Ethinyl Estradiol And Norelgestromin

Introduction Overview

Generic Name

ethinyl estradiol and norelgestromin

Brand Name

Xulane

Dosage Form

transdermal patch

Drug Class

Contraceptives

Pharmacokinetics

Absorption: Xulane is a transdermal contraceptive patch designed to deliver a controlled amount of ethinyl estradiol (an estrogen) and norelgestromin (a progestin) through the skin into the systemic circulation. The hormones are absorbed via the skin's epidermis and dermis layers, bypassing the gastrointestinal tract and first-pass hepatic metabolism. Steady-state plasma levels of norelgestromin and ethinyl estradiol are generally achieved within 48 hours of patch application. The transdermal route results in approximately 60% higher systemic estrogen exposure compared to an equivalent oral contraceptive containing 35 mcg ethinyl estradiol, which has clinical implications for both effectiveness and side effect profile. Absorption can be influenced by factors such as patch placement site, skin integrity, temperature, and adherence quality.

Distribution: Following absorption, both ethinyl estradiol and norelgestromin extensively bind to plasma proteins, primarily albumin and sex hormone-binding globulin (SHBG). The volume of distribution reflects distribution into body tissues, with norelgestromin having a moderate distribution influenced by its lipophilicity. Because Xulane delivers hormones systemically rather than locally, plasma concentrations reflect systemic circulation levels. Distribution characteristics are critical for maintaining adequate serum hormone levels to suppress ovulation continuously.

Metabolism: Both hormones undergo hepatic metabolism primarily via cytochrome P450 enzymes. Ethinyl estradiol is extensively metabolized by CYP3A4 enzymes to hydroxylated metabolites, which undergo further conjugation via sulfation and glucuronidation. Norelgestromin also undergoes phase I and phase II metabolism in the liver, producing inactive metabolites. Transdermal delivery bypasses initial hepatic first-pass metabolism, leading to altered pharmacokinetics compared to oral formulations, including higher systemic estrogen exposure and different metabolite profiles.

Elimination: The metabolites of ethinyl estradiol and norelgestromin are predominantly excreted via renal and fecal routes following conjugation. The elimination half-life of norelgestromin delivered via Xulane is approximately 28 hours, supporting once-weekly patch changes. Complete elimination typically occurs over several days after patch removal. Factors such as hepatic or renal impairment may affect drug clearance and hormone levels, necessitating careful clinical monitoring.

Dosage Forms

Available Dosage Forms: Xulane is supplied as a single strength transdermal system (patch) measuring 14 cm². Each patch is peach-colored and printed with "Xulane® (norelgestromin and ethinyl estradiol) 150/35 mcg per day" in brown ink. The patch contains 4.86 mg of norelgestromin, USP and 0.53 mg of ethinyl estradiol, USP, designed to deliver a daily dose of 150 mcg norelgestromin and 35 mcg ethinyl estradiol over seven days.

Dosages for Adults and Adolescents: The recommended dosing regimen for Xulane involves applying one patch once weekly for three consecutive weeks (21 days), followed by a patch-free week (Week 4) during which withdrawal bleeding typically occurs. This 28-day cycle is then repeated. The patch should be applied to clean, dry, intact skin on the upper outer arm, abdomen, buttock, or back, avoiding the breasts and areas subject to friction. The patch should not be cut or altered. Consistent weekly application on the same day each week is necessary to maintain contraceptive effectiveness.

Specific Patient Populations: Xulane is approved for use in women of reproductive age with a body mass index (BMI) below 30 kg/m², as higher BMI has been associated with reduced efficacy and increased risk of thromboembolic events. Use is contraindicated in women with BMI ≥30 kg/m². Safety and efficacy in adolescents under the age of menarche have not been established. Special caution is advised in women with risk factors for cardiovascular events, history of thromboembolism, or hepatic impairment. In these populations, use of alternative contraceptive methods may be preferable.

Mechanism Of Action

Xulane exerts its contraceptive effects through the combined actions of its two hormonal components: ethinyl estradiol, a synthetic estrogen, and norelgestromin, a synthetic progestin. The primary molecular mechanism involves suppression of the hypothalamic-pituitary-ovarian axis, leading to inhibition of ovulation. Specifically, these hormones inhibit the surge of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) necessary for follicular development and ovulation.

At the cellular level, ethinyl estradiol facilitates stabilization of the endometrial lining and enhances expression of progesterone receptors, while norelgestromin exerts progestogenic effects by binding to progesterone receptors in reproductive tissues. This results in thickening of cervical mucus, creating a barrier to sperm penetration, and induces changes in the endometrium that reduce the likelihood of implantation.

Biochemically, the steady release of hormones from the transdermal patch ensures consistent plasma levels that maintain inhibition of ovulation and alterations in cervical mucus throughout the dosing cycle. The transdermal administration bypasses gastrointestinal absorption and first-pass metabolism, resulting in higher systemic estrogen exposure and potentially different pharmacodynamics compared to oral contraceptives.

Clinical studies have demonstrated that Xulane’s mechanism effectively prevents egg release with contraceptive efficacy comparable to combined oral contraceptives. When compared to other hormonal contraceptives, such as vaginal rings or oral pills, Xulane’s transdermal delivery offers the advantage of weekly dosing, potentially improving adherence. However, the higher systemic estrogen exposure also confers a slightly increased risk of estrogen-related side effects, including thromboembolic events, necessitating patient-specific risk assessment.

Pharmacological Actions

Suppression of ovulation by inhibiting mid-cycle LH and FSH surges.
Thickening of cervical mucus to impair sperm penetration.
Altering endometrial lining to prevent implantation of fertilized egg.
Delivery of combination estrogen and progestin hormones through transdermal absorption.
Provision of steady-state hormone levels over a week to maintain contraceptive efficacy.
Reduction in menstrual blood loss and regulation of menstrual bleeding patterns.
Potential modulation of gonadotropin release via negative feedback mechanisms.
Improved patient adherence due to weekly dosing schedule.
Bypassing first-pass hepatic metabolism leading to altered hormone bioavailability.
Effect on lipid metabolism leading to changes in serum cholesterol and triglyceride levels.
Influence on coagulation factors increasing risk of thromboembolism.
Alteration of insulin sensitivity and carbohydrate metabolism in some users.
Suppression of follicular development and ovarian cyst formation.
Modulation of progesterone receptor expression in reproductive tissues.
Potential impact on mood and cognitive function via neuroendocrine pathways.

Therapeutic Or Clinical Uses

Prevention of pregnancy in women with BMI less than 30 kg/m².
Contraceptive option for women preferring a non-oral, once-weekly hormone delivery system.
Alternative to combined oral contraceptives for patients with gastrointestinal malabsorption.
Use in women seeking reversible birth control with regular menstrual cycles.
Management of menstrual disorders through regulation of bleeding patterns.
Provision of contraception during the postpartum period after appropriate interval.
Contraception in women transitioning from other hormonal contraceptives.
Potential reduction in dysmenorrhea symptoms associated with menstruation.
Option for women who have difficulty remembering daily oral pill dosing.
Suitable for women desiring a discreet contraceptive method without daily administration.
Use in clinical scenarios requiring predictable menstrual cycles.
Contraceptive method that may improve compliance due to ease of weekly patch application.

Side Or Adverse Effects

Increased risk of serious blood clots including deep vein thrombosis and pulmonary embolism.
Local skin irritation at patch application site including redness, itching, swelling, and rash.
Breast tenderness, discomfort, or swelling.
Headache, including migraine exacerbation.
Nausea and gastrointestinal discomfort.
Menstrual disorders such as spotting, breakthrough bleeding, or altered bleeding patterns.
Mood changes, anxiety, and affective disorders.
Weight gain and fluid retention (bloating).
Acne flare or hormonal acne development.
Decreased libido or sexual desire.
Potential elevated blood pressure or worsening of pre-existing hypertension.
Gallbladder disease or biliary stasis.
Liver enzyme abnormalities and rare liver tumors.
Rarely, changes in glucose tolerance and lipid profiles.
Visual disturbances including intolerance to contact lenses.

Precautions

Do not use in women with BMI 30 kg/m² or greater due to decreased efficacy and increased clot risk.
Avoid use in women who smoke and are over 35 years old due to heightened cardiovascular risk.
Cautious use in women with history of thromboembolic events or inherited clotting disorders.
Monitor blood pressure regularly during use, especially in women with pre-existing hypertension.
Use with caution in women with migraines, particularly those with aura or over age 35.
Discontinue prior to elective surgery due to increased risk of postoperative blood clots.
Advise women regarding the lack of protection against HIV and other sexually transmitted infections.
Avoid use in patients with liver disease or liver tumors.
Consider alternative contraception in women with history or current breast cancer.
Inform patients about potential for breakthrough bleeding and the importance of adherence.
Use backup contraception during first 7 days if patch is started late or after interruption.
Patients should report any signs of blood clots or unusual bleeding immediately.
Be aware of potential interactions with medications that induce or inhibit hepatic enzymes.
Consider impact on mood disorders and monitor psychiatric symptoms during use.
Educate patients about correct application sites and avoidance of irritated or damaged skin.

Warnings

Smoking while using Xulane significantly increases the risk of serious cardiovascular side effects, including death from heart attack, blood clots, or stroke.
Women over age 35 who smoke should not use Xulane.
Increased risk of venous thromboembolism compared to non-users and oral contraceptive users, particularly in the first months of use.
Discontinue use immediately if symptoms of blood clots arise, such as leg pain, chest pain, sudden shortness of breath, or sudden vision loss.
May cause liver problems including hepatic tumors; discontinue if jaundice or severe liver dysfunction develops.
May cause gallbladder disease or exacerbate pre-existing cholelithiasis.
Do not use if pregnant or suspected pregnancy; although not teratogenic, it is contraindicated during pregnancy.
Not effective as an emergency contraceptive and does not protect against sexually transmitted infections.
May elevate blood pressure; continuous monitoring is advised.
Potential risk of breast and cervical cancers with prolonged hormonal contraceptive use.
Patients should avoid exposing patches to heat or prolonged sunlight to maintain efficacy.
Patch adherence failure can result in decreased contraceptive efficacy and risk of pregnancy.
May reduce milk production in breastfeeding women; alternative contraception is recommended during lactation.
Potential for altered laboratory test results during use of hormonal contraceptives.
Use caution when co-administered with medications that affect hepatic enzyme activity.

Contraindication

Current cigarette smoking in women older than 35 years.
Known or suspected thrombophlebitis, venous thromboembolism, or history of these conditions.
Known hereditary or acquired thrombophilia that predisposes to thromboembolism.
History of cerebrovascular accident (stroke) or coronary artery disease (heart attack).
Severe hypertension that is uncontrolled by medication.
Diabetes mellitus with vascular complications such as nephropathy, retinopathy, neuropathy, or vascular disease.
Severe migraine headaches with aura or focal neurological symptoms, particularly in women over 35.
Active liver disease, including liver tumors or unexplained persistent elevation of liver enzymes.
Current or past history of breast cancer or any estrogen-dependent neoplasm.
Known or suspected pregnancy.
Unexplained vaginal bleeding pending diagnosis.
Concurrent use with hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir.
Hypersensitivity to any component of the patch.

Drug Interactions

Anticonvulsants such as carbamazepine, felbamate, oxcarbazepine, phenytoin, rufinamide, and topiramate can reduce the effectiveness of Xulane by inducing hepatic enzymes.
Aprepitant may decrease hormonal contraceptive levels, reducing efficacy.
Barbiturates induce cytochrome P450 enzymes leading to increased clearance of contraceptive hormones.
Bosentan use may reduce contraceptive hormone levels and efficacy.
Griseofulvin can lower hormonal contraceptive effectiveness via enzyme induction.
Certain HIV medications such as nelfinavir, ritonavir, and ritonavir-boosted protease inhibitors reduce contraceptive effectiveness.
Non-nucleoside reverse transcriptase inhibitors like nevirapine may induce metabolism of contraceptive hormones.
Rifampin and rifabutin significantly reduce plasma concentrations of hormones, compromising contraceptive efficacy.
St. John’s Wort, an herbal product, induces hepatic enzymes and reduces hormone levels.
Drugs that inhibit hepatic metabolism (itraconazole, ketoconazole, voriconazole, fluconazole) may increase ethinyl estradiol levels.
Certain HIV protease inhibitors (atazanavir, indinavir) can increase hormone concentrations.
Statins such as atorvastatin and rosuvastatin may have increased systemic levels when co-administered with Xulane.
Etravirine may interact with contraceptive hormones, affecting levels.
Lamotrigine levels may decrease when used with hormonal contraceptives; dose adjustment may be necessary.
Thyroid hormone requirements may increase during concomitant use of Xulane.

Preparations Of The Drug

Ethinyl estradiol and norelgestromin transdermal system (Xulane) containing 150 mcg/day norelgestromin and 35 mcg/day ethinyl estradiol.
Peach-colored, 14 cm² transdermal patch labeled with dosing information and batch number printed in brown ink.
Inactive ingredients include crospovidone, dipropylene glycol, fluoropolymer coated polyester film, light mineral oil, non-woven polyester fabric, oleyl alcohol, polyethylene/polyester film, and polyisobutene adhesive.
Manufactured by Mylan Pharmaceuticals Inc., Morgantown, WV, USA.
Supplied as individually sealed foil pouches to maintain patch integrity and prevent contamination.
Do not cut or alter the patch to ensure consistent hormone delivery.
Each patch delivers hormones continuously over a 7-day period and should be replaced weekly.
Packaging includes clear dosing instructions and storage recommendations to maintain efficacy.
Available only by prescription; storage at controlled room temperature (20°C-25°C) is recommended.
Disposal instructions include folding sticky sides together and disposing safely in child-proof containers to prevent accidental exposure.
Not to be refrigerated or frozen; exposure to extreme temperatures may degrade active ingredients.
Advised against use if the patch is damaged, sticky properties are compromised, or contamination is evident.
Designed for single-patient use; do not share or reuse patches.
Contains visual markers for batch identification and quality control.
The patch system is designed to optimize skin adhesion and hormone release kinetics.