Etonogestrel

The dosage of etonogestrel is determined by the specific delivery system prescribed by your healthcare provider.

Subdermal Implant (e.g., Nexplanon)

• Standard Dose: A single 68 mg implant inserted subdermally.
• Duration: The implant provides continuous contraception for up to 3 years. It must be removed or replaced by the end of the third year.
• Timing of Insertion: If no hormonal contraceptive was used in the past month, the implant should ideally be inserted between Day 1 and Day 5 of the natural menstrual cycle to ensure immediate efficacy.

Vaginal Ring (e.g., NuvaRing)

• Standard Dose: One ring inserted vaginally for 3 consecutive weeks, followed by a 1-week ring-free interval.
• Release Rate: The ring releases approximately 0.120 mg of etonogestrel and 0.015 mg of ethinyl estradiol every 24 hours.
• Cycle: A new ring is inserted exactly 7 days after the previous one was removed, even if menstrual bleeding has not finished.

Etonogestrel is indicated for use in females of reproductive age. It is not intended for use before menarche (the start of the first menstrual period). Safety and efficacy studies have shown that the profile in post-pubertal adolescents under 18 is similar to that in adults. Dosage adjustments are not required for adolescents once they have reached menarche.

Renal Impairment

No specific studies have been conducted in patients with renal (kidney) impairment. However, because etonogestrel is primarily metabolized by the liver, significant dosage adjustments are generally not expected to be necessary for patients with mild to moderate renal disease. Your healthcare provider will monitor your condition closely.

Hepatic Impairment

Etonogestrel is contraindicated (should not be used) in patients with active liver disease or liver tumors. Because the liver is the primary site of metabolism, impaired hepatic function can lead to increased systemic levels of the hormone, potentially increasing the risk of adverse effects.

Elderly Patients

Etonogestrel is not indicated for use in postmenopausal women. It is specifically designed for individuals of reproductive potential.

Subdermal Implant

• Insertion: Must be performed by a healthcare professional trained in the procedure. A local anesthetic is used to numb the area on the inner side of your non-dominant upper arm. The implant is then placed just under the skin using a specialized applicator.
• Verification: Immediately after insertion, both you and your healthcare provider should verify the presence of the implant by feeling it (palpation). If it cannot be felt, imaging (X-ray or ultrasound) may be required.
• Storage: The product is stored by the pharmacy/clinic at room temperature (25°C/77°F) until insertion.

Vaginal Ring

• Insertion: You can insert the ring yourself. Wash your hands, choose a comfortable position (standing, squatting, or lying down), squeeze the sides of the ring, and tuck it into the vagina. The exact position does not affect efficacy.
• Removal: After 3 weeks, remove the ring by hooking your index finger under the rim and pulling it out.
• Storage: Prior to dispensing, the rings are refrigerated. After dispensing, they can be stored at room temperature for up to 4 months.

• Implant: There is no 'missed dose' as the device works automatically. However, if you do not have it replaced after 3 years, you are at risk of pregnancy.
• Vaginal Ring: If the ring is out of the vagina for more than 3 hours during the 3-week use period, contraceptive efficacy may be reduced. Reinsert the ring as soon as possible and use a backup method (like condoms) for the next 7 days.

Overdose is highly unlikely with the subdermal implant. With the vaginal ring, accidental insertion of multiple rings could occur. Symptoms of hormonal overdose may include nausea, vomiting, and vaginal bleeding in young females. In the event of suspected overdose, contact your healthcare provider or a poison control center immediately.

> Important: Follow your healthcare provider's dosing instructions. Do not adjust your dose or attempt to remove the implant yourself without medical guidance.

Side effects are a common reason for the discontinuation of hormonal contraceptives. Patients using etonogestrel frequently report the following:

• Changes in Menstrual Bleeding Patterns: This is the most common side effect. According to clinical data from the FDA, approximately 1 in 10 women will stop using the implant because of bleeding changes. This may include frequent bleeding, prolonged bleeding, spotting between periods, or the complete absence of periods (amenorrhea). These patterns often stabilize after the first few months but can remain unpredictable.
• Headache: Tension-type or migraine headaches are reported by approximately 15-20% of users.
• Vaginitis: Inflammation of the vagina, often presenting as discharge or itching, is common, particularly with the vaginal ring.
• Acne: Some users may experience new or worsening acne due to the progestin's residual androgenic activity, though this is less common than with older progestins.
• Breast Tenderness: Mild pain or swelling in the breast tissue (mastalgia) may occur as the body adjusts to the hormone.
• Weight Gain: Clinical studies have shown an average weight gain of less than 5 pounds over several years, but individual experiences vary significantly.

• Mood Swings and Depression: Some users report increased irritability, anxiety, or a depressed mood. If you have a history of clinical depression, discuss this with your doctor.
• Nausea and Abdominal Pain: Mild gastrointestinal upset may occur, especially during the first few weeks of use.
• Decreased Libido: A reduction in sex drive has been noted by some users.
• Dizziness: Feeling lightheaded or faint, particularly shortly after insertion of the implant.

• Implant Migration: In rare cases, the subdermal implant may move from the original insertion site. There have been rare reports of the implant migrating into the blood vessels, including the pulmonary artery.
• Injection/Insertion Site Reactions: Permanent scarring, bruising, or infection at the site where the implant was placed.
• Gallbladder Disease: Hormonal contraceptives may slightly increase the risk of developing gallstones.

> Warning: Stop taking Etonogestrel and call your doctor immediately if you experience any of these serious symptoms.

• Blood Clots (Thrombosis): Seek help if you experience sudden leg pain, swelling, warmth, or redness (Deep Vein Thrombosis), or sudden shortness of breath and chest pain (Pulmonary Embolism).
• Severe Allergic Reaction (Anaphylaxis): Symptoms include hives, swelling of the face, lips, or tongue, and difficulty breathing.
• Ectopic Pregnancy: If you become pregnant while using etonogestrel, there is a higher risk that the pregnancy will occur outside the uterus. Seek immediate help for severe lower abdominal pain.
• Liver Problems: Yellowing of the skin or eyes (jaundice), dark urine, or severe upper abdominal pain can indicate liver dysfunction or tumors.
• Severe Depression: If you experience suicidal thoughts or profound changes in mental health, contact a crisis line or your doctor immediately.
• High Blood Pressure: New-onset hypertension or significant increases in blood pressure readings.

• Bone Mineral Density: There is ongoing research into whether long-term use of progestin-only contraceptives affects bone density. Current data suggests that etonogestrel does not have a clinically significant negative impact on bone health in most women.
• Cervical Cancer Risk: Some studies suggest a slight increase in the risk of cervical cancer with long-term use of combined hormonal contraceptives (like the ring), though this may be related to other factors like HPV exposure.

No FDA black box warnings exist for the Etonogestrel-only implant (Nexplanon).

However, for the Etonogestrel/Ethinyl Estradiol Vaginal Ring, there is a Black Box Warning regarding Cigarette Smoking and Serious Cardiovascular Events. Smoking increases the risk of serious cardiovascular side effects from combination hormonal contraceptives, including heart attack, blood clots, and stroke. This risk increases with age (particularly over 35) and with the number of cigarettes smoked. Women who use combined hormonal contraceptives are strongly advised not to smoke.

Report any unusual symptoms to your healthcare provider to ensure your contraceptive method remains safe and effective.

Before starting etonogestrel, it is vital to understand that while it is highly effective at preventing pregnancy, it does not protect against HIV/AIDS or other sexually transmitted infections (STIs). Patients should continue to use barrier protection (condoms) if they are at risk for STIs. Additionally, the efficacy of etonogestrel may be reduced in women who are significantly overweight; data for women weighing more than 130% of their ideal body weight is limited.

As noted in the side effects section, the etonogestrel-only implant does not carry a black box warning. However, the combined vaginal ring (Etonogestrel + Ethinyl Estradiol) carries a strict warning against smoking. Clinical data indicates that women over 35 who smoke and use combined hormonal contraceptives have a significantly elevated risk of fatal cardiovascular events.

• Thromboembolic Disorders: There is a risk of blood clots (venous thromboembolism). Etonogestrel should be discontinued if a blood clot occurs. It should also be removed at least 4 weeks before and 2 weeks after major surgery or prolonged immobilization to reduce the risk of clots.
• Hepatotoxicity and Liver Tumors: While rare, hormonal contraceptives are associated with an increased risk of benign and malignant liver tumors. If you develop jaundice or unexplained liver pain, the device must be removed.
• Carbohydrate and Lipid Metabolism: Etonogestrel may induce mild insulin resistance. Diabetic patients should monitor their blood glucose levels closely, as insulin or medication requirements may change.
• Fluid Retention: Because progestins can cause some fluid retention, patients with conditions that might be aggravated by this (e.g., epilepsy, migraines, asthma, or cardiac dysfunction) should be monitored carefully.
• Depression: Patients with a history of clinical depression should be observed closely. If the depression recurs to a serious degree, the etonogestrel method should be discontinued.

Your healthcare provider will typically require the following monitoring:

• Blood Pressure: Checked at baseline and during follow-up visits.
• Physical Exams: Annual pelvic exams and breast exams are recommended.
• Cytology (Pap Smear): Regular screening as per standard guidelines.
• Implant Site Check: Periodic palpation to ensure the implant has not migrated or been expelled.

Etonogestrel is not known to impair the ability to drive or operate heavy machinery. However, if you experience side effects such as dizziness or vision changes, you should avoid these activities until the symptoms resolve.

There are no known direct interactions between alcohol and etonogestrel. However, excessive alcohol consumption can increase the risk of liver stress and may interfere with the consistent use/monitoring of the vaginal ring.

One of the primary benefits of etonogestrel is that its effects are rapidly reversible.

• Implant: Must be removed by a healthcare professional. Fertility typically returns within 7 to 30 days of removal.
• Vaginal Ring: Simply stop inserting new rings. Fertility usually returns within the first cycle after discontinuation.
• Withdrawal: There is no 'withdrawal syndrome' in the traditional sense, but you may experience a 'withdrawal bleed' (similar to a period) as the hormone levels drop.

> Important: Discuss all your medical conditions with your healthcare provider before starting Etonogestrel, especially if you have a history of blood clots, liver disease, or breast cancer.

Certain medications can significantly decrease the levels of etonogestrel in the blood, leading to contraceptive failure and unintended pregnancy. You must never use these with etonogestrel without strict medical supervision and backup contraception:

• Strong CYP3A4 Inducers: Medications like Rifampin (used for TB) and Rifabutin drastically increase the metabolism of etonogestrel. Clinical studies show that these drugs can reduce progestin levels by over 50%, making the contraceptive ineffective.
• Certain Anticonvulsants: Drugs such as Phenytoin, Carbamazepine, Phenobarbital, and Primidone are potent enzyme inducers that can lead to 'breakthrough' ovulation.

• HIV Protease Inhibitors: Drugs like Ritonavir, Nelfinavir, and Nevirapine can alter the metabolism of etonogestrel. In some cases, they decrease levels; in others, they may increase them. Close monitoring is required.
• Hepatitis C Medications: Some combinations (e.g., Ombitasvir/Paritaprevir/Ritonavir) have been associated with liver enzyme elevations when used with ethinyl estradiol-containing products (like the ring).

• Antifungals: Azole antifungals like Ketoconazole, Itraconazole, and Fluconazole are CYP3A4 inhibitors. They may increase the concentration of etonogestrel in the blood, potentially increasing the risk of side effects like breast tenderness or nausea.
• Antibiotics: While most common antibiotics (like Amoxicillin) do not affect etonogestrel, some healthcare providers still recommend backup contraception during short courses of antibiotics to be cautious.

• Grapefruit and Grapefruit Juice: Grapefruit is a known inhibitor of the CYP3A4 enzyme. Consuming large amounts of grapefruit juice may increase the systemic exposure to etonogestrel. While usually not dangerous, it may increase the frequency of minor side effects.
• Alcohol: No direct pharmacological interaction, but heavy drinking can impair the liver's ability to process hormones.

• St. John's Wort (*Hypericum perforatum*): This is a major concern. St. John's Wort is a potent inducer of liver enzymes and has been documented to cause contraceptive failure in women using etonogestrel implants. Do not use this supplement while using hormonal contraception.
• Vitex (Chasteberry): This herb can affect the pituitary gland and may interfere with the hormonal balance etonogestrel is trying to maintain.

Etonogestrel may affect the results of certain laboratory tests:

• Thyroid Function: It may increase thyroid-binding globulin, leading to higher total T4 levels, though free T4 usually remains normal.
• Glucose Tolerance: As mentioned, it can slightly decrease glucose tolerance.
• Lipid Profiles: It may cause minor changes in LDL, HDL, and triglyceride levels.

For each major interaction, the mechanism involves the Cytochrome P450 3A4 pathway. Inducers speed up the 'clearing' of the drug, leading to reduced efficacy. Inhibitors slow down the 'clearing', leading to increased toxicity/side effects.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking, including over-the-counter pain relievers and vitamins.

Etonogestrel must NEVER be used in the following circumstances because the risks significantly outweigh any potential benefits:

1. 1Pregnancy: Etonogestrel is intended to prevent pregnancy and has no role during an active pregnancy. If pregnancy is suspected, the device must be removed immediately.
2. 2Current or Past Breast Cancer: Progestin-sensitive tumors may be stimulated by etonogestrel. Even if the cancer is in remission, hormonal contraception is generally avoided.
3. 3Active Liver Disease: This includes acute hepatitis, severe cirrhosis, or liver tumors (benign or malignant). The liver cannot properly metabolize the hormone, leading to toxic accumulation.
4. 4Undiagnosed Abnormal Vaginal Bleeding: Before starting etonogestrel, the cause of any unexplained bleeding must be identified to rule out malignancy (cancer).
5. 5Active Blood Clots: Patients with current Deep Vein Thrombosis (DVT) or Pulmonary Embolism (PE) must not use etonogestrel.
6. 6Hypersensitivity: Any known allergy to etonogestrel or the components of the delivery system (e.g., the ethylene vinyl acetate copolymer in the implant).

These conditions require a careful risk-benefit analysis by a specialist:

• History of Heavy Smoking: Especially in women over 35 using the vaginal ring.
• Severe Hypertension: Uncontrolled high blood pressure (e.g., >160/100 mmHg).
• Diabetes with Vascular Complications: Such as nephropathy (kidney damage) or retinopathy (eye damage).
• History of Gallbladder Disease: Specifically related to previous hormonal use.
• Hyperlipidemia: Very high cholesterol or triglycerides that are not controlled by medication.

Patients who have had severe allergic reactions to other progestins, such as Desogestrel or Levonorgestrel, may be at a higher risk for a reaction to etonogestrel. While not a guarantee of a reaction, your healthcare provider should be informed of any past 'hormone allergies.'

> Important: Your healthcare provider will evaluate your complete medical history, including family history of strokes or clots, before prescribing Etonogestrel.

Etonogestrel is classified as Pregnancy Category X (or the equivalent in modern labeling, meaning it is contraindicated in pregnancy). Extensive epidemiological studies have revealed no increased risk of birth defects in women who used oral contraceptives containing progestins prior to pregnancy. However, etonogestrel provides no benefit during pregnancy. If you become pregnant while the implant is in place, it should be removed. There is a slightly higher risk of the pregnancy being ectopic (outside the uterus) if the contraceptive fails.

Small amounts of etonogestrel are excreted in human milk. However, studies have shown that it does not significantly affect the production or quality of breast milk, nor does it adversely affect the physical or psychomotor development of the nursing infant. The CDC Medical Eligibility Criteria suggest that progestin-only methods like the etonogestrel implant can generally be started 4 weeks postpartum in breastfeeding women without concerns.

Safety and efficacy have been established in females of reproductive age. Use of this product before menarche is not indicated. There is no evidence that etonogestrel affects bone mineral density or growth in adolescents differently than in adults. It is frequently prescribed to adolescents due to its high efficacy and lack of daily adherence requirements.

Etonogestrel is not indicated for use in geriatric populations. It is a contraceptive for individuals of childbearing potential. Clinical trials did not include women over the age of 65.

Specific studies in patients with renal impairment are lacking. However, because renal excretion of the parent drug is minimal (most is metabolized by the liver), it is generally considered safe for use in patients with mild to moderate kidney disease. Patients with end-stage renal disease (ESRD) on dialysis should be monitored for fluid retention.

Etonogestrel is strictly contraindicated in patients with significant hepatic impairment (Child-Pugh Class B or C) or active liver tumors. The drug's clearance is significantly reduced in these patients, which can lead to dangerously high hormone levels.

> Important: Special populations, particularly those with chronic liver or kidney issues, require individualized medical assessment and frequent follow-up.

Etonogestrel is a 19-nortestosterone derivative and the biologically active metabolite of desogestrel. It acts as a potent agonist at the Progesterone Receptor (PR). By binding to these receptors in the hypothalamic-pituitary-ovarian axis, it suppresses the release of Gonadotropin-Releasing Hormone (GnRH) and Luteinizing Hormone (LH). This 'negative feedback' loop prevents the mid-cycle LH surge, thereby inhibiting ovulation. It also exerts direct effects on the endometrium and cervical mucus, as detailed in the clinical overview.

The pharmacodynamic effect of etonogestrel is characterized by a rapid onset of ovulatory suppression. Within 24 hours of implant insertion, etonogestrel levels are sufficient to inhibit ovulation in most women. The duration of effect is sustained for 3 years with the implant, after which the release rate drops below the threshold required for 100% ovulatory inhibition. Tolerance to the contraceptive effect does not develop over the recommended use period.

| Parameter | Value |

|---|---|

| Bioavailability | 100% (Implant), ~80% (Vaginal Ring) |

| Protein Binding | 98% (32% to SHBG, 66% to Albumin) |

| Half-life | 25–30 hours |

| Tmax | 1–13 days (Implant), 2–3 days (Ring) |

| Metabolism | Hepatic (CYP3A4) |

| Excretion | Renal (45%), Fecal (35%) |

• Molecular Formula: C22H28O2
• Molecular Weight: 324.46 g/mol
• Solubility: Practically insoluble in water; soluble in ethanol and organic solvents.
• Structure: It features a 13-ethyl group and an ethinyl group at the 17-position, which enhances its progestogenic potency and oral/subdermal activity.

Etonogestrel is a Progestin (Third-Generation). It is closely related to other gonane progestins like Levonorgestrel and Desogestrel. Unlike older progestins (like Medroxyprogesterone), etonogestrel has high selectivity for the progesterone receptor and low affinity for androgen receptors, reducing side effects like oily skin.