Yaz - Drug Monograph

Introduction

Yaz is a combination oral contraceptive (COC) containing the progestin drospirenone and the estrogen ethinyl estradiol. It is widely used for pregnancy prevention and is also approved for the management of premenstrual dysphoric disorder (PMDD) and moderate acne vulgaris in women who desire oral contraception. Its unique progestin component confers antimineralocorticoid and antiandrogenic properties that distinguish it from earlier-generation COCs.

Drug Class and Overview

• Class: Combination hormonal contraceptive (estrogen + progestin); 4th-generation oral contraceptive.
• Components: Drospirenone 3 mg (a spironolactone-derived progestin) + ethinyl estradiol 0.020 mg (20 mcg).
• Regimen: 24 active tablets followed by 4 placebo tablets (24/4 regimen), which shortens the hormone-free interval compared with traditional 21/7 COCs.
• Distinguishing features: Drospirenone has antimineralocorticoid activity (reduces fluid retention) and antiandrogenic activity (may improve acne and hirsutism), but lacks the androgenic activity seen in older progestins such as levonorgestrel.

Mechanism of Action

• Primary contraceptive effect: Negative feedback inhibition of the hypothalamic-pituitary-ovarian axis → suppression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) → inhibition of ovulation.
• Secondary effects: Thickening of cervical mucus (impairs sperm penetration) and induction of endometrial atrophy (reduces implantation likelihood).
• Drospirenone-specific actions: Antagonism of the mineralocorticoid receptor (reduces sodium/water retention, may modestly affect potassium balance) and antagonism of the androgen receptor (antiandrogen effect).
• Ethinyl estradiol: Stabilizes the endometrium, reduces breakthrough bleeding, and contributes to gonadotropin suppression.

Indications

• Prevention of pregnancy in women of reproductive age.
• Treatment of premenstrual dysphoric disorder (PMDD) in women who choose to use an oral contraceptive for contraception.
• Treatment of moderate acne vulgaris in women ≥14 years of age who have achieved menarche, desire contraception, and have no contraindications to COC therapy.

Dosage and Administration

• Adult dosing: One tablet daily at approximately the same time each day for 28 consecutive days (24 active tablets containing hormone, then 4 placebo tablets). A new pack is started immediately after the previous pack; there is no hormone-free interval longer than 4 days.
• Initiation:
• Day 1 start: Begin on the first day of menstrual bleeding (no backup contraception needed).
• Sunday start: Begin on the first Sunday after menstruation begins (backup contraception recommended for 7 days unless otherwise directed).
• Quick start / Same-day start: Acceptable per CDC Selected Practice Recommendations; backup contraception advised for 7 days.
• Missed tablets: Follow CDC SPR guidance — generally, missed 1 tablet (<24 h late): take as soon as remembered; missed 2+ tablets in a row or ≥2 days late in active phase: take most recent missed tablet immediately, discard others, use backup contraception for 7 days.
• Renal impairment: Not recommended in patients with renal insufficiency or acute renal failure (risk of hyperkalemia due to antimineralocorticoid effect).
• Hepatic impairment: Contraindicated in severe hepatic disease; use with caution in mild-to-moderate impairment.
• Pediatric: Approved for acne in postmenarchal adolescents ≥14 years; otherwise used per adult dosing in reproductive-age adolescents.
• Geriatric: Not indicated; use in postmenopausal women is not recommended.
• Pregnancy: Contraindicated; discontinue if pregnancy occurs.

Pharmacokinetics

• Drospirenone:
• Absorption: Rapidly absorbed; peak plasma concentration in ~1–2 hours.
• Distribution: Approximately 95–97% protein-bound (to albumin, not sex hormone-binding globulin).
• Metabolism: Extensively metabolized in the liver, primarily via CYP3A4, with minimal CYP1A1 and CYP2C9 involvement.
• Elimination: Excreted in feces (~50%) and urine (~33%) as metabolites.
• Half-life: Approximately 30 hours.
• Ethinyl estradiol:
• Absorption: Rapid; undergoes significant first-pass metabolism.
• Distribution: Highly protein-bound to albumin; induces hepatic synthesis of sex hormone-binding globulin and other proteins.
• Metabolism: Hepatic, via CYP3A4 (and others), with extensive enterohepatic recycling.
• Elimination: Excreted in urine and feces as conjugates.
• Half-life: Approximately 12–24 hours (variable).

Contraindications

• Thrombophlebitis, deep vein thrombosis (DVT), pulmonary embolism (PE), or history thereof.
• Active or recent (within 1 year) cerebrovascular disease, coronary artery disease, or myocardial infarction.
• Known or suspected estrogen- or progestin-dependent neoplasia (e.g., breast cancer).
• Undiagnosed abnormal genital bleeding.
• Pregnancy or suspected pregnancy.
• Active hepatic disease or severe hepatic dysfunction.
• Known or suspected pregnancy.
• Migraine with aura (per CDC MEC category 4).
• Hypersensitivity to any component.
• Adrenal insufficiency (relative concern due to antimineralocorticoid activity).
• Use in combination with hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir (with or without dasabuvir) due to risk of hepatic toxicity.

Warnings and Precautions

• Thromboembolic risk: COCs increase the risk of venous thromboembolism (VTE). The risk is higher with drospirenone-containing products than with levonorgestrel-containing COCs in some epidemiologic studies, though absolute risk remains low in reproductive-age women. Risk increases with smoking, especially in women ≥35 years.
• Cardiovascular risk: Increased risk of myocardial infarction, stroke, and thromboembolism in women with predisposing conditions (hypertension, diabetes with vascular disease, hyperlipidemia, smoking, obesity).
• Hyperkalemia: Drospirenone's antimineralocorticoid activity may raise serum potassium. Use cautiously with other potassium-sparing drugs (e.g., ACE inhibitors, ARBs, potassium-sparing diuretics, aldosterone antagonists, heparin) and in patients with renal insufficiency.
• Hepatic effects: Rare hepatic adenomas and, very rarely, hepatocellular carcinoma have been reported with COC use.
• Migraine with aura: Increased stroke risk; contraindicated.
• Breast and cervical cancer: COCs may modestly increase breast cancer risk in current/recent users; cervical cancer risk may be increased with long-term use (related to HPV persistence).
• Glucose tolerance: May impair glucose tolerance; monitor in diabetic patients.
• Lipid effects: May increase triglycerides; consider in patients with severe hypertriglyceridemia.
• Depression: Monitor for mood changes; discontinue if significant depression recurs.
• Bleeding irregularities: Breakthrough bleeding and spotting are common, especially in the first 3 months.

Drug Interactions

• CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, phenobarbital, primidone, topiramate, St. John's wort, bosentan, efavirenz): Reduce hormone levels → increased risk of contraceptive failure and breakthrough bleeding. Use nonhormonal backup or alternative contraception.
• CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, grapefruit juice): May increase hormone exposure.
• Antibiotics (non-rifampin): Most do not significantly reduce efficacy; rifampin and rifabutin are the main exceptions.
• Potassium-sparing agents (ACE inhibitors, ARBs, spironolactone, eplerenone, amiloride, triamterene, heparin, NSAIDs in renally impaired patients): Additive risk of hyperkalemia.
• Hepatitis C antivirals (ombitasvir/paritaprevir/ritonavir ± dasabuvir, glecaprevir/pibrentasvir): Contraindicated due to risk of hepatotoxicity.
• Lamotrigine: COCs may reduce lamotrigine levels; dose adjustment may be needed.
• Thyroid replacement: Estrogen may increase thyroxine-binding globulin; monitor thyroid function.
• Smoking: Synergistic increase in cardiovascular risk, particularly in women ≥35 years.

Adverse Effects

• Common: Nausea, headache, breast tenderness, breakthrough bleeding/spotting, mood changes, acne (usually improves), weight changes, abdominal pain.
• Less common: Vomiting, diarrhea, decreased libido, vaginitis, fluid retention, melasma, photosensitivity.
• Serious (rare): Venous thromboembolism (DVT, PE), arterial thromboembolism (stroke, MI), hepatic adenoma, gallbladder disease, severe hypertension, pancreatitis (with severe hypertriglyceridemia), anaphylaxis, angioedema, exacerbation of systemic lupus erythematosus, retinal thrombosis.

Monitoring Parameters

• Baseline: Blood pressure, body mass index, personal and family history of thromboembolism, cardiovascular disease, migraine with aura, breast and pelvic examination, cervical cytology per guidelines, lipid panel in selected patients.
• Ongoing: Annual blood pressure; assessment of smoking status (especially in women ≥35 years); evaluation of mood, breakthrough bleeding pattern, and adverse effects at routine visits.
• Laboratory monitoring: Not routinely required; check serum potassium if co-administered with potassium-sparing drugs or in patients with renal impairment. Lipid and glucose monitoring as clinically indicated.
• Discontinue immediately if signs of VTE, stroke, MI, severe migraine, jaundice, or pregnancy occur.

Patient Education

• Take one tablet daily at the same time each day; do not skip placebo tablets.
• Use backup contraception (e.g., condoms) for 7 days when starting or after missed pills.
• Yaz does not protect against sexually transmitted infections, including HIV.
• Report immediately: leg pain or swelling, chest pain, shortness of breath, severe headache, vision changes, sudden numbness/weakness, jaundice, or breast lumps.
• Smoking, especially if ≥35 years old, greatly increases cardiovascular risk — avoid smoking while taking Yaz.
• Nausea can be reduced by taking the tablet with food or at bedtime.
• Breakthrough bleeding is common in the first few months; report persistent or heavy bleeding.
• Inform all healthcare providers and pharmacists of Yaz use before starting new medications, including over-the-counter and herbal products (especially St. John's wort).
• Avoid prolonged immobility (e.g., long flights, post-surgical recovery) due to VTE risk.

Clinical Pearls

1. Yaz uses a 24/4 regimen (24 active + 4 placebo tablets), which shortens the hormone-free interval and may reduce hormone-withdrawal symptoms compared with traditional 21/7 COCs.
2. Drospirenone's antimineralocorticoid activity can cause hyperkalemia — avoid co-administration with strong potassium-sparing drugs and use cautiously in renal impairment.
3. Drospirenone-containing COCs have been associated with a modestly higher VTE risk than levonorgestrel-containing COCs in some epidemiologic studies; counsel patients accordingly, especially those with additional thrombotic risk factors.
4. Yaz is one of the few COCs FDA-approved for PMDD and for moderate acne in women who also need contraception — a useful dual-purpose option.
5. Per CDC Medical Eligibility Criteria, COCs are contraindicated (category 4) in migraine with aura, <21 days postpartum, ≥21 days postpartum with VTE risk factors, and in smokers ≥35 years (≥15 cigarettes/day).
6. Always rule out pregnancy before initiation and counsel patients that Yaz is contraindicated in pregnancy.

References

1. U.S. Food and Drug Administration. Yaz (drospirenone/ethinyl estradiol) Prescribing Information. Bayer HealthCare Pharmaceuticals.
2. Centers for Disease Control and Prevention. U.S. Medical Eligibility Criteria for Contraceptive Use (US MEC), 2024.
3. Centers for Disease Control and Prevention. U.S. Selected Practice Recommendations for Contraceptive Use (US SPR), 2024.
4. American College of Obstetricians and Gynecologists. Committee Opinion: Combined Hormonal Contraceptives and the Risk of Venous Thromboembolism.
5. World Health Organization. Medical Eligibility Criteria for Contraceptive Use, 5th Edition.
6. Brunton LL, Knollmann BC, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th Edition. McGraw-Hill.
7. Speroff L, Fritz MA. Clinical Gynecologic Endocrinology and Infertility, 9th Edition. Lippincott Williams & Wilkins.
8. Lexicomp Online. Drospirenone/Ethinyl Estradiol. Wolters Kluwer Clinical Drug Information.
9. American Society of Reproductive Medicine. Hormonal Contraception Clinical Guidelines.
10. Practice Committee of the American Academy of Dermatology. Guidelines of Care for the Management of Acne Vulgaris.