Rosen Plus

FDA-Approved Indications:

• Oral Contraceptive:
• Prevention of pregnancy in women of reproductive age.
• Premenstrual Dysphoric Disorder (PMDD):
• Treatment of PMDD in women opting to use oral contraceptives for birth control.
• Acne Vulgaris (Moderate):
• Treatment in females ≥14 years who have achieved menarche and desire contraception.
• Folate Supplementation:
• To provide folate support during contraceptive therapy for women of childbearing potential to reduce the risk of neural tube defects if pregnancy occurs.

Clinically Accepted Off-Label Uses:

• Polycystic Ovary Syndrome (PCOS):
• Used to regulate menstruation and manage acne/hirsutism in women requiring contraception.
• Menstrual Cycle Regulation:
• Useful in controlling dysmenorrhea and cycle irregularities.

Adults (Females of Reproductive Age):

• One tablet orally once daily for 28 consecutive days per cycle.
• Active tablets (Days 1–24): Contain drospirenone 3 mg + ethinyl estradiol 0.02 mg + levomefolate calcium 0.451 mg
• Inactive tablets (Days 25–28): Contain levomefolate calcium 0.451 mg only
• Start regimen on the first day of menstrual bleeding or on the first Sunday after menstruation begins.

Missed Dose Instructions:

• 1 missed tablet: Take as soon as remembered.
• ≥2 missed tablets: Follow package instructions; backup contraception may be needed for 7 days.

Pediatrics:

• Approved for postmenarchal females ≥14 years for acne treatment with contraceptive need.

Elderly:

• Not indicated for postmenopausal women.

Renal Impairment:

• Contraindicated in moderate to severe impairment (eGFR <50 mL/min) due to risk of hyperkalemia.

Hepatic Impairment:

• Contraindicated in hepatic dysfunction or hepatic tumors.

This fixed-dose combination prevents ovulation by suppressing the mid-cycle surge of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Drospirenone is a fourth-generation progestin with antiandrogenic and antimineralocorticoid activity, reducing sebum production and fluid retention. Ethinyl estradiol, a synthetic estrogen, stabilizes the endometrium and enhances progestin activity. Levomefolate calcium, the active form of folic acid, provides supplemental folate to reduce the risk of fetal neural tube defects if pregnancy occurs. Together, these components ensure effective contraception, hormonal regulation, and folate support.

• Absorption:
  Rapid and complete after oral administration.
  Time to peak levels: ~1–2 hours for drospirenone and ethinyl estradiol.
• Bioavailability:
• Drospirenone: ~76–85%
• Ethinyl Estradiol: ~38–48%
• Levomefolate Calcium: ~92%
• Distribution:
• Drospirenone: 95–97% protein-bound
• Ethinyl Estradiol: ~98% bound (to albumin and SHBG)
• Levomefolate: Well distributed to tissues and fetal circulation
• Metabolism:
• Drospirenone: Hepatic metabolism via non-CYP pathways
• Ethinyl Estradiol: CYP3A4 metabolism
• Levomefolate: Hepatic transformation to methylated folates
• Half-life:
• Drospirenone: ~30 hours
• Ethinyl Estradiol: ~24 hours
• Levomefolate: ~17 hours
• Excretion:
• Drospirenone: Primarily via urine and feces
• Ethinyl Estradiol: Biliary and urinary routes
• Levomefolate: Urinary excretion as metabolites

• Pregnancy:
  FDA Category X – Contraindicated during pregnancy. No benefit and potential fetal risk (though folate is protective).
• Lactation:
  Not recommended during early breastfeeding. Estrogen may reduce milk production. Small amounts of all components can be excreted into breast milk.

• Primary Class: Combined Oral Contraceptive (COC)
• Subclasses:
• Progestin: Drospirenone (4th generation, antimineralocorticoid, antiandrogenic)
• Estrogen: Ethinyl Estradiol (synthetic)
• Supplement: Levomefolate Calcium (active folate form)

• Known hypersensitivity to drospirenone, ethinyl estradiol, levomefolate, or excipients
• Pregnancy
• Renal impairment (moderate/severe)
• Hepatic impairment or liver tumors
• Adrenal insufficiency
• History of thromboembolic disorders (DVT, PE, stroke, MI)
• Breast or estrogen-sensitive cancer
• Uncontrolled hypertension
• Migraine with aura
• Smokers ≥35 years

• Thromboembolism Risk:
  Higher risk in women >35 who smoke or have other risk factors.
• Hyperkalemia Risk:
  Monitor potassium in patients using potassium-sparing medications or with renal impairment.
• Carcinoma Risk:
  Potential increased risk of breast and cervical cancers with prolonged use.
• Liver Disease:
  Discontinue if jaundice, elevated liver enzymes, or liver mass occurs.
• Mood and Neurological Effects:
  Monitor for depression, headache, and migraine (especially with aura).
• Folate Deficiency Masking:
  Levomefolate may mask vitamin B12 deficiency—evaluate as needed.

Common:

• Gastrointestinal: Nausea, vomiting, abdominal pain
• Neurological: Headache, mood changes, fatigue
• Reproductive: Breast tenderness, irregular bleeding, amenorrhea
• General: Weight change, bloating

Serious/Rare:

• Cardiovascular: DVT, PE, stroke, myocardial infarction
• Hepatic: Hepatitis, cholestasis, hepatic adenoma
• Endocrine: Hyperkalemia, adrenal suppression
• Allergic: Rash, hypersensitivity reactions
• Oncologic: Breast cancer, cervical cancer (long-term use)

• Potassium-Sparing Agents: (e.g., ACE inhibitors, spironolactone, NSAIDs)
  May increase hyperkalemia risk due to drospirenone.
• CYP3A4 Inducers: (e.g., rifampin, phenytoin, carbamazepine)
  May reduce ethinyl estradiol levels, lowering contraceptive effectiveness.
• CYP3A4 Inhibitors: (e.g., ketoconazole, erythromycin)
  May increase levels of ethinyl estradiol.
• Antibiotics:
  Rifampin affects hormone levels. Most others (e.g., amoxicillin) do not significantly impair contraceptive effect.
• Lamotrigine:
  Estrogens may reduce lamotrigine levels, increasing seizure risk.
• Thyroid Hormones:
  Estrogens can increase thyroid-binding globulin, altering thyroid hormone dose requirements.

• Folate-Integrated COC Endorsements:
  Recent clinical guidelines support inclusion of levomefolate to reduce neural tube defect risk if unintended pregnancy occurs.
• Labeling Emphasis:
  FDA and EMA highlight thromboembolic risk in specific patient groups (e.g., older smokers, migraine with aura).
• Contraceptive Formulations:
  Drospirenone-based COCs favored for women with acne, fluid retention, or PCOS.
• ACOG/NAMS Statements:
  Reinforce COC safety in healthy nonsmoking women <35, support folate supplementation in reproductive health.

• Temperature Range:
  Store at 20°C to 25°C (68°F to 77°F)
  Allowable excursion: 15°C to 30°C
• Humidity:
  Store in a dry place; avoid high humidity environments.
• Light Protection:
  Store in original blister pack away from direct light.
• Handling:
  Do not remove tablets until ready to take.
  Keep out of reach of children.
  Discard after expiration date.