Cyproterone Acetate + Ethinyl Estradiol

Approved Indications:

• Moderate to severe acne associated with androgen sensitivity (especially with seborrhea or inflammation)
• Hirsutism (excess facial and body hair in females due to androgen excess)
• Polycystic Ovary Syndrome (PCOS) with androgenic symptoms
• Oral contraception in women who require treatment for androgen-related conditions
• Seborrhea and androgenic alopecia (female pattern hair loss)

Clinically Accepted Off-label Uses:

• Premenstrual Dysphoric Disorder (PMDD)
• Endometriosis-related pain (used with caution)
• Hormonal regulation in transgender women (as antiandrogen component)

Note: This combination is not indicated solely for contraception unless associated with androgenic conditions.

Route of Administration: Oral

Adult Females:

• Standard Dose (Common Brand Formulation):
  Cyproterone Acetate 2 mg + Ethinyl Estradiol 35 mcg
  Take one tablet daily for 21 consecutive days, followed by a 7-day tablet-free interval. Repeat cycle every 28 days.

Acne/Hirsutism/PCOS:

• Use for several cycles (typically 3–6 months) for therapeutic benefit.
• Treatment may be extended based on severity and recurrence.

Contraceptive Effect: Begins after 7 consecutive days of use. Use additional contraception during the first 7 days.

Missed Dose:

• If missed within 12 hours, take as soon as remembered.
• If >12 hours late, follow missed pill protocol and use backup contraception.

Pediatrics:

• Not recommended before menarche or in those under 18 years without specialist guidance.

Elderly/Postmenopausal:

• Not indicated for use.

Renal/Hepatic Impairment:

• Hepatic impairment: Contraindicated in active liver disease.
• Renal impairment: Use with caution; no specific dose adjustment, but monitor electrolytes.

Cyproterone acetate is a synthetic antiandrogen and progestogen that competitively inhibits androgen receptors, blocking the effects of circulating androgens (e.g., testosterone, DHT) at target tissues such as sebaceous glands, hair follicles, and ovaries. It also suppresses gonadotropin secretion (LH), reducing ovarian androgen production. Ethinyl estradiol, a synthetic estrogen, provides negative feedback on the hypothalamic-pituitary axis, suppressing FSH release, thereby inhibiting follicular development and stabilizing the endometrium. Together, they reduce sebum production, prevent ovulation, and improve androgen-related conditions like acne and hirsutism.

Cyproterone Acetate:

• Absorption: Rapid and complete after oral administration
• Bioavailability: ~88%
• Peak Plasma Time: ~1.6 hours
• Distribution: High protein binding (~96% to albumin)
• Metabolism: Hepatic (CYP3A4-mediated)
• Half-life: ~39 hours
• Elimination: Primarily in feces (biliary excretion); ~15% in urine

Ethinyl Estradiol:

• Absorption: Rapid and well absorbed
• Bioavailability: ~45% (first-pass hepatic metabolism)
• Peak Plasma Time: 1–2 hours
• Distribution: Highly protein-bound (albumin and SHBG)
• Metabolism: Hepatic (CYP3A4); undergoes enterohepatic recycling
• Half-life: ~20 hours
• Elimination: Urine and feces (conjugated and unchanged)

• Pregnancy:
  Contraindicated during pregnancy. Both cyproterone and ethinyl estradiol can interfere with fetal development. No indication for use in pregnant women.
• Lactation:
  Contraindicated. Both components are excreted in breast milk and may reduce milk production and affect the infant (e.g., hormonal exposure). Use alternative non-hormonal contraception during breastfeeding.
• Recommendation:
  Ensure pregnancy is ruled out before initiating therapy. Avoid during lactation.

• Primary Class: Hormonal Therapy – Estrogen and Progestogen Combination
• Subclass: Combined Oral Contraceptive (Antiandrogenic)

• Known hypersensitivity to cyproterone acetate, ethinyl estradiol, or any excipients
• History of or current venous or arterial thromboembolism (e.g., DVT, PE, MI, stroke)
• Hereditary or acquired thrombophilia (e.g., Factor V Leiden, protein C/S deficiency)
• Migraine with aura
• Uncontrolled hypertension
• Diabetes with vascular complications
• Active or recent liver disease (e.g., hepatitis, hepatic adenoma, liver failure)
• Breast or estrogen-dependent cancers
• Pregnancy and lactation
• History of idiopathic jaundice or pruritus during pregnancy
• Unexplained vaginal bleeding

• Thromboembolic Risk: Increased risk of VTE and arterial thrombosis; avoid in smokers >35 years, obese women, and those with family history of thrombosis
• Liver Toxicity: Monitor liver enzymes; discontinue if significant elevation
• Breast and Cervical Cancer Risk: Long-term use may be associated with a slight increase in risk
• Mood Changes/Depression: Monitor patients with history of mood disorders
• Hypertension: Monitor blood pressure regularly
• Hyperkalemia: Cyproterone has anti-mineralocorticoid effects; monitor serum potassium, especially in renal impairment or with concurrent potassium-sparing drugs
• Chloasma (melasma): Avoid sun exposure in susceptible individuals

Common:

• Gastrointestinal: Nausea, abdominal pain
• Neurological: Headache, migraine
• Breast: Tenderness, enlargement
• Menstrual: Breakthrough bleeding, amenorrhea
• Dermatologic: Melasma, acne improvement, seborrhea reduction
• Weight gain, mood swings, libido changes

Serious:

• Venous thromboembolism (VTE): DVT, pulmonary embolism
• Arterial events: Stroke, myocardial infarction
• Liver disorders: Hepatitis, hepatic adenomas
• Gallbladder disease
• Depression, suicidal ideation (rare but reported)

Timing:

• Most side effects occur within the first few months; thrombotic risks persist as long as therapy continues

Enzyme Involvement:
Both components metabolized primarily by CYP3A4

Drugs that Decrease Efficacy:

• CYP3A4 inducers (↑ metabolism):
• Rifampin, carbamazepine, phenytoin, barbiturates, St. John’s Wort → may reduce contraceptive effect
• Antibiotics (e.g., ampicillin, tetracyclines): May reduce enterohepatic circulation of ethinyl estradiol

Drugs Affected by Estrogens/Progestins:

• May increase serum levels of cyclosporine, corticosteroids
• May decrease efficacy of lamotrigine
• May increase potassium with ACE inhibitors, ARBs, spironolactone

Alcohol and Tobacco:

• Smoking increases thromboembolic risk, especially in women >35 years

• EMA & WHO: Continued recommendation to limit use of cyproterone-containing products to patients with androgen-related conditions; not recommended solely as a contraceptive
• Risk minimization measures updated to emphasize VTE risk awareness
• Updated product labeling in some regions includes warnings about meningioma risk with prolonged high-dose cyproterone use (≥25 mg/day) – not applicable at contraceptive doses

• Temperature: Store below 25°C
• Humidity & Light: Store in original packaging; protect from moisture and direct sunlight
• Handling: No special precautions
• Shelf Life: Refer to individual manufacturer’s label; typically 24–36 months