The Food and Drug Administration (FDA) has approved Nextstellis® (drospirenone and estetrol; Mayne Pharma) for the prevention of pregnancy.

Nextstellis is a novel combined oral contraceptive pill containing drospirenone 3mg and estetrol 14.2mg. Estetrol is a synthetic analogue of a native estrogen present during pregnancy, which is selective for nuclear estrogen receptor-α (ER-α) and ER-β. Nextstellis may be less effective in females with a body mass index (BMI) greater than or equal to 30kg/m2.

The approval was based on data from 2 multicenter, open-label, single-arm phase 3 studies (US/Canada [ NCT02817841] and E4 FREEDOM EU/RU [ NCT02817828]) that evaluated the safety, acceptability, efficacy, and cycle control of Nextstellis in 3725 women aged 16 to 50. The primary end point was contraceptive efficacy as measured by the number of on-treatment pregnancies per 100 women per 12 months of exposure among the 16 to 35-year-old participants at study entry. 

Findings from both studies showed that Nextstellis met the primary end point. For the US/Canada trial, a total of 26 on-treatment pregnancies occurred in 1524 females contributing 12,763 at-risk cycles. The overall Pearl Index (PI) was 2.65 (95% CI, 1.73-3.88) per 100 woman-years of use. Study results also showed decreasing effectiveness with increasing BMI:

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  • BMI under 30kg/m2: PI was 2.57 (95%, 1.57-3.97) based on 10,113 at-risk cycles
  • BMI 30 to under 35kg/m2: PI was 2.94 (95% CI, 1.08-6.41) based on 2650 at-risk cycles.

In addition, results from the EU/RU study which were announced in June 2020 showed a PI of 0.45 (95% CI, 0.19-1.09) among women 18-35 years of age, and 0.28 (95% CI, 0.09-0.86) for the overall population (18-50 years of age). 

As for safety, the most common adverse reactions (incidence of greater than or equal to 2%) were bleeding irregularities, mood disturbance, headache, breast symptoms, dysmenorrhea, acne, increased weight, and decreased libido. Across the clinical development program, 1 thromboembolic event was reported in a patient with BMI under 25kg/m2 who had been taking Nextstellis for 75 days.

Nextstellis is expected to be available by the end of June 2021 in blister cards, each holding 24 pink active tablets containing 3mg of drospirenone and 14.2mg of estetrol and 4 white inert tablets.


  1. Mayne Pharma and Mithra announce FDA approval of new oral contraceptive Nextstellis®. [press release]. Adelaide, Australia and Liege, Belgium: Mayne Pharma Group Limited and Mithra Pharmaceuticals, SA; April 16, 2021. 
  2. Nextstellis® [package insert]. Greenville, NC: Mayne Pharma LLC; 2021.