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Estradiol and Dienogest

Pronunciation

(es tra DYE ole & dye EN oh jest)

Index Terms

  • Dienogest and Estradiol
  • Estradiol Valerate and Dienogest
  • Estradiol Valerate/Dienogest

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, oral [four-phasic formulation]:

Natazia®:

Days 1-2: Estradiol valerate 3 mg [2 dark yellow tablets]

Days 3-7: Estradiol valerate 2 mg and dienogest 2 mg [5 medium red tablets]

Days 8-24: Estradiol valerate 2 mg and dienogest 3 mg [17 light yellow tablets]

Days 25-26: Estradiol valerate 1 mg [2 dark red tablets]

Days 27-28: 2 white inactive tablets (28s)

Brand Names: U.S.

  • Natazia®

Pharmacologic Category

  • Contraceptive
  • Estrogen and Progestin Combination

Pharmacology

Combination hormonal contraceptives inhibit ovulation and may also cause changes in the cervical mucus, rendering it unfavorable for sperm penetration even if ovulation occurs. The four-phasic formulation provides the estrogen in decreasing concentrations and the progestin in increasing concentrations over the 28-day cycle.

Distribution

Estradiol: Vd: 1.2 L/kg; Dienogest: Vdss; 46 L

Metabolism

Hepatic via CYP3A4

Estradiol: Partially metabolized in the gastrointestinal mucosa, also undergoes significant first-pass metabolism; forms active metabolites (estrone, estrone sulfate, estrone glucuronide)

Dienogest: Forms inactive metabolites

Excretion

Urine; feces

Time to Peak

Estradiol: ~6 hours; Dienogest: ~1 hour

Half-Life Elimination

Estradiol: ~14 hours; Dienogest: ~11 hours

Protein Binding

Estradiol: Albumin (60%) and sex hormone binding globulin (38%); Dienogest: Albumin (90%)

Use: Labeled Indications

Prevention of pregnancy; treatment of heavy menstrual bleeding

Use: Unlabeled

Pain associated with endometriosis; dysmenorrhea; treatment of polycystic ovary syndrome (PCOS) in women with menstrual irregularities and hirsutism/acne

Contraindications

Breast cancer or other estrogen- or progestin-dependent neoplasms (current or a history of), hepatic tumors or disease, pregnancy, undiagnosed abnormal uterine bleeding

Use is also contraindicated in women at high risk of arterial or venous thrombotic diseases including: Cerebrovascular disease, coronary artery disease, diabetes mellitus with vascular disease, DVT or PE (current or history of), hypercoagulopathies (inherited or acquired), headaches with focal neurological symptoms, hypertension (uncontrolled), migraine headaches if >35 years of age, thrombogenic valvular or rhythm diseases of the heart (eg, subacute bacterial endocarditis with valvular disease or atrial fibrillation), women >35 years of age who smoke.

Dosing: Adult

Contraception or treatment of heavy menstrual bleeding: Females: Oral: Take 1 tablet daily in the order presented in the blister pack

Initial dosing: Start on day 1 of menstrual period (first day of bleeding). A nonhormonal contraceptive should be used for the first 9 days.

Switching from another combination oral contraceptive tablet: Take the first dark yellow tablet on the first day of withdrawal bleeding; do not continue taking tablets from previous contraceptive pack. If withdrawal bleeding does not occur, rule-out pregnancy before starting therapy. A nonhormonal contraceptive should be used for the first 9 days.

Switching from a vaginal ring or patch: Take the first dark yellow tablet on the day the ring or patch is removed. A nonhormonal contraceptive should be used for the first 9 days.

Switching from a progestin-only contraceptive: Take the first dark yellow tablet on the day of the next progestin-only tablet would have been given, or the day the progestin implant or IUD is removed, or on the day the next injection would have been given. A nonhormonal contraceptive should be used for the first 9 days.

Missed doses: If ≤12 hours late, take tablet as soon as remembering and take the next tablet at the usual time. If >12 hours late, instructions vary by day of cycle and number of tablets missed:

If missed ONE dose:

Days 1-17: Take missed tablet immediately; take next tablet at usual time; use back-up (nonhormonal) contraception for the next 9 days; continue taking 1 tablet each day for the rest of the cycle

Days 18-24: Do not continue using current blister pack (throw away); take day 1 of new blister pack; use back-up (nonhormonal) contraception for the next 9 days; continue taking 1 tablet each day for the rest of the cycle

Days 25-28: Take missed tablet immediately; take next tablet at usual time; continue taking 1 tablet each day for the rest of the cycle; no backup method of contraception is needed.

If missed TWO doses in a row:

Days 1-17: Do not take missed tablets; start by taking the tablet for the day it was first noticed that the tablet was missed; use back-up (nonhormonal) contraception for the next 9 days; continue taking 1 tablet each day for the rest of the cycle. If tablets were missed on days 17 and 18, follow directions for missed tablets on days 17-25.

Days 17-25: Do not continue using current blister pack (throw away); take day 3 of new blister pack; use back-up (nonhormonal) contraception for the next 9 days; continue taking 1 tablet each day for the rest of the cycle. If tablets were missed on days 25 and 26, follow directions for missed tablets on days 25-28.

Days 25-28: Do not continue using current blister pack (throw away); start a new pack on the same day, or start a new pack the day it would normally be started; continue taking 1 tablet each day for the rest of the cycle; no backup method of contraception is needed.

Dosing: Pediatric

Contraception: Oral: Refer to adult dosing. Not to be used prior to menarche.

Dosing: Renal Impairment

Safety and efficacy have not been evaluated; dose adjustment not expected to be required.

Dosing: Hepatic Impairment

Use is contraindicated with hepatic disease. Discontinue if hepatic dysfunction occurs.

Administration

Tablets should be taken at the same time each day in the order presented in the blister pack. Do not delay administration by >12 hours. In case of vomiting or diarrhea within 3-4 hours of taking a colored tablet, treat as if the dose was missed (or can take another tablet of the same color from an extra blister pack). Patients should be instructed not to take more than 2 tablets in any one day. A nonhormonal contraceptive (eg, condom or spermicide) should be used for the first 9 days of therapy. If patient is unsure of number of tablets missed, they should continue taking one tablet each day and use a back-up form of contraception.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°°C (5°9F to 86°F).

Drug Interactions

Acitretin: May diminish the therapeutic effect of Contraceptives (Progestins). Contraceptive failure is possible. Management: Given the potential for progestin-only preparations to fail to prevent pregnancy during acitretin therapy, such products should not be relied upon. Alternative, nonhormonal forms of contraception must be employed during acitretin therapy. Consider therapy modification

Ajmaline: Estrogen Derivatives may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased. Monitor therapy

Amodiaquine: CYP2C8 Inhibitors may increase the serum concentration of Amodiaquine. Avoid combination

Anastrozole: Estrogen Derivatives may diminish the therapeutic effect of Anastrozole. Avoid combination

Anthrax Immune Globulin (Human): Estrogen Derivatives may enhance the thrombogenic effect of Anthrax Immune Globulin (Human). Monitor therapy

Anticoagulants: Estrogen Derivatives may diminish the anticoagulant effect of Anticoagulants. More specifically, the potential prothrombotic effects of some estrogens and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of estrogens against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Consider therapy modification

Anticoagulants: Progestins may diminish the therapeutic effect of Anticoagulants. More specifically, the potential prothrombotic effects of some progestins and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of progestins against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Consider therapy modification

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Aprepitant: May decrease the serum concentration of Contraceptives (Progestins). Management: Alternative or additional methods of contraception should be used both during treatment with aprepitant or fosaprepitant and for at least one month following the last aprepitant/fosaprepitant dose. Consider therapy modification

Artemether: May decrease the serum concentration of Contraceptives (Progestins). Management: Consider the use of an alternative (i.e., non-hormonal) means of contraception in all women of childbearing potential who are using artemether. Consider therapy modification

Ascorbic Acid: May increase the serum concentration of Estrogen Derivatives. Monitor therapy

Atazanavir: May increase the serum concentration of Contraceptives (Progestins). However, atazanavir may lead to decreased ethinyl estradiol concentrations and decreased effectiveness of oral contraceptive products. Management: Consider an alternative or additional method of contraception, particularly with combined estrogen/progestin products. Depot medroxyprogesterone acetate may be used without a need for additional contraception. Consider therapy modification

Barbiturates: May diminish the therapeutic effect of Contraceptives (Progestins). Contraceptive failure is possible. Management: Use of alternative, nonhormonal contraceptives is recommended. Consider therapy modification

Bexarotene (Systemic): May decrease the serum concentration of Contraceptives (Progestins). Management: Women of childbearing potential receiving bexarotene should use two reliable forms of contraception (including at least one nonhormonal form). Consider therapy modification

Bile Acid Sequestrants: May decrease the serum concentration of Contraceptives (Progestins). Management: Administer oral progestin-containing contraceptives at least 1-4 hours prior to or 4-6 hours after administration of a bile acid sequestrant. Consider therapy modification

Boceprevir: May increase the serum concentration of Contraceptives (Progestins). This has been seen specifically with norethindrone. Boceprevir may increase the serum concentration of Contraceptives (Progestins). This has been seen specifically with drospirenone. Management: Patients receiving boceprevir, ribavirin, and peginterferon alfa should use two reliable forms of contraception. Norethindrone/ethinyl estradiol may be used for one of these when norethindrone dose is at least 1 mg/day. Avoid drospirenone. Consider therapy modification

Bosentan: May decrease the serum concentration of Contraceptives (Progestins). Management: Use an alternative (i.e., non-hormonal) means of contraception for all women of childbearing potential who are using bosentan, and do not rely on hormonal contraceptives alone. Consider therapy modification

C1 inhibitors: Estrogen Derivatives may enhance the thrombogenic effect of C1 inhibitors. Monitor therapy

C1 inhibitors: Progestins may enhance the thrombogenic effect of C1 inhibitors. Monitor therapy

Cannabis: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

Carfilzomib: May enhance the thrombogenic effect of Contraceptives (Progestins). Management: Consider alternative, non-hormonal methods of contraception in patients requiring therapy with carfilzomib. Consider therapy modification

Chenodiol: Estrogen Derivatives may diminish the therapeutic effect of Chenodiol. Management: Monitor clinical response to chenodiol closely when used together with any estrogen derivative. Monitor therapy

CloBAZam: May decrease the serum concentration of Contraceptives (Progestins). Consider therapy modification

Cobicistat: May increase the serum concentration of Contraceptives (Progestins). Management: Consider an alternative, non-hormone-based contraceptive in patients receiving cobicistat-containing products. Consider therapy modification

Corticosteroids (Systemic): Estrogen Derivatives may increase the serum concentration of Corticosteroids (Systemic). Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Dienogest. Management: Avoid use of dienogest for contraception when using medications that induce CYP3A4 and for at least 28 days after discontinuation of a CYP3A4 inducer. An alternative form of contraception should be used during this time. Avoid combination

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Dienogest. Monitor therapy

Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dabrafenib: May decrease the serum concentration of Contraceptives (Progestins). Management: Females of reproductive potential should use an alternative, highly effective, non-hormonal means of contraception during and at least 2 weeks (dabrafenib alone) or 4 months (dabrafenib + trametinib) after discontinuation of dabrafenib treatment. Consider therapy modification

Darunavir: May decrease the serum concentration of Contraceptives (Progestins). Management: Consider using an alternative or additional means of contraception. Injected depot medroxyprogesterone acetate may be used without a need for additional contraception. Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Dehydroepiandrosterone: May enhance the adverse/toxic effect of Estrogen Derivatives. Avoid combination

Efavirenz: May decrease the serum concentration of Contraceptives (Progestins). Management: Use an alternative or additional method of contraception due to possibly decreased contraceptive effectiveness. Injected depot medroxyprogesterone acetate does not appear to participate in this interaction. Consider therapy modification

Eslicarbazepine: May decrease the serum concentration of Contraceptives (Progestins). Management: Alternative, non-hormonal means of birth control should be considered for women of child-bearing potential. Consider therapy modification

Exemestane: Estrogen Derivatives may diminish the therapeutic effect of Exemestane. Avoid combination

Felbamate: May decrease the serum concentration of Contraceptives (Progestins). Management: Contraceptive failure is possible. Use of an alternative, nonhormonal method of contraception is recommended. Consider therapy modification

Flibanserin: Contraceptives (Progestins) may increase the serum concentration of Flibanserin. Monitor therapy

Fosamprenavir: Contraceptives (Progestins) may decrease serum concentrations of the active metabolite(s) of Fosamprenavir. Fosamprenavir may decrease the serum concentration of Contraceptives (Progestins). Management: Consider using an alternative or additional means of contraception. Injected depot medroxyprogesterone acetate may be used without a need for additional contraception. Consider therapy modification

Fosaprepitant: May decrease the serum concentration of Contraceptives (Progestins). The active metabolite aprepitant is likely responsible for this effect. Management: Alternative or additional methods of contraception should be used both during treatment with aprepitant or fosaprepitant and for at least one month following the last aprepitant/fosaprepitant dose. Consider therapy modification

Griseofulvin: May diminish the therapeutic effect of Contraceptives (Progestins). Contraceptive failure is possible. Avoid combination

Hemin: Estrogen Derivatives may diminish the therapeutic effect of Hemin. Avoid combination

Herbs (Estrogenic Properties): May enhance the adverse/toxic effect of Estrogen Derivatives. Monitor therapy

Herbs (Progestogenic Properties) (eg, Bloodroot, Yucca): May enhance the adverse/toxic effect of Progestins. Monitor therapy

Hyaluronidase: Estrogen Derivatives may diminish the therapeutic effect of Hyaluronidase. Management: Patients receiving estrogens (particularly at larger doses) may not experience the desired clinical response to standard doses of hyaluronidase. Larger doses of hyaluronidase may be required. Consider therapy modification

Immune Globulin: Estrogen Derivatives may enhance the thrombogenic effect of Immune Globulin. Monitor therapy

Indium 111 Capromab Pendetide: Estrogen Derivatives may diminish the diagnostic effect of Indium 111 Capromab Pendetide. Avoid combination

LamoTRIgine: May decrease the serum concentration of Contraceptives (Progestins). Management: Women using progestin-only “minipill” products may be at risk for contraceptive failure; it is unclear if other progestin-containing products would be significantly impacted. Alternative, non-hormonal, means of contraception are recommended. Consider therapy modification

Lenalidomide: Estrogen Derivatives may enhance the thrombogenic effect of Lenalidomide. Monitor therapy

Lesinurad: May decrease the serum concentration of Contraceptives (Progestins). Management: Use of an additional, nonhormonal contraceptive is recommended in patients being treated with lesinurad who desire effective contraception. Consider therapy modification

Lixisenatide: May decrease the serum concentration of Contraceptives (Progestins). Management: Administer oral contraceptives 1 hour before or at least 11 hours after administration of lixisenatide. Consider therapy modification

Lopinavir: May decrease the serum concentration of Contraceptives (Progestins). Lopinavir may increase the serum concentration of Contraceptives (Progestins). Management: Consider using an alternative or additional means of contraception. Injected depot medroxyprogesterone acetate and etonogestrel implants may be used without a need for additional contraception. Consider therapy modification

Metreleptin: May decrease the serum concentration of Contraceptives (Progestins). Metreleptin may increase the serum concentration of Contraceptives (Progestins). Monitor therapy

MiFEPRIStone: May diminish the therapeutic effect of Contraceptives (Progestins). MiFEPRIStone may increase the serum concentration of Contraceptives (Progestins). Management: Women of childbearing potential should use an effective, nonhormonal means of contraception during and 4 weeks following mifepristone treatment. Consider therapy modification

Mycophenolate: May decrease the serum concentration of Contraceptives (Progestins). Management: Use of an additional or alternative (nonhormonal) method of contraception should be considered. Consider therapy modification

Nelfinavir: May decrease the serum concentration of Contraceptives (Progestins). Management: Use an alternative or additional method of contraception due to possibly decreased contraceptive effectiveness. Injected depot medroxyprogesterone acetate does not appear to participate in this interaction. Consider therapy modification

Nevirapine: May decrease the serum concentration of Contraceptives (Progestins). Management: Instruct patients receiving nevirapine to use an alternative or additional nonhormonal contraceptive. Nevirapine product labeling however suggests that depo-medroxyprogesterone acetate may be used as a sole method of contraception. Consider therapy modification

NSAID (COX-2 Inhibitor): May enhance the thrombogenic effect of Estrogen Derivatives. NSAID (COX-2 Inhibitor) may increase the serum concentration of Estrogen Derivatives. Monitor therapy

Ospemifene: Estrogen Derivatives may enhance the adverse/toxic effect of Ospemifene. Estrogen Derivatives may diminish the therapeutic effect of Ospemifene. Avoid combination

OXcarbazepine: May decrease the serum concentration of Contraceptives (Progestins). Management: Contraceptive failure is possible. Use of an additional or alternative, nonhormonal method of contraception is recommended. Consider therapy modification

Perampanel: May decrease the serum concentration of Contraceptives (Progestins). Management: Patients should use an alternative, non-hormonal based form of contraception for the duration of concurrent perampanel. Both oral and non-oral progestin-based contraceptives are likely to be impacted by this interaction. Consider therapy modification

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

Pomalidomide: May enhance the thrombogenic effect of Estrogen Derivatives. Management: Canadian pomalidomide labeling recommends caution with use of hormone replacement therapy and states that hormonal contraceptives are not recommended. US pomalidomide labeling does not contain these specific recommendations. Consider therapy modification

Pomalidomide: Progestins may enhance the thrombogenic effect of Pomalidomide. Management: Canadian pomalidomide labeling recommends caution with use of hormone replacement therapy and states that hormonal contraceptives are not recommended. US pomalidomide labeling does not contain these specific recommendations. Consider therapy modification

Prucalopride: May decrease the serum concentration of Contraceptives (Progestins). Consider therapy modification

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Retinoic Acid Derivatives: May diminish the therapeutic effect of Contraceptives (Progestins). Retinoic Acid Derivatives may decrease the serum concentration of Contraceptives (Progestins). Management: Two forms of effective contraception should be used in patients receiving retinoic acid derivatives. Particularly, microdosed progesterone-only preparations may be inadequately effective. Exceptions: Adapalene; Bexarotene (Topical); Tretinoin (Topical). Consider therapy modification

ROPINIRole: Estrogen Derivatives may increase the serum concentration of ROPINIRole. Monitor therapy

Saquinavir: May decrease the serum concentration of Contraceptives (Progestins). Management: Use an alternative or additional method of contraception due to possibly decreased contraceptive effectiveness. Injected depot medroxyprogesterone acetate does not appear to participate in this interaction. Consider therapy modification

Selegiline: Contraceptives (Progestins) may increase the serum concentration of Selegiline. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Somatropin: Estrogen Derivatives may diminish the therapeutic effect of Somatropin. Shown to be a concern with oral hormone replacement therapy in postmenopausal women. Management: Monitor for reduced growth hormone efficacy. A larger somatropin dose may be required to reach treatment goal. This interaction does not appear to apply to non-orally administered estrogens (e.g., transdermal, vaginal ring). Consider therapy modification

St John's Wort: May decrease the serum concentration of Dienogest. Avoid combination

Sugammadex: May decrease the serum concentration of Contraceptives (Progestins). Management: Patients receiving any hormonal contraceptive (oral or non-oral) should use an additional, nonhormonal contraceptive method during and for 7 days following sugammadex treatment. Consider therapy modification

Telaprevir: May decrease the serum concentration of Contraceptives (Progestins). Management: Two different nonhormonal forms of contraception are required for women of childbearing potential taking telaprevir. Hormonal contraceptives may be less effective during concurrent telaprevir and for up to 2 weeks after telaprevir discontinuation. Consider therapy modification

Teriflunomide: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy

Thalidomide: Contraceptives (Progestins) may enhance the thrombogenic effect of Thalidomide. Monitor therapy

Thalidomide: Estrogen Derivatives may enhance the thrombogenic effect of Thalidomide. Monitor therapy

Theophylline Derivatives: Estrogen Derivatives may increase the serum concentration of Theophylline Derivatives. Exceptions: Dyphylline. Monitor therapy

Thyroid Products: Estrogen Derivatives may diminish the therapeutic effect of Thyroid Products. Monitor therapy

Tipranavir: Estrogen Derivatives may enhance the dermatologic adverse effect of Tipranavir. The combination of tipranavir/ritonavir and ethinyl estradiol/norethindrone was associated with a high incidence of skin rash. Tipranavir may decrease the serum concentration of Estrogen Derivatives. Management: Women using hormonal contraceptives should consider alternative, non-hormonal forms of contraception. Consider therapy modification

Tipranavir: May increase the serum concentration of Contraceptives (Progestins). Management: Use an alternative or additional method of contraception due to possibly decreased contraceptive effectiveness. Injected depot medroxyprogesterone acetate does not appear to participate in this interaction. Consider therapy modification

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Topiramate: May decrease the serum concentration of Contraceptives (Progestins). Management: Caution patients that this combination may be associated with reduced contraceptive effectiveness. Consider adding an additional (non-hormonal) contraceptive method. Consider therapy modification

Tranexamic Acid: Contraceptives (Progestins) may enhance the thrombogenic effect of Tranexamic Acid. Avoid combination

Ulipristal: May diminish the therapeutic effect of Progestins. Progestins may diminish the therapeutic effect of Ulipristal. Management: Ulipristal for uterine fibroids (Canadian indication): avoid progestins within 12 days of stopping ulipristal; as emergency contraceptive (U.S. indication): avoid progestins within 5 days of stopping ulipristal. Avoid combination

Ursodiol: Estrogen Derivatives may diminish the therapeutic effect of Ursodiol. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Contraceptives (Progestins) may diminish the anticoagulant effect of Vitamin K Antagonists. In contrast, enhanced anticoagulant effects have also been noted with some products. Management: When possible, concomitant hormonal contraceptives and coumarin derivatives should be avoided in order to eliminate the risk of thromboembolic disorders. Consider using an alternative, nonhormonal contraceptive. Consider therapy modification

Voriconazole: May increase the serum concentration of Contraceptives (Progestins). Contraceptives (Progestins) may increase the serum concentration of Voriconazole. Monitor therapy

Adverse Reactions

>10%: Central nervous system: Headache (13%, including migraine)

1% to 10%:

Central nervous system: Mood changes (3%, including depression)

Dermatologic: Acne vulgaris (4%)

Endocrine & metabolic: Menstrual disease (≤7% to 8%), breast changes (discomfort: ≤7%), weight gain (3%)

Gastrointestinal: Nausea (≤7%), vomiting (≤7%)

Genitourinary: Uterine hemorrhage (≤7% to 8%), breast tenderness (≤7%), mastalgia (≤7%)

ALERT: U.S. Boxed Warning

Cigarette smoke and serious cardiovascular events:

Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptives use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, combination oral contraceptives should not be used by women who are over 35 years of age and smoke.

Warnings/Precautions

Concerns related to adverse effects:

• Breast cancer: The use of combination hormonal contraceptives has been associated with a slight increase in frequency of breast cancer; however, studies are not consistent. Use is contraindicated in women with (or history of) breast cancer.

• Carbohydrate intolerance: May have adverse effects on glucose tolerance; use caution in women with diabetes.

• Chloasma: Risk of occurrence may be increased with history of chloasma gravidarum. Women with history of chloasma should avoid exposure to sun or ultraviolet radiation during therapy.

• Cholestasis: Risk of cholestasis may be increased with previous cholestatic jaundice of pregnancy or jaundice with prior oral contraceptive use.

• Lipid effects: Combination hormonal contraceptives may affect serum triglyceride and lipoprotein levels. Estrogen compounds are generally associated with lipid effects such as increased HDL-cholesterol and decreased LDL-cholesterol. Triglycerides may also be increased; use with caution in patients with familial defects of lipoprotein metabolism.

• Retinal vascular thrombosis: Estrogens may cause retinal vascular thrombosis; discontinue if migraine, loss of vision, proptosis, diplopia or other visual disturbances occur; discontinue permanently if papilledema or retinal vascular lesions are observed on examination.

• Thromboembolism: May increase the risk of thromboembolism; discontinue use of combination hormonal contraceptives if an arterial or venous thrombotic event occurs. Women with inherited thrombophilias (eg, protein C or S deficiency) may have increased risk of venous thromboembolism (DeSancho, 2010; van Vlijmen, 2011).

• Vaginal bleeding: Presentation of irregular, unresolving vaginal bleeding warrants further evaluation including endometrial sampling, if indicated, to rule out malignancy.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with risk factors for coronary artery disease (eg, hypertension, hypercholesterolemia, morbid obesity, diabetes, or women who smoke); may lead to increased risk of myocardial infarction. May have a dose-related risk of vascular disease and hypertension; women with hypertension should be encouraged to use a nonhormonal form of contraception.

• Depression: Use with caution in patients with depression.

• Diseases exacerbated by fluid retention: Combination hormonal contraceptives should be used with caution in patients with diseases which may be exacerbated by fluid retention, including asthma, epilepsy, migraine, diabetes, or renal dysfunction.

• Gallbladder disease: May have a dose-related risk of gallbladder disease; may worsen existing gallbladder disease.

• Hepatic adenomas: Extremely rare adenomas and focal nodular hyperplasia resulting in fatal intra-abdominal hemorrhage have been reported in association with long-term oral contraceptive use. Presentation of an abdominal mass, acute abdominal pain, or intra-abdominal bleeding warrants further evaluation to rule out source.

• Hepatic impairment: Combination hormonal contraceptives may be poorly metabolized in women with hepatic impairment. Discontinue if jaundice develops during therapy. This product has not been studied in women with hepatic impairment; discontinue if liver function becomes abnormal. Use is contraindicated with hepatic disease.

• Hereditary angioedema: May induce or exacerbate symptoms of hereditary angioedema.

• Migraine: Use with caution in patients with a history of migraine. Evaluate new, recurrent, severe or persistent headaches. Use with migraine headaches with or without aura if >35 years of age is contraindicated.

• Renal impairment: This product has not been studied in women with renal impairment; however a dose adjustment is not likely to be required.

Concurrent drug therapy issues:

• High potential for interactions: Use with caution in patients taking CYP3A4 inducers or inhibitors. Alternate forms of contraception may be preferred.

• Thyroid replacement therapy: Estrogens may increase thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels. Women on thyroid replacement therapy may require higher doses of thyroid hormone while receiving estrogens.

Special populations:

• Obese: This product has not been studied in women with a BMI >30 kg/m2.

• Pediatric: Not for use prior to menarche.

• Smokers: [U.S. Boxed Warning]: The risk of cardiovascular side effects is increased in women who smoke cigarettes; risk increases with age (especially women >35 years of age) and the number of cigarettes smoked; women who use combination hormonal contraceptives should be strongly advised not to smoke. Use is contraindicated in patients >35 years of age who smoke.

• Surgical patients: Whenever possible, should be discontinued at least 4 weeks prior to and for 2 weeks following elective surgery associated with an increased risk of thromboembolism or during periods of prolonged immobilization.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

Other warnings/precautions:

• Heavy menstrual bleeding: For use only in females who have heavy bleeding without organic pathology and who also desire combination hormonal contraceptive therapy.

• HIV infection protection: Combination hormonal contraceptives do not protect against HIV infection or other sexually-transmitted diseases.

• Laboratory changes: The use of estrogens and/or progestins may change the results of some laboratory tests (eg, coagulation factors, lipids, glucose tolerance, binding proteins). The dose, route, and the specific estrogen/progestin influences these changes. In addition, personal risk factors (eg, cardiovascular disease, smoking, diabetes, age) also contribute to adverse events; use of specific products may be contraindicated in women with certain risk factors.

Monitoring Parameters

Before starting therapy, a physical exam with reference to the breasts and pelvis are recommended, including a Papanicolaou smear. Exam may be deferred if appropriate; pregnancy should be ruled out prior to use. Monitor patient closely for loss of vision, sudden onset of proptosis, diplopia, migraine; blood pressure; signs and symptoms of thromboembolic disorders; signs or symptoms of depression; glycemic control in patients with diabetes; lipid profiles in patients being treated for hyperlipidemias. Adequate diagnostic measures, including endometrial sampling, if indicated, should be performed to rule out malignancy in all cases of undiagnosed abnormal vaginal bleeding.

Pregnancy Considerations

Pregnancy should be ruled out prior to treatment and discontinued if pregnancy occurs. In general, the use of combination hormonal contraceptives when inadvertently taken early in pregnancy has not been associated with teratogenic effects. Hormonal contraceptives may be less effective in obese patients. An increase in oral contraceptive failure was noted in women with a BMI >27.3 kg/m2. Similar findings were noted in patients weighing ≥90 kg (198 lb) using the contraceptive patch. This product was not studied in women with a BMI >30 kg/m2.

Due to increased risk of venous thromboembolism (VTE) postpartum, combination hormonal contraceptives should not be started in any woman <21 days following delivery. Women without risk factors for VTE and who are not breast-feeding may start combination hormonal contraceptives during 21-42 days postpartum. After 42 days postpartum, restrictions for use are not related to postpartum status and should be based on other medical conditions (CDC, 2011). The manufacturer states that combination hormonal contraceptives should not be started until ≥4 weeks after delivery in women who choose not to breastfeed, or ≥4 weeks after a second trimester abortion or miscarriage

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience acne, weight gain, cramps, bloating, enlarged breasts, menstrual irregularities, decreased libido, or dark patches on face. Have patient report immediately to prescriber signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight), signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), coughing up blood, shortness of breath, angina, severe dizziness, passing out, severe nausea, vomiting, severe headache, depression, loss of strength and energy, severe abdominal pain, edema, lump in breast, breast soreness or pain, nipple discharge, vaginitis, vaginal bleeding, bulging eyes, vision changes, or contact lens discomfort (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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