What is the proper usage and potential side effects of Nextstellis (Estetrol + drospirenone) 14.2mg/3mg for a female of reproductive age with no known medical conditions?

Nextstellis (Estetrol 14.2mg + Drospirenone 3mg): Proper Usage and Considerations

Nextstellis is a combined oral contraceptive containing a novel plant-synthesized fetal estrogen (estetrol) and drospirenone, taken as one tablet daily at the same time each day for 28 consecutive days (24 active pink tablets followed by 4 inactive white tablets), FDA-approved for pregnancy prevention in females of reproductive age. 1

Proper Administration

• Take one tablet by mouth at the same time every day, with or without food, following the order on the blister pack 1
• The 28-day regimen consists of 24 pink active tablets (each containing drospirenone 3mg and estetrol 14.2mg) followed by 4 white inert tablets 1
• Begin each subsequent 28-day pack on the same day of the week as the first cycle pack (the day after taking the last tablet) 1
• If starting on Day 1 of menses, contraceptive protection begins immediately; if not starting on the first day of menses, use backup non-hormonal contraception (condoms/spermicide) until one active tablet has been taken daily for 7 consecutive days 1

Mechanism and Unique Properties

Estetrol represents a fundamentally different estrogen compared to traditional combined oral contraceptives:

• Estetrol has lower binding affinity for estrogen receptor-α (ER-α) compared to estradiol and displays antagonistic properties against membrane ER-α in breast tissue while retaining agonistic activity on nuclear receptors 2
• This tissue-selective activity results in neutral impact on endocrine, metabolic and hemostatic parameters compared to other oral contraceptives, potentially contributing to reduced thrombotic risk 3, 2
• Drospirenone provides antimineralocorticoid and anti-androgenic effects 4

Contraceptive Efficacy

• Pearl Index of 2.65 pregnancies per 100 woman-years (95% CI 1.73-3.88) in North American trials 5
• Method-failure Pearl Index of 1.43 per 100 woman-years (95% CI 0.7-2.39) 5
• European/Russian trials demonstrated superior efficacy with Pearl Index of 0.47 (95% CI 0.15-1.11) 6
• Important limitation: Nextstellis may be less effective in females with BMI ≥30 kg/m2, with decreasing effectiveness associated with increasing BMI 1

Expected Bleeding Pattern

The estetrol-drospirenone combination provides a predictable and regular bleeding profile distinct from progestin-only formulations:

• Scheduled bleeding/spotting occurs in 82.9-94.4% of women per cycle, with median duration of 4-5 days 6, 5
• Unscheduled bleeding decreases from 30.3% in Cycle 1 to 15.5-22.1% by Cycles 2-4 and remains stable thereafter 6, 5
• Most unscheduled bleeding is reported as spotting only 4

Common Adverse Effects

The most frequently reported adverse events include:

• Headache (5.0-7.7%) 6, 5
• Metrorrhagia (4.6-5.5%) 6, 5
• Vaginal hemorrhage (4.8%) 6
• Acne (4.2%) 6
• Mood disturbances, breast symptoms, dysmenorrhea, weight increase, and decreased libido (each ≥2%) 1

Discontinuation rates due to adverse events range from 7.1-9.1%, most commonly for metrorrhagia (0.9%) and menorrhagia (0.8%) 6, 5

Absolute Contraindications

Nextstellis is contraindicated in the following conditions 1:

• Females over 35 years of age who smoke (due to increased cardiovascular risk)
• High risk of arterial or venous thrombotic diseases
• Current or history of deep vein thrombosis or pulmonary embolism
• Breast cancer or history of breast cancer
• Hepatic adenoma, hepatocellular carcinoma, acute hepatitis, or decompensated cirrhosis
• Co-administration with hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir (with or without dasabuvir)
• Abnormal uterine bleeding of undiagnosed etiology
• Renal impairment
• Adrenal insufficiency

Critical Safety Warnings

Cardiovascular Risk

• Cigarette smoking increases the risk of serious cardiovascular events from combined hormonal contraceptive use, with risk increasing with age (particularly over 35 years) and number of cigarettes smoked 1
• Do not start earlier than 4 weeks after delivery due to increased thromboembolism risk 1
• Consider all cardiovascular risk factors before initiating, particularly with multiple risk factors present 1

Hyperkalemia Risk

• Check serum potassium concentration during the first treatment cycle in females on long-term medications that may increase serum potassium (ACE inhibitors, angiotensin II receptor antagonists, potassium-sparing diuretics, heparin, aldosterone antagonists, NSAIDs) 1
• Drospirenone has antimineralocorticoid activity that can increase potassium levels 4

Thromboembolism Considerations

• One treatment-related serious adverse event of lower extremity venous thromboembolism was reported in European trials 6
• No thromboembolic events occurred in North American trials 5
• Validated hemostatic assays demonstrate that estetrol-drospirenone has limited impact on hemostasis parameters, potentially offering reduced thrombotic risk compared to traditional combined oral contraceptives 4, 2

Required Monitoring

• Blood pressure measurement before initiating and periodically during use; discontinue if blood pressure rises significantly 1
• Pregnancy testing may be necessary prior to initiation in females with irregular menstrual cycles 1
• Discontinue if new, recurrent, persistent, or severe migraines occur 1
• Monitor glucose in females with prediabetes or diabetes 1

Drug Interactions

• CYP3A inducers may lead to contraceptive failure and/or breakthrough bleeding; avoid concomitant use or use alternative/backup contraception during co-administration and up to 28 days after discontinuation 1
• Rifampin and griseofulvin demonstrably reduce combined oral contraceptive effectiveness 7

Special Populations

• Discontinue immediately if pregnancy occurs 1
• Nextstellis can decrease milk production in postpartum females 1
• Not evaluated for acne treatment (FDA approval is for contraception only) 7

Important Clinical Caveats

• The novel estetrol component provides advantages of regular, predictable bleeding profile with minimal impact on hemostasis parameters compared to traditional combined oral contraceptives 4
• Efficacy may be compromised in obese women (BMI ≥30 kg/m2), requiring counseling about potentially reduced effectiveness 1
• Cases of migraines with aura, deep vein thrombosis, hyperkalemia, and depression were rarely reported during phase III trials 2