Dosing and uses of Natazia (dienogest/estradiol valerate)
Adult dosage forms and strengths
tablet
- Contains 4 phases of doses for estrogen or combined estrogen/progestin throughout the 28-day cycle
- Days 1-2: estradiol valerate 3 mg
- Days 3-7: estradiol valerate 2 mg and dienogest 2 mg
- Days 8-24: estradiol valerate 2 mg and dienogest 3 mg
- Days 25-26: estradiol valerate 1 mg
- Days 27-28: inert tablets
Contraception
1 tab PO qDay; take at same time each day and in precise order as directed on blister pack
Do not skip tablets or delay intake by more than 12 hr
Initiate by beginning pack on day 1 of menstrual cycle and use nonhormonal contraceptive back-up method (eg, condoms and foam) during first 9 days
Initiating after pregnancy
- Increased risk for venous thromboembolism (VTE) following delivery with combined hormonal contraceptives; risk declines rapidly after 21 days, but does not return to normal until 42 days after delivery
- CDC guidelines recommend waiting 3-6 weeks in postpartum women without additional VTE risks (MMWR July 7, 2011)
- Initiating after vaginal birth: Wait at least 3 weeks
- Initiating after caesarean section birth: Wait at least 6 weeks
- Women with other risk factors for VTE in addition to postpartum: Do not use combined hormonal contraceptives
Pediatric dosage forms and strengths
tablet
- Contains 4 phases of doses for estrogen or combined estrogen/progestin throughout the 28-day cycle
- Days 1-2: estradiol valerate 3 mg
- Days 3-7: estradiol valerate 2 mg and dienogest 2 mg
- Days 8-24: estradiol valerate 2 mg and dienogest 3 mg
- Days 25-26: estradiol valerate 1 mg
- Days 27-28: inert tablets
Contraception
Safety and efficacy established in women of reproductive age; efficacy is expected to be the same for postpubertal adolescents under the age of 18 as for users 18 years and older
Adolescents requiring contraception: As adults
1 tab PO qDay; take at same time each day and in precise order as directed on blister pack
Do not skip tablets or delay intake by more than 12 hr
Initiate by beginning pack on day 1 of menstrual cycle and use nonhormonal contraceptive back-up method (eg, condoms and foam) during first 9 days
Initiating after pregnancy
- Increased risk for venous thromboembolism (VTE) following delivery with combined hormonal contraceptives; risk declines rapidly after 21 days, but does not return to normal until 42 days after delivery
- CDC guidelines recommend waiting 3-6 weeks in postpartum women without additional VTE risks (MMWR July 7, 2011)
- Initiating after vaginal birth: Wait at least 3 weeks
- Initiating after caesarean section birth: Wait at least 6 weeks
- Women with other risk factors for VTE in addition to postpartum: Do not use combined hormonal contraceptives
Natazia (dienogest/estradiol valerate) adverse (side) effects
>10%
Headache, including migraines (13.2%)
1-10%
Metrorrhagia and irregular menstruation (8%)
Breast pain, discomfort, or tenderness (6.6%)
Nausea or vomiting (6.5%)
Acne (3.9%)
Weight gain (2.85)
<1%
Venous thromboembolism
Jaundice or cholestasis
Gallbladder disease
Depression
Warnings
Black box warnings
Cigarette smoking
- Cigarette smoking increases risk of serious cardiovascular adverse effects from combination hormonal contraceptive use
- This risk increases with age (>35 yr) and heavy smoking (15 or more cigarettes/day)
- Advise women who use hormonal oral contraceptives not to smoke
Contraindications
Pregnancy
Hypersensitivity
Breast Cancer, or other estrogen- or progestin-sensitive cancer
A high risk of arterial or venous thromboembolic disorders
Undiagnosed uterine bleeding
Cautions
Poorly metabolized with hepatic impairment
Use caution in patients with history of migraine, seizure disorder,
Not recommended for women smokers >35 years
Oral contraceptives can reduce production of milk in breastfeeding mothers
Evaluate significant change in headaches and discontinue therapy if indicated
Women taking strong CYP3A4 inducers (for example, carbamazepine, phenytoin, rifampicin, and St. John’s wort) should choose an alternate oral contraceptive due to the possibility of decreased contraceptive efficacy
Discontinue therapy if jaundice occurs
Not for administration for women with uncontrolled hypertension or hypertension with vascular disease
Monitor prediabetic and diabetic women receiving therapy
Consider an alternate contraceptive method for women with uncontrolled dyslipidemia
Evaluate uterine bleeding or amenorrhea
Thromboembolic disease may occur; stop therapy for at least 4 weeks before and through 2 weeks after major surgery; initiate therapy no sooner than 4 weeks after delivery, in women who are not breastfeeding
Safety and efficacy not established for BMI >30 kg/m²
CDC guidelines recommend waiting at least 3 weeks following vaginal birth or 6 weeks after cesarean section to decrease risk for venous thromboembolism before initiating combined hormonal contraceptives; women with additional risk factors for VTE (besides postpartum) should not use combined hormonal contraceptives (MMWR July 7, 2011)
Pregnancy and lactation
Pregnancy considerations: There is little or no increased risk of birth defects in women who inadvertently use combined oral contraceptives (COCs) during early pregnancy; epidemiologic studies and meta-analyses have not found increased risk of genital or non-genital birth defects following exposure to low dose COCs prior to conception or during early pregnancy; the administration of COCs to induce withdrawal bleeding should not be used as a test for pregnancy; COCs should not be used during pregnancy to treat threatened or habitual abortion; women who do not breastfeed may start COCs no earlier than four weeks postpartum.
Lactation: May decrease breast milk production; enters milk; not recommended
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.
Pharmacology of Natazia (dienogest/estradiol valerate)
Mechanism of action
Estrogen/progestin combined oral contraceptive; decreases risk of becoming pregnant primarily by suppressing ovulation May also cause cervical mucus changes that inhibit sperm penetration and endometrial changes that decrease ability for implantation
Pharmaockinetics
Bioavailability: 91% (dienogest)
Vd: 1.2 L/kg (estradiol IV)
Peak Plasma Time: 6 hr (17-beta estradiol); 11 hr (dienogest)
Peak Plasma Concentration: 73.3 pg/mL (17-beta estradiol); 91.7 ng/mL (dienogest)
Protein Bound: 60% (estradiol); 90% (dienogest)
Half-life elimination
- estradiol: 14 hr
- dienogest: 1 hr
Excretion
- estradiol and its metabolites: feces (10%), urine (90%)
- dienogest: predominantly via urine as metabolites and unchanged dienogest
