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| Clinical data | |
|---|---|
| Trade names | Circlet, Implanon, Nexplanon, others |
| Other names | ORG-3236; SCH-900702 (withEETooltip ethinylestradiol); 3-Ketodesogestrel; 3-Oxodesogestrel; 11-Methylenelevonorgestrel;[1] 11-Methylene-17α-ethynyl-18-methyl-19-nortestosterone; 11-Methylene-17α-ethynyl-18-methylestr-4-en-17β-ol-3-one |
| AHFS/Drugs.com | Professional Drug Facts |
| MedlinePlus | a604032 |
| Pregnancy category |
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| Routes of administration | Subcutaneous implant,vaginal ring |
| Drug class | Progestogen;Progestin |
| ATC code | |
| Legal status | |
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| Pharmacokinetic data | |
| Bioavailability | Implant: 100%[4] Vaginal ring: 100%[5] |
| Protein binding | ≥98% (66% toalbumin, 32% toSHBGTooltip sex hormone-binding globulin)[4] |
| Metabolism | Liver (CYP3A4)[4][5] |
| Eliminationhalf-life | 21–38 hours[6][7][4][5] |
| Excretion | Urine (major),feces (minor)[4][5] |
| Identifiers | |
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| CAS Number | |
| PubChemCID | |
| IUPHAR/BPS | |
| DrugBank |
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| ChemSpider |
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| UNII | |
| KEGG |
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| ChEBI | |
| ChEMBL | |
| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.053.561 |
| Chemical and physical data | |
| Formula | C22H28O2 |
| Molar mass | 324.464 g·mol−1 |
| 3D model (JSmol) | |
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| Etonogestrel birth control implant | |
|---|---|
 Implanon | |
| Background | |
| Type | Hormonal Progestin-only implant |
| First use | 1998 Indonesia |
| Synonyms | Etonogestrel contraceptive implant |
| Trade names | Implanon, Nexplanon, others |
| AHFS/Drugs.com | FDA Professional Drug Information |
| Failure rates (first year) | |
| Perfect use | 0.05%[8] |
| Typical use | 0.05%[8] |
| Usage | |
| Duration effect | 3 to 5 years[9][10] |
| Reversibility | Yes |
| User reminders | Requires removal after the 3–5 years[11] |
| Advantages and disadvantages | |
| STI protection | No |
| Weight | May cause weight gain |
| Period disadvantages | May cause irregular or prolonged bleeding |
| Period advantages | Minimizes pain. In 33% no periods. |
| Benefits | Long-term contraception. |
Etonogestrel is a medication which is used as a means ofbirth control for women.[4][5][12][13] It is available as an implant placed under the skin of the upper arm under the brand namesNexplanon andImplanon. It is aprogestin that is also used in combination withethinylestradiol, anestrogen, as avaginal ring under the brand namesNuvaRing andCirclet.[14] Etonogestrel is effective as a means of birth control and lasts at least three or four years with some data showing effectiveness for five years.[9][11] Following removal,fertility quickly returns.[15]
Side effects of etonogestrel includemenstrual irregularities,breast tenderness,mood changes,acne, headaches,vaginitis, and others.[4] Etonogestrel is aprogestin, or a syntheticprogestogen, and hence is anagonist of theprogesterone receptor, thebiological target of progestogens likeprogesterone.[16] It works by stoppingovulation, thickening themucus around the opening of thecervix, and altering the lining of theuterus.[17] It has very weakandrogenic andglucocorticoid activity and no other importanthormonal activity.[16]
Etonogestrel was patented in 1972 and introduced for medical use in 1998.[18][19][20] It became available in the United States in 2006.[18][19] Etonogestrel implants are approved in more than 90 countries and used by about three million women globally as of 2010.[17][21]
A closely related and more widely known and used progestin,desogestrel, is aprodrug of etonogestrel in the body.[16]
Etonogestrel is used in hormonal contraception in form of the etonogestrel contraceptive implant[4] and thecontraceptive vaginal ring (brand names NuvaRing, Circlet), the latter in combination withethinylestradiol.[5]
Etonogestrel birth control implants are a type oflong-acting reversible contraception, which has been shown to be one of the most effective form of birth control.[22] The failure rate of the implants is 0.05% for both perfect use and typical use because the method requires no user action after placement.[23] Studies of one type, which include over 2,467 women-years of exposure, found no pregnancies.[24][25][26]
Other studies have found some failures with this method, some attributed to failures of the method itself and others to improper placement, drug interactions, or conception prior to method insertion.[27]
In comparison, tubal sterilization has a failure rate of 0.5% and IUDs have a failure rate of 0.2–0.8%.[23] A single implant is approved for three years with data showing effectiveness for five years.[28][11]
Etonogestrel implants should not be used on patients who already are or already may be pregnant, have unexplained vaginal bleeding, or have severeliver disease.[29][30]
Irregular bleeding and spotting: Many women will experience some type of irregular, unpredictable, prolonged, frequent, or infrequent bleeding.[31] Some women also experienceamenorrhea. For some women, prolonged bleeding will decline after the first three months of use. However, other women may experience this bleeding pattern through all five years of use. While these patterns are not dangerous, they are the most common reason that women give for discontinuing the use of the implant. After removal, bleeding patterns return to previous patterns in most women.[24][25][26]
Insertion complications: Some minor side effects such as bruising, skin irritation, or pain around the insertion site are common.[24] However, there are some rare complications that can occur, such as infection or expulsion.[24][32] In some cases, a serious complication occurs when the provider fails to insert, and the rod is left in the inserter. An Australian study reported 84 pregnancies as a result of such failure.[27]
Migration: Although very rare, the rod can sometimes move slightly within the arm. This can make removal more difficult. It is possible that insertion in the same site as a previous implant increases the likelihood of migration.[32] Rods can be located only through high-frequency ultrasound or magnetic resonance imaging (MRI).[24] It can be located using traditional X-ray or CT-scan because of the inclusion of barium sulphate. There have been rare reports of implants having reached the lung via the pulmonary artery.[33] Correct subdermal insertion over the triceps muscle reduces the risk of these events.
Possible weight gain: Some women may experience slight weight gain when using the implant.[24] However, current studies are not conclusive because they do not compare the weight of women using implants with a control group of women not using the implant. The average increase in body weight in studies was less than 5 pounds (2.25 kg) over 2 years.[25]
Ovarian cysts: A small portion of women using implants and other contraceptive implants developovarian cysts.[24] Usually these cysts will disappear without treatment.[34]
Pregnancy: It is recommended that implants be removed if a pregnancy does occur. However, there is no evidence to suggest that the implant has a negative effect on pregnancy or a developing fetus.[24]
Acne: Acne has been self-reported to be a side effect, and is listed as a side effect by the FDA. However, a study of users found that a majority of users with acne before their insertion reported that their acne had decreased, and only 16% of those who did not have acne before insertion developed acne.[25]
Other possible symptoms: Other symptoms that have been reported in trials of implants include headache,emotional lability, depression, abdominal pain, loss of libido, and vaginal dryness.[24] However, there have been no studies that conclusively determine that these symptoms are caused by the implant.[25][26]
No serious side effects are expected when overdosing contraceptives in general.[35]
Efavirenz, aninducer of the liver enzymeCYP3A4, appears to decrease etonogestrel levels[36] and increase rates of undesired pregnancy among implant users.
Similar effects are expected for other CYP3A4 inducers, but it is not known whether these are clinically relevant. The opposite is true of CYP3A4 inhibitors such asketoconazole,itraconazole andclarithromycin: they might increase etonogestrel concentrations in the body.[35]
Nexplanon/Implanon consists of a single rod made of ethylene vinylacetate copolymer that is 4 cm long and 2 mm in diameter.[31] It is similar to a matchstick in size. The rod contains 68 mg of etonogestrel (sometimes called 3-keto-destrogestrel), a type of progestin.[24] Peak serum etonogestrel concentrations have been found to reach 781–894 pg/mL in the first few weeks, gradually decreasing 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 and contraceptive efficacy.[37] Serum levels maintain relatively stable through 36 months, which implies that the method may be effective for longer than three years.[38]
Although not formally approved by the manufacturer for more than three years, studies have shown it remains a highly effective contraceptive for five years.[28]
It is a type ofprogestogen-only contraception.
An experienced clinician must perform the insertion of implants to ensure proper insertion and minimize the risk of nerve damage or misplacement, which could result in pregnancy.[39] Before insertion, the arm is washed with a cleaning solution and a local anesthetic is applied to the upper arm around the insertion area.[24] A needle-like applicator is used to insert the rod under the skin into the subdermal tissue on the inner side of the arm posterior to the groove between the biceps and triceps muscles.[40] The average time for insertion is 0.5 to 1 minute.[25][26] A bandage should be kept on the insertion site for 24 hours afterwards. Bruising and mild discomfort are common after insertion.[24] Serious insertion site complications such as infection can occur very rarely, in less than 1% of patients. If a woman receives an implant outside the first five days of her period, she should wait to have sex or use a backup method of contraception (such as acondom,female condom,diaphragm, sponge, oremergency contraception) for the following week after insertion to prevent pregnancy. However, if the implant is inserted during the first five days of a woman's period, the drug typically is effective for that cycle and beyond.[41]
Implants can be removed at any time if pregnancy is desired. The rod must also be removed by an experienced clinician. At removal, a local anesthetic is again used around the implant area at the distal end.[24] If the provider cannot feel the implant, imaging tests may be necessary to locate the rod before it can be removed. A small incision is made in the skin over the end of the implant site. In some cases, a fibrous sheath may have formed around the implant, in which case the sheath must be incised.[24] The implant is removed using forceps. The removal procedure lasts, on average, 3 to 3.5 minutes.[25][26]
Within a week of removal, the hormones from the device leave the body and etonogestrel is undetectable in most users.[24] Most women will begin to ovulate within six weeks of removal.[38][42]Fertility levels will return to what they were before implant insertion.[15]
Nexplanon and Implanon NXT are essentially identical to Implanon except Nexplanon and Implanon NXT have 15 mg ofbarium sulphate added to the core, so it is detectable by x-ray.[43][28] Nexplanon and Implanon NXT also has a pre-loaded applicator for easier insertion.[44]
The mechanism of action ofprogestin-only contraceptives depends on the progestin activity and dose.[45] Intermediate dose progestin-only contraceptives like Nexplanon or Implanon allow some follicular development but inhibit ovulation in almost all cycles as the primary mechanism of action. Ovulation was not observed in studies of Implanon in the first two years of use and only rarely in the third year with no pregnancies. A secondary mechanism of action is the progestogenic increase in cervical mucus viscosity which inhibits sperm penetration.[46] Hormonal contraceptives also have effects on the endometrium that theoretically could affect implantation, however no scientific evidence indicates that prevention of implantation actually results from their use.[47]
Etonogestrel is aprogestogen, or anagonist of theprogesterone receptor.[16] It is lessandrogenic thanlevonorgestrel andnorethisterone,[48][49] and it does not cause a decrease insex hormone-binding globulin levels.[50] However, it is still associated withacne in up to 13.5% of patients when used as an implant, though this side effect only accounts for 1.3% of premature removals of the implant.[51] In addition to its progestogenic and weak androgenic activity, etonogestrel binds to theglucocorticoid receptor with about 14% of theaffinity ofdexamethasone (relative to 1% for levonorgestrel) and has very weakglucocorticoid activity.[16] Etonogestrel has no other hormonal activity (e.g.,estrogenic,antimineralocorticoid).[16] Someinhibition of 5α-reductase and hepaticcytochrome P450 enzymes has been observed with etonogestrelin vitro, similarly to other19-nortestosterone progestins.[16]
| Compound | PRTooltip Progesterone receptor | ARTooltip Androgen receptor | ERTooltip Estrogen receptor | GRTooltip Glucocorticoid receptor | MRTooltip Mineralocorticoid receptor | SHBGTooltip Sex hormone-binding globulin | CBGTooltip Corticosteroid binding globulin |
|---|---|---|---|---|---|---|---|
| Etonogestrel | 150 | 20 | 0 | 14 | 0 | 15 | 0 |
| 5α-Dihydroetonogestrel | 9 | 17 | 0 | ? | ? | ? | ? |
| Sources: Values are percentages (%). Referenceligands (100%) wereprome-gestone for thePRTooltip progesterone receptor,metribolone for theARTooltip androgen receptor,E2 for theERTooltip estrogen receptor,DEXATooltip dexamethasone for theGRTooltip glucocorticoid receptor,aldosterone for theMRTooltip mineralocorticoid receptor,DHTTooltip dihydrotestosterone forSHBGTooltip sex hormone-binding globulin, andcortisol forCBGTooltip Corticosteroid-binding globulin.Sources:[52][16] | |||||||
| Steroid | Class | TRTooltip Thrombin receptor (↑)a | GRTooltip glucocorticoid receptor (%)b |
|---|---|---|---|
| Dexamethasone | Corticosteroid | ++ | 100 |
| Ethinylestradiol | Estrogen | – | 0 |
| Etonogestrel | Progestin | + | 14 |
| Gestodene | Progestin | + | 27 |
| Levonorgestrel | Progestin | – | 1 |
| Medroxyprogesterone acetate | Progestin | + | 29 |
| Norethisterone | Progestin | – | 0 |
| Norgestimate | Progestin | – | 1 |
| Progesterone | Progestogen | + | 10 |
| Footnotes:a =Thrombin receptor (TR)upregulation (↑) invascular smooth muscle cells (VSMCs).b =RBATooltip Relative binding affinity (%) for theglucocorticoid receptor (GR).Strength: – = No effect. + = Pronounced effect. ++ = Strong effect.Sources:[53] | |||
Thebioavailability of etonogestrel when given as asubcutaneous implant or as avaginal ring is 100%.[4][5]Steady-state levels of etonogestrel are achieved within one week upon insertion as an implant or vaginal ring.[4][5] The meanvolume of distribution of etonogestrel is 201 L.[4] Theplasma protein binding of the medication is at least 98%, with 66% bound toalbumin and 32% bound tosex hormone-binding globulin.[4][5] Etonogestrel ismetabolized in theliver byCYP3A4.[4][5] Thebiological activity of itsmetabolites is unknown.[4][5] Theelimination half-life of etonogestrel is about 25 to 29 hours.[4][5] Following removal of an etonogestrel-containing implant, levels of the medication were below the limits of assay detection by one week.[4] The major portion of etonogestrel iseliminated inurine and a minor portion is eliminated infeces.[4][5]
Etonogestrel, also known as 11-methylene-17α-ethynyl-18-methyl-19-nortestosterone or as 11-methylene-17α-ethynyl-18-methylestr-4-en-17β-ol-3-one, is a syntheticestrane steroid and aderivative oftestosterone.[12][14] It is more specifically a derivative ofnorethisterone (17α-ethynyl-19-nortestosterone) and is a member of thegonane (18-methylestrane) subgroup of the19-nortestosterone family of progestins.[54][55] Etonogestrel is the C3ketone derivative ofdesogestrel and the C11methylene derivative oflevonorgestrel and is also known as 3-ketodesogestrel and as 11-methylenelevonorgestrel.[1]
The possibility of the subdermal contraceptive implant began when silicone was discovered in the 1940s and found to be bio-compatible with the human body.[56]In 1964, Folkman and Long published the first study demonstrating that such a rod could be used to deliver drugs.[57]In 1966 Dziuk and Cook published a study that looked at release rates and suggested that the rods could be well suited for contraception.[58] After a study that used implants with progestogens for contraception, the Population Council developed and patentedNorplant andJadelle.[59] Norplant has six rods and is considered a first-generation implant. Jadelle (Norplant II), a two-rod implant, and other single rod implants that followed, were developed because of complications resulting from Norplant's six-rod system. The Jadelle system contains two silicone rods mixed with levonorgestrel. In 1990 De Nijs patented a co-axial extrusion technique of ethylene vinylacetate copolymers and 3-keto-desogestrel (etonogestrel) for the preparation of long-acting contraceptive devices, such as Implanon, Nexplanon and Nuvaring.[60] The single rods were less visible under the skin and used etonogestrel as opposed to levonorgestrel in the hopes that it would reduce side effects.[56]
Desogestrel (3-deketoetonogestrel), aprodrug of etonogestrel, was introduced for medical use in 1981.[6][61]
Norplant was used internationally beginning in 1983 and was marketed in the United States and the United Kingdom in 1993. There were many complications associated with Norplant removal in the United States and it was taken off the market in 2002. Although Jadelle was approved by the FDA, it has never been marketed in the United States, but it is widely used in Africa and Asia.[59]
Etonogestrel itself was first introduced as Implanon in Indonesia in 1998,[18][19] was marketed in the United Kingdom shortly thereafter,[62] and approved for use in the United States in 2006.[18][19] Nexplanon was developed to eliminate the problem of non-insertion and localization of Implanon by changing the inserter device and making the rod radiopaque.[43] As of January 2012, Implanon is no longer being marketed and Nexplanon is the only available single-rod implant.
Etonogestrel is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name,USANTooltip United States Adopted Name, andBANTooltip British Approved Name.[12][14] It is also known by its developmental code nameORG-3236.[12][14]
Etonogestrel is marketed under the brand names Circlet, Implanon, Nexplanon, and NuvaRing.[12][14]
Etonogestrel is available widely throughout the world, including in the United States, Canada, the United Kingdom, Ireland, elsewhere throughout Europe, South Africa, Latin America,South,East, and Southeast Asia, and elsewhere in the world.[14]
An etonogestrel-releasingintrauterine device was under development for use as a form of birth control for women but development was discontinued in 2015.[63]
Etonogestrel has been studied for use as a potentialmale contraceptive.[64]
The elimination half-life for 3-keto-desogestrel is approximately 38 ± 20 hours at steady state.
{{cite book}}: CS1 maint: location missing publisher (link)In 1981, desogestrel was marketed as a new low dose oral contraceptive under the trade names Marvelon and Desogen.32
