Xulane - Drug Monograph

Introduction

Xulane (norelgestromin/ethinyl estradiol transdermal system) is a combination hormonal contraceptive patch indicated for the prevention of pregnancy. It delivers continuous systemic levels of norelgestromin (a progestin) and ethinyl estradiol (an estrogen) through transdermal absorption. Xulane represents an alternative to oral contraceptive formulations for women who prefer a weekly dosing regimen.

Mechanism of Action

Xulane works through multiple mechanisms to prevent pregnancy:

• Suppression of ovulation: The progestin component (norelgestromin) inhibits gonadotropin secretion, preventing follicular development and ovulation
• Cervical mucus alteration: Progestin thickens cervical mucus, creating a barrier to sperm penetration
• Endometrial changes: Progestin causes endometrial thinning, making implantation less likely

The transdermal delivery system provides steady-state hormone concentrations that avoid the peak-trough fluctuations associated with oral administration.

Indications

• Prevention of pregnancy in women who choose to use a transdermal patch as their method of contraception

• Management of menstrual-related symptoms (dysmenorrhea, menorrhagia)
• Treatment of acne in women seeking contraception
• Management of premenstrual dysphoric disorder (PMDD)

Dosage and Administration

• One patch applied weekly for 3 consecutive weeks, followed by 1 patch-free week
• Apply to clean, dry, intact skin on buttock, abdomen, upper outer arm, or upper torso (excluding breasts)
• Rotate application sites to minimize skin irritation

• Renal impairment: No dosage adjustment required
• Hepatic impairment: Contraindicated in women with hepatic impairment
• Geriatric: Not indicated in postmenopausal women
• Pediatric: Safety and efficacy established for women of reproductive potential

• If patch detachment occurs <24 hours: Reapply same patch or apply new patch
• If patch detached >24 hours or unknown duration: Apply new patch and start new cycle; use backup contraception for 7 days

Pharmacokinetics

• Norelgestromin: Cmax ~4.5 ng/mL reached at approximately 48 hours
• Ethinyl estradiol: Cmax ~100 pg/mL reached at approximately 48 hours
• Steady-state concentrations achieved during Week 2 of use

• Norelgestromin: Highly bound to serum proteins (SHBG and albumin)
• Ethinyl estradiol: ~98% bound to serum albumin

• Norelgestromin: Extensive hepatic metabolism via CYP3A4
• Ethinyl estradiol: Hepatic metabolism via hydroxylation, methylation, and conjugation

• Norelgestromin: Terminal half-life ~28 hours
• Ethinyl estradiol: Terminal half-life ~17 hours
• Excretion primarily in urine and feces

Contraindications

• Current or history of thrombophlebitis or thromboembolic disorders
• Known or suspected estrogen-dependent neoplasia
• Known or suspected pregnancy
• Undiagnosed abnormal genital bleeding
• Liver dysfunction or disease
• History of cerebrovascular or coronary artery disease
• Hypertension (uncontrolled)
• Diabetes with vascular involvement
• Headaches with focal neurological symptoms
• Major surgery with prolonged immobilization
• Smoking in women over 35 years of age
• Hypersensitivity to any component of Xulane

Warnings and Precautions

• Cigarette smoking increases risk of serious cardiovascular side effects; women over 35 who smoke should not use Xulane

• Thromboembolic disorders: Increased risk of venous thromboembolism, arterial thromboembolism, stroke, and myocardial infarction
• Hypertension: Regular blood pressure monitoring required
• Liver disease: Discontinue if jaundice develops
• Carbohydrate metabolism: May decrease glucose tolerance
• Lipid metabolism: May alter serum triglycerides and other lipid levels
• Gallbladder disease: May worsen existing gallbladder disease
• Headache: New, persistent, or recurrent headache requires evaluation
• Bleeding irregularities: Irregular bleeding common during first few months
• Ectopic pregnancy: Higher risk if pregnancy occurs while using patch
• Depression: May exacerbate depression; monitor mood changes

Drug Interactions

• Enzyme inducers: Carbamazepine, phenytoin, rifampin, St. John's wort—may decrease efficacy (consider alternative contraception)
• Antibiotics: Broad-spectrum antibiotics may reduce efficacy (case reports)
• HIV medications: Protease inhibitors and NNRTIs may alter hormone levels
• Anticoagulants: May decrease anticoagulant effect
• Cyclosporine: Increased cyclosporine levels possible
• Lamotrigine: May decrease lamotrigine levels
• Thyroid hormones: May alter thyroid hormone requirements
• CYP3A4 inhibitors: Ketoconazole, itraconazole, clarithromycin may increase hormone levels

Adverse Effects

• Application site reactions (erythema, irritation)
• Headache
• Nausea
• Breast tenderness
• Menstrual cramps
• Abdominal pain

• Vomiting
• Diarrhea
• Emotional lability
• Weight gain
• Upper respiratory infection
• Dysmenorrhea

• Venous thromboembolism
• Arterial thromboembolism
• Hypertension
• Hepatic adenomas
• Gallbladder disease
• Ischemic colitis
• Retinal thrombosis

Monitoring Parameters

• Blood pressure
• BMI
• Personal and family medical history
• Smoking status
• Lipid profile (if indicated)
• Liver function tests (if indicated)

• Blood pressure at 3-6 month intervals
• Annual comprehensive history and physical examination
• Symptom assessment for thromboembolism, depression, and other adverse effects
• Patient adherence and patch application technique
• Skin evaluation for local reactions

• Pre-surgical evaluation for thrombotic risk
• Glucose monitoring in diabetic patients
• Lipid monitoring in patients with hyperlipidemia

Patient Education

• Apply to clean, dry skin without lotions, oils, or powders
• Press firmly for 10 seconds ensuring complete contact
• Avoid applying to irritated, cut, or shaved skin
• Do not apply to same site within 7 days

• Patch does not protect against sexually transmitted infections
• Report any severe leg pain, chest pain, sudden shortness of breath, or neurological symptoms immediately
• Notify healthcare provider if severe headaches, visual changes, or jaundice occur
• Use backup contraception for first 7 days of initial use
• If patch becomes detached, follow specific instructions based on duration of detachment
• Store patches at room temperature
• Dispose of used patches folded onto themselves to prevent accidental exposure

• Suspected pregnancy
• Prolonged patch detachment
• Severe abdominal pain
• Heavy vaginal bleeding
• Symptoms of allergic reaction
• Signs of blood clot (leg pain, chest pain, breathing difficulties)

References

1. FDA Prescribing Information: Xulane (norelgestromin and ethinyl estradiol) transdermal system. 2021. 2. Archer DF, et al. Contraceptive efficacy and safety of the transdermal contraceptive patch. Am J Obstet Gynecol. 2002;187(3):709-715. 3. Zieman M, et al. Contraceptive efficacy and cycle control with the Ortho Evra/Evra transdermal system: the analysis of pooled data. Fertil Steril. 2002;77(2 Suppl 2):S13-S18. 4. Sibai BM, et al. Thrombotic risk associated with hormonal contraceptives and hormone replacement therapy. Obstet Gynecol. 2004;104(6):1285-1295. 5. Practice Bulletin No. 206: Use of Hormonal Contraception in Women with Coexisting Medical Conditions. Obstet Gynecol. 2019;133(2):e128-e150. 6. Curtis KM, et al. U.S. Medical Eligibility Criteria for Contraceptive Use, 2016. MMWR Recomm Rep. 2016;65(3):1-103. 7. Teal S, et al. Transdermal contraception: patch and ring. In: Hatcher RA, et al, eds. Contraceptive Technology. 21st ed. New York, NY: Ardent Media; 2018:395-414.