Drospirenone + Estradiol

FDA-Approved Indications:

• Menopausal Hormone Therapy:
• Treatment of moderate to severe vasomotor symptoms due to menopause (e.g., hot flashes).
• Prevention of postmenopausal osteoporosis in women at significant risk.
• Contraception: (Specific formulations only)
• Certain low-dose combinations of drospirenone and estradiol (e.g., 4 mg DRSP + 1 mg E2) are used in fixed-dose oral contraceptives for women who need contraception and hormone replacement.

Off-Label and Clinically Accepted Uses:

• Premature Ovarian Insufficiency:
• Used for estrogen replacement in younger women with hypoestrogenism.
• Postmenopausal Urogenital Symptoms:
• May relieve vulvovaginal atrophy when systemic therapy is needed.
• Polycystic Ovary Syndrome (PCOS):
• Employed to regulate menstruation and counter androgenic effects in select cases requiring estrogen.

Adults (Postmenopausal Women):

• Vasomotor Symptoms/Osteoporosis Prevention:
  Drospirenone 2 mg + Estradiol 1 mg orally once daily.
• Alternative Regimens:
  May also be available as continuous-combined regimens (28 tablets per cycle, no interruption).

Contraceptive Use (if formulation indicated):

• Fixed-dose regimens, e.g., Drospirenone 4 mg + Estradiol 1 mg
  One tablet daily for 28-day cycle (24 active + 4 placebo tablets)

Pediatrics:

• Not recommended in children or adolescents; only for postmenopausal or adult reproductive-aged women under specific indications.

Elderly:

• Use with caution; consider cardiovascular, thrombotic, and breast cancer risks.

Renal Impairment:

• Contraindicated in moderate to severe renal dysfunction due to potassium retention risk.

Hepatic Impairment:

• Contraindicated in hepatic disease or impaired liver function.

Drospirenone is a synthetic progestin derived from spironolactone with anti-mineralocorticoid and antiandrogenic properties. Estradiol is a bioidentical form of endogenous estrogen. Together, they act on estrogen and progesterone receptors in target tissues to regulate gene transcription. In menopausal therapy, estradiol replenishes deficient estrogen, alleviating vasomotor symptoms and reducing bone resorption. Drospirenone opposes estrogen’s effects on the endometrium, minimizing the risk of hyperplasia and providing cycle control. Additionally, drospirenone’s aldosterone antagonism helps mitigate fluid retention and hypertension.

• Absorption:
  Rapid and complete after oral administration.
• Time to peak plasma concentration: 1–2 hours for both components.
• Bioavailability:
• Drospirenone: ~76–85%
• Estradiol: Subject to first-pass metabolism; oral bioavailability ~5%–10%
• Distribution:
• Both are highly protein-bound:
• Drospirenone to albumin (~95–97%)
• Estradiol to albumin and sex hormone-binding globulin (SHBG)
• Metabolism:
• Drospirenone: Non-CYP mediated hepatic metabolism
• Estradiol: Primarily metabolized via CYP3A4 and conjugation pathways (sulfation/glucuronidation)
• Elimination Half-life:
• Drospirenone: ~30 hours
• Estradiol: 13–27 hours (varies by formulation)
• Excretion:
• Primarily via urine and feces, as inactive metabolites.

• Pregnancy:
  FDA Category X – Contraindicated in pregnancy.
  Not indicated in pregnant women due to no benefit and potential risk to fetal development.
• Lactation:
• Not recommended.
  Both hormones are excreted into breast milk in small amounts and may affect milk production and infant development.

• Primary Class:
• Estrogen-Progestin Combination Hormone Therapy
• Subclasses:
• Estrogen: Bioidentical estradiol
• Progestin: Spironolactone-derived drospirenone (4th generation)

• Known hypersensitivity to drospirenone, estradiol, or excipients
• Active or history of thromboembolic disorders (DVT, PE)
• Arterial thrombotic events (e.g., stroke, myocardial infarction)
• Breast cancer or other estrogen/progestin-sensitive tumors
• Undiagnosed abnormal uterine bleeding
• Liver dysfunction or hepatic tumors
• Known or suspected pregnancy
• Renal impairment (moderate to severe)
• Adrenal insufficiency
• Smoking in women over 35 (if used for contraception)

• Cardiovascular Risk:
  Increased risk of stroke, MI, and VTE, particularly in smokers or older women.
• Breast & Endometrial Cancer:
  Use may increase risk, especially with prolonged exposure. Drospirenone reduces but does not eliminate endometrial risk.
• Hyperkalemia:
  Drospirenone can elevate potassium levels, especially in patients taking potassium-sparing drugs. Monitor serum potassium if needed.
• Dementia Risk:
  Estrogen-containing therapies may increase dementia risk in postmenopausal women ≥65 years.
• Liver Injury:
  Discontinue if jaundice or liver dysfunction occurs.
• Visual Disturbances or Migraine with Aura:
  May signal thrombotic events; discontinue immediately.

Common:

• Gastrointestinal: Nausea, abdominal pain, bloating
• Reproductive: Breast tenderness, breakthrough bleeding, amenorrhea
• Neurological: Headache, mood changes, dizziness
• General: Fatigue, weight changes, fluid retention

Serious/Rare:

• Cardiovascular: VTE, PE, stroke, hypertension
• Endocrine/Metabolic: Hyperkalemia, adrenal suppression
• Hepatic: Elevated liver enzymes, cholestasis, hepatic adenomas
• Oncologic: Breast or endometrial cancer (long-term risk)
• Allergic: Anaphylaxis, angioedema (rare)

• Potassium-Retaining Agents (e.g., ACE inhibitors, ARBs, NSAIDs, Spironolactone):
  May increase risk of hyperkalemia.
• CYP3A4 Inducers (e.g., rifampin, phenytoin, carbamazepine):
  May reduce estradiol effectiveness by accelerating metabolism.
• CYP3A4 Inhibitors (e.g., ketoconazole, clarithromycin):
  May increase estradiol plasma levels.
• Thyroid Hormones:
  Estrogen may increase thyroid-binding globulin, requiring thyroid dose adjustment.
• Anticoagulants (e.g., warfarin):
  Estrogen may reduce anticoagulant effect; monitor INR.

• FDA Updates (Recent Years):
  Labeling changes include reinforcement of risks for thromboembolic and cardiovascular events in hormone replacement therapies.
• Clinical Guidelines (NAMS, NICE):
• Indicated for shortest duration at lowest effective dose for menopausal symptoms.
• Not recommended for chronic disease prevention (e.g., CVD, dementia).
• Use individualized based on symptom severity and patient risk profile.
• New Formulations Approved:
  Several newer lower-dose formulations aim to minimize estrogen-associated risks while maintaining efficacy.

• Temperature:
  Store at 20°C to 25°C (68°F to 77°F).
  Allowable range: 15°C to 30°C.
• Humidity:
  Store in a dry environment; avoid exposure to moisture.
• Light Protection:
  Protect from light; store in original blister packaging until use.
• Handling Precautions:
  Keep out of reach of children.
  Do not use if tablets are discolored or packaging is damaged.