Etonogestrel: Difference between revisions

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* Undiagnosed abnormal genital bleeding
* Undiagnosed abnormal genital bleeding
* Known or suspected breast cancer, personal history of breast cancer, or other progestin-sensitive cancer, now or in the past
* Known or suspected breast cancer, personal history of breast cancer, or other progestin-sensitive cancer, now or in the past
* Allergic reaction to any of the components of IMPLANON
* Allergic reaction to any of the components of etonogestrel
|warnings======Complications of Insertion and Removal=====
|warnings======Complications of Insertion and Removal=====
Etonogestrel should be inserted subdermally so that it will be palpable after insertion, and this should be confirmed by palpation immediately after insertion. Failure to insert IMPLANON properly may go unnoticed unless it is palpated immediately after insertion. Undetected failure to insert the implant may lead to an unintended pregnancy. Complications related to insertion and removal procedures, such as pain, paresthesias, bleeding, hematoma, scarring or infection, may occur. Occasionally in post-marketing use, implant insertions have failed because the implant fell out of the needle or remained in the needle during insertion.
Etonogestrel should be inserted subdermally so that it will be palpable after insertion, and this should be confirmed by palpation immediately after insertion. Failure to insert etonogestrel properly may go unnoticed unless it is palpated immediately after insertion. Undetected failure to insert the implant may lead to an unintended pregnancy. Complications related to insertion and removal procedures, such as pain, paresthesias, bleeding, hematoma, scarring or infection, may occur. Occasionally in post-marketing use, implant insertions have failed because the implant fell out of the needle or remained in the needle during insertion.


If IMPLANON is inserted too deeply (intramuscular or in the fascia), neural or vascular injury may occur. To reduce the risk of neural or vascular injury, IMPLANON should be inserted at the inner side of the non-dominant upper arm about 8-10 cm (3-4 inches) above the medial epicondyle of the humerus. IMPLANON should be inserted subdermally just under the skin to avoid the large blood vessels and nerves that lie deeper in the subcutaneous tissues in the sulcus between the triceps and biceps muscles. Deep insertions of IMPLANON have been associated with paraesthesia (due to neural injury) and migration of the implant (due to intramuscular or fascial insertion), and in a very few cases with intravascular insertion. If infection develops at the insertion site, start suitable treatment. If the infection persists, the implant should be removed. Incomplete insertions or infections may lead to expulsion. In postmarketing use there have been cases of failure to localize and remove the implant, probably due to deep insertion. There has been 1 case of an intravascular insertion reported post-marketing which led to inability to remove the implant.
If etonogestrel is inserted too deeply (intramuscular or in the fascia), neural or vascular injury may occur. To reduce the risk of neural or vascular injury, etonogestrel should be inserted at the inner side of the non-dominant upper arm about 8-10 cm (3-4 inches) above the medial epicondyle of the humerus. etonogestrel should be inserted subdermally just under the skin to avoid the large blood vessels and nerves that lie deeper in the subcutaneous tissues in the sulcus between the triceps and biceps muscles. Deep insertions of etonogestrel have been associated with paraesthesia (due to neural injury) and migration of the implant (due to intramuscular or fascial insertion), and in a very few cases with intravascular insertion. If infection develops at the insertion site, start suitable treatment. If the infection persists, the implant should be removed. Incomplete insertions or infections may lead to expulsion. In postmarketing use there have been cases of failure to localize and remove the implant, probably due to deep insertion. There has been 1 case of an intravascular insertion reported post-marketing which led to inability to remove the implant.


Implant removal may be difficult or impossible if the implant is not inserted correctly, is inserted too deeply, not palpable, encased in fibrous tissue, or has migrated. Deep insertions may lead to difficult localization of the implant and may also result in the need for a surgical procedure in an operating room in order to remove the implant. Exploratory surgery without knowledge of the exact location of the implant is strongly discouraged. Removal of deeply inserted implants should be conducted with caution in order to prevent injury to deeper neural or vascular structures in the arm and be performed by healthcare providers familiar with the anatomy of the arm. Failure to remove the implant may result in continued effects of etonogestrel, such as compromised fertility, ectopic pregnancy, or persistence or occurrence of a drug-related adverse event.
Implant removal may be difficult or impossible if the implant is not inserted correctly, is inserted too deeply, not palpable, encased in fibrous tissue, or has migrated. Deep insertions may lead to difficult localization of the implant and may also result in the need for a surgical procedure in an operating room in order to remove the implant. Exploratory surgery without knowledge of the exact location of the implant is strongly discouraged. Removal of deeply inserted implants should be conducted with caution in order to prevent injury to deeper neural or vascular structures in the arm and be performed by healthcare providers familiar with the anatomy of the arm. Failure to remove the implant may result in continued effects of etonogestrel, such as compromised fertility, ectopic pregnancy, or persistence or occurrence of a drug-related adverse event.


=====Changes in Menstrual Bleeding Patterns=====
=====Changes in Menstrual Bleeding Patterns=====
After starting IMPLANON, women are likely to have a change from their normal menstrual bleeding pattern. These may include changes in bleeding frequency (absent, less, more frequent or continuous), intensity (reduced or increased) or duration. In clinical trials, bleeding patterns ranged from amenorrhea (1 in 5 women) to frequent and/or prolonged bleeding (1 in 5 women). The bleeding pattern experienced during the first three months of IMPLANON use is broadly predictive of the future bleeding pattern for many women. Women should be counseled regarding the bleeding pattern changes they may experience so that they know what to expect. Abnormal bleeding should be evaluated as needed to exclude pathologic conditions or pregnancy.
After starting etonogestrel, women are likely to have a change from their normal menstrual bleeding pattern. These may include changes in bleeding frequency (absent, less, more frequent or continuous), intensity (reduced or increased) or duration. In clinical trials, bleeding patterns ranged from amenorrhea (1 in 5 women) to frequent and/or prolonged bleeding (1 in 5 women). The bleeding pattern experienced during the first three months of etonogestrel use is broadly predictive of the future bleeding pattern for many women. Women should be counseled regarding the bleeding pattern changes they may experience so that they know what to expect. Abnormal bleeding should be evaluated as needed to exclude pathologic conditions or pregnancy.


In clinical studies of IMPLANON, reports of changes in bleeding pattern were the most common reason for stopping treatment (11.1%). Irregular bleeding (10.8%) was the single most common reason women stopped treatment, while amenorrhea (0.3%) was cited less frequently. In these studies, women had an average of 17.7 days of bleeding or spotting every 90 days (based on 3,315 intervals of 90 days recorded by 780 patients). The percentages of patients having 0, 1-7, 8-21, or >21 days of spotting or bleeding over a 90-day interval while using the IMPLANON implant are shown in TABLE 1.
In clinical studies of etonogestrel, reports of changes in bleeding pattern were the most common reason for stopping treatment (11.1%). Irregular bleeding (10.8%) was the single most common reason women stopped treatment, while amenorrhea (0.3%) was cited less frequently. In these studies, women had an average of 17.7 days of bleeding or spotting every 90 days (based on 3,315 intervals of 90 days recorded by 780 patients). The percentages of patients having 0, 1-7, 8-21, or >21 days of spotting or bleeding over a 90-day interval while using the etonogestrel implant are shown in TABLE 1.


[[File:Etonogestrel Changes in Menstrual Bleeding Patterns table 1.png|thumb|none|500px]]
[[File:Etonogestrel Changes in Menstrual Bleeding Patterns table 1.png|thumb|none|500px]]


Bleeding patterns observed with use of IMPLANON for up to 2 years, and the proportion of 90-day intervals with these bleeding patterns, are summarized in TABLE 2.
Bleeding patterns observed with use of etonogestrel for up to 2 years, and the proportion of 90-day intervals with these bleeding patterns, are summarized in TABLE 2.


[[File:Etonogestrel Changes in Menstrual Bleeding Patterns table 2.png|thumb|none|500px]]
[[File:Etonogestrel Changes in Menstrual Bleeding Patterns table 2.png|thumb|none|500px]]
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=====Ectopic Pregnancies=====
=====Ectopic Pregnancies=====
As with all progestin-only contraceptive products, be alert to the possibility of an ectopic pregnancy among women using IMPLANON who become pregnant or complain of lower abdominal pain. Although ectopic pregnancies are uncommon among women using IMPLANON, a pregnancy that occurs in a woman using IMPLANON may be more likely to be ectopic than a pregnancy occurring in a woman using no contraception.
As with all progestin-only contraceptive products, be alert to the possibility of an ectopic pregnancy among women using etonogestrel who become pregnant or complain of lower abdominal pain. Although ectopic pregnancies are uncommon among women using etonogestrel, a pregnancy that occurs in a woman using etonogestrel may be more likely to be ectopic than a pregnancy occurring in a woman using no contraception.


=====Thrombotic and Other Vascular Events=====
=====Thrombotic and Other Vascular Events=====
The use of combination hormonal contraceptives (progestin plus estrogen) increases the risk of vascular events, including arterial events (strokes and myocardial infarctions) or deep venous thrombotic events (venous thromboembolism, deep venous thrombosis, retinal vein thrombosis, and pulmonary embolism). IMPLANON is a progestin-only contraceptive. It is unknown whether this increased risk is applicable to etonogestrel alone. It is recommended, however, that women with risk factors known to increase the risk of venous and arterial thromboembolism be carefully assessed.
The use of combination hormonal contraceptives (progestin plus estrogen) increases the risk of vascular events, including arterial events (strokes and myocardial infarctions) or deep venous thrombotic events (venous thromboembolism, deep venous thrombosis, retinal vein thrombosis, and pulmonary embolism). etonogestrel is a progestin-only contraceptive. It is unknown whether this increased risk is applicable to etonogestrel alone. It is recommended, however, that women with risk factors known to increase the risk of venous and arterial thromboembolism be carefully assessed.


There have been postmarketing reports of serious arterial and venous thromboembolic events, including cases of pulmonary emboli (some fatal), deep vein thrombosis, myocardial infarction, and strokes, in women using IMPLANON. IMPLANON should be removed in the event of a thrombosis.
There have been postmarketing reports of serious arterial and venous thromboembolic events, including cases of pulmonary emboli (some fatal), deep vein thrombosis, myocardial infarction, and strokes, in women using etonogestrel. etonogestrel should be removed in the event of a thrombosis.


Due to the risk of thromboembolism associated with pregnancy and immediately following delivery, IMPLANON should not be used prior to 21 days postpartum. Women with a history of thromboembolic disorders should be made aware of the possibility of a recurrence.
Due to the risk of thromboembolism associated with pregnancy and immediately following delivery, etonogestrel should not be used prior to 21 days postpartum. Women with a history of thromboembolic disorders should be made aware of the possibility of a recurrence.


Evaluate for retinal vein thrombosis immediately if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions.
Evaluate for retinal vein thrombosis immediately if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions.


Consider removal of the IMPLANON implant in case of long-term immobilization due to surgery or illness.
Consider removal of the etonogestrel implant in case of long-term immobilization due to surgery or illness.


=====Ovarian Cysts=====
=====Ovarian Cysts=====
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=====Liver Disease=====
=====Liver Disease=====
Disturbances of liver function may necessitate the discontinuation of hormonal contraceptive use until markers of liver function return to normal. Remove IMPLANON if jaundice develops.
Disturbances of liver function may necessitate the discontinuation of hormonal contraceptive use until markers of liver function return to normal. Remove etonogestrel if jaundice develops.


Hepatic adenomas are associated with combination hormonal contraceptives use. An estimate of the attributable risk is 3.3 cases per 100,000 for combination hormonal contraceptives users. It is not known whether a similar risk exists with progestin-only methods like IMPLANON.
Hepatic adenomas are associated with combination hormonal contraceptives use. An estimate of the attributable risk is 3.3 cases per 100,000 for combination hormonal contraceptives users. It is not known whether a similar risk exists with progestin-only methods like etonogestrel.


The progestin in IMPLANON may be poorly metabolized in women with liver impairment. Use of IMPLANON in women with active liver disease or liver cancer is contraindicated.
The progestin in etonogestrel may be poorly metabolized in women with liver impairment. Use of etonogestrel in women with active liver disease or liver cancer is contraindicated.


=====Weight Gain=====
=====Weight Gain=====
In clinical studies, mean weight gain in US IMPLANON users was 2.8 pounds after 1 year and 3.7 pounds after 2 years. How much of the weight gain was related to the implant is unknown. In studies, 2.3% of the users reported weight gain as the reason for having the implant removed.
In clinical studies, mean weight gain in US etonogestrel users was 2.8 pounds after 1 year and 3.7 pounds after 2 years. How much of the weight gain was related to the implant is unknown. In studies, 2.3% of the users reported weight gain as the reason for having the implant removed.


=====Elevated Blood Pressure=====
=====Elevated Blood Pressure=====
Women with a history of hypertension-related diseases or renal disease should be discouraged from using hormonal contraception. For women with well-controlled hypertension, use of IMPLANON can be considered. Women with hypertension using IMPLANON should be closely monitored. lf sustained hypertension develops during the use of IMPLANON, or if a significant increase in blood pressure does not respond adequately to antihypertensive therapy, IMPLANON should be removed.
Women with a history of hypertension-related diseases or renal disease should be discouraged from using hormonal contraception. For women with well-controlled hypertension, use of etonogestrel can be considered. Women with hypertension using etonogestrel should be closely monitored. lf sustained hypertension develops during the use of etonogestrel, or if a significant increase in blood pressure does not respond adequately to antihypertensive therapy, etonogestrel should be removed.


=====Gallbladder Disease=====
=====Gallbladder Disease=====
Studies suggest a small increased relative risk of developing gallbladder disease among combination hormonal contraceptive users. It is not known whether a similar risk exists with progestin-only methods like IMPLANON.
Studies suggest a small increased relative risk of developing gallbladder disease among combination hormonal contraceptive users. It is not known whether a similar risk exists with progestin-only methods like etonogestrel.


=====Carbohydrate and Lipid Metabolic Effects=====
=====Carbohydrate and Lipid Metabolic Effects=====
Use of IMPLANON may induce mild insulin resistance and small changes in glucose concentrations of unknown clinical significance. Carefully monitor prediabetic and diabetic women using IMPLANON.
Use of etonogestrel may induce mild insulin resistance and small changes in glucose concentrations of unknown clinical significance. Carefully monitor prediabetic and diabetic women using etonogestrel.


Women who are being treated for hyperlipidemia should be followed closely if they elect to use IMPLANON. Some progestins may elevate LDL levels and may render the control of hyperlipidemia more difficult.
Women who are being treated for hyperlipidemia should be followed closely if they elect to use etonogestrel. Some progestins may elevate LDL levels and may render the control of hyperlipidemia more difficult.


=====Depressed Mood=====
=====Depressed Mood=====
Women with a history of depressed mood should be carefully observed. Consideration should be given to removing IMPLANON in patients who become significantly depressed.
Women with a history of depressed mood should be carefully observed. Consideration should be given to removing etonogestrel in patients who become significantly depressed.


=====Return to Ovulation=====
=====Return to Ovulation=====
In clinical trials with IMPLANON, the etonogestrel levels in blood decreased below sensitivity of the assay by one week after removal of the implant. In addition, pregnancies were observed to occur as early as 7 to 14 days after removal. Therefore, a woman should re-start contraception immediately after removal of the implant if continued contraceptive protection is desired.
In clinical trials with etonogestrel, the etonogestrel levels in blood decreased below sensitivity of the assay by one week after removal of the implant. In addition, pregnancies were observed to occur as early as 7 to 14 days after removal. Therefore, a woman should re-start contraception immediately after removal of the implant if continued contraceptive protection is desired.


=====Fluid Retention=====
=====Fluid Retention=====
Hormonal contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention. It is unknown if IMPLANON causes fluid retention.
Hormonal contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention. It is unknown if etonogestrel causes fluid retention.


=====Contact Lenses=====
=====Contact Lenses=====
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|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.


In clinical trials including 942 women who were evaluated for safety, change in menstrual bleeding patterns (irregular menses) was the most common adverse reaction causing discontinuation of use of IMPLANON (11.1% of women).
In clinical trials including 942 women who were evaluated for safety, change in menstrual bleeding patterns (irregular menses) was the most common adverse reaction causing discontinuation of use of etonogestrel (11.1% of women).


Adverse reactions that resulted in a rate of discontinuation of ≥1% are shown in TABLE 3.
Adverse reactions that resulted in a rate of discontinuation of ≥1% are shown in TABLE 3.
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[[File:Etonogestrel Adverse Reactions Leading to Discontinuation of Treatment.png|thumb|none|500px]]
[[File:Etonogestrel Adverse Reactions Leading to Discontinuation of Treatment.png|thumb|none|500px]]


Other adverse reactions that were reported by at least 5% of subjects in clinical trials of IMPLANON are listed in TABLE 4.
Other adverse reactions that were reported by at least 5% of subjects in clinical trials of etonogestrel are listed in TABLE 4.


[[File:Etonogestrel Common Adverse Reactions Reported.png|thumb|none|500px]]
[[File:Etonogestrel Common Adverse Reactions Reported.png|thumb|none|500px]]


Implant site complications were reported by 3.6% of subjects during any of the assessments in clinical trials. Pain was the most frequent implant site complication, reported during and/or after insertion, occurring in 2.9% of subjects. Additionally, hematoma, redness, and swelling were reported by 0.1%, 0.3%, and 0.3% of patients, respectively.
Implant site complications were reported by 3.6% of subjects during any of the assessments in clinical trials. Pain was the most frequent implant site complication, reported during and/or after insertion, occurring in 2.9% of subjects. Additionally, hematoma, redness, and swelling were reported by 0.1%, 0.3%, and 0.3% of patients, respectively.
|postmarketing=The following additional adverse reactions have been identified during post-approval use of IMPLANON. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
|postmarketing=The following additional adverse reactions have been identified during post-approval use of etonogestrel. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
* Gastrointestinal disorders: constipation, diarrhea, flatulence, vomiting.
* Gastrointestinal disorders: constipation, diarrhea, flatulence, vomiting.
* General disorders and administration site conditions: edema, fatigue, implant site reaction, pyrexia.
* General disorders and administration site conditions: edema, fatigue, implant site reaction, pyrexia.
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Complications related to insertion or removal of the implant reported include: bruising, slight local irritation, pain or itching, fibrosis at the implant site, paresthesia or paresthesia-like events, scarring and abscess.
Complications related to insertion or removal of the implant reported include: bruising, slight local irritation, pain or itching, fibrosis at the implant site, paresthesia or paresthesia-like events, scarring and abscess.
|drugInteractions======Changes in Contraceptive Effectiveness Associated with Coadministration of Other Products=====
|drugInteractions======Changes in Contraceptive Effectiveness Associated with Coadministration of Other Products=====
Drugs or herbal products that induce enzymes, including CYP3A4, that metabolize progestins may decrease the plasma concentrations of progestins, and may decrease the effectiveness of IMPLANON. In women on long-term treatment with hepatic enzyme inducing drugs, it is recommended to remove the implant and to advise a contraceptive method that is unaffected by the interacting drug.
Drugs or herbal products that induce enzymes, including CYP3A4, that metabolize progestins may decrease the plasma concentrations of progestins, and may decrease the effectiveness of etonogestrel. In women on long-term treatment with hepatic enzyme inducing drugs, it is recommended to remove the implant and to advise a contraceptive method that is unaffected by the interacting drug.


Some of these drugs or herbal products that induce enzymes, including CYP3A4, include:
Some of these drugs or herbal products that induce enzymes, including CYP3A4, include:
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|useInPregnancyFDA=Etonogestrel is not indicated for use during pregnancy [see CONTRAINDICATIONS (4)].
|useInPregnancyFDA=Etonogestrel is not indicated for use during pregnancy [see CONTRAINDICATIONS (4)].


Teratology studies have been performed in rats and rabbits using oral administration up to 390 and 790 times the human IMPLANON dose (based upon body surface) and revealed no evidence of fetal harm due to etonogestrel exposure.
Teratology studies have been performed in rats and rabbits using oral administration up to 390 and 790 times the human etonogestrel dose (based upon body surface) and revealed no evidence of fetal harm due to etonogestrel exposure.


Studies have revealed no increased risk of birth defects in women who have used combination oral contraceptives before pregnancy or during early pregnancy. There is no evidence that the risk associated with IMPLANON is different from that of combination oral contraceptives.
Studies have revealed no increased risk of birth defects in women who have used combination oral contraceptives before pregnancy or during early pregnancy. There is no evidence that the risk associated with etonogestrel is different from that of combination oral contraceptives.


Etonogestrel should be removed if maintaining a pregnancy.
Etonogestrel should be removed if maintaining a pregnancy.
|useInNursing=Based on limited clinical data, IMPLANON may be used during breastfeeding after the fourth postpartum week. Use of IMPLANON before the fourth postpartum week has not been studied. Small amounts of etonogestrel are excreted in breast milk. During the first months after insertion of IMPLANON, when maternal blood levels of etonogestrel are highest, about 100 ng of etonogestrel may be ingested by the child per day based on an average daily milk ingestion of 658 mL. Based on daily milk ingestion of 150 mL/kg, the mean daily infant etonogestrel dose one month after insertion of IMPLANON is about 2.2% of the weight-adjusted maternal daily dose, or about 0.2% of the estimated absolute maternal daily dose. The health of breast-fed infants whose mothers began using IMPLANON during the fourth to eighth week postpartum (n=38) was evaluated in a comparative study with infants of mothers using a non-hormonal IUD (n=33). They were breast-fed for a mean duration of 14 months and followed up to 36 months of age. No significant effects and no differences between the groups were observed on the physical and psychomotor development of these infants. No differences between groups in the production or quality of breast milk were detected.
|useInNursing=Based on limited clinical data, etonogestrel may be used during breastfeeding after the fourth postpartum week. Use of etonogestrel before the fourth postpartum week has not been studied. Small amounts of etonogestrel are excreted in breast milk. During the first months after insertion of etonogestrel, when maternal blood levels of etonogestrel are highest, about 100 ng of etonogestrel may be ingested by the child per day based on an average daily milk ingestion of 658 mL. Based on daily milk ingestion of 150 mL/kg, the mean daily infant etonogestrel dose one month after insertion of etonogestrel is about 2.2% of the weight-adjusted maternal daily dose, or about 0.2% of the estimated absolute maternal daily dose. The health of breast-fed infants whose mothers began using etonogestrel during the fourth to eighth week postpartum (n=38) was evaluated in a comparative study with infants of mothers using a non-hormonal IUD (n=33). They were breast-fed for a mean duration of 14 months and followed up to 36 months of age. No significant effects and no differences between the groups were observed on the physical and psychomotor development of these infants. No differences between groups in the production or quality of breast milk were detected.


Healthcare providers should discuss both hormonal and non-hormonal contraceptive options, as steroids may not be the initial choice for these patients.
Healthcare providers should discuss both hormonal and non-hormonal contraceptive options, as steroids may not be the initial choice for these patients.
|useInPed=Safety and efficacy of IMPLANON have been established in women of reproductive age. Safety and efficacy of IMPLANON are expected to be the same for postpubertal adolescents. However, no clinical studies have been conducted in women less than 18 years of age. Use of this product before menarche is not indicated.
|useInPed=Safety and efficacy of etonogestrel have been established in women of reproductive age. Safety and efficacy of etonogestrel are expected to be the same for postpubertal adolescents. However, no clinical studies have been conducted in women less than 18 years of age. Use of this product before menarche is not indicated.
|useInGeri=This product has not been studied in women over 65 years of age and is not indicated in this population.
|useInGeri=This product has not been studied in women over 65 years of age and is not indicated in this population.
|useInRenalImpair=No studies were conducted to evaluate the effect of renal disease on the disposition of IMPLANON.
|useInRenalImpair=No studies were conducted to evaluate the effect of renal disease on the disposition of etonogestrel.
|useInHepaticImpair=No studies were conducted to evaluate the effect of hepatic disease on the disposition of IMPLANON. The use of IMPLANON in women with active liver disease is contraindicated.
|useInHepaticImpair=No studies were conducted to evaluate the effect of hepatic disease on the disposition of etonogestrel. The use of etonogestrel in women with active liver disease is contraindicated.
|useInReproPotential=Fertility returned after withdrawal from treatment.
|useInReproPotential=Fertility returned after withdrawal from treatment.
|othersTitle=Overweight Women
|othersTitle=Overweight Women
|useInOthers=The effectiveness of IMPLANON in women who weighed more than 130% of their ideal body weight has not been defined because such women were not studied in clinical trials. Serum concentrations of etonogestrel are inversely related to body weight and decrease with time after implant insertion. It is therefore possible that IMPLANON may be less effective in overweight women, especially in the presence of other factors that decrease serum etonogestrel concentrations such as concomitant use of hepatic enzyme inducers.
|useInOthers=The effectiveness of etonogestrel in women who weighed more than 130% of their ideal body weight has not been defined because such women were not studied in clinical trials. Serum concentrations of etonogestrel are inversely related to body weight and decrease with time after implant insertion. It is therefore possible that etonogestrel may be less effective in overweight women, especially in the presence of other factors that decrease serum etonogestrel concentrations such as concomitant use of hepatic enzyme inducers.
|administration=Intradermal
|administration=Intradermal
|monitoring=A woman who is using IMPLANON should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated health care.
|monitoring=A woman who is using etonogestrel should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated health care.
|overdose=Overdosage may result if more than 1 implant is inserted. In case of suspected overdose, the implant should be removed.
|overdose=Overdosage may result if more than 1 implant is inserted. In case of suspected overdose, the implant should be removed.
|mechAction=The contraceptive effect of IMPLANON is achieved by suppression of ovulation, increased viscosity of the cervical mucus, and alterations in the endometrium.
|mechAction=The contraceptive effect of etonogestrel is achieved by suppression of ovulation, increased viscosity of the cervical mucus, and alterations in the endometrium.
|structure=Etonogestrel structurally derived from 19-nortestosterone, is the synthetic biologically active metabolite of the synthetic progestin desogestrel. It has a molecular weight of 324.46 and the following structural formula:
|structure=Etonogestrel structurally derived from 19-nortestosterone, is the synthetic biologically active metabolite of the synthetic progestin desogestrel. It has a molecular weight of 324.46 and the following structural formula:


[[File:Etonogestrel chemical structure.png|thumb|none|500px]]
[[File:Etonogestrel chemical structure.png|thumb|none|500px]]
|PD=Exposure-response relationships of IMPLANON are unknown.
|PD=Exposure-response relationships of etonogestrel are unknown.
|PK=======Absorption======
|PK=======Absorption======
After subdermal insertion of the etonogestrel implant, etonogestrel is released into the circulation and is approximately 100% bioavailable.
After subdermal insertion of the etonogestrel implant, etonogestrel is released into the circulation and is approximately 100% bioavailable.
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The elimination half-life of etonogestrel is approximately 25 hours. Excretion of etonogestrel and its metabolites, either as free steroid or as conjugates, is mainly in urine and to a lesser extent in feces. After removal of the implant, etonogestrel concentrations decreased below sensitivity of the assay by 1 week.
The elimination half-life of etonogestrel is approximately 25 hours. Excretion of etonogestrel and its metabolites, either as free steroid or as conjugates, is mainly in urine and to a lesser extent in feces. After removal of the implant, etonogestrel concentrations decreased below sensitivity of the assay by 1 week.
|nonClinToxic======Carcinogenesis and Mutagenesis=====
|nonClinToxic======Carcinogenesis and Mutagenesis=====
In a 24-month carcinogenicity study in rats with subdermal implants releasing 10 and 20 mcg etonogestrel per day (equal to approximately 1.8-3.6 times the systemic steady state exposure in women using IMPLANON), no drug-related carcinogenic potential was observed. Etonogestrel was not genotoxic in the in vitro Ames/Salmonella reverse mutation assay, the chromosomal aberration assay in Chinese hamster ovary cells or in the in vivo mouse micronucleus test.
In a 24-month carcinogenicity study in rats with subdermal implants releasing 10 and 20 mcg etonogestrel per day (equal to approximately 1.8-3.6 times the systemic steady state exposure in women using etonogestrel), no drug-related carcinogenic potential was observed. Etonogestrel was not genotoxic in the in vitro Ames/Salmonella reverse mutation assay, the chromosomal aberration assay in Chinese hamster ovary cells or in the in vivo mouse micronucleus test.
|clinicalStudies=====Pregnancy====
|clinicalStudies=====Pregnancy====
In clinical trials of up to 3 years duration that involved 923 subjects, 18 - 40 years of age at entry, and 1,756 women-years of IMPLANON use, the total exposures expressed as 28-day cycle equivalents by study year were:
In clinical trials of up to 3 years duration that involved 923 subjects, 18 - 40 years of age at entry, and 1,756 women-years of etonogestrel use, the total exposures expressed as 28-day cycle equivalents by study year were:
* Year 1: 10,866 cycles
* Year 1: 10,866 cycles
* Year 2: 8,581 cycles
* Year 2: 8,581 cycles
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* Were chronically taking medications that induce liver enzymes
* Were chronically taking medications that induce liver enzymes


In the subgroup of women 18 to 35 years of age at entry, 6 pregnancies during 20,648 cycles of use were reported. Two pregnancies occurred in each of Years 1, 2 and 3. Each conception was likely to have occurred shortly before or within 2 weeks after IMPLANON removal. With these 6 pregnancies, the cumulative Pearl Index was 0.38 pregnancies per 100 women-years of use.
In the subgroup of women 18 to 35 years of age at entry, 6 pregnancies during 20,648 cycles of use were reported. Two pregnancies occurred in each of Years 1, 2 and 3. Each conception was likely to have occurred shortly before or within 2 weeks after etonogestrel removal. With these 6 pregnancies, the cumulative Pearl Index was 0.38 pregnancies per 100 women-years of use.


====Return to Ovulation====
====Return to Ovulation====
In clinical trials with IMPLANON, the etonogestrel levels in blood decreased below sensitivity of the assay by one week after removal of the implant. In addition, pregnancies were observed to occur as early as 7 to 14 days after removal. Therefore, a woman should re-start contraception immediately after removal of the implant if continued contraceptive protection is desired.
In clinical trials with etonogestrel, the etonogestrel levels in blood decreased below sensitivity of the assay by one week after removal of the implant. In addition, pregnancies were observed to occur as early as 7 to 14 days after removal. Therefore, a woman should re-start contraception immediately after removal of the implant if continued contraceptive protection is desired.
|howSupplied=Single implant containing 68 mg etonogestrel that is 4 cm in length and 2 mm in diameter, which is pre-loaded in the needle of a disposable applicator.
|howSupplied=Single implant containing 68 mg etonogestrel that is 4 cm in length and 2 mm in diameter, which is pre-loaded in the needle of a disposable applicator.
* NDC 0052-0272-01
* NDC 0052-0272-01
|storage=Store at 25°C (77°F)
|storage=Store at 25°C (77°F)
|packLabel=[[File:Etonogestrel FDA package label.png|thumb|none|600px]]
|packLabel=[[File:Etonogestrel FDA package label.png|thumb|none|600px]]
|fdaPatientInfo=* Counsel women about the insertion and removal procedure of the IMPLANON implant. Provide the woman with a copy of the Patient Labeling and ensure that she understands the information in the Patient Labeling before insertion and removal. A USER CARD and consent form are included in the packaging. Have the woman complete a consent form and retain it in your records. The USER CARD should be filled out and given to the patient after insertion of the IMPLANON implant so that she will have a record of the location of the implant in the upper arm and when it should be removed.
|fdaPatientInfo=* Counsel women about the insertion and removal procedure of the etonogestrel implant. Provide the woman with a copy of the Patient Labeling and ensure that she understands the information in the Patient Labeling before insertion and removal. A USER CARD and consent form are included in the packaging. Have the woman complete a consent form and retain it in your records. The USER CARD should be filled out and given to the patient after insertion of the etonogestrel implant so that she will have a record of the location of the implant in the upper arm and when it should be removed.




* Counsel women that IMPLANON does not protect against HIV infection (AIDS) or other sexually transmitted diseases.
* Counsel women that etonogestrel does not protect against HIV infection (AIDS) or other sexually transmitted diseases.




* Counsel women that the use of IMPLANON may be associated with changes in their normal menstrual bleeding patterns so that they know what to expect.
* Counsel women that the use of etonogestrel may be associated with changes in their normal menstrual bleeding patterns so that they know what to expect.
|alcohol=Alcohol-Etonogestrel interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|alcohol=Alcohol-Etonogestrel interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
}}
}}
Line 251: Line 251:
}}
}}
{{SI}}
{{SI}}
'''Etonogestrel''' is a molecule used in [[hormonal]] [[contraceptives]], most notably the subdermal implant [[Implanon]].
'''Etonogestrel''' is a molecule used in [[hormonal]] [[contraceptives]], most notably the subdermal implant [[etonogestrel]].


Etonogestrel, the specific progestin used in NuvaRing, is the active metabolite of the inactive prodrug desogestrel, one of two third-generation progestins found in some epidemiological studies of combined oral contraceptive pills to be associated with a higher risk of venous thrombosis than combined oral contraceptive pills containing certain second-generation progestins. Because hormones are released continuously from NuvaRing, peak and total estrogen and progestin doses are significantly lower than with combined oral contraceptives, although it is not known whether this lowers the risk of blood clots.
Etonogestrel, the specific progestin used in NuvaRing, is the active metabolite of the inactive prodrug desogestrel, one of two third-generation progestins found in some epidemiological studies of combined oral contraceptive pills to be associated with a higher risk of venous thrombosis than combined oral contraceptive pills containing certain second-generation progestins. Because hormones are released continuously from NuvaRing, peak and total estrogen and progestin doses are significantly lower than with combined oral contraceptives, although it is not known whether this lowers the risk of blood clots.

Revision as of 16:26, 2 February 2015

Etonogestrel
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [2]

Disclaimer

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Overview

Etonogestrel is a progestin that is FDA approved for the prophylaxis of pregnancy. Common adverse reactions include {{{adverseReactions}}}.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Etonogestrel is indicated for use by women to prevent pregnancy.

  • Dosage:
  • Etonogestrel is insert subdermally just under the skin at the inner side of the non-dominant upper arm.
  • Etonogestrel must be removed no later than by the end of the third year.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Etonogestrel in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Etonogestrel in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

  • Clinical studies have not been conducted in women less than 18 years of age
  • Safety and efficacy are expected to be identical for postpubertal adolescents
  • Use before menarche is not indicated

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Etonogestrel in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Etonogestrel in pediatric patients.

Contraindications

Etonogestrel should not be used in women who have

  • Known or suspected pregnancy
  • Current or past history of thrombosis or thromboembolic disorders
  • Liver tumors, benign or malignant, or active liver disease
  • Undiagnosed abnormal genital bleeding
  • Known or suspected breast cancer, personal history of breast cancer, or other progestin-sensitive cancer, now or in the past
  • Allergic reaction to any of the components of etonogestrel

Warnings

Complications of Insertion and Removal

Etonogestrel should be inserted subdermally so that it will be palpable after insertion, and this should be confirmed by palpation immediately after insertion. Failure to insert etonogestrel properly may go unnoticed unless it is palpated immediately after insertion. Undetected failure to insert the implant may lead to an unintended pregnancy. Complications related to insertion and removal procedures, such as pain, paresthesias, bleeding, hematoma, scarring or infection, may occur. Occasionally in post-marketing use, implant insertions have failed because the implant fell out of the needle or remained in the needle during insertion.

If etonogestrel is inserted too deeply (intramuscular or in the fascia), neural or vascular injury may occur. To reduce the risk of neural or vascular injury, etonogestrel should be inserted at the inner side of the non-dominant upper arm about 8-10 cm (3-4 inches) above the medial epicondyle of the humerus. etonogestrel should be inserted subdermally just under the skin to avoid the large blood vessels and nerves that lie deeper in the subcutaneous tissues in the sulcus between the triceps and biceps muscles. Deep insertions of etonogestrel have been associated with paraesthesia (due to neural injury) and migration of the implant (due to intramuscular or fascial insertion), and in a very few cases with intravascular insertion. If infection develops at the insertion site, start suitable treatment. If the infection persists, the implant should be removed. Incomplete insertions or infections may lead to expulsion. In postmarketing use there have been cases of failure to localize and remove the implant, probably due to deep insertion. There has been 1 case of an intravascular insertion reported post-marketing which led to inability to remove the implant.

Implant removal may be difficult or impossible if the implant is not inserted correctly, is inserted too deeply, not palpable, encased in fibrous tissue, or has migrated. Deep insertions may lead to difficult localization of the implant and may also result in the need for a surgical procedure in an operating room in order to remove the implant. Exploratory surgery without knowledge of the exact location of the implant is strongly discouraged. Removal of deeply inserted implants should be conducted with caution in order to prevent injury to deeper neural or vascular structures in the arm and be performed by healthcare providers familiar with the anatomy of the arm. Failure to remove the implant may result in continued effects of etonogestrel, such as compromised fertility, ectopic pregnancy, or persistence or occurrence of a drug-related adverse event.

Changes in Menstrual Bleeding Patterns

After starting etonogestrel, women are likely to have a change from their normal menstrual bleeding pattern. These may include changes in bleeding frequency (absent, less, more frequent or continuous), intensity (reduced or increased) or duration. In clinical trials, bleeding patterns ranged from amenorrhea (1 in 5 women) to frequent and/or prolonged bleeding (1 in 5 women). The bleeding pattern experienced during the first three months of etonogestrel use is broadly predictive of the future bleeding pattern for many women. Women should be counseled regarding the bleeding pattern changes they may experience so that they know what to expect. Abnormal bleeding should be evaluated as needed to exclude pathologic conditions or pregnancy.

In clinical studies of etonogestrel, reports of changes in bleeding pattern were the most common reason for stopping treatment (11.1%). Irregular bleeding (10.8%) was the single most common reason women stopped treatment, while amenorrhea (0.3%) was cited less frequently. In these studies, women had an average of 17.7 days of bleeding or spotting every 90 days (based on 3,315 intervals of 90 days recorded by 780 patients). The percentages of patients having 0, 1-7, 8-21, or >21 days of spotting or bleeding over a 90-day interval while using the etonogestrel implant are shown in TABLE 1.

Bleeding patterns observed with use of etonogestrel for up to 2 years, and the proportion of 90-day intervals with these bleeding patterns, are summarized in TABLE 2.

In case of undiagnosed, persistent, or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy.

Ectopic Pregnancies

As with all progestin-only contraceptive products, be alert to the possibility of an ectopic pregnancy among women using etonogestrel who become pregnant or complain of lower abdominal pain. Although ectopic pregnancies are uncommon among women using etonogestrel, a pregnancy that occurs in a woman using etonogestrel may be more likely to be ectopic than a pregnancy occurring in a woman using no contraception.

Thrombotic and Other Vascular Events

The use of combination hormonal contraceptives (progestin plus estrogen) increases the risk of vascular events, including arterial events (strokes and myocardial infarctions) or deep venous thrombotic events (venous thromboembolism, deep venous thrombosis, retinal vein thrombosis, and pulmonary embolism). etonogestrel is a progestin-only contraceptive. It is unknown whether this increased risk is applicable to etonogestrel alone. It is recommended, however, that women with risk factors known to increase the risk of venous and arterial thromboembolism be carefully assessed.

There have been postmarketing reports of serious arterial and venous thromboembolic events, including cases of pulmonary emboli (some fatal), deep vein thrombosis, myocardial infarction, and strokes, in women using etonogestrel. etonogestrel should be removed in the event of a thrombosis.

Due to the risk of thromboembolism associated with pregnancy and immediately following delivery, etonogestrel should not be used prior to 21 days postpartum. Women with a history of thromboembolic disorders should be made aware of the possibility of a recurrence.

Evaluate for retinal vein thrombosis immediately if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions.

Consider removal of the etonogestrel implant in case of long-term immobilization due to surgery or illness.

Ovarian Cysts

If follicular development occurs, atresia of the follicle is sometimes delayed, and the follicle may continue to grow beyond the size it would attain in a normal cycle. Generally, these enlarged follicles disappear spontaneously. On rare occasion, surgery may be required.

Carcinoma of the Breast and Reproductive Organs

Women who currently have or have had breast cancer should not use hormonal contraception because breast cancer may be hormonally sensitive. Some studies suggest that the use of combination hormonal contraceptives might increase the incidence of breast cancer; however, other studies have not confirmed such findings.

Some studies suggest that the use of combination hormonal contraceptives is associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there is controversy about the extent to which such findings are due to differences in sexual behavior and other factors.

Women with a family history of breast cancer or who develop breast nodules should be carefully monitored.

Liver Disease

Disturbances of liver function may necessitate the discontinuation of hormonal contraceptive use until markers of liver function return to normal. Remove etonogestrel if jaundice develops.

Hepatic adenomas are associated with combination hormonal contraceptives use. An estimate of the attributable risk is 3.3 cases per 100,000 for combination hormonal contraceptives users. It is not known whether a similar risk exists with progestin-only methods like etonogestrel.

The progestin in etonogestrel may be poorly metabolized in women with liver impairment. Use of etonogestrel in women with active liver disease or liver cancer is contraindicated.

Weight Gain

In clinical studies, mean weight gain in US etonogestrel users was 2.8 pounds after 1 year and 3.7 pounds after 2 years. How much of the weight gain was related to the implant is unknown. In studies, 2.3% of the users reported weight gain as the reason for having the implant removed.

Elevated Blood Pressure

Women with a history of hypertension-related diseases or renal disease should be discouraged from using hormonal contraception. For women with well-controlled hypertension, use of etonogestrel can be considered. Women with hypertension using etonogestrel should be closely monitored. lf sustained hypertension develops during the use of etonogestrel, or if a significant increase in blood pressure does not respond adequately to antihypertensive therapy, etonogestrel should be removed.

Gallbladder Disease

Studies suggest a small increased relative risk of developing gallbladder disease among combination hormonal contraceptive users. It is not known whether a similar risk exists with progestin-only methods like etonogestrel.

Carbohydrate and Lipid Metabolic Effects

Use of etonogestrel may induce mild insulin resistance and small changes in glucose concentrations of unknown clinical significance. Carefully monitor prediabetic and diabetic women using etonogestrel.

Women who are being treated for hyperlipidemia should be followed closely if they elect to use etonogestrel. Some progestins may elevate LDL levels and may render the control of hyperlipidemia more difficult.

Depressed Mood

Women with a history of depressed mood should be carefully observed. Consideration should be given to removing etonogestrel in patients who become significantly depressed.

Return to Ovulation

In clinical trials with etonogestrel, the etonogestrel levels in blood decreased below sensitivity of the assay by one week after removal of the implant. In addition, pregnancies were observed to occur as early as 7 to 14 days after removal. Therefore, a woman should re-start contraception immediately after removal of the implant if continued contraceptive protection is desired.

Fluid Retention

Hormonal contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention. It is unknown if etonogestrel causes fluid retention.

Contact Lenses

Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.

Adverse Reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical trials including 942 women who were evaluated for safety, change in menstrual bleeding patterns (irregular menses) was the most common adverse reaction causing discontinuation of use of etonogestrel (11.1% of women).

Adverse reactions that resulted in a rate of discontinuation of ≥1% are shown in TABLE 3.

Other adverse reactions that were reported by at least 5% of subjects in clinical trials of etonogestrel are listed in TABLE 4.

Implant site complications were reported by 3.6% of subjects during any of the assessments in clinical trials. Pain was the most frequent implant site complication, reported during and/or after insertion, occurring in 2.9% of subjects. Additionally, hematoma, redness, and swelling were reported by 0.1%, 0.3%, and 0.3% of patients, respectively.

Postmarketing Experience

The following additional adverse reactions have been identified during post-approval use of etonogestrel. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

  • Gastrointestinal disorders: constipation, diarrhea, flatulence, vomiting.
  • General disorders and administration site conditions: edema, fatigue, implant site reaction, pyrexia.
  • Immune system disorders: anaphylactic reactions
  • Infections and infestations: rhinitis, urinary tract infection.
  • Investigations: clinically relevant rise in blood pressure, weight decreased.
  • Metabolism and nutrition disorders: increased appetite.
  • Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal pain, myalgia.
  • Nervous system disorders: convulsions, migraine, somnolence.
  • Pregnancy, puerperium and perinatal conditions: ectopic pregnancy.
  • Psychiatric disorders: anxiety, insomnia, libido decreased.
  • Renal and urinary disorders: dysuria.
  • Reproductive system and breast disorders: breast discharge, breast enlargement, ovarian cyst, pruritus genital, vulvovaginal discomfort.
  • Skin and subcutaneous tissue disorders: angioedema, aggravation of angioedema and/or aggravation of hereditary angioedema, alopecia, chloasma, hypertrichosis, pruritus, rash, seborrhea, urticaria.
  • Vascular disorders: hot flush.

Complications related to insertion or removal of the implant reported include: bruising, slight local irritation, pain or itching, fibrosis at the implant site, paresthesia or paresthesia-like events, scarring and abscess.

Drug Interactions

Changes in Contraceptive Effectiveness Associated with Coadministration of Other Products

Drugs or herbal products that induce enzymes, including CYP3A4, that metabolize progestins may decrease the plasma concentrations of progestins, and may decrease the effectiveness of etonogestrel. In women on long-term treatment with hepatic enzyme inducing drugs, it is recommended to remove the implant and to advise a contraceptive method that is unaffected by the interacting drug.

Some of these drugs or herbal products that induce enzymes, including CYP3A4, include:

  • barbiturates
  • bosentan
  • carbamazepine
  • felbamate
  • griseofulvin
  • oxcarbazepine
  • phenytoin
  • rifampin
  • St. John's wort
  • Topiramate
HIV Antiretrovirals

Significant changes (increase or decrease) in the plasma levels of progestin have been noted in some cases of co-administration with HIV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors. Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.

Increase in Plasma Concentrations of Etonogestrel Associated with Coadministered Drugs

CYP3A4 inhibitors such as itraconazole or ketoconazole may increase plasma concentrations of etonogestrel.

Changes in Plasma Concentrations of Coadministered Drugs

Hormonal contraceptives may affect the metabolism of other drugs. Consequently, plasma concentrations may either increase (for example, cyclosporin) or decrease (for example, lamotrigine). Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): Etonogestrel is not indicated for use during pregnancy [see CONTRAINDICATIONS (4)].

Teratology studies have been performed in rats and rabbits using oral administration up to 390 and 790 times the human etonogestrel dose (based upon body surface) and revealed no evidence of fetal harm due to etonogestrel exposure.

Studies have revealed no increased risk of birth defects in women who have used combination oral contraceptives before pregnancy or during early pregnancy. There is no evidence that the risk associated with etonogestrel is different from that of combination oral contraceptives.

Etonogestrel should be removed if maintaining a pregnancy.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Etonogestrel in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Etonogestrel during labor and delivery.

Nursing Mothers

Based on limited clinical data, etonogestrel may be used during breastfeeding after the fourth postpartum week. Use of etonogestrel before the fourth postpartum week has not been studied. Small amounts of etonogestrel are excreted in breast milk. During the first months after insertion of etonogestrel, when maternal blood levels of etonogestrel are highest, about 100 ng of etonogestrel may be ingested by the child per day based on an average daily milk ingestion of 658 mL. Based on daily milk ingestion of 150 mL/kg, the mean daily infant etonogestrel dose one month after insertion of etonogestrel is about 2.2% of the weight-adjusted maternal daily dose, or about 0.2% of the estimated absolute maternal daily dose. The health of breast-fed infants whose mothers began using etonogestrel during the fourth to eighth week postpartum (n=38) was evaluated in a comparative study with infants of mothers using a non-hormonal IUD (n=33). They were breast-fed for a mean duration of 14 months and followed up to 36 months of age. No significant effects and no differences between the groups were observed on the physical and psychomotor development of these infants. No differences between groups in the production or quality of breast milk were detected.

Healthcare providers should discuss both hormonal and non-hormonal contraceptive options, as steroids may not be the initial choice for these patients.

Pediatric Use

Safety and efficacy of etonogestrel have been established in women of reproductive age. Safety and efficacy of etonogestrel are expected to be the same for postpubertal adolescents. However, no clinical studies have been conducted in women less than 18 years of age. Use of this product before menarche is not indicated.

Geriatic Use

This product has not been studied in women over 65 years of age and is not indicated in this population.

Gender

There is no FDA guidance on the use of Etonogestrel with respect to specific gender populations.

Race

There is no FDA guidance on the use of Etonogestrel with respect to specific racial populations.

Renal Impairment

No studies were conducted to evaluate the effect of renal disease on the disposition of etonogestrel.

Hepatic Impairment

No studies were conducted to evaluate the effect of hepatic disease on the disposition of etonogestrel. The use of etonogestrel in women with active liver disease is contraindicated.

Females of Reproductive Potential and Males

Fertility returned after withdrawal from treatment.

Immunocompromised Patients

There is no FDA guidance one the use of Etonogestrel in patients who are immunocompromised.

Overweight Women

The effectiveness of etonogestrel in women who weighed more than 130% of their ideal body weight has not been defined because such women were not studied in clinical trials. Serum concentrations of etonogestrel are inversely related to body weight and decrease with time after implant insertion. It is therefore possible that etonogestrel may be less effective in overweight women, especially in the presence of other factors that decrease serum etonogestrel concentrations such as concomitant use of hepatic enzyme inducers.

Administration and Monitoring

Administration

Intradermal

Monitoring

A woman who is using etonogestrel should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated health care.

IV Compatibility

There is limited information regarding the compatibility of Etonogestrel and IV administrations.

Overdosage

Overdosage may result if more than 1 implant is inserted. In case of suspected overdose, the implant should be removed.

Pharmacology

There is limited information regarding Etonogestrel Pharmacology in the drug label.

Mechanism of Action

The contraceptive effect of etonogestrel is achieved by suppression of ovulation, increased viscosity of the cervical mucus, and alterations in the endometrium.

Structure

Etonogestrel structurally derived from 19-nortestosterone, is the synthetic biologically active metabolite of the synthetic progestin desogestrel. It has a molecular weight of 324.46 and the following structural formula:

Pharmacodynamics

Exposure-response relationships of etonogestrel are unknown.

Pharmacokinetics

Absorption

After subdermal insertion of the etonogestrel implant, etonogestrel is released into the circulation and is approximately 100% bioavailable.

The mean peak serum concentrations in 3 pharmacokinetic studies ranged between 781 and 894 pg/mL and were reached within the first few weeks after insertion. The mean serum etonogestrel concentration decreases gradually over time declining to 192 to 261 pg/mL at 12 months (n=41), 154 to 194 pg/mL at 24 months (n=35), and 156 to 177 pg/mL at 36 months (n=17).

Distribution

The apparent volume of distribution averages about 201 L. Etonogestrel is approximately 32% bound to sex hormone binding globulin (SHBG) and 66% bound to albumin in blood.

Metabolism

In vitro data shows that etonogestrel is metabolized in liver microsomes by the cytochrome P450 3A4 isoenzyme. The biological activity of etonogestrel metabolites is unknown.

Excretion

The elimination half-life of etonogestrel is approximately 25 hours. Excretion of etonogestrel and its metabolites, either as free steroid or as conjugates, is mainly in urine and to a lesser extent in feces. After removal of the implant, etonogestrel concentrations decreased below sensitivity of the assay by 1 week.

Nonclinical Toxicology

Carcinogenesis and Mutagenesis

In a 24-month carcinogenicity study in rats with subdermal implants releasing 10 and 20 mcg etonogestrel per day (equal to approximately 1.8-3.6 times the systemic steady state exposure in women using etonogestrel), no drug-related carcinogenic potential was observed. Etonogestrel was not genotoxic in the in vitro Ames/Salmonella reverse mutation assay, the chromosomal aberration assay in Chinese hamster ovary cells or in the in vivo mouse micronucleus test.

Clinical Studies

Pregnancy

In clinical trials of up to 3 years duration that involved 923 subjects, 18 - 40 years of age at entry, and 1,756 women-years of etonogestrel use, the total exposures expressed as 28-day cycle equivalents by study year were:

  • Year 1: 10,866 cycles
  • Year 2: 8,581 cycles
  • Year 3: 3,442 cycles


The clinical trials excluded women who:

  • Weighed more than 130% of their ideal body weight
  • Were chronically taking medications that induce liver enzymes

In the subgroup of women 18 to 35 years of age at entry, 6 pregnancies during 20,648 cycles of use were reported. Two pregnancies occurred in each of Years 1, 2 and 3. Each conception was likely to have occurred shortly before or within 2 weeks after etonogestrel removal. With these 6 pregnancies, the cumulative Pearl Index was 0.38 pregnancies per 100 women-years of use.

Return to Ovulation

In clinical trials with etonogestrel, the etonogestrel levels in blood decreased below sensitivity of the assay by one week after removal of the implant. In addition, pregnancies were observed to occur as early as 7 to 14 days after removal. Therefore, a woman should re-start contraception immediately after removal of the implant if continued contraceptive protection is desired.

How Supplied

Single implant containing 68 mg etonogestrel that is 4 cm in length and 2 mm in diameter, which is pre-loaded in the needle of a disposable applicator.

  • NDC 0052-0272-01

Storage

Store at 25°C (77°F)

Images

Drug Images

{{#ask: Page Name::Etonogestrel |?Pill Name |?Drug Name |?Pill Ingred |?Pill Imprint |?Pill Dosage |?Pill Color |?Pill Shape |?Pill Size (mm) |?Pill Scoring |?NDC |?Drug Author |format=template |template=DrugPageImages |mainlabel=- |sort=Pill Name }}

Package and Label Display Panel

{{#ask: Label Page::Etonogestrel |?Label Name |format=template |template=DrugLabelImages |mainlabel=- |sort=Label Page }}

Patient Counseling Information

  • Counsel women about the insertion and removal procedure of the etonogestrel implant. Provide the woman with a copy of the Patient Labeling and ensure that she understands the information in the Patient Labeling before insertion and removal. A USER CARD and consent form are included in the packaging. Have the woman complete a consent form and retain it in your records. The USER CARD should be filled out and given to the patient after insertion of the etonogestrel implant so that she will have a record of the location of the implant in the upper arm and when it should be removed.


  • Counsel women that etonogestrel does not protect against HIV infection (AIDS) or other sexually transmitted diseases.


  • Counsel women that the use of etonogestrel may be associated with changes in their normal menstrual bleeding patterns so that they know what to expect.

Precautions with Alcohol

Alcohol-Etonogestrel interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Etonogestrel Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Etonogestrel Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

Etonogestrel
Clinical data
Routes of
administration		Subdermal as slow-release implant
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
MetabolismHepatic (P450 3A4)
Elimination half-life25 hours
ExcretionUrinary (majority) and fecal
Identifiers
CAS Number
PubChem CID
DrugBank
E number{{#property:P628}}
ECHA InfoCard{{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value).
Chemical and physical data
FormulaC22H28O2
Molar mass324.457 g/mol

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Etonogestrel is a molecule used in hormonal contraceptives, most notably the subdermal implant etonogestrel.

Etonogestrel, the specific progestin used in NuvaRing, is the active metabolite of the inactive prodrug desogestrel, one of two third-generation progestins found in some epidemiological studies of combined oral contraceptive pills to be associated with a higher risk of venous thrombosis than combined oral contraceptive pills containing certain second-generation progestins. Because hormones are released continuously from NuvaRing, peak and total estrogen and progestin doses are significantly lower than with combined oral contraceptives, although it is not known whether this lowers the risk of blood clots.

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