Dienogest + Estradiol Valerate

A. Approved Indications

• Hormonal Contraception
• Prevention of pregnancy through combined estrogen-progestin oral contraceptive
• Treatment of Moderate to Severe Acne Vulgaris (in women seeking contraception)
• Management of Endometriosis (symptom control and lesion suppression)
• Menstrual Disorders
• Regulation of menstrual cycles
• Treatment of dysmenorrhea

B. Clinically Accepted Off-label Uses

• Hormone replacement therapy (in select cases)
• Treatment of heavy menstrual bleeding (idiopathic or related to endometriosis)

Route: Oral

Adults:

• One tablet daily, taken at the same time every day, preferably with food
• Typical dose contains 2 mg dienogest + 1–3 mg estradiol valerate depending on formulation
• Taken continuously for 21 days followed by 7-day tablet-free interval (or as per specific brand instructions)
• Treatment duration varies based on indication (contraception usually long-term; endometriosis treatment typically 3–6 months)

Pediatrics:

• Not recommended for use before menarche or in adolescents without specialist supervision

Elderly:

• Not indicated for postmenopausal women

Renal/Hepatic Impairment:

• Use with caution in hepatic impairment; contraindicated in severe hepatic dysfunction
• No specific dosage adjustment for renal impairment

Dienogest + Estradiol Valerate combines a selective progestin (dienogest) and a natural estrogen (estradiol valerate) to provide effective hormonal contraception and therapeutic benefits. Estradiol valerate mimics endogenous estradiol, regulating the menstrual cycle by suppressing follicle-stimulating hormone (FSH) release, preventing follicular development. Dienogest binds selectively to progesterone receptors, exerting anti-gonadotropic effects, suppressing luteinizing hormone (LH) surge, and inducing endometrial atrophy. This combined effect inhibits ovulation, thickens cervical mucus to prevent sperm penetration, alters tubal motility, and creates a less receptive endometrial lining, resulting in contraception and reduced endometriotic lesion activity.

• Absorption: Both components are well absorbed orally
• Estradiol Valerate:
• Rapidly hydrolyzed to estradiol after absorption
• Peak plasma concentration within 1–2 hours
• Dienogest:
• Peak plasma concentration ~1.5 hours post-dose
• Bioavailability: Estradiol ~5–10% (due to first-pass metabolism), Dienogest ~91%
• Protein Binding: Estradiol binds mainly to SHBG and albumin; dienogest binds mostly to albumin
• Metabolism:
• Estradiol valerate metabolized in liver to estradiol and estrone
• Dienogest metabolized by CYP3A4 to inactive metabolites
• Half-life:
• Estradiol: ~13–20 hours (varies by metabolite)
• Dienogest: ~9–10 hours
• Elimination: Primarily renal as metabolites, some fecal excretion

• Pregnancy:
• Contraindicated in pregnancy; should not be used if pregnancy is confirmed or suspected
• Lactation:
• May reduce milk production
• Estradiol and dienogest are excreted in breast milk in small amounts
• Use not recommended during breastfeeding

• Primary Class: Combined hormonal contraceptive (estrogen + progestin)
• Subclass: 19-nortestosterone derivative (dienogest) + natural estrogen (estradiol valerate)

• Known hypersensitivity to dienogest, estradiol valerate, or excipients
• History or current venous thromboembolism or thrombophlebitis
• Arterial thromboembolism (e.g., stroke, myocardial infarction)
• Severe hepatic impairment or liver tumors
• Hormone-dependent malignancies (e.g., breast or endometrial cancer)
• Undiagnosed vaginal bleeding
• Pregnancy or suspected pregnancy

• Increased risk of thromboembolic events, particularly in smokers and women over 35
• Monitor blood pressure during treatment
• Use cautiously in patients with migraine, especially with aura
• May cause mood changes and depression
• Caution in patients with liver disease or history of hormone-sensitive tumors
• Regular clinical evaluation recommended for long-term users
• Breakthrough bleeding or spotting may occur initially

Common:

• Nausea
• Headache
• Breast tenderness or enlargement
• Irregular bleeding or spotting
• Mood swings or depression
• Weight changes

Less Common:

• Acne or oily skin
• Abdominal pain
• Decreased libido
• Fluid retention

Serious/Rare:

• Venous or arterial thromboembolism
• Hypertension
• Liver dysfunction
• Allergic reactions

• CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin): May reduce contraceptive efficacy
• CYP3A4 inhibitors (e.g., ketoconazole, erythromycin): May increase hormone levels
• Antibiotics (e.g., broad-spectrum): Potential decreased efficacy, though evidence is limited
• St. John’s Wort: May reduce effectiveness
• Other hormonal medications: Potential interactions affecting efficacy and side effects

• Increasing preference for estradiol valerate over ethinylestradiol in contraceptives due to better metabolic and cardiovascular profile
• EMA and FDA recommend caution in prescribing hormonal contraceptives to women with cardiovascular risk factors
• Newer guidelines suggest monitoring mood and mental health during treatment
• Updates emphasize individual risk assessment for thromboembolism before initiation

• Store at 20°C to 25°C (68°F to 77°F)
• Protect from moisture and light
• Keep in original packaging until use
• Keep out of reach of children