estetrol/drospirenone (Rx)

Brand and Other Names:Nextstellis
  • Print

Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

estetrol/drospirenone

tablet

  • 14.2mg/3mg

Contraception

Indicated for use by females of reproductive potential to prevent pregnancy

Days 1-24: 1 active tablet (3 mg drospirenone [DRSP]/14.2 mg estetrol [E4]) PO qDay, THEN

Days 25-28: 1 inert tablet PO qDay

Dosage Modifications

Renal impairment

  • All severities of renal impairment: Contraindicated
  • CrCl 30-49 mL/min: Serum DRSP concentrations were ~37 higher than control group
  • Females with renal impairment whose serum potassium is in upper reference range and are concomitantly using potassium-sparing drugs may potentially develop hyperkalemia

Hepatic impairment

  • All severities of hepatic impairment: Contraindicated
  • Moderate: Mean exposure to DRSP was ~3x higher than females with normal liver function
  • Severe: Not studied

Dosing Considerations

Initiating with no current use of hormonal contraception

  • Females with irregular menstrual cycles: Consider pregnancy testing before initiation
  • Days 1-24: Take 1 pink active tablet once daily starting on first day of menses
  • Days 25-28: Take 1 white inert tablet daily
  • Each subsequent 28-day pack: Begin on same day of week as first cycle pack (eg, on day after taking the last tablet)
  • If not starting on first day of menses, use nonhormonal contraceptive (eg, condoms and/or spermicide) as backup until 1 active tablet has been taken daily for 7 days in a row

Switching from another contraceptive method

  • Combined oral contraceptive (COC): Start when new pack of previous COC would have started
  • Transdermal system, vaginal insert, or injection: Start when next administration would have been scheduled
  • Intrauterine system (IUS) or implant: Start after removal
  • Progestin-only pill: Start after last tablet was taken

Initiating after delivery (>20 weeks gestation)

  • Do not start <4 weeks after delivery
  • Menstrual cycles have resumed: Follow instructions for “starting estetrol/drospirenone in females with no current use of hormonal contraception”
  • Menstrual cycles have not resumed: Consider possibility of ovulation and pregnancy; if not pregnant, use additional nonhormonal contraception for first 7 days of use

Starting DRSP/E4 after delivery (>20 weeks gestation)

  • ≤14 weeks gestation
    • Starting ≤7 days of complete first trimester abortion or miscarriage: Use additional contraception for next 7 days
    • Starting >7 days: Follow instructions for “starting DRSP/E4 in females with no current use of hormonal contraception”
  • >14 weeks to ≤20 weeks gestation
    • Start after 4 weeks following second trimester abortion or miscarriage; consider duration of pregnancy and increased risk of thromboembolism
    • Menstrual cycles have resumed: Follow instructions for “starting DRSP/E4 in females with no current use of hormonal contraception”
    • Menstrual cycles have not resumed: Consider possibility of ovulation and pregnancy; if not pregnant, use additional nonhormonal contraception for first 7 days of use

Limitation of use

  • May be less effective in females with a body mass index (BMI) ≥30 kg/m2; decreased effectiveness may be associated with increased BMI

Dosage Forms & Strengths

estetrol/drospirenone

tablet

  • 14.2mg/3mg

Contraception

Indicated for use by females of reproductive potential to prevent pregnancy

Study was done on females of reproductive potential aged 16-50 years

Days 1-24: 1 active tablet (3 mg drospirenone [DRSP]/14.2 mg estetrol [E4]) PO qDay, THEN

Days 25-28: 1 inert tablet PO qDay

Dosage Modifications

Renal impairment

  • All severities of renal impairment: Contraindicated
  • CrCl 30-49 mL/min: Serum DRSP concentrations were ~37 higher than control group
  • Females with renal impairment whose serum potassium is in upper reference range and are concomitantly using potassium-sparing drugs may potentially develop hyperkalemia

Hepatic impairment

  • All severities of hepatic impairment: Contraindicated
  • Moderate: Mean exposure to DRSP was ~3x higher than females with normal liver function
  • Severe: Not studied

Dosing Considerations

Initiating with no current use of hormonal contraception

  • Females with irregular menstrual cycles: Consider pregnancy testing before initiation
  • Days 1-24: Take 1 pink active tablet once daily starting on first day of menses
  • Days 25-28: Take 1 white inert tablet daily
  • Each subsequent 28-day pack: Begin on same day of week as first cycle pack (eg, on day after taking the last tablet)
  • If not starting on first day of menses, use nonhormonal contraceptive (eg, condoms and/or spermicide) as backup until 1 active tablet has been taken daily for 7 days in a row

Switching from another contraceptive method

  • Combined oral contraceptive (COC): Start when new pack of previous COC would have started
  • Transdermal system, vaginal insert, or injection: Start when next administration would have been scheduled
  • Intrauterine system (IUS) or implant: Start after removal
  • Progestin-only pill: Start after last tablet was taken

Initiating after delivery (>20 weeks gestation)

  • Do not start <4 weeks after delivery
  • Menstrual cycles have resumed: Follow instructions for “starting estetrol/drospirenone in females with no current use of hormonal contraception”
  • Menstrual cycles have not resumed: Consider possibility of ovulation and pregnancy; if not pregnant, use additional nonhormonal contraception for first 7 days of use

Starting DRSP/E4 after delivery (>20 weeks gestation)

  • ≤14 weeks gestation
    • Starting ≤7 days of complete first trimester abortion or miscarriage: Use additional contraception for next 7 days
    • Starting >7 days: Follow instructions for “starting DRSP/E4 in females with no current use of hormonal contraception”
  • >14 weeks to ≤20 weeks gestation
    • Start after 4 weeks following second trimester abortion or miscarriage; consider duration of pregnancy and increased risk of thromboembolism
    • Menstrual cycles have resumed: Follow instructions for “starting DRSP/E4 in females with no current use of hormonal contraception”
    • Menstrual cycles have not resumed: Consider possibility of ovulation and pregnancy; if not pregnant, use additional nonhormonal contraception for first 7 days of use

Limitation of use

  • May be less effective in females with a body mass index (BMI) ≥30 kg/m2; decreased effectiveness may be associated with increased BMI
Next:

Interactions

Interaction Checker

and estetrol/drospirenone

No Results

     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

            All Interactions Sort By:
             activity indicator 
            Previous
            Next:

            Adverse Effects

            >10%

            Bleeding irregularities (9.7-10.8%)

            Mood disturbance (9.1-10.9%)

            1-10%

            Headache (4.8-6.3%)

            Breast symptoms (5.3-5.4%)

            Dysmenorrhea (3.7-4.1%)

            Weight increased (3-3.3%)

            Acne (3.2-3.7%)

            Libido decreased/lost (1.3-2%)

            Depression (1.7%)

            Frequency Not Defined

            Thromboembolic event reported in a female who had been taking therapy for 75 days and had normal BMI < 25 kg/m2

            Previous
            Next:

            Warnings

            Black Box Warnings

            Cigarette smoking and serious cardiovascular events

            • Cigarette smoking increases risk of serious cardiovascular adverse effects from CHC use
            • This risk increases with age, particularly in females aged >35 years, and number of cigarettes smoked
            • CHCs, including DRSP/E4, are contraindicated in females aged ≥35 years and smoke

            Contraindications

            History of, increased risk for, or current arterial or venous thrombotic/thromboembolic diseases

            • Examples include females with the following conditions
              • Smoking, if aged ≥35 years
              • Current or history of deep vein thrombosis or pulmonary embolism
              • Cerebrovascular disease
              • Coronary artery disease
              • Thrombogenic valvular or thrombogenic rhythm diseases of the heart (eg, subacute bacterial endocarditis with valvular disease, atrial fibrillation)
              • Inherited or acquired hypercoagulopathies
              • Uncontrolled hypertension or hypertension with vascular disease
              • Diabetes mellitus with hypertension or end-organ damage; or diabetes mellitus of >20 years duration
              • Migraine headaches with aura

            Current or history of a hormonally-sensitive malignancy (eg, breast cancer)

            Hepatic adenoma, hepatocellular carcinoma, acute hepatitis, or severe (decompensated) cirrhosis

            Use of hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir

            Abnormal uterine bleeding with undiagnosed etiology

            Renal impairment

            Adrenal insufficiency

            Cautions

            Increased blood pressure (BP) reported in females using COCs; increase is more likely in older females with extended duration of use; monitor BP periodically and discontinue if BP rises significantly

            Migraine headaches with aura increase the risk for stroke; stroke risk is further increased in females who have migraine headaches with aura with use of CHCs; discontinue if new migraine headaches develop that are recurrent, persistent, or severe or increased frequency or severity of migraine headaches (which may be prodromal of a cerebrovascular event)

            May promote growth of any hormone receptor–positive tumor, both within and external to female reproductive tract (eg, hormone receptor–positive include melanoma, adenocarcinoma of the lung, meningioma); discontinue if a hormonally sensitive malignancy is diagnosed

            May cause elevated liver enzymes; withhold or permanently discontinue for persistent or significant elevation of liver enzymes

            CHCs increase the risk of hepatic tumors, particularly hepatic adenomas; rupture of hepatic adenomas may cause death from abdominal hemorrhage

            May decrease glucose tolerance; carefully monitor females with prediabetes and diabetes during therapy

            Females with hypertriglyceridemia or with family history may have increase serum triglyceride concentrations during use, which may increase risk of pancreatitis; consider alternative contraception

            Studies suggest an increased risk of developing gallbladder disease among CHC users; use of CHCs may also worsen existing gallbladder disease; females with a history of pregnancy-related cholestasis may be at an increased risk for CHC-related cholestasis; consider discontinuing treatment in females with symptomatic gallbladder disease or cholestatic disease

            Limited data are available on association of COCs with onset of depression or exacerbation of existing depression; monitor females with a history of depression and discontinue if depression recurs to a serious degree

            Causal relationship between use of CHCs and development of cervical cancer and intraepithelial neoplasia has not been clearly established

            Exogenous estrogens may induce or exacerbate symptoms of hereditary angioedema; avoid in females with hereditary angioedema

            Chloasma may occur with use, especially in females with history of chloasma gravidarum; avoid in females with a history of chloasma gravidarum or increased sensitivity to sun and/or ultraviolet radiation exposure

            Bleeding irregularities and amenorrhea

            • May experience unscheduled (breakthrough or intracyclic) bleeding and spotting, especially during first 4 months of use
            • Bleeding irregularities may resolve over time or by changing to a different contraceptive product; if bleeding persists or occurs after previously regular cycles, evaluate for causes (eg, pregnancy, malignancy)
            • Females may also experience absence of scheduled (withdrawal) bleeding, even if they are not pregnant; if scheduled bleeding does not occur, consider possibility of pregnancy
            • If patient has not adhered to prescribed dosing schedule (missed 1 or 2 active tablets or started taking them on a day later than prescribed), consider possibility of pregnancy at time of the first missed period and perform appropriate diagnostic measures
            • After discontinuation, amenorrhea or oligomenorrhea may occur, especially if these conditions were preexistent

            Thromboembolic disorders

            • Before starting, evaluate any medical history or family history of thrombotic or thromboembolic disorders; consider whether history suggests an inherited or acquired hypercoagulopathy
            • Use of CHCs increases the risk of cardiovascular events and cerebrovascular events, (eg, myocardial infarction, stroke); risk is greater among females aged >40, smokers, and females with hypertension, dyslipidemia, diabetes, or obesity; risk increases with age, particularly in females aged ≥35 years, and with number of cigarettes smoked or use of other nicotine-containing products
            • Use of CHCs also increases the risk of venous thromboembolic events (VTEs) (eg, deep vein thrombosis, pulmonary embolism); risk of VTE is highest during first year of CHC use and when restarting hormonal contraception after a break ≥4 weeks; risk of VTE returns to baseline ~3 months after CHC discontinued
            • Postpartum VTE
              • VTE is increased during first 6 weeks postpartum compared with risk in nonpregnant, nonpostpartum females
              • Risk highest in first 3 weeks postpartum; remains higher than baseline until at least 6 weeks postpartum
              • Multiple risk factors for VTE may further increase the risk
              • Obstetric complications may extend elevated risk up to 12 weeks postpartum
            • Discontinue for the following
              • Thrombotic event occurs
              • Unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions and evaluate for retinal vein thrombosis immediately
              • During prolonged immobilization

            Hyperkalemia

            • Contraindicated in females with conditions that predispose to hyperkalemia (eg, renal impairment, hepatic impairment, adrenal insufficiency)
            • Females receiving daily, long-term treatment for chronic conditions or diseases with medications that may increase serum potassium concentration should have their serum potassium concentration checked during first treatment cycle and monitored
            • Product contains drospirenone, a progestin, which has anti-mineralocorticoid activity, including potential for hyperkalemia in high-risk females, comparable to a 25-mg dose of spironolactone

            Drug interaction overview

            • DRSP: CYP3A4 substrate
            • CYP3A4 inducers
              • Strong CYP3A4 inducers: Avoid coadministration; if unavoidable, use alternant contraceptive method (eg, IUS) or backup nonhormonal contraceptive during coadministration and up to 28 days after discontinuing strong CYP3A4 inducer
              • Moderate and weak CYP3A4 inducers: Use alternant or backup contraceptive method during coadministration and up to 28 days after discontinuing CYP3A inducer, unless prescribing information of specific moderate or weak CYP3A inducer indicates there is no clinically significant interaction
              • Strong CYP3A inducers or certain moderate or weak CYP3A inducers may decrease DRSP exposure, which may lead to contraceptive failure
            • Strong CYP3A4 inhibitors
              • May increase drospirenone/estetrol systemic exposure
              • Consider monitoring serum potassium concentration in patients who take a strong CYP3A4 inhibitor long-term and concomitantly with DRSP/E4
            • Drugs that may reduce absorption
              • Separate administration times of DRSP/E4 and concomitant drug; refer to concomitant drug's prescribing information for additional information
              • Drugs such as bile acid sequestrants may decrease the E4 and DRSP exposure, which may lead to contraceptive failure and/or an increased breakthrough bleeding
            • Antidiabetic drugs
              • Increase frequency of glucose monitoring and increase antidiabetic drug dosage, as needed, based on glucose levels
              • DRSP/E4 may reduce blood glucose–lowering effects of antidiabetic drugs
              Drugs that may increase serum potassium concentration
              • Monitor serum potassium concentration in females at increased risk for hyperkalemia
              • DRSP/E4 may increase serum potassium concentration in females concurrently taking other drugs that may increase serum potassium
            • Lamotrigine
              • Adjust lamotrigine dosage as recommended by prescribing information
              • DRSP/E4 may decrease exposure and efficacy of lamotrigine
            • Systemic corticosteroids
              • Follow recommendations in accordance with prescribing information of corticosteroids consider more frequent monitoring for corticosteroid adverse reactions
              • DRSP/E4 may increase exposure and toxicities of systemic corticosteroids (owing to increased corticosteroid-binding globulin) and mineralocorticoids (owing to increased aldosterone)
            • Hepatitis C treatment
              • CHCs are contraindicated for use with hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir (with or without dasabuvir)
              • Discontinue DRSP/E4 before starting therapy with combination drug regimen ombitasvir/paritaprevir/ritonavir (with or without dasabuvir)
              • May restart ~2 weeks following completion of treatment with this hepatitis C combination drug regimen
              • During clinical trials with these hepatitis C combination drug regimens, ALT elevations >5x ULN, including some cases >20x ULN, were significantly more frequent in females using ethinyl estradiol (EE) containing drugs, such as CHCs
            • Thyroid hormone replacement therapy
              • Increase thyroid hormone replacement dose as needed
              • Estrogen component may increase the serum concentrations of thyroxine-binding globulin
            • Sex hormones
              • Coadministration may decrease androstenedione, progesterone, and free testosterone owing to increased sex hormone-binding globulin
            Previous
            Next:

            Pregnancy & Lactation

            Pregnancy

            Discontinue if pregnancy occurs

            Epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (eg, cardiac anomalies, limb-reduction defects) following COC exposure before conception or during early pregnancy

            Animal studies

            • Reproductive toxic studies performed with E4 alone have shown expected pharmacologic effects in animals, which are consistent with estrogen exposure

            Lactation

            Contraceptive hormones and/or metabolites are present in human milk

            COCs can reduce milk production in breastfeeding females; reduction may occur at any time, but less likely to occur once breastfeeding is well established

            When possible, advise nursing females to use other methods of contraception until breastfeeding is discontinued

            After oral administration of DRSP 3 mg/ethinyl estradiol 30 mcg, about 0.02% of the DRSP dose was excreted into the breast milk of postpartum females within 24 hr; results in a potential maximal daily dose <1 mcg DRSP in an infant

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

            Previous
            Next:

            Pharmacology

            Mechanism of Action

            Estetrol (E4): Synthetic analogue of a native estrogen present during pregnancy, that is selective for nuclear estrogen receptor-alpha (ER-alpha) and ER-beta; treatment results in decrease of follicle-stimulating hormone and luteinizing hormone, ultimately leading to ovulation suppression

            Drospirenone: Progestin; spironolactone analogue with anti-mineralocorticoid and anti-androgenic activity that provides contraception primarily by suppressing ovulation

            Absorption

            Peak plasma concentration

            • E4: 17.9 ng/mL
            • DRSP: 48.7 ng/mL

            Peak plasma time

            • E4: 0.5 hr
            • DRSP: 1 hr

            AUC

            • E4: 59.1 ng·hr/mL
            • DRSP: 519 ng·hr/mL

            Time to steady-state

            • E4: 4 days
            • DRSP: 10 days

            Effects of high-fat meal (relative to fasting)

            • Geometric mean peak plasma concentration ratio: 0.5 (E4); 0.75 (DRSP)
            • Geometric mean AUC ratio: 1.01 (E4); 1.08 (DRSP)

            Distribution

            Protein bound

            • E4: 46-50%
            • DRSP: 95-97%

            Metabolism

            E4

            • Phase 2 metabolism to form glucuronide and sulphate conjugates which have negligible in-vitro estrogenic activity
            • In vitro studies show that UGT2B7 is dominant UGT isoform that catalyzes the formation of E4-16-glucuronide

            DRSP

            • Metabolized by CYP3A4
            • Two main metabolites (not active): acid form of DRSP generated by opening of lactone ring and 4,5 dihydrodrospirenone formed by reduction followed by sulfation

            Elimination

            Half-life

            • E4: 27 hr (bound to albumin)
            • DRSP: 34 hr

            Excretion

            • E4: Urine (69%); feces (22%; 100% unchanged)
            • DRSP: Urine (38%); feces (44%)
            Previous
            Next:

            Administration

            Oral Administration

            Take at the same time every day and in the order directed by blister pack

            May take with or without food

            Swallow both pink pills and white pills whole

            Missed dose

            • Missed 1 pink active tablet
              • Take missed dose as soon as possible and take next tablet at scheduled time, even if 2 active tablets are taken in 1 day
              • Continue taking 1 tablet a day until pack is finished
            • Missed ≥2 pink active tablets in Week 1 or 2
              • Take missed dose as soon as possible and take next tablet at scheduled time, even if 2 active tablets are taken in 1 day and discard other missed tablets
              • Continue taking 1 tablet a day until pack is finished
              • Use additional nonhormonal contraception as backup until pink tablets have been taken for 7 consecutive days
            • Missed ≥2 pink active tablets in Week 3
              • Take missed dose as soon as possible and take next tablet at scheduled time, even if 2 active tablets are taken in 1 day and discard other missed tablets
              • Finish active tablets and discard inactive tablets in pack; start a new pack of tablets the next day
              • Use additional nonhormonal contraception as backup until pink tablets have been taken for 7 consecutive days
            • Missed ≥1 white inert tablets
              • Skip missed doses and continue taking 1 tablet a day until pack is finished
            • After vomiting or acute diarrhea
              • Vomiting or acute diarrhea occurs within 3-4 hr after taking active tablet: Take new active tablet (scheduled for next day) as soon as possible; if possible, take new tablet [wrap]within 12 hr of next scheduled dose
              • Missed >2 tablets: Follow advice above concerning missed tablets

            Storage

            Store at 20-25°C; excursion permitted to 15-30°C (50-86°F)

            Dispose unused medication via a take-back option if available

            Otherwise, follow FDA instructions for disposing medication in household trash, www.fda.gov/drugdisposal; do NOT flush down the toilet

            Previous
            Next:

            Images

            Previous
            Next:

            Formulary

            FormularyPatient Discounts

            Adding plans allows you to compare formulary status to other drugs in the same class.

            To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

            Adding plans allows you to:

            • View the formulary and any restrictions for each plan.
            • Manage and view all your plans together – even plans in different states.
            • Compare formulary status to other drugs in the same class.
            • Access your plan list on any device – mobile or desktop.

            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
            Additional Offers
            Email to Patient

            From:

            To:

            The recipient will receive more details and instructions to access this offer.

            By clicking send, you acknowledge that you have permission to email the recipient with this information.

            Email Forms to Patient

            From:

            To:

            The recipient will receive more details and instructions to access this offer.

            By clicking send, you acknowledge that you have permission to email the recipient with this information.

            Previous
            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.