Estellis

FDA-Approved Indications:

• Contraception:
• Indicated for the prevention of pregnancy in females of reproductive potential.

Clinically Accepted Off-Label/Investigational Uses:

• Polycystic Ovary Syndrome (PCOS):
• For cycle regulation, androgenic symptom relief (e.g., acne, hirsutism), and menstrual control when contraception is also desired.
• Hormonal Acne:
• In women who need birth control and are also being treated for acne, especially androgen-driven.
• Dysmenorrhea and Menstrual Regulation:
• Off-label use for menstrual pain and bleeding control due to the hormonal profile of the combination.

Adults (Reproductive-Aged Women):

• Standard Dose:
  Drospirenone 3 mg + Estetrol 14.2 mg
  One tablet orally once daily for 28 consecutive days per cycle (24 active + 4 inert tablets).
• Start Options:
• Day 1 Start: Begin on the first day of menstrual bleeding.
• Sunday Start: Begin on the first Sunday after the start of menstruation (requires backup contraception for 7 days).

Missed Dose Management:

• If one tablet is missed: Take as soon as remembered.
• If two or more tablets are missed: Follow product-specific guidance; use backup contraception.

Pediatrics:

• Not recommended before menarche.
• Safety and efficacy established in postmenarcheal females requiring contraception.

Elderly:

• Not indicated for postmenopausal women.

Renal Impairment:

• Contraindicated in moderate to severe renal impairment due to drospirenone’s antimineralocorticoid effect and risk of hyperkalemia.

Hepatic Impairment:

• Contraindicated in hepatic disease or liver tumors.

Drospirenone + Estetrol works primarily through suppression of ovulation and alteration of the endometrium and cervical mucus to prevent fertilization. Drospirenone, a synthetic progestin derived from spironolactone, inhibits the secretion of luteinizing hormone (LH), suppresses ovulation, and exerts antiandrogenic and antimineralocorticoid effects. Estetrol (E4) is a native fetal estrogen that selectively activates estrogen receptors in hepatic and reproductive tissues but has minimal action in breast tissue. The combination delivers contraceptive efficacy while reducing the risk of venous thromboembolism (VTE) compared to traditional ethinyl estradiol–based products due to Estetrol’s unique pharmacodynamic profile.

• Absorption:
• Rapidly absorbed after oral administration.
• Peak plasma concentrations: ~1–2 hours for drospirenone; ~1–3 hours for estetrol.
• Bioavailability:
• Drospirenone ~76–85%; Estetrol ~70–75%.
• Distribution:
• Drospirenone: ~95–97% protein-bound (mainly to albumin).
• Estetrol: ~50% protein-bound.
• Metabolism:
• Drospirenone: Hepatic metabolism, mainly via non-CYP pathways.
• Estetrol: Phase II metabolism (glucuronidation and sulfation).
• Elimination Half-life:
• Drospirenone: ~30 hours
• Estetrol: ~24–28 hours
• Excretion:
• Drospirenone: 38% urine, 58% feces
• Estetrol: Primarily fecal via hepatic excretion

• Pregnancy:
  FDA Pregnancy Category X.
  Contraindicated during pregnancy. No role in gestation and no known teratogenicity, but use is avoided once pregnancy is confirmed.
• Lactation:
  Not recommended during breastfeeding.
  Estetrol and drospirenone may pass into breast milk in small amounts. Progestin-only contraceptives are preferred postpartum.

• Primary Class: Combined Oral Contraceptive (COC)
• Subclass: Progestin (drospirenone) + Estrogen (natural estrogen class - estetrol)

• Known hypersensitivity to drospirenone, estetrol, or any formulation component
• Pregnancy
• History of or current thromboembolic disorders (DVT, PE)
• Cerebrovascular or coronary artery disease
• Uncontrolled hypertension
• Diabetes with vascular involvement
• Migraine with aura
• Moderate to severe hepatic impairment or liver tumors
• Renal impairment (moderate to severe)
• Adrenal insufficiency
• Undiagnosed abnormal genital bleeding
• Breast cancer or other estrogen- or progestin-sensitive tumors

• Thromboembolic Risk:
  Estetrol may carry a lower VTE risk compared to ethinyl estradiol, but caution still required in smokers >35 years, obese women, or those with clotting disorders.
• Hyperkalemia:
  Due to drospirenone’s potassium-sparing effect; avoid in patients using potassium-sparing agents or with renal impairment. Monitor serum potassium as needed.
• Liver Disease:
  Contraindicated in active hepatic disease. Estrogens may exacerbate cholestasis.
• Breast Cancer:
  Avoid in active or past history of breast cancer.
• Depression:
  Mood changes, including depression, may occur; monitor for symptoms.
• Migraine:
  Discontinue if new-onset migraine with aura develops.

Common:

• Reproductive/Endocrine:
  Irregular menstrual bleeding, breast tenderness, decreased libido
• Gastrointestinal:
  Nausea, abdominal pain, bloating
• CNS:
  Headache, mood changes, fatigue
• Dermatologic:
  Acne (usually improves), rash

Serious/Rare:

• Thromboembolic Events:
  Deep vein thrombosis, pulmonary embolism, stroke
• Cardiac:
  Hypertension, arrhythmias (rare)
• Endocrine:
  Hyperkalemia, adrenal insufficiency (rare)
• Liver:
  Elevated transaminases, hepatic adenomas
• Neoplasms:
  Breast cancer risk not excluded

• Potassium-sparing drugs (e.g., ACE inhibitors, ARBs, spironolactone, NSAIDs):
  May increase the risk of hyperkalemia.
• CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin):
  May reduce contraceptive effectiveness.
• CYP3A4 inhibitors (e.g., ketoconazole, itraconazole):
  May increase plasma levels of drospirenone.
• Antibiotics (rifampin, griseofulvin):
  Can reduce contraceptive efficacy.
• Anticoagulants (e.g., warfarin):
  Monitor INR closely due to potential estrogen interaction.
• Antidiabetic agents:
  May alter insulin sensitivity.

• FDA Approval (2021):
  First combined oral contraceptive containing estetrol approved under the brand name Nextstellis®.
• EMA Recognition:
  Estetrol acknowledged as a natural estrogen with selective receptor activity, showing a more favorable hepatic safety profile.
• Clinical Trials:
  Demonstrated high contraceptive efficacy and lower impact on hepatic protein synthesis compared to ethinyl estradiol.
• Thromboembolic Profile:
  Ongoing studies suggest lower VTE risk than EE-based COCs, but larger post-marketing studies are still under evaluation.

• Temperature:
  Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C.
• Humidity:
  Store in a dry place; protect from excessive moisture.
• Light:
  Protect from direct light; keep in original blister until use.
• Handling Precautions:
  No special precautions needed; store out of reach of children.
  Do not use if blister is damaged or tablets are discolored.