Clinical Context

Natazia is a combination oral contraceptive (COC) consisting of estradiol valerate and estradiol valerate/dienogest. The US Food and Drug Administration (FDA) first approved Natazia in May 2010 to prevent pregnancy. On March 14, 2012, the FDA also approved Natazia to treat heavy menstrual bleeding (HMB), making it the first and only OC indicated for this purpose.

Approval was based on findings from 2 multicenter, randomized, double-blind, placebo-controlled clinical trials.

Study Synopsis and Perspective

Estradiol valerate and estradiol valerate/dienogest (Natazia, Bayer HealthCare Pharmaceuticals Inc) oral contraceptive tablets were approved March 14 for the treatment of HMB.

According to a company press release, this agent is the first and only oral contraceptive indicated for the treatment of HMB.

The drug was approved in May 2010 for the prevention of pregnancy. The current approval was based on results from 2 multicenter, randomized, double-blind, placebo-controlled clinical trials including 421 women.

Women in the study were at least 18 years old and were diagnosed with dysfunctional uterine bleeding, described as heavy, prolonged and/or frequent, and without organic pathology. HMB was defined as "menstrual blood loss of 80 mL or more in at least 2 bleeding episodes during a 90-day run in phase."

Patients were randomly assigned to receive either treatment or placebo for 7 menstrual cycles. Complete symptom relief during a 90-day efficacy assessment phase was reported in 29.2% and 29.5% of the treatment groups in each study compared with 2.9% and 1.2% of the placebo groups, respectively.

Overall, there was a significant reduction in blood loss for those with HMB in the treatment groups compared with those in the placebo groups (P < .0001 for both studies).

The most common adverse effects associated with treatment, present in at least 2% of treated patients, were headache/migraine, breast pain/discomfort/tenderness, menstrual disorders, nausea or vomiting, acne, mood changes, and weight gain.

Although the drug was approved for pregnancy prevention in May 2010, the contraceptive efficacy of Natazia has not been determined in women with a body mass index (BMI) greater than 30 kg/m².

"Heavy menstrual bleeding is a common disorder reported by around three million women of reproductive age each year in the United States," Pamela A. Cyrus, MD, vice president and head of US Medical Affairs, Bayer HealthCare Pharmaceuticals, noted in a news release. "As the first oral contraceptive treatment approved for heavy menstrual bleeding in women without organic pathology who choose an OC for contraception, Natazia represents a new treatment approach for appropriate women with this medical condition."

Updates to Warnings and Precautions

As of February 2012, the prescribing information was updated regarding a new warning for thromboembolic disorders and other vascular problems. If an arterial or venous thrombotic event (VTE) occurs, women should stop taking Natazia. Although pregnancy is associated with an increased risk for VTE comparable to or greater than that associated with COC use, the risk for VTE in women using COCs is approximately 3 to 9 per 10,000 woman-years. The risk for VTE is highest during the first year of use, particularly during the first 6 months, and after initially starting a COC or restarting the same or a different COC after at least a 4-week interval without using COCs.

The risks for stroke, myocardial infarction, and other arterial thromboses are also increased with COC use, particularly in women with other risk factors. After COC use is discontinued, the effect on thromboembolic disease risk gradually disappears. Natazia should be held, if feasible, starting at least 4 weeks before and through 2 weeks after major surgery or other procedures associated with an increased risk for thromboembolism.

In women who are not breast-feeding, Natazia should be started no sooner than 4 weeks postpartum. After the third postpartum week, the risk for postpartum thromboembolism decreases, but the risk for ovulation increases.

Thromboembolic risk, as well as the risk for hemorrhagic stroke, associated with COC use is greatest among women smokers older than 35 years who have hypertension. COCs are also associated with increased stroke risk in women with other underlying risk factors and must be used with caution in women with risk factors for cardiovascular disease. Women in whom unexplained loss of vision, proptosis, double vision, papilledema, or retinal vascular lesions develop while taking Natazia should stop the drug and be immediately examined for possible retinal vein thrombosis.

Previous Boxed Warnings and Precautions

A previous boxed warning notes that smokers older than 35 years should not use Natazia, as cigarette smoking is associated with an increased risk for serious cardiovascular events from COC use.

Women in whom jaundice develops while taking Natazia should stop the drug. Women with uncontrolled hypertension or hypertension with vascular disease should not take Natazia, and those with prediabetes and diabetes should be monitored while taking the drug. Another contraceptive method should be considered for women with uncontrolled dyslipidemia.

Women who experience a significant change in headaches, irregular bleeding, or amenorrhea while taking Natazia should be assessed and the drug discontinued if indicated.

Strong cytochrome P450 3A4 inducers, such as carbamazepine, phenytoin, rifampicin, and St. John's wort may reduce the contraceptive efficacy of Natazia, and another contraceptive should be used in these women.

Use in Special Populations

Natazia may reduce milk production and is therefore not recommended in breast-feeding mothers.

In women with a BMI exceeding 30 kg/m

More information on Natazia is available on the FDA Web site.

Clinical Implications

• The FDA has approved Natazia for treatment of HMB. Two randomized trials in women with dysfunctional uterine bleeding showed a significant reduction in blood loss for those with HMB in the treatment groups, compared with those in the placebo groups.
• Prescribing information for Natazia was updated regarding a new warning for thromboembolic disorders and other vascular problems. If arterial thrombosis or VTE occurs, women should stop taking Natazia. The risk for VTE is highest during the first year of use, particularly during the first 6 months. Thromboembolic risk, as well as the risk for hemorrhagic stroke, associated with COC use is greatest among women smokers older than 35 years who have hypertension.
• A previous boxed warning notes that smokers older than 35 years should not use Natazia because of an increased risk for serious cardiovascular events from COC use. Women in whom jaundice develops while taking Natazia should stop the drug, and women with uncontrolled hypertension or hypertension with vascular disease should not take Natazia. Those with prediabetes and diabetes should be monitored while taking Natazia.

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