1.1 Oral Contraception

Estradiol Valerate and Estradiol Valerate/Dienogest is indicated for use by women to prevent pregnancy.

The efficacy of Estradiol Valerate and Estradiol Valerate/Dienogest in women with a body mass index (BMI) of > 30 kg/m2 has not been evaluated.

1.2 Heavy Menstrual Bleeding

Estradiol Valerate and Estradiol Valerate/Dienogest is also indicated for the treatment of heavy menstrual bleeding in women without organic pathology who choose to use an oral contraceptive as their method of contraception [see Clinical Studies (14.2)].

2.1 How to Take Estradiol Valerate and Estradiol Valerate/Dienogest

To achieve maximum contraceptive effectiveness, Estradiol Valerate and Estradiol Valerate/Dienogest must be taken exactly as directed. Take one tablet by mouth at the same time every day. Tablets must be taken in the order directed on the blister pack. Tablets should not be skipped or intake delayed by more than 12 hours. For patient instructions for missed pills, see FDA-Approved Patient Labeling.

2.2 How to Start Estradiol Valerate and Estradiol Valerate/Dienogest

Instruct the patient to begin taking Estradiol Valerate and Estradiol Valerate/Dienogest on Day 1 of her menstrual cycle (that is, the first day of her menstrual bleeding). See FDA-Approved Patient Labeling. Instruct the patient to use a non-hormonal contraceptive as back-up during the first 9 days.

For postpartum women who do not breastfeed or after a second trimester abortion, start Estradiol Valerate and Estradiol Valerate/Dienogest no earlier than 4 weeks postpartum due to the increased risk of thromboembolism. If the patient starts on Estradiol Valerate and Estradiol Valerate/Dienogest postpartum and has not yet had a period, evaluate for possible pregnancy, and instruct her to use an additional method of contraception until she has taken Estradiol Valerate and Estradiol Valerate/Dienogest for 9 consecutive days. The possibility of ovulation and conception prior to initiation of medication should also be considered.

If the patient is switching from a combination hormonal method such as a:

 

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Another pill

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Vaginal ring

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Patch

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Instruct her to take the first dark yellow pill on the first day of her withdrawal bleed. She should not continue taking the pills from her previous birth control pack. If she does not have a withdrawal bleed, rule out pregnancy before starting Estradiol Valerate and Estradiol Valerate/Dienogest.

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If she previously used a vaginal ring or transdermal patch, she should start using Estradiol Valerate and Estradiol Valerate/Dienogest on the day the ring or patch is removed.

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Instruct the patient to use a non-hormonal back-up method such as a condom or spermicide for the first 9 days.

If the patient is switching from a progestin-only method such as a:

 

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Progestin-only pill

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Implant

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Intrauterine system

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Injection

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Instruct her to take the first dark yellow pill on the day she would have taken her next progestin-only pill or on the day of removal of her implant or intrauterine system or on the day when she would have had her next injection.

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Instruct the patient to use a non-hormonal back-up method such as a condom or spermicide for the first 9 days.

2.3 Advice in Case of Gastrointestinal Disturbances

In case of severe vomiting or diarrhea, absorption may not be complete and additional contraceptive measures should be taken. If vomiting or diarrhea occurs within 3-4 hours after taking a colored tablet, this can be regarded as a missed tablet.

5.1 Thromboembolic Disorders and Other Vascular Problems

Stop Estradiol Valerate and Estradiol Valerate/Dienogest if an arterial or venous thrombotic event (VTE) occurs.

The use of COCs increases the risk of venous thromboembolism. However, pregnancy increases the risk of venous thromboembolism as much or more than the use of COCs. The risk of VTE in women using COCs has been estimated to be 3 to 9 per 10,000 woman-years. The risk of VTE is highest during the first year of use. Data from a large, prospective cohort safety study of various COCs suggest that this increased risk, as compared to that in non-COC users, is greatest during the first 6 months of COC use. Data from this safety study indicate that the greatest risk of VTE is present after initially starting a COC or restarting (following a 4 week or greater pill-free interval) the same or a different COC.

Use of COCs also increases the risk of arterial thromboses such as strokes and myocardial infarctions, especially in women with other risk factors for these events.

The risk of thromboembolic disease due to oral contraceptives gradually disappears after COC use is discontinued.

If feasible, stop Estradiol Valerate and Estradiol Valerate/Dienogest at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism.

Start Estradiol Valerate and Estradiol Valerate/Dienogest no earlier than 4 weeks after delivery, in women who are not breastfeeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week.

COCs have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years of age), hypertensive women who also smoke. COCs also increase the risk for stroke in women with other underlying risk factors.

Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.

Stop Estradiol Valerate and Estradiol Valerate/Dienogest if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately. [See Adverse Reactions (6).]

5.2 Carcinoma of the Breasts and Reproductive Organs

Women who currently have or have had breast cancer should not use Estradiol Valerate and Estradiol Valerate/Dienogest because breast cancer is a hormonally-sensitive tumor.

There is substantial evidence that COCs do not increase the incidence of breast cancer. Although some past studies have suggested that COCs might increase the incidence of breast cancer, more recent studies have not confirmed such findings.

Some studies suggest that COCs are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there is controversy about the extent to which these findings may be due to differences in sexual behavior and other factors.

Endometrial biopsies performed in a subset of subjects in a Phase 3 Estradiol Valerate and Estradiol Valerate/Dienogest clinical trial did not reveal any unexpected or concerning findings for subjects taking COCs. [See Adverse Reactions (6.1).]

5.3 Liver Disease

Discontinue Estradiol Valerate and Estradiol Valerate/Dienogest if jaundice develops. Steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded.

Hepatic adenomas are associated with COC use. An estimate of the attributable risk is 3.3 cases/100,000 COC users. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage.

Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (> 8 years) COC users. However, the attributable risk of liver cancers in COC users is less than one case per million users.

Oral contraceptive-related cholestasis may occur in women with a history of pregnancy-related cholestasis. Women with a history of COC-related cholestasis may have the condition recur with subsequent COC use.

5.4 High Blood Pressure

For women with well-controlled hypertension, monitor blood pressure and stop Estradiol Valerate and Estradiol Valerate/Dienogest if blood pressure rises significantly. Women with uncontrolled hypertension or hypertension with vascular disease should not use COCs.

An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women and with extended duration of use. The incidence of hypertension increases with increasing concentration of progestin.

5.5 Gallbladder Disease

Studies suggest a small increased relative risk of developing gallbladder disease among COC users.

5.6 Carbohydrate and Lipid Metabolic Effects

Carefully monitor prediabetic and diabetic women who are taking Estradiol Valerate and Estradiol Valerate/Dienogest. COCs may decrease glucose tolerance in a dose-related fashion.

Consider alternative contraception for women with uncontrolled dyslipidemia. A small proportion of women will have adverse lipid changes while on COCs.

Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs.

5.7 Headache

If a woman taking Estradiol Valerate and Estradiol Valerate/Dienogest develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue Estradiol Valerate and Estradiol Valerate/Dienogest if indicated.

An increase in frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of the COC.

5.8 Bleeding Irregularities

Breakthrough bleeding and spotting sometimes occur in patients on COCs, especially during the first three months of use. If bleeding persists or occurs after previously regular cycles, check for causes such as pregnancy or malignancy. If pathology and pregnancy are excluded, bleeding irregularities may resolve over time or with a change to a different COC.

Women who are not pregnant and use Estradiol Valerate and Estradiol Valerate/Dienogest, may experience amenorrhea. Based on patient diaries, amenorrhea occurs in approximately 16% of cycles in women using Estradiol Valerate and Estradiol Valerate/Dienogest. Pregnancy should be ruled out in the event of amenorrhea occurring in two or more consecutive cycles. Some women may encounter amenorrhea or oligomenorrhea after stopping COCs, especially when such a condition was pre-existent.

Based on patient diaries from three clinical trials evaluating the safety and efficacy of Estradiol Valerate and Estradiol Valerate/Dienogest for contraception, 10-23% of women experienced intracyclic bleeding per cycle.

5.9 COC Use Before or During Early Pregnancy

Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb-reduction defects are concerned, when taken inadvertently during early pregnancy. Oral contraceptive use should be discontinued if pregnancy is confirmed.

The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy [see Use in Specific Populations (8.1)].

5.10 Depression

Women with a history of depression should be carefully observed and Estradiol Valerate and Estradiol Valerate/Dienogest discontinued if depression recurs to a serious degree.

5.11 Interference with Laboratory Tests

The use of COCs may change the results of some laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentrations of thyroid-binding globulin increase with use of COCs [see Drug Interactions (7.2)].

5.12 Monitoring

A woman who is taking COCs should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated healthcare.

5.13 Drug Interactions

Women who take medications that are strong cytochrome P450 3A4 (CYP3A4) inducers (for example, carbamazepine, phenytoin, rifampicin, and St. John’s wort) should not choose Estradiol Valerate and Estradiol Valerate/Dienogest as their oral contraceptive while using these inducers and for at least 28 days after discontinuation of these inducers due to the possibility of decreased contraceptive efficacy. [See Drug Interactions (7.1) and Clinical Pharmacology (12.3).]

5.14 Other Conditions

In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while taking COCs.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Estradiol Valerate and Estradiol Valerate/Dienogest. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Vascular disorders: Venous and arterial thromboembolic events (including pulmonary emboli, deep vein thrombosis, cerebral thrombosis, myocardial infarction and stroke), hypertension

Hepatobiliary disorders: Gallbladder disease, hepatitis

Immune system disorders: Hypersensitivity

Metabolism and nutrition disorders: Fluid retention, hypertriglyceridemia

Nervous system disorders: Dizziness

Skin and subcutaneous tissue disorders: Chloasma, angioedema, erythema nodosum, erythema multiforme

Gastrointestinal disorders: Gastrointestinal symptoms (for example, abdominal pain)

Infections and infestations: Vulvovaginal candidiasis

7.1 Effects of Other Drugs on Combined Oral Contraceptives

Interactions between oral contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive failure. The following interactions have been reported in the literature for COCs in general or were studied in clinical trials with Estradiol Valerate and Estradiol Valerate/Dienogest.

CYP3A4 Inducers: Drugs or herbal products that induce certain enzymes, including CYP3A4, may decrease the effectiveness of COCs or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include barbiturates, bosentan, felbamate, griseofulvin, oxcarbazepine, and topiramate. Counsel women to use an alternative method of contraception or a back-up method when moderate or weak enzyme inducers are used with COCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability.

Dienogest is a substrate of CYP3A4. Women who take medications that are strong CYP3A4 inducers (for example, carbamazepine, phenytoin, rifampicin, and St. John’s wort) should not choose Estradiol Valerate and Estradiol Valerate/Dienogest as their oral contraceptive while using these inducers and for at least 28 days after discontinuation of these inducers due to the possibility of decreased contraceptive efficacy.

The effect of the CYP3A4 inducer rifampicin was studied in healthy postmenopausal women. Co-administration of rifampicin with estradiol valerate/dienogest tablets led to a 52 % and 83% decrease in the mean Cmax and AUC (0–24hr), respectively, for dienogest and a 25% and 44% decrease in Cmax and AUC (0–24hr), respectively, for estradiol at steady state.

Strong CYP3A4 Inhibitors: Strong CYP3A4 inhibitors such as ketoconazole increased hormone serum concentrations. In a study investigating the effect of ketoconazole on dienogest and estradiol pharmacokinetics, co-administration with the strong CYP3A4 inhibitor ketoconazole resulted in a 186% increase of AUC (0–24hr) at steady state for dienogest and a 57% increase for estradiol. There was also a 94% and 65% increase of Cmax at steady state for dienogest and estradiol when co-administered with ketoconazole.

Moderate CYP3A4 Inhibitors: The AUC (0–24hr) of dienogest and estradiol at steady state were increased by 62% and 33%, respectively, when co-administered with a moderate CYP3A4 inhibitor, erythromycin. There was also a 33% and 51% increase of Cmax at steady state for dienogest and estradiol, respectively, when co-administered with erythromycin.

Other known CYP3A4 inhibitors like azole antifungals, cimetidine, verapamil, macrolides, diltiazem, antidepressants, and grapefruit juice may increase plasma concentrations of dienogest.

Human Immunodeficiency Virus (HIV)/Hepatitis C Virus (HCV) Protease Inhibitors and Non-Nucleoside Reverse Transcriptase Inhibitors: Significant changes (increase and decrease) in plasma concentrations of estrogen and progestin have been noted in some cases of co-administration of HIV/HCV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors.

Antibiotics: There have been reports of pregnancy while taking hormonal contraceptives and antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of antibiotics on plasma concentrations of synthetic steroids.

7.2 Effects of Combined Oral Contraceptives on Other Drugs

COCs containing ethinyl estradiol may inhibit the metabolism of other compounds. COCs have been shown to significantly decrease plasma concentrations of lamotrigine, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. Consult the labeling of the concurrently-used drug to obtain further information about interactions with COCs or the potential for enzyme alterations.

In vitro studies with human CYP enzymes did not indicate an inhibitory potential of dienogest at clinically relevant concentrations.

Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentrations of thyroid-binding globulin increase with use of COCs.

7.3 Interference with Laboratory Tests

The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins [see Warnings and Precautions (5.11) and Drug Interactions (7.2)].

8.1 Pregnancy

There is little or no increased risk of birth defects in women who inadvertently use COCs during early pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction 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.

8.3 Nursing Mothers

When possible, advise the nursing mother to use other forms of contraception until she has weaned her child. Estrogen-containing COCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well-established; however, it can occur at any time in some women. Small amounts of oral contraceptive steroids and/or metabolites are present in breast milk.

8.4 Pediatric Use

Safety and efficacy of Estradiol Valerate and Estradiol Valerate/Dienogest have been established in women of reproductive age. Efficacy is expected to be the same for postpubertal adolescents under the age of 18 and for users 18 years and older. Use of this product before menarche is not indicated.

8.5 Geriatric Use

Estradiol Valerate and Estradiol Valerate/Dienogest has not been studied in postmenopausal women and is not indicated in this population.

8.6 Patients with Renal Impairment

The pharmacokinetics of Estradiol Valerate and Estradiol Valerate/Dienogest has not been studied in subjects with renal impairment, but an effect requiring dose adjustment is unlikely to be present [see Clinical Pharmacology (12.3)].

8.7 Patients with Hepatic Impairment

The pharmacokinetics of Estradiol Valerate and Estradiol Valerate/Dienogest has not been studied in subjects with hepatic impairment. Steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal. [See Contraindications (4) and Warnings and Precautions (5.3).)]

8.8 Body Mass Index

The safety and efficacy of Estradiol Valerate and Estradiol Valerate/Dienogest in women with a BMI of > 30 kg/m2 has not been evaluated.

12.1 Mechanism of Action

COCs lower the risk of becoming pregnant primarily by suppressing ovulation. Other possible mechanisms may include cervical mucus changes that inhibit sperm penetration and endometrial changes that reduce the likelihood of implantation.

12.2 Pharmacodynamics

The estrogen in Estradiol Valerate and Estradiol Valerate/Dienogest is estradiol valerate, a synthetic prodrug of 17ß-estradiol.

The progestin in Estradiol Valerate and Estradiol Valerate/Dienogest is dienogest (DNG). DNG displays properties of 19-nortestosterone derivatives as well as properties associated with progesterone derivatives. [See Nonclinical Toxicology (13.2).]

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 24 month carcinogenicity study in mice dosed orally with dienogest by gavage with doses of 5, 15 and 50 mg/kg/day (males) and 10, 30 and 100 mg/kg/day (females), the systemic exposures in the females were 1.1, 3.5, and 10.6 times the exposure (AUC of dienogest) of women taking a 3 mg dose. A statistically significantly higher incidence of stromal polyps of the uterus was observed in females given 100 mg/kg. In a similar study in rats given 1, 3, and 10 mg/kg for 104 weeks, 0.2, 1.4, and 6.1 times the exposure of women taking a 3 mg dose, there were no statistically significant drug-related neoplasms.

Dienogest was not mutagenic in in vitro reverse mutation tests in bacteria, in chromosome aberration tests in human peripheral lymphocytes, mouse lymphoma cells, and Chinese hamster lung cells, and tests of unscheduled DNA synthesis (UDS) in rat and human liver cells. Dienogest was also negative in an in vivo mouse micronucleus test, a rat liver initiation-promotion model, and an in vitro/in vivo UDS test in female rats.

13.2 Animal Toxicology and/or Pharmacology

Nonclinical studies in animals and in vitro, have shown that besides progestogenic activities, DNG is devoid of estrogenic, androgenic, glucocorticoid and mineralocorticoid activities.

14.1 Oral Contraceptive Clinical Trials

The study conducted in North America (U.S. and Canada) was a multicenter, open-label, single-arm, unintended pregnancy study. There were 490 healthy subjects between 18 and 35 years of age (mean age: 25.1 years) who were treated for up to 28 cycles of 28 days each. The racial demographic of enrolled women was: Caucasian (76%), Hispanic (13%), African-American (7%), Asian (3%), and Other (1%). The weight range for treated women was 40 to 100 kg (mean weight: 62.5 kg) and the BMI range was 14 to 30 kg/m2 (mean BMI: 23.3 kg/m2). Of treated women, 15% discontinued the study treatment due to an adverse event, 13% were lost to follow up, 10% withdrew their consent, 8% discontinued due to other reason, 1% discontinued due to protocol deviation, and 1% discontinued due to pregnancy.

The study conducted in Europe (Germany, Austria and Spain) was a multicenter, open-label, single-arm contraceptive reliability study. There were 1,377 healthy subjects between 18 and 50 years of age (mean age: 30.3 years) who were treated for 20 cycles of 28 days each. The racial demographic of enrolled women was predominantly Caucasian (99.2%). The weight range for treated women was 38 to 98 kg (mean weight: 63.8 kg) and the BMI range was 15 to 31.8 kg/m2 (mean BMI: 22.8 kg/m2). Of treated women, 10% discontinued the study treatment due to an adverse event, 5% discontinued due to other reason, 2% were lost to follow up, 2% discontinued due to protocol deviation, 2% withdrew their consent, and 1% discontinued due to pregnancy.

The Pearl Index (PI) was the primary efficacy endpoint used to assess contraceptive reliability and was assessed in each of the two studies, assuming all subjects were at risk of pregnancy in all medication cycles unless back-up contraception was documented. The PI is based on pregnancies that occurred after the onset of treatment and within 7 days after the last pill intake. Cycles in which conception did not occur, but which included the use of back-up contraception, were not included in the calculation of the PI. The PI also includes patients who did not take the drug correctly. The estimated PI for the North American study is 1.64 and the estimated PI for the European study is 1.04. The Kaplan-Meier method was also used to calculate the contraceptive failure rate.

The summary of the Pearl Indexes and cumulative contraceptive failure rates are provided in Table 2:

14.2 Heavy Menstrual Bleeding Clinical Trials

The efficacy and safety of Estradiol Valerate and Estradiol Valerate/Dienogest were evaluated in two multi-regional, multicenter, double-blind, randomized, placebo-controlled clinical trials. Study 308960 was performed in the United States and Canada and Study 308961 was performed in Australia and 9 European countries. The studies were identical in design. The studies enrolled women, 18 years of age or older, with a diagnosis of dysfunctional uterine bleeding characterized as heavy, prolonged and/or frequent bleeding without organic pathology. Heavy menstrual bleeding (HMB) was defined as menstrual blood loss of 80 mL or more in at least 2 bleeding episodes. The diagnosis of HMB was documented through the collection of used sanitary protection (pads and tampons) to quantify blood loss assessed by the alkaline hematin method. Overall, about 85% of the subjects qualified for the study because they had heavy menstrual bleeding symptoms.

A total of 421 women with a mean age of 38.2 and a mean BMI of 25.5 were randomized to the two clinical studies, for a total of 269 women in the Estradiol Valerate and Estradiol Valerate/Dienogest group and 152 women in the placebo group, and treated for seven 28-day cycles. Approximately 81% were Caucasian, 13% were Black, and 6% were Hispanic or Asian or Other.

The primary efficacy variable was the proportion of subjects who were completely relieved of symptoms, which was defined by the number of subjects with the absence of any dysfunctional bleeding symptom and who met up to 8 strictly defined criteria for success during the 90-day efficacy assessment phase. In Study 308960, the proportion of the intent-to-treat subjects with complete symptom relief was 29.2% in the Estradiol Valerate and Estradiol Valerate/Dienogest group compared to 2.9% in the placebo group. In Study 308961, the proportion of the intent-to-treat subjects with complete symptom relief was 29.5% in the Estradiol Valerate and Estradiol Valerate/Dienogest group compared to 1.2% in the placebo group.

In both studies, Natazia was effective in treating the symptoms of HMB in the subset of women who entered the study with symptoms specific to HMB. Among patients with HMB, menstrual blood loss (MBL) was statistically significantly reduced in the group treated with Natazia compared with placebo (p<0.0001 for both studies). Evaluating data based on 28-day cycles, the median menstrual blood volume at Cycle 7 was reduced from the baseline median by 90% in one trial and 87% in the other. For women treated with placebo, the median menstrual blood volume at Cycle 7 was reduced from the baseline median by 14% and 32% in the two trials, respectively. Figures 1 and 2 display the MBL volume by cycle and by study.

Figure 1 Median Menstrual Blood Loss Volume by Cycle (Study 308960)

Figure 2 Median Menstrual Blood Loss Volume by Cycle (Study 308961)

16.1 How Supplied

Estradiol Valerate and Estradiol Valerate/Dienogest tablets are available in packages of three blister packs (NDC 50419-409-03).

The active and inert film-coated tablets are rounded with biconvex faces, one side is embossed with a regular hexagon shape with the letters DD or DJ or DH or DN or DT.

Each blister pack (28 film-coated tablets) contains in the following order:

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2 round biconvex dark yellow film-coated tablets with embossed “DD” in a regular hexagon on one side each containing 3 mg estradiol valerate

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5 round biconvex medium red film-coated tablets with embossed “DJ” in a regular hexagon on one side each containing 2 mg estradiol valerate and 2 mg dienogest

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17 round biconvex light yellow film-coated tablets with embossed “DH” in a regular hexagon on one side each containing 2 mg estradiol valerate and 3 mg dienogest

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2 round biconvex dark red film-coated tablets with embossed “DN” in a regular hexagon on one side each containing 1 mg estradiol valerate

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2 white round biconvex white film-coated tablets with embossed “DT” in a regular hexagon on one side (inert)

16.2 Storage

Store at 25º C (77º F); excursions permitted to 15–30oC (59–86oF) [see USP Controlled Room Temperature].