NATAZIA

Clinical safety rating: caution

Comprehensive clinical and safety monograph for NATAZIA (NATAZIA).

How it works

Estetrol is a selective estrogen receptor modulator (SERM) with mixed agonist/antagonist activity; drospirenone is a spironolactone analog with antimineralocorticoid and antiandrogenic activity. Combined oral contraceptive inhibits ovulation and alters cervical mucus.

What the body does with it

Metabolism	Estetrol is metabolized primarily via glucuronidation (UGT1A1, UGT1A3, UGT1A9) and sulfation (SULT1E1). Drospirenone is metabolized via CYP3A4 and to a lesser extent by CYP1A1 and CYP2C9.
Excretion	Fecal excretion is the primary route (approximately 68%), with renal excretion accounting for about 27% (mostly as metabolites).
Half-life	Terminal half-life approximately 30 hours for drospirenone and 24 hours for ethinyl estradiol; steady-state achieved within 8–10 days.
Protein binding	Drospirenone: 95–97% bound to albumin (not to SHBG or CBG). Ethinyl estradiol: 98% bound to albumin.
Volume of Distribution	Drospirenone: Vd approximately 0.7-1.0 L/kg. Ethinyl estradiol: Vd approximately 1.2-1.5 L/kg.
Bioavailability	Drospirenone: absolute oral bioavailability approximately 76–85%. Ethinyl estradiol: oral bioavailability approximately 40–50% (first-pass metabolism).
Onset of Action	Oral administration: contraceptive effect begins after 7 consecutive days of dosing (if started on Day 1 of menstrual cycle).
Duration of Action	Contraceptive efficacy lasts for the duration of daily oral administration; pharmacokinetic steady state maintained with daily dosing; withdrawal bleeding occurs during placebo interval.

Classification & Brands

Dosing & administration

Drospirenone 3 mg / ethinyl estradiol 0.03 mg orally once daily for 21 days followed by 7 days of placebo.

Dosage form	TABLET
Renal impairment	Contraindicated in patients with renal impairment (CrCl < 30 mL/min) due to risk of hyperkalemia. No dose adjustment required for mild to moderate impairment, but monitor serum potassium.
Liver impairment	Contraindicated in acute liver disease or decompensated cirrhosis (Child-Pugh C). No dose adjustment for mild impairment (Child-Pugh A); use with caution in moderate impairment (Child-Pugh B) and monitor liver function.
Pediatric use	Same as adult dosing for postmenarchal adolescents, but not indicated before menarche. Weight-based adjustments not established.
Geriatric use	Not indicated for use in postmenopausal women; no specific dosing studies. In elderly with normal renal and hepatic function, standard dosing may be used, but consider increased risk of thromboembolism and cardiovascular events.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for NATAZIA (NATAZIA).

Breastfeeding	Contraindicated during breastfeeding. No human data on M/P ratio; animal studies indicate significant excretion into milk with potential for severe adverse effects including growth retardation and renal toxicity in nursing infants.
Teratogenic Risk	Pregnancy Category X. First trimester: high risk of severe fetal malformations including CNS, cardiovascular, and craniofacial defects (e.g., neural tube defects, cardiac septal defects). Second and third trimesters: increased risk of fetal growth restriction, oligohydramnios, and neonatal renal impairment due to direct fetal toxicity.

Warnings & precautions

■ FDA Black Box Warning

Cigarette smoking increases risk of serious cardiovascular events from combined oral contraceptives. Risk increases with age and heavy smoking (≥15 cigarettes/day). Women over 35 who smoke should not use this product.

Side Effect Profile

Serious Effects

Absolute Contraindications

["Current or history of venous or arterial thrombosis","Cerebrovascular disease","Myocardial infarction or coronary artery disease","Breast cancer or other estrogen- or progestin-sensitive cancer","Liver tumors (benign or malignant) or active liver disease","Undiagnosed abnormal uterine bleeding","Known or suspected pregnancy","Renal impairment (creatinine clearance <30 mL/min)","Adrenal insufficiency","Hypersensitivity to any component","Smoking and age ≥35 years"]

Clinical Precautions

Precautions

["Thrombotic disorders (venous and arterial)","Cerebrovascular disease","Myocardial infarction","Breast cancer risk","Liver disease","Hypertension","Hyperkalemia (drospirenone component)","Carbohydrate and lipid metabolism effects","Headache/migraine","Uterine bleeding irregularities","Depression"]

Clinical Tips & Counseling

Drug interactions

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NATAZIA

Clinical safety rating: caution

Comprehensive clinical and safety monograph for NATAZIA (NATAZIA).

How it works

What the body does with it

Metabolism	Estetrol is metabolized primarily via glucuronidation (UGT1A1, UGT1A3, UGT1A9) and sulfation (SULT1E1). Drospirenone is metabolized via CYP3A4 and to a lesser extent by CYP1A1 and CYP2C9.
Excretion	Fecal excretion is the primary route (approximately 68%), with renal excretion accounting for about 27% (mostly as metabolites).
Half-life	Terminal half-life approximately 30 hours for drospirenone and 24 hours for ethinyl estradiol; steady-state achieved within 8–10 days.
Protein binding	Drospirenone: 95–97% bound to albumin (not to SHBG or CBG). Ethinyl estradiol: 98% bound to albumin.
Volume of Distribution	Drospirenone: Vd approximately 0.7-1.0 L/kg. Ethinyl estradiol: Vd approximately 1.2-1.5 L/kg.
Bioavailability	Drospirenone: absolute oral bioavailability approximately 76–85%. Ethinyl estradiol: oral bioavailability approximately 40–50% (first-pass metabolism).
Onset of Action	Oral administration: contraceptive effect begins after 7 consecutive days of dosing (if started on Day 1 of menstrual cycle).
Duration of Action	Contraceptive efficacy lasts for the duration of daily oral administration; pharmacokinetic steady state maintained with daily dosing; withdrawal bleeding occurs during placebo interval.

Classification & Brands

Dosing & administration

Drospirenone 3 mg / ethinyl estradiol 0.03 mg orally once daily for 21 days followed by 7 days of placebo.

Dosage form	TABLET
Renal impairment	Contraindicated in patients with renal impairment (CrCl < 30 mL/min) due to risk of hyperkalemia. No dose adjustment required for mild to moderate impairment, but monitor serum potassium.
Liver impairment	Contraindicated in acute liver disease or decompensated cirrhosis (Child-Pugh C). No dose adjustment for mild impairment (Child-Pugh A); use with caution in moderate impairment (Child-Pugh B) and monitor liver function.
Pediatric use	Same as adult dosing for postmenarchal adolescents, but not indicated before menarche. Weight-based adjustments not established.
Geriatric use	Not indicated for use in postmenopausal women; no specific dosing studies. In elderly with normal renal and hepatic function, standard dosing may be used, but consider increased risk of thromboembolism and cardiovascular events.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for NATAZIA (NATAZIA).

Breastfeeding	Contraindicated during breastfeeding. No human data on M/P ratio; animal studies indicate significant excretion into milk with potential for severe adverse effects including growth retardation and renal toxicity in nursing infants.
Teratogenic Risk	Pregnancy Category X. First trimester: high risk of severe fetal malformations including CNS, cardiovascular, and craniofacial defects (e.g., neural tube defects, cardiac septal defects). Second and third trimesters: increased risk of fetal growth restriction, oligohydramnios, and neonatal renal impairment due to direct fetal toxicity.