ANGELIQ
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ANGELIQ (ANGELIQ).
Angeliq combines drospirenone, a spironolactone analogue with antimineralocorticoid and antiandrogenic activity, and estradiol, an estrogen that replaces endogenous estrogen and regulates gonadotropin secretion.
| Metabolism | Drospirenone is extensively metabolized via CYP3A4; estradiol is metabolized primarily via CYP1A2 and CYP3A4. |
| Excretion | Estradiol: renal (90%) as conjugates (glucuronide and sulfate), fecal (10%). Drospirenone: renal (50%) as inactive metabolites, fecal (50%) as metabolites; less than 1% excreted unchanged. |
| Half-life | Estradiol: terminal half-life 13-18 hours; Drospirenone: terminal half-life 25-32 hours, allowing once-daily dosing. |
| Protein binding | Estradiol: 97-99% bound to albumin and sex hormone-binding globulin (SHBG); Drospirenone: 95-97% bound to albumin (not to SHBG or corticosteroid-binding globulin). |
| Volume of Distribution | Estradiol: 1.2 L/kg; Drospirenone: 4.6 L/kg, indicating extensive distribution into tissues. |
| Bioavailability | Estradiol: approximately 5% absolute bioavailability due to extensive first-pass metabolism; Drospirenone: 76% absolute bioavailability, high with minimal first-pass effect. |
| Onset of Action | Oral: For estradiol-related symptoms (e.g., hot flashes) first effects observed within 2-4 weeks; full effect may take 8-12 weeks. Drospirenone's antiandrogenic and antimineralocorticoid effects become apparent after 1-2 weeks of continuous dosing. |
| Duration of Action | Duration of estradiol's effects on climacteric symptoms is 24 hours with once-daily dosing; Drospirenone's effects on blood pressure and fluid balance persist over the 24-hour dosing interval. |
| Action Class | Macrolides |
| Brand Substitutes | Azax 500 Tablet, Zady 500 Tablet, Trulimax 500mg Tablet, Azifast 500 Tablet, Zithrox 500 Tablet |
One tablet (drospirenone 0.5 mg/estradiol 1 mg) orally once daily.
| Dosage form | TABLET |
| Renal impairment | Contraindicated in patients with severe renal impairment (CrCl <30 mL/min). No dose adjustment required for mild to moderate impairment (CrCl 30-80 mL/min). |
| Liver impairment | Contraindicated in patients with Child-Pugh Class C (severe hepatic impairment). For Child-Pugh Class A or B, use with caution; maximum dose is drospirenone 0.25 mg/estradiol 0.5 mg (half tablet) once daily if benefit outweighs risk. |
| Pediatric use | Not indicated for use in pediatric patients. Safety and efficacy have not been established. |
| Geriatric use | Limited data; use lowest effective dose for shortest duration. Consider baseline renal function; contraindicated if CrCl <30 mL/min. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for ANGELIQ (ANGELIQ).
| Breastfeeding | Estradiol and drospirenone are excreted in human breast milk. Estradiol reduces milk production and quality. The M/P ratio for estradiol is approximately 0.2. Use during breastfeeding is not recommended due to potential adverse effects on the nursing infant, including jaundice and galactorrhea. |
| Teratogenic Risk | ANGELIQ (estradiol/drospirenone) is contraindicated in pregnancy. Exposure during the first trimester is associated with a risk of congenital anomalies including cardiovascular and limb defects. Use during the second and third trimesters may cause fetal harm, including urogenital abnormalities and potential long-term reproductive effects. Estrogens can also cause fetal feminization in male offspring. |
■ FDA Black Box Warning
Estrogen plus progestin therapy may increase risk of cardiovascular disorders (e.g., myocardial infarction, stroke, venous thromboembolism), probable dementia, and invasive breast cancer. Concomitant use with progestins has been associated with these risks.
| Serious Effects |
Undiagnosed abnormal genital bleeding, known or suspected pregnancy, known or suspected breast cancer (except in certain cases), known or suspected estrogen-dependent neoplasia, active or history of venous thromboembolism, active or history of arterial thromboembolism, known thrombophilic disorders, known protein C, S, or antithrombin deficiency, liver impairment or disease, renal impairment (CrCl < 30 mL/min), hyperkalemia (>5.0 mEq/L), and hypersensitivity to any component.
| Precautions | Cardiovascular disorders (e.g., coronary artery disease, stroke, venous thromboembolism), probable dementia, breast cancer, endometrial cancer (if used without progestin), hyperkalemia (due to drospirenone's antimineralocorticoid effect), gallbladder disease, visual abnormalities, elevated blood pressure, and hepatic hemangiomas. |
| Food/Dietary |
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| Fetal Monitoring | Monitor for signs of thromboembolism, hypertension, and hepatic dysfunction. In pregnant patients inadvertently exposed, perform a detailed fetal ultrasound to assess for anomalies. Monitor fetal growth due to potential for low birth weight. |
| Fertility Effects | ANGELIQ suppresses ovulation and is used as a contraceptive. Upon discontinuation, fertility returns may be delayed for up to 3 months. No permanent effects on fertility have been reported. |
| Avoid grapefruit and grapefruit juice as they may alter estrogen metabolism. High-potassium foods (bananas, oranges, spinach, potatoes, tomatoes, avocados, salt substitutes) should be consumed consistently; monitor potassium intake with concurrent medications that increase potassium. |
| Clinical Pearls | ANGELIQ combines estradiol (estrogen) and drospirenone (progestin). Drospirenone has antimineralocorticoid activity, which may increase serum potassium; monitor renal function and potassium levels, especially in patients on ACE inhibitors, ARBs, NSAIDs, or potassium-sparing diuretics. Avoid in patients with adrenal insufficiency due to drospirenone's antiandrogenic effects. Use lowest effective dose for shortest duration; consider transdermal route for lower thromboembolic risk. |
| Patient Advice | Take tablet at same time daily with food to minimize GI upset. · Report symptoms of blood clots (leg pain/swelling, sudden chest pain, shortness of breath), stroke (sudden numbness/weakness, vision changes, severe headache), or high potassium (muscle weakness, palpitations). · Do not use if pregnant or breastfeeding; use effective non-hormonal contraception. · Smoking increases risk of cardiovascular events; advise smoking cessation. · Regular monitoring of blood pressure, potassium, and renal function is required. · Missed dose: take as soon as remembered; if >24 hours late, skip and resume next day; do not double. |