What combined oral contraceptive pill (COC) with ethinyl estradiol is equivalent to Nextstellis (estetrol and drospirenone)?

Nextstellis (Estetrol/Drospirenone) Equivalence to Ethinyl Estradiol COCPs

Nextstellis (estetrol 15 mg/drospirenone 3 mg) is most comparable to a combined oral contraceptive pill containing 20-30 μg ethinyl estradiol with drospirenone, such as Yaz or Yasmin, though Nextstellis has a potentially improved safety profile due to estetrol's unique properties.

Understanding Estetrol vs. Ethinyl Estradiol

Estetrol (E4) is fundamentally different from ethinyl estradiol (EE) in several important ways:

• Potency comparison: 15 mg of estetrol has approximately similar contraceptive efficacy to 20-30 μg of ethinyl estradiol 1
• Receptor binding: Estetrol has lower binding affinity for estrogen receptors than ethinyl estradiol, making it less potent 1
• Metabolism: Unlike ethinyl estradiol, estetrol undergoes very limited metabolism and has higher bioavailability 1
• Tissue selectivity: Estetrol acts as a natural selective estrogen receptor modulator with differential effects on nuclear and membrane estrogen α-receptors 2, 3

Drospirenone Component

The drospirenone component in Nextstellis (3 mg) is identical to that found in several ethinyl estradiol-containing COCPs:

• Drospirenone is a fourth-generation progestin with anti-androgenic and anti-mineralocorticoid properties 4
• It's the same progestin found in Yaz (EE 20 μg/drospirenone 3 mg) and Yasmin (EE 30 μg/drospirenone 3 mg) 4
• Drospirenone has beneficial effects for conditions like acne and PMDD 4

Clinical Considerations

Efficacy

• Pearl Index (pregnancies per 100 woman-years) for estetrol/drospirenone is 2.65 in the US and 0.44 in the EU 2
• This efficacy is comparable to ethinyl estradiol/drospirenone formulations 2

Safety Profile

• Venous thromboembolism (VTE) risk:
  • Standard EE/drospirenone COCPs have a VTE risk of approximately 10 per 10,000 woman-years 5
  • Estetrol/drospirenone may have reduced thrombotic risk due to lower impact on hemostasis parameters 2, 6
  • However, long-term comparative data are still limited 1

Bleeding Profile

• Estetrol/drospirenone provides a predictable and regular bleeding profile for most users 2
• High stable rate of scheduled bleeding and low rate of unscheduled bleeding (primarily spotting) 2

Clinical Decision-Making Algorithm

1. For patients seeking contraception with anti-androgenic benefits:

   • Nextstellis offers similar anti-androgenic properties to EE/drospirenone formulations like Yaz or Yasmin
   • Consider Nextstellis for patients who might benefit from potentially reduced impact on hemostasis

2. For patients with VTE risk factors:

   • Nextstellis may offer theoretical advantages over EE/drospirenone formulations
   • However, caution is still warranted as long-term safety data are still accumulating

3. For patients with concerns about side effects:

   • Nextstellis may have fewer estrogen-related side effects due to estetrol's lower potency and unique receptor activity 6

Important Caveats

• While estetrol/drospirenone shows promise for reduced thrombotic risk compared to ethinyl estradiol formulations, definitive long-term comparative safety data are still needed
• Common contraindications for all COCPs still apply to Nextstellis, including age ≥35 years with smoking, history of DVT/PE, ischemic heart disease, migraines with aura, and severe liver disease 4
• The unique properties of estetrol make direct equivalence to ethinyl estradiol difficult to establish precisely

In summary, while Nextstellis represents a novel approach to hormonal contraception with potential safety advantages, its closest ethinyl estradiol-containing equivalents are the 20-30 μg EE/drospirenone formulations like Yaz and Yasmin.