Etonogestrel

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# Overview
Etonogestrel is a progestin that is FDA approved for the prophylaxis of pregnancy.   Common adverse reactions include headache, weight gain and abdominal pain.

# 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.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-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.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Women with a history of depressed mood should be carefully observed. Consideration should be given to removing etonogestrel in patients who become significantly depressed.
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.
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 peripheral edema.
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
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
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.
CYP3A4 inhibitors such as itraconazole or ketoconazole may increase plasma concentrations of etonogestrel.
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.
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

## 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
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).
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.
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.
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
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 25C (77F)

# Images

## Drug Images

## Package and Label Display Panel

# 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
- Implanon 
- Nexplanon

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

# Drug Shortage Status

# Price