estetrol/drospirenone (Rx)

>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

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

Breast cancer

• Epidemiology studies have not found a consistent association between use of combined oral contraceptives (COCs) and breast cancer risk; studies do not show an association between ever (current or past) use of COCs and risk of breast cancer
• Some studies report a small increase in risk of breast cancer among current or recent users(<6 months since last use) and current users with longer duration of COC use
• A woman's risk depends on conditions where naturally high hormone levels persist for long periods of time including early-onset menstruation before age 12, late-onset menopause, after age 55, first child after age 30, nulliparity

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

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.

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%)

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