and radiopaque rod.