Natazia (Estradiol valerate and estradiol valerate/dienogest) ™ is indicated for use by women to prevent pregnancy.

The efficacy of Natazia (Estradiol valerate and estradiol valerate/dienogest) in women with a body mass index (BMI) of > 30 kg/m has not been evaluated.

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Instruct the patient to begin taking Natazia (Estradiol valerate and estradiol valerate/dienogest) on Day 1 of her menstrual cycle (that is, the first day of her menstrual bleeding) 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, Natazia (Estradiol valerate and estradiol valerate/dienogest) may be started no earlier than 4 weeks postpartum. Recommend use of a non-hormonal back-up method for the first 9 days. When combined oral contraceptives (COCs) are used during the postpartum period, the increased risk of thromboembolic disease associated with the postpartum period must be considered. The possibility of ovulation and conception before starting COCs should also be considered.

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

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

Natazia (Estradiol valerate and estradiol valerate/dienogest) tablets are available in blister packs.

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

Do not prescribe Natazia (Estradiol valerate and estradiol valerate/dienogest) to women who are known to have the following:

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Stop COCs if an arterial or deep venous thrombotic (VTE) event occurs. Although the use of COCs increases the risk of venous thromboembolism, pregnancy increases the risk of venous thromboembolism as much or more than the use of COCs. The risk of venous thromboembolism in women using COCs is 3 to 9 per 10,000 woman-years. The excess risk is highest during the first year of use of a 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 COCs at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism.

Start COCs 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 COCs if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately.

Women who currently have or have had breast cancer should not use COCs 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 Natazia (Estradiol valerate and estradiol valerate/dienogest) clinical trial did not reveal any unexpected or concerning findings for subjects taking COCs.

Discontinue COCs 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.

For women with well-controlled hypertension, monitor blood pressure and stop COCs 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.

Carefully monitor prediabetic and diabetic women who are taking COCs. 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.

If a woman taking COCs develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue COCs 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.

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 Natazia (Estradiol valerate and estradiol valerate/dienogest) , may experience amenorrhea. Based on patient diaries, amenorrhea occurs in approximately 16% of cycles in women using Natazia (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 Natazia (Estradiol valerate and estradiol valerate/dienogest) , 10-23% of women experienced intracyclic bleeding per cycle. A total of 38 subjects out of 2,266 (1.7%) discontinued due to metrorrhagia or irregular menstruation.

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 .

The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling:

Adverse reactions commonly reported by COC users are:

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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 Natazia (Estradiol valerate and estradiol valerate/dienogest) .

Dienogest is a substrate of cytochrome P450 (CYP) 3A4. Women who take medications that are strong CYP3A4 inducers (for example, carbamazepine, phenytoin, rifampicin, and St. John’s wort) should not choose Natazia (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 C and AUC(0 –24hr), respectively, for dienogest and a 25% and 44% decrease in C and AUC(0–24hr), respectively, for estradiol at steady state.

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Other known CYP.3A4 inhibitors like azole antifungals, cimetidine, verapamil, macrolides, diltiazem, antidepressants, and grapefruit juice may increase plasma levels of dienogest.

Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.

COCs containing ethinyl estradiol (or mestranol), 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.

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There have been no reports of serious ill effects from overdose of oral contraceptives, including ingestion by children. Overdosage may cause nausea, and withdrawal bleeding may occur in females.

Natazia (Estradiol valerate and estradiol valerate/dienogest) tablets provide an oral contraceptive regimen consisting of 26 active film-coated tablets that contain the active ingredients specified for each tablet below, followed by two inert tablets:

Natazia (Estradiol valerate and estradiol valerate/dienogest) also contains the excipients lactose monohydrate, maize starch, maize starch pre-gelatinized, povidone 25, magnesium stearate, hypromellose, macrogol 6000, talc, titanium dioxide, and ferric oxide pigment, yellow, or ferric oxide pigment, red.

The empirical formula of estradiol valerate is C H Oand the chemical structure is:

Estradiol Valerate

The chemical name of estradiol valerate is Estra-1,3,5(10)-triene-3,17-diol(17ß)-,17-pentanoate.

The empirical formula of dienogest is C H NO and the chemical structure is:

Dienogest

The chemical name of dienogest is (17α)-17-Hydroxy-3-oxo-19-norpregna-4,9-diene-21-nitrile.

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The contraceptive effect of COCs is based on the interaction of various factors, the most important of which are the inhibition of ovulation and the changes in the cervical secretion. The estrogen in Natazia (Estradiol valerate and estradiol valerate/dienogest) is estradiol valerate, a synthetic prodrug of 17ß-estradiol.

The progestin in Natazia (Estradiol valerate and estradiol valerate/dienogest) is dienogest (DNG). DNG displays properties of 19-nortestosterone derivatives as well as properties associated with progesterone derivatives.

The effect of Natazia (Estradiol valerate and estradiol valerate/dienogest) on QT prolongation was evaluated in a randomized, double-blind, positive (moxifloxacin 400 mg) and negative (placebo) controlled crossover study in healthy subjects. A total of 53 subjects were administered Natazia (Estradiol valerate and estradiol valerate/dienogest) (containing 3 mg dienogest and 2 mg estradiol valerate), dienogest 10 mg, and placebo as once daily doses for 4 days, and moxifloxacin 400 mg as a single oral dose. The upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc based on Fridericia’s correction method (QTcF) was below 10 msec, the threshold for regulatory concern.

After oral administration of estradiol valerate, cleavage to 17β-estradiol and valeric acid takes place during absorption by the intestinal mucosa or in the course of the first liver passage. This gives rise to estradiol and its metabolites, estrone and other metabolites. Maximum serum estradiol concentrations of 73.3 pg/mL are reached at a median of approximately 6 hours (range: 1.5–12 hours) and the area under the estradiol concentration curve [AUC(0–24hr)] was 1301 pg·hr/mL after single ingestion of a tablet containing 3 mg estradiol valerate under fasted condition on Day 1 of the 28-day sequential regimen.

Bioavailability of dienogest is about 91%. Maximum serum dienogest concentrations of 91.7 ng/mL are reached at a median of approximately 1 hour (range: 0.5–1.5 hour) and the area under the dienogest concentration curve [AUC(0–24hr)] was 964 ng/mL after single oral administration of Natazia (Estradiol valerate and estradiol valerate/dienogest) tablet containing 2 mg estradiol valerate/3 mg dienogest under fasted condition. The pharmacokinetics of dienogest are dose-proportional within the dose range of 1–8 mg. Steady state is reached after 4 days of the same dosage of 2 mg dienogest. The mean accumulation ratio for AUC (0–24hr) is approximately 1.24.

The mean plasma pharmacokinetic parameters at steady state following repeated oral doses of a 2 mg estradiol valerate/3 mg dienogest combination tablet in fertile women under fasted condition are reported in Table 1.

Concomitant food intake in women resulted in a 28% decrease for dienogest C and 23% increase of estradiol C while the exposure (AUC) of both dienogest and estradiol did not change.

In serum, 38% of estradiol is bound to sex hormone-binding globulin (SHBG), 60% to albumin and 2–3% circulates in free form. An apparent volume of distribution of approximately 1.2 L/kg was determined after intravenous (IV) administration.

A relatively high fraction (10%) of circulating dienogest is present in the free form, with approximately 90% being bound non-specifically to albumin. Dienogest does not bind to SHBG and corticosteroid-binding globulin (CBG). The volume of distribution at steady state (V) of dienogest is 46 L after the IV administration of 85 mcg H-dienogest.

After oral administration of estradiol valerate, approximately 3% of the dose is directly bioavailable as estradiol. Estradiol undergoes an extensive first-pass effect and a considerable part of the dose administered is already metabolized in the gastrointestinal mucosa. The CYP 3A family is known to play the most important role in human estradiol metabolism. Together with the pre-systemic metabolism in the liver, about 95% of the orally administered dose becomes metabolized before entering the systemic circulation. The main metabolites are estrone and its sulfate or glucuronide conjugates.

Dienogest is extensively metabolized by the known pathways of steroid metabolism (hydroxylation, conjugation), with the formation of endocrinologically mostly inactive metabolites. CYP3A4 was identified as a predominant enzyme catalyzing the metabolism of dienogest.

Estradiol and its metabolites are mainly excreted in urine, with about 10% being excreted in the feces. The terminal half-life of estradiol is approximately 14 hours.

Dienogest is mainly excreted renally in the form of metabolites and unchanged dienogest is the dominating fraction in plasma. The terminal half-life of dienogest is approximately 11 hours.

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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 Natazia (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 an open-label, non-randomized, single center study in 16 healthy postmenopausal women. All volunteers received a treatment regimen of 2 mg estradiol valerate and 3 mg dienogest combination tablets, dosed once daily over 17 days, and of rifampicin, which was administered once daily in an oral dose of 600 mg on Days 12 to 16. 24–hr pharmacokinetics of estradiol and dienogest on Days 11 and 17 were compared. Co-administration of rifampicin with estradiol valerate/dienogest tablets led to a 52 % and 83% decrease in the mean C and AUC(0–24hr), respectively, for dienogest and a 25% and 44% decrease in C and AUC(0–24hr), respectively, for estradiol at steady state.

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Other known CYP3A4 inhibitors such as azole antifungals, cimetidine, verapamil, macrolides, diltiazem, antidepressants, and grapefruit juice may increase plasma levels of dienogest and estradiol.

Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.

In vitro

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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 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 mouse micronucleus test, a rat liver initiation-promotion model, and an UDS test in female rats.

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Natazia (Estradiol valerate and estradiol valerate/dienogest) tablets are available in 28 tablets per blister packs (NDC 54868-6183-0).

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:

Keep out of reach of children.

See FDA-Approved Patient Labeling.

28 tabletsoral

This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against HIV infection (AIDS) and other sexually transmitted diseases.