Estradiol valerate/dienogest (Natazia): The first 4-phasic oral contraceptive tablets for the prevention of pregnancy

New Molecular Entity: Estradiol valerate/dienogest (Natazia) was approved in May 2010 for the prevention of pregnancy.

It is estimated that nearly 12 million women in the United States currently use oral contraceptives. Estradiol valerate and estradiol valerate/dienogest is a unique addition to the US market because it is a 4-phasic alternative (the doses of progestin and estrogen varying at 4 times throughout each 28-day treatment cycle) and because it contains an estrogen called estradiol valerate (a synthetic estrogen that is converted to estradiol in a woman's body). All previously marketed combination oral contraceptives contained ethinyl estradiol. Combination oral contraceptives lower the risk of becoming pregnant primarily by suppressing ovulation. However, other possible mechanisms may include cervical mucus changes that inhibit sperm penetration and endometrial changes that reduce the likelihood of implantation.

Efficacy. Estradiol valerate and estradiol valerate/dienogest was found to be an effective hormonal contraceptive in 2 multicenter, open-label, single-arm phase 3 clinical trials conducted in North America and Europe. Combined, the trials involved 1,867 women followed for nearly 30,000 28-day treatment cycles. The Pearl Index (PI) was the primary measure for assessing contraceptive reliability for 2 of the trials. The PI calculation was based on criteria established by FDA (pregnancies that occurred in women aged 18 to 35 years during cycles 1 to 13 including pregnancies 7 days post-treatment). In the North American study, 5 pregnancies occurred over 3,969 exposure cycles (PI=1.64; failure rate at the end of year 1 was 0.016). Similarly, 9 pregnancies occurred over 11,275 exposure cycles in the European trial (PI=1.04; failure rate at the end of year 1 was 0.010). The efficacy of estradiol valerate and estradiol valerate/dienogest in women with a body mass index >30 kg/m2 has not been evaluated.

Safety. Approximately 11% of women taking estradiol valerate and estradiol valerate/dienogest dropped out of the clinical trials because of an adverse reaction. The most common treatment-emergent adverse reactions (≥2%) were: headache (including migraines) (13.2%), metrorrhagia and irregular menstruation (8.0%), breast pain, discomfort, or tenderness (6.6%), nausea or vomiting (6.5%), acne (3.9%), and increased weight (2.8%). The most concerning adverse effects of estradiol valerate and estradiol valerate/dienogest (all combination oral contraceptives) are increased risks of venous and arterial thrombotic and thromboembolic events (such as myocardial infarction, thromboembolism, stroke), hepatic neoplasia, gallbladder disease, hypertension, ruptured ovarian cyst, and uterine leiomyoma. Consequently, estradiol valerate and estradiol valerate/dienogest should not be used in women with a high risk of arterial or venous thrombotic diseases, undiagnosed abnormal genital bleeding, breast cancer or other estrogen- or progestin-sensitive cancer, liver tumors (benign or malignant), or liver disease. The excess risk of thromboembolic events is highest during the first year of use. The risk also increases with age, particularly in women >35 years of age, and with the number of cigarettes smoked. For this reason, estradiol valerate and estradiol valerate/dienogest should not be used by women who are >35 years of age and smoke.