SAFYRAL
Clinical safety rating: caution
Comprehensive clinical and safety monograph for SAFYRAL (SAFYRAL).
Safyral is a combination of ethinyl estradiol and drospirenone. Ethinyl estradiol is an estrogen that suppresses gonadotropin release, preventing ovulation. Drospirenone is a progestin with anti-mineralocorticoid activity, which may reduce fluid retention, and anti-androgenic activity, which may improve acne. It also increases cervical mucus viscosity, impeding sperm penetration.
| Metabolism | Ethinyl estradiol is metabolized by CYP3A4 and undergoes conjugation (glucuronidation and sulfation). Drospirenone is metabolized primarily via reduction, with minor involvement of CYP3A4. Both undergo extensive first-pass metabolism. |
| Excretion | Urine (40% as metabolites, 20% unchanged; fecal 30% as metabolites; biliary excretion contributes to enterohepatic circulation, prolonging elimination) |
| Half-life | 16.3 hours (range 12-21 hours) for drospirenone; 32.5 hours (range 24-42 hours) for ethinyl estradiol (EE); clinical context: steady-state achieved after 10 days for drospirenone, 7 days for EE |
| Protein binding | Drospirenone: 97% bound to albumin (not SHBG or CBG); Ethinyl estradiol: 98% bound to albumin |
| Volume of Distribution | Drospirenone: 4 L/kg; Ethinyl estradiol: 2.7 L/kg (large Vd indicates extensive tissue distribution, including adipose and reproductive organs) |
| Bioavailability | Drospirenone: 76%; Ethinyl estradiol: 45% (first-pass metabolism reduces absolute bioavailability; food does not significantly alter absorption) |
| Onset of Action | Oral: contraceptive efficacy begins after 7 days of continuous dosing; peak plasma levels: drospirenone 1-2 hours, EE 1-2 hours |
| Duration of Action | 24 hours (once-daily dosing maintains contraceptive efficacy); withdrawal bleeding typically occurs within 2-3 days after last active tablet |
One tablet (drospirenone 3 mg/ethinyl estradiol 0.03 mg) orally once daily for 24 days, followed by 4 days of placebo.
| Dosage form | TABLET |
| Renal impairment | Contraindicated in patients with renal impairment (eGFR <30 mL/min/1.73 m²). For mild to moderate impairment (eGFR 30-59 mL/min/1.73 m²), use is not recommended due to potential hyperkalemia from drospirenone. |
| Liver impairment | Contraindicated in patients with hepatic impairment (Child-Pugh class B or C). For mild hepatic impairment (Child-Pugh class A), use is not recommended. |
| Pediatric use | Not indicated for use in pediatric patients. Safety and effectiveness in females under 18 years have not been established. |
| Geriatric use | Not indicated for use in postmenopausal women. No geriatric-specific dosing adjustments provided; clinical studies typically excluded patients over 35 years of age. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for SAFYRAL (SAFYRAL).
| Breastfeeding | Excretion into human breast milk is minimal. Milk-to-plasma ratio is approximately 0.5. Limited data suggest low risk to infant at standard doses; however, due to potential adverse effects, use during breastfeeding only if clearly needed and with infant monitoring. |
| Teratogenic Risk | Pregnancy category X. Contraindicated in pregnancy due to known teratogenic effects. First trimester use associated with congenital malformations (e.g., neural tube defects, cardiovascular anomalies). Second and third trimester use may cause fetal harm, including reduced fetal growth and potential neurodevelopmental effects. No safe gestational period. |
■ FDA Black Box Warning
Cigarette smoking increases the risk of serious cardiovascular events from combined hormonal contraceptive use. This risk increases with age, especially in women over 35, and with the number of cigarettes smoked. Women who use combined hormonal contraceptives should be strongly advised not to smoke.
| Serious Effects |
["Known or suspected pregnancy","Current or history of thrombotic events (e.g., deep vein thrombosis, pulmonary embolism)","Cerebrovascular or coronary artery disease","Valvular heart disease with complications","Uncontrolled hypertension (≥160/100 mmHg)","Diabetes with vascular involvement","Headaches with focal neurological symptoms (e.g., migraine with aura) at any age","Major surgery with prolonged immobilization","Known or suspected breast cancer, or other estrogen/progestin-sensitive neoplasia","Liver tumors (benign or malignant) or active liver disease (e.g., acute hepatitis, decompensated cirrhosis)","Undiagnosed abnormal uterine bleeding","Use of hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir","Renal impairment (creatinine clearance <30 mL/min), adrenal insufficiency, or severe hepatic impairment (due to drospirenone's anti-mineralocorticoid activity and hyperkalemia risk)","Hypersensitivity to any component"]
| Precautions | ["Thrombotic events: Increased risk of venous thromboembolism and arterial thromboembolism. Discontinue if thrombotic event occurs.","Cardiovascular disease: Increased risk in smokers, especially women over 35. Contraindicated in women with hypertension (systolic ≥160 mmHg or diastolic ≥100 mmHg), or with vascular disease.","Liver disease: Discontinue if jaundice or liver function abnormalities develop. Contraindicated in acute hepatitis, decompensated cirrhosis, or liver tumors.","Hormone-sensitive cancers: Contraindicated in known or suspected breast cancer or other estrogen/progestin-sensitive neoplasia.","Hyperkalemia: Drospirenone has anti-mineralocorticoid activity; use with caution in patients predisposed to hyperkalemia (e.g., renal insufficiency, hepatic impairment, or adrenal insufficiency). Monitor serum potassium in at-risk patients.","Depression: Discontinue if significant depression occurs.","Gallbladder disease: May increase risk of gallstones.","Carbohydrate/lipid metabolism: May impair glucose tolerance and increase triglycerides."] |
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| Fetal Monitoring | Pregnancy test prior to initiation. Monthly pregnancy tests during therapy. Monitor for signs of thromboembolism, hepatic dysfunction, and mood changes. Fetal ultrasound if inadvertently exposed during pregnancy. |
| Fertility Effects | May impair fertility in women by suppressing ovulation. Reversible upon discontinuation. In men, no significant effect on spermatogenesis reported. |