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Estradiol Valerate And Estradiol Valerate/Dienogest

FDA Drug Information • Also known as: Estradiol Valerate And Estradiol Valerate/Dienogest, Natazia

Brand Names
Estradiol Valerate And Estradiol Valerate/Dienogest, Natazia
Dosage Form
KIT
Product Type
HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptives (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs should not be used by women who are over 35 years of age and smoke. [See Contraindications ( 4 ).] WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS See full prescribing information for complete boxed warning.

  • Women over 35 years old who smoke should not use Estradiol Valerate and Estradiol Valerate/Dienogest . ( 4 )
  • Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. ( 4 )

    • Description

    11 DESCRIPTION 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 film-coated tablets:

  • 2 dark yellow tablets each containing 3 mg estradiol valerate
  • 5 medium red tablets each containing 2 mg estradiol valerate and 2 mg dienogest
  • 17 light yellow tablets each containing 2 mg estradiol valerate and 3 mg dienogest
  • 2 dark red tablets each containing 1 mg estradiol valerate
  • 2 white tablets (inert) 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 23 H 32 O 3 and the chemical structure is: Estradiol Valerate 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 20 H 25 NO 2 and the chemical structure is: Dienogest Dienogest The chemical name of dienogest is (17α)-17-Hydroxy-3-oxo-19-norpregna-4,9-diene-21-nitrile. EV Chem Struc Dien Chem Struc

    • What Is Estradiol Valerate And Estradiol Valerate/Dienogest Used For?

    1 INDICATIONS AND USAGE

  • Estradiol Valerate and Estradiol Valerate/Dienogest is an estrogen/progestin COC indicated for use by women to prevent pregnancy. ( 1 )
  • Treatment of heavy menstrual bleeding in women without organic pathology who choose to use an oral contraceptive as their method of contraception. ( 1.2 )
  • The efficacy of Estradiol Valerate and Estradiol Valerate/Dienogest in women with a body mass index (BMI) of >30 kg/m 2 has not been evaluated. ( 1 , 8.8 ) 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/m 2 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 )].

    • Dosage and Administration

    2 DOSAGE AND ADMINISTRATION

  • Take one tablet daily by mouth at the same time every day. ( 2.1 )
  • Tablets must be taken in the order directed on the blister pack. ( 2.1 )
  • Do not skip or delay intake by more than 12 hours. ( 2.1 ) 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:
  • Another pill
  • Vaginal ring
  • Patch
  • 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.
  • 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.
  • 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:
  • Progestin-only pill
  • Implant
  • Intrauterine system
  • Injection
  • 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.
  • 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...

    • Side Effects (Adverse Reactions)

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

  • Serious cardiovascular events and stroke [see Boxed Warning and Warnings and Precautions ( 5.1 )]
  • Vascular events [see Warnings and Precautions ( 5.1 )]
  • Liver disease [see Warnings and Precautions ( 5.3 )] Adverse reactions commonly reported by COC users are:
  • Irregular uterine bleeding
  • Nausea
  • Breast tenderness
  • Headache The most common adverse reactions (≥ 2%) in clinical trials for Estradiol Valerate and Estradiol Valerate/Dienogest are headaches, irregular uterine bleeding,headache (including migraines) 13%, breast tenderness,pain 7%, menstrual disorders 7%, nausea/ or vomiting, 6%, acne 4%, mood changes (3%) and increased weight. 3%. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 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. Contraception and Heavy Menstrual Bleeding Studies A total of 2,131 women, 18 to 54 years of age, who took at least one dose of Estradiol Valerate and Estradiol Valerate/Dienogest were enrolled in four clinical phase 3 trials. A total of 1,867 subjects were included in two clinical phase 3 studies with a treatment duration up to 28 cycles with Estradiol Valerate and Estradiol Valerate/Dienogest as an oral contraceptive and 264 subjects in the two phase 3 clinical trials with a treatment duration of 7 cycles evaluating Estradiol Valerate and Estradiol Valerate/Dienogest in the treatment of heavy, prolonged, and/or frequent menstrual bleeding in women without organic pathology. [See Clinical Studies ( 14.1 , 14.2 .)] Adverse Reactions Leading to Study Discontinuation : 11.4% of the women discontinued from the clinical trials due to an adverse reaction; the most frequent adverse reactions leading to discontinuation were menstrual disorder (metrorrhagia, menorrhagia, menstruation irregular, genital hemorrhage, vaginal hemorrhage, dysfunctional uterine bleeding) (2.3%); mood changes (depression, mood swings, mood altered, depressed mood, dysthymic disorder, crying) (1.2%); acne (1.1%), headache (including migraines) (1.1%), and weight increased (0.7 %). Common Adverse Reactions (≥ 2%): headache (including migraines) (12.7%), breast pain, discomfort or tenderness (7.0%), menstrual disorders (metrorrhagia, menstruation irregular, menorrhagia, vaginal hemorrhage, dysfunctional uterine bleeding, genital hemorrhage, abnormal withdrawal bleeding, uterine hemorrhage) (6.9%), nausea or vomiting (6.0%), acne (3.9%), mood changes (depression, mood swings, depressed mood, mood altered, affect lability, dysthymic disorder, crying) (3.0%) and increased weight (2.9%). Serious Adverse Reactions: myocardial infarction (2 cases), ruptured ovarian cyst (2 cases), deep vein thrombosis, focal nodular hyperplasia of the liver, uterine leiomyoma, acute cholecystitis, and chronic acalculous cholecystitis. 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:...

    • Drug Interactions

    7 DRUG INTERACTIONS Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations . Drugs or herbal products that induce certain enzymes (for example, CYP3A4) may decrease the effectiveness of COCs or increase breakthrough bleeding. Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with COCs. ( 7.1 ) 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 C max and AUC (0–24hr), respectively, for dienogest and a 25% and 44% decrease in C max 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 C max 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...

    Contraindications

    4 CONTRAINDICATIONS Do not prescribe Estradiol Valerate and Estradiol Valerate/Dienogest to women who are known to have the following:

  • A high risk of arterial or venous thrombotic diseases. Examples include women who are known to:
  • Smoke, if over age 35 [see Boxed Warning and Warnings and Precautions ( 5.1 )]
  • Have deep vein thrombosis or pulmonary embolism, now or in the past [see Warnings and Precautions ( 5.1 )]
  • Have cerebrovascular disease [see Warnings and Precautions ( 5.1 )]
  • Have coronary artery disease [see Warnings and Precautions ( 5.1 )]
  • Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see Warnings and Precautions ( 5.1 )]
  • Have inherited or acquired hypercoagulopathies [see Warnings and Precautions ( 5.1 )]
  • Have uncontrolled hypertension [see Warnings and Precautions ( 5.4 )]
  • Have diabetes mellitus with vascular disease [see Warnings and Precautions ( 5.6 )]
  • Have headaches with focal neurological symptoms or have migraine headaches with or without aura if over age 35 [see Warnings and Precautions ( 5.7 )]
  • Undiagnosed abnormal uterine bleeding [see Warnings and Precautions ( 5.8 )]
  • Breast cancer or other estrogen- or progestin-sensitive cancer, now or in the past [see Warnings and Precautions ( 5.2 )]
  • Liver tumors, benign or malignant, or liver disease [see Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.7 ) and Clinical Pharmacology ( 12.3 )] .
  • Pregnancy, because there is no reason to use COCs during pregnancy [see Warnings and Precautions ( 5.9 ) and Use in Specific Populations ( 8.1 )] .
  • A high risk of arterial or venous thrombotic diseases ( 4 )
  • Undiagnosed abnormal uterine bleeding ( 4 )
  • Breast cancer or other estrogen- or progestin-sensitive cancer ( 4 )
  • Liver tumors or liver disease ( 4 )
  • Pregnancy ( 4 )

    • Pregnancy and Breastfeeding

    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.

    Overdosage

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

    How Supplied

    16 HOW SUPPLIED/STORAGE AND HANDLING 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:

  • 2 round biconvex dark yellow film-coated tablets with embossed “DD” in a regular hexagon on one side each containing 3 mg estradiol valerate
  • 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
  • 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
  • 2 round biconvex dark red film-coated tablets with embossed “DN” in a regular hexagon on one side each containing 1 mg estradiol valerate
  • 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 15–30 o C (59–86 o F) [see USP Controlled Room Temperature] .

    • About This Information

    This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

    What are side effects?

    Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

    What are drug interactions?

    Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.