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Ethinyl Estradiol and Etonogestrel

Medically reviewed by Drugs.com. Last updated on Nov 27, 2023.

Pronunciation

(ETH in il es tra DYE ole & et oh noe JES trel)

Index Terms

Dosage Forms

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

Ring, Vaginal:

EluRyng: Ethinyl estradiol 0.015 mg and etonogestrel 0.12 mg per 24 hours (1 ea)

NuvaRing: Ethinyl estradiol 0.015 mg and etonogestrel 0.12 mg per 24 hours (1 ea) [latex free]

Generic: Ethinyl estradiol 0.015 mg and etonogestrel 0.12 mg per 24 hours (1 ea)

Brand Names: U.S.

Pharmacologic Category

Pharmacology

Combination hormonal contraceptives inhibit ovulation via a negative feedback mechanism on the hypothalamus, which alters the normal pattern of gonadotropin secretion of a follicle-stimulating hormone (FSH) and luteinizing hormone by the anterior pituitary. The follicular phase FSH and midcycle surge of gonadotropins are inhibited. In addition, combination hormonal contraceptives produce alterations in the genital tract, including changes in the cervical mucus, rendering it unfavorable for sperm penetration even if ovulation occurs. Changes in the endometrium may also occur, producing an unfavorable environment for nidation. Combination hormonal contraceptive drugs may alter the tubal transport of the ova through the fallopian tubes. Progestational agents may also alter sperm fertility (Rivera 1999).

Absorption

Ethinyl estradiol and etonogestrel: Rapid

Tampons do not interfere with absorption.

Metabolism

Ethinyl estradiol: Hepatic via CYP3A4; forms metabolites (weak estrogenic activity)

Etonogestrel: Hepatic via CYP3A4; forms metabolites (activity not known)

Excretion

Ethinyl estradiol and etonogestrel: Urine, bile, and feces

Time to Peak

Vaginal: Ethinyl estradiol: 59 hours; Etonogestrel: 200 hours

Duration of Action

Serum levels (contraceptive effectiveness) decrease after 3 weeks of continuous use

Half-Life Elimination

Ethinyl estradiol: 45 hours; Etonogestrel: 29 hours

Protein Binding

Ethinyl estradiol: 98.5%, primarily to albumin

Etonogestrel: ~32% to sex hormone-binding globulin (SHBG) and ~66% to albumin; SHBG capacity is affected by plasma ethinyl estradiol levels

Special Populations: Hepatic Function Impairment

Steroid hormones may be poorly metabolized in women with impaired liver function.

Use: Labeled Indications

Contraception: Prevention of pregnancy.

Off Label Uses

Abnormal uterine bleeding

Based on the American College of Obstetricians and Gynecologists committee opinion on the management of acute abnormal uterine bleeding in nonpregnant reproductive-aged women, ethinyl estradiol and etonogestrel (among other oral contraceptive combinations) is effective and recommended for the management of abnormal uterine bleeding [ACOG 2013].

Dysmenorrhea

Based on the American College of Obstetricians and Gynecologists Practice Bulletin on Noncontraceptive Uses of Hormonal Contraceptives, ethinyl estradiol and etonogestrel (among other oral contraceptive combinations) is effective and recommended for the management of dysmenorrhea [ACOG 2010].

Menstrual bleeding (menorrhagia)

Based on the American College of Obstetricians and Gynecologists Practice Bulletin on Noncontraceptive Uses of Hormonal Contraceptives, ethinyl estradiol and etonogestrel (among other oral contraceptive combinations) is effective and recommended for the management of menstrual bleeding (menorrhagia) [ACOG 2010].

Polycystic ovary syndrome (PCOS) in women with menstrual irregularities and hirsutism/acne

Based on the Endocrine Society Clinical Practice Guideline for the Diagnosis and Treatment of Polycystic Ovary Syndrome, ethinyl estradiol and etonogestrel (among other oral contraceptive combinations) is effective and recommended for the treatment of menstrual irregularities and hirsutism/acne in women with PCOS [ES [Legro 2013]].

Contraindications

Hypersensitivity, including anaphylaxis and angioedema, to ethinyl estradiol, etonogestrel, or any component of the formulation; breast cancer or other estrogen- or progestin-sensitive cancer (current or a history of); hepatic tumors (benign or malignant) or hepatic disease; pregnancy; undiagnosed abnormal uterine bleeding; concurrent use of hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir.

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); headaches with focal neurological symptoms; migraine headaches with aura or migraine headaches if >35 years of age; hypertension (uncontrolled); thrombogenic valvular or rhythm diseases of the heart (eg, subacute bacterial endocarditis with valvular disease, atrial fibrillation); women >35 years of age who smoke; inherited or acquired hypercoagulopathies.

Canadian labeling: Additional contraindications (not in US labeling): Prodromi of a thrombosis (eg, angina pectoris or transient ischemic attack); severe dyslipoproteinemia; major surgery with prolonged immobilization, any ocular lesion from ophthalmic vascular disease such as partial or complete loss of vision or defect in visual fields; pancreatitis or history of pancreatitis with severe hypertriglyceridemia

Documentation of allergenic cross-reactivity for progestins and estrogens is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Dosing: Adult

Contraception: Females: Vaginal: One ring, inserted vaginally and left in place continuously for 3 consecutive weeks, then removed for 1 week. A new ring is inserted 7 days after the last was removed (even if bleeding is not complete) and should be inserted at approximately the same time of day the ring was removed the previous week.

Initial treatment:

No hormonal contraceptive use in the past month: Insert ring on the first day of menstrual cycle ("Day 1"). May also insert on days 2 to 5 even if bleeding is not complete, however, a spermicide or barrier method of contraception should be used for the following 7 days.*

Switching from combination hormonal contraceptive: Ring can be inserted on any day but at the latest on the day following the usual hormone free interval, if she is using the hormonal method consistently and correctly, or if it is reasonably sure she is not pregnant.

Switching from progestin-only contraceptive: A spermicide or barrier method of contraception should be used for the following 7 days with any of the following.*

If previously using a progestin-only mini-pill, insert the ring on any day of the month; insert the vaginal ring on the day after the last mini-pill; do not skip days between the last pill and insertion of the ring.

If previously using an implant, insert the ring on the same day of implant removal.

If previously using a progestin-containing IUD, insert the ring on day of IUD removal.

If previously using a progestin injection, insert the ring on the day the next injection would be given.

Following complete 1st trimester abortion or miscarriage: Insert ring within the first 5 days of abortion or miscarriage. If not inserted within 5 days, follow instructions for "No hormonal contraceptive use within the past month" and instruct patient to use a nonhormonal contraceptive in the interim.

Following delivery or 2nd trimester abortion or miscarriage: Insert ring 4 weeks postpartum (in women who are not breast-feeding) or following 2nd trimester abortion or miscarriage. A spermicide or barrier method of contraception should be used for the following 7 days.*

Additional contraceptive considerations:

Inadvertent removal or expulsion: If the ring is accidentally removed from the vagina at any time during the 3-week period of use, it may be rinsed with cool or lukewarm water (not hot) and reinserted as soon as possible. If the ring is not reinserted within 3 hours, contraceptive effectiveness will be decreased. If the ring is accidently removed from the vagina for >3 continuous hours during weeks 1 and 2, the ring should be reinserted as soon as the woman remembers and a spermicide or barrier method of contraception should be used until the ring has been in place for 7 consecutive days.* If the ring is accidently removed from the vagina for >3 hours during week 3, the ring should be discarded. A new ring may be inserted immediately, restarting a new 3-week cycle, OR a new ring may be inserted ≤7 days from the time the previous ring was removed or expelled (the second option should only be done if a vaginal ring was in continuous use for ≥7 days prior to the inadvertent expulsion/removal). With either option, a spermicide or barrier method of contraception should be used until the ring has been in place for 7 consecutive days.*

If the ring has been removed for longer than 1 week or for an unknown period of time, pregnancy must be ruled out prior to restarting therapy. A spermicide or barrier method of contraception should be used for the following 7 days.*

Additional guidelines are available following delayed insertion/reinsertion of vaginal ring (Curtis 2016a).

Prolonged use: If the ring has been left in place for up to 1 extra week (up to 4 weeks total); a new ring should be inserted following a 1-week (ring-free) interval. Protection continues during week 4, however, if the ring is left in place >4 weeks, pregnancy must be ruled out prior to insertion and a spermicide or barrier method of contraception should be used for the following 7 days.*

Disconnected ring: In the event the ring disconnects at the weld joint, discard and replace with a new ring.

*Note: Certain female barrier methods (eg, diaphragm, female condom) may interfere with proper ring placement, and therefore, are not recommended for use as an additional form of contraception.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Pediatric

Contraception: Females: Children and Adolescents: Vaginal: Refer to adult dosing; not to be used prior to menarche.

Administration

Wash hands and remove ring from protective pouch (keep pouch for later ring disposal). Press sides of ring together between thumb and index finger and insert folded ring into vagina. An optional alternative is to insert using the ring applicator (available separately). Specific placement is not required for ring to be effective, but ring should be inserted far enough into the vagina as to be comfortable. To remove, hook index finger around rim and pull out. Vaginal ring cannot be disposed of in the toilet. New rings should be inserted at approximately the same time of day the ring was removed the previous week. If the ring accidentally falls out, it may be rinsed with cool or warm (not hot) water and replaced. However, it must be replaced within 3 hours. Refer to dosing if ring is out of place for >3 hours. Regularly check for the presence of the ring in the vagina (eg, before and after intercourse). Tampons do not interfere with the effectiveness of the ring; caution should be used when removing tampon not to remove ring. Certain female barrier methods (eg, diaphragm, female condom) may interfere with proper ring placement, and therefore, are not recommended for use as a back-up method of contraception. Ensure proper vaginal placement of the ring to avoid inadvertent urinary bladder insertion.

Storage

Prior to dispensing, store refrigerated at 2°C to 8°C (36°F to 46°F). After dispensing, can be stored for up to 4 months at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Avoid direct sunlight or temperatures above 30°C (86°F).

Drug Interactions

Acitretin: May diminish the therapeutic effect of Progestins (Contraceptive). 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

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

Antihepaciviral Combination Products: Ethinyl Estradiol may enhance the hepatotoxic effect of Antihepaciviral Combination Products. Management: Use of ethinyl estradiol must be discontinued prior to use of this combination; ethinyl estradiol can be restarted 2 weeks after cessation of the antihepaciviral combination product. Avoid combination

Aprepitant: May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Management: Use of a non-hormone-based contraceptive is recommended. Consider therapy modification

Aprepitant: May decrease the serum concentration of Progestins (Contraceptive). 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

Armodafinil: May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Management: Use alternative or concomitant methods of contraception in patients taking armodafinil and for one month after armodafinil discontinuation. Consider therapy modification

Armodafinil: May decrease the serum concentration of Progestins (Contraceptive). Management: Use alternative or concomitant methods of contraception in patients taking armodafinil and for one month after armodafinil discontinuation. Consider therapy modification

Artemether: May decrease the serum concentration of Estrogen Derivatives (Contraceptive). 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

Artemether: May decrease the serum concentration of Progestins (Contraceptive). 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

Asunaprevir: May decrease the serum concentration of Ethinyl Estradiol. Management: For patients using hormone-based contraception, a high-dose oral contraceptive containing at least 30 mcg of ethinyl estradiol combined with norethindrone acetate/norethindrone is recommended during treatment with asunaprevir. Consider therapy modification

Atazanavir: May increase the serum concentration of Progestins (Contraceptive). 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 Estrogen Derivatives (Contraceptive). Contraceptive failure is possible. Management: Use of a non-hormonal contraceptive is recommended. Breakthrough bleeding, though an important sign regarding the diminished effect of oral contraceptives, might not be present in spite of the occurrence of an interaction. Consider therapy modification

Barbiturates: May diminish the therapeutic effect of Progestins (Contraceptive). Contraceptive failure is possible. Management: Use of alternative, nonhormonal contraceptives is recommended. When using levonorgestrel as emergency contraception, non-US guidelines suggest doubling the dose of levonorgestrel to 3 mg in women who have used enzyme inducing drugs in the past 4 weeks. Consider therapy modification

Bexarotene (Systemic): May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Management: Women of childbearing potential receiving bexarotene should use two reliable forms of contraception (including at least one nonhormonal form) due to the risk of decreased systemic hormone concentrations and fetal harm. Consider therapy modification

Bexarotene (Systemic): May decrease the serum concentration of Progestins (Contraceptive). Management: Women of childbearing potential receiving bexarotene should use two reliable forms of contraception (including at least one nonhormonal form) due to the risk of decreased systemic hormone concentrations and fetal harm. Consider therapy modification

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

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

Bosentan: May decrease the serum concentration of Estrogen Derivatives (Contraceptive). 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

Bosentan: May decrease the serum concentration of Progestins (Contraceptive). 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

Brigatinib: May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Management: Females of childbearing potential should use an alternative, non-hormonal contraceptive during brigatinib therapy and for at least 4 months after the final brigatinib dose. Consider therapy modification

Brigatinib: May decrease the serum concentration of Progestins (Contraceptive). Management: Females of childbearing potential should use an alternative, non-hormonal contraceptive during brigatinib therapy and for at least 4 months after the final brigatinib dose. 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

CarBAMazepine: May diminish the therapeutic effect of Estrogen Derivatives (Contraceptive). Contraceptive failure is possible. Management: Use of a nonhormonal contraceptive is recommended. Breakthrough bleeding, though an important sign regarding the diminished effect of oral contraceptives, might not be present in spite of the occurrence of an interaction. Consider therapy modification

CarBAMazepine: May diminish the therapeutic effect of Progestins (Contraceptive). Contraceptive failure is possible. Management: Use of alternative, nonhormonal contraceptives is recommended. When using levonorgestrel as an emergency contraceptive, non-US recommendations suggest doubling the levonorgestrel dose to 3 mg if carbamazepine was used in the past 4 weeks. Consider therapy modification

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

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

Cenobamate: May decrease the serum concentration of Hormonal Contraceptives. Management: Women should use additional or alternative non-hormonal birth control while taking cenobamate. 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

Cladribine: May diminish the therapeutic effect of Hormonal Contraceptives. Management: Women using systemically acting hormonal contraceptives should add a barrier method during cladribine dosing and for at least 4 weeks after the last dose in each treatment course. Consider therapy modification

CloBAZam: May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Management: Use additional non-hormonal forms of contraception in patients treated with clobazam due to the potential for reduced contraceptive efficacy. Consider therapy modification

CloBAZam: May decrease the serum concentration of Progestins (Contraceptive). Management: Use additional non-hormonal forms of contraception in patients treated with clobazam due to the potential for reduced contraceptive efficacy. Consider therapy modification

CloZAPine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine. Monitor therapy

Cobicistat: May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Management: Consider an alternative, nonhormone-based contraceptive in patients receiving cobicistat-containing products. Consider therapy modification

Cobicistat: May increase the serum concentration of Progestins (Contraceptive). Management: Consider an alternative, nonhormone-based contraceptive in patients receiving cobicistat-containing products. Drospirenone is specifically contraindicated with atazanavir and cobicistat. Consider therapy modification

Colesevelam: May decrease the serum concentration of Ethinyl Estradiol. Management: Oral contraceptives containing ethinyl estradiol and norethindrone should be administered at least 4 hours before colesevelam. Consider therapy modification

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

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

Cosyntropin: Estrogen Derivatives may diminish the diagnostic effect of Cosyntropin. Management: Discontinue estrogen containing drugs 4 to 6 weeks prior to cosyntropin (ACTH) testing. Consider therapy modification

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

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Estrogen Derivatives. Monitor therapy

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

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to concomitant therapy when possible. If concomitant therapy cannot be avoided, monitor for reduced clinical effects of the CYP3A4 substrate. Consider therapy modification

Dabrafenib: May decrease the serum concentration of Estrogen Derivatives (Contraceptive). 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

Dabrafenib: May decrease the serum concentration of Progestins (Contraceptive). 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

Dantrolene: Estrogen Derivatives may enhance the hepatotoxic effect of Dantrolene. Monitor therapy

Darunavir: May decrease the serum concentration of Progestins (Contraceptive). 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

Dasabuvir: Ethinyl Estradiol may enhance the hepatotoxic effect of Dasabuvir. Avoid combination

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

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

Efavirenz: May decrease the serum concentration of Progestins (Contraceptive). 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

Elagolix: Estrogen Derivatives (Contraceptive) may diminish the therapeutic effect of Elagolix. Management: Use an alternative, non-hormonal contraceptive during treatment with elagolix and for at least 1 week following discontinuation of elagolix treatment. Consider therapy modification

Elexacaftor, Tezacaftor, and Ivacaftor: Hormonal Contraceptives may enhance the adverse/toxic effect of Elexacaftor, Tezacaftor, and Ivacaftor. Specifically, the risk for rash may be increased. Monitor therapy

Elvitegravir: May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Management: Consider the use of an alternative, non-hormone-based contraceptive, in patients who are being treated with elvitegravir-containing products. Consider therapy modification

Encorafenib: May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Avoid combination

Encorafenib: May decrease the serum concentration of Progestins (Contraceptive). Avoid combination

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

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

Eslicarbazepine: May decrease the serum concentration of Progestins (Contraceptive). 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

Exenatide: May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Management: Administer oral contraceptives at least one hour prior to exenatide. Consider therapy modification

Exenatide: May decrease the serum concentration of Progestins (Oral Contraceptive). Management: Administer oral contraceptives at least one hour prior to exenatide. Consider therapy modification

Felbamate: May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Contraceptive failure is possible. Management: Use of a nonhormonal contraceptive is recommended. Use of higher doses of hormonal contraceptives may achieve adequate concentrations of hormones; monitoring serum hormn concentrations may be necessary. Monitor closely. Consider therapy modification

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

Flibanserin: Estrogen Derivatives (Contraceptive) may increase the serum concentration of Flibanserin. Monitor therapy

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

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

Fosaprepitant: May decrease the serum concentration of Progestins (Contraceptive). 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

Fosphenytoin: May diminish the therapeutic effect of Estrogen Derivatives (Contraceptive). Contraceptive failure is possible. Management: Use of an alternative, nonhormonal means of contraception is recommended. Consider therapy modification

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

Fostemsavir: May increase the serum concentration of Ethinyl Estradiol. Management: Ethinyl estradiol daily dose should not exceed 30 mcg during coadministration with fostemsavir. Monitor patients closely for any evidence of a thromboembolism. Consider therapy modification

Glecaprevir and Pibrentasvir: Ethinyl Estradiol may enhance the adverse/toxic effect of Glecaprevir and Pibrentasvir. Specifically, the risk for ALT elevation may be increased with this combination. Avoid combination

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

Growth Hormone Analogs: Estrogen Derivatives may diminish the therapeutic effect of Growth Hormone Analogs. Management: Initiate somapacitan at 2 mg once weekly in patients receiving oral estrogens. Monitor for reduced efficacy of growth hormone analogs; increased doses may be required. Consider therapy modification

Guanethidine: Estrogen Derivatives (Contraceptive) may diminish the therapeutic effect of Guanethidine. Monitor therapy

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. Monitor therapy

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

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

Ivosidenib: May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Management: Consider alternative methods of contraception (ie, non-hormonal) in patients receiving ivosidenib. Consider therapy modification

Ivosidenib: May decrease the serum concentration of Progestins (Contraceptive). Management: Consider alternative methods of contraception (ie, non-hormonal) in patients receiving ivosidenib. Consider therapy modification

Ixazomib: May decrease the serum concentration of Progestins (Contraceptive). More specifically, use of ixazomib with dexamethasone may decrease the serum concentrations of contraceptive progestins. Management: Patients of childbearing potential should use a nonhormonal barrier contraceptive during and 90 days following ixazomib treatment. Avoid combination

Lactic Acid, Citric Acid, and Potassium Bitartrate: Ethinyl Estradiol may diminish the therapeutic effect of Lactic Acid, Citric Acid, and Potassium Bitartrate. Avoid combination

LamoTRIgine: Estrogen Derivatives (Contraceptive) may decrease the serum concentration of LamoTRIgine. Management: Larger doses of lamotrigine may be needed when combined with estrogens. Specific dosing recommendations vary based on other concomitant medications and which medication is being initiated or discontinued. See interaction monograph for details. Consider therapy modification

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

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

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

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

Lomitapide: Ethinyl Estradiol may increase the serum concentration of Lomitapide. Management: Patients on lomitapide 5 mg/day may continue that dose. Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half. The lomitapide dose may then be titrated up to a max adult dose of 40 mg/day. Consider therapy modification

Lopinavir: May decrease the serum concentration of Progestins (Contraceptive). Lopinavir may increase the serum concentration of Progestins (Contraceptive). 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

Lumacaftor and Ivacaftor: May decrease the serum concentration of Hormonal Contraceptives. Management: Do not rely on hormone-based contraceptives with concurrent use of lumacaftor/ivacaftor; an alternative, non-hormonal, method of contraception should be used if this combination is required. Consider therapy modification

Metreleptin: May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Metreleptin may increase the serum concentration of Estrogen Derivatives (Contraceptive). Monitor therapy

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

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

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

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

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

Modafinil: May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Management: Use alternative or concomitant methods of contraception in patients taking modafinil and for one month after modafinil discontinuation. Consider therapy modification

Modafinil: May decrease the serum concentration of Progestins (Contraceptive). Management: Use alternative or concomitant methods of contraception in patients taking modafinil and for one month after modafinil discontinuation. Consider therapy modification

Mycophenolate: May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Average AUC values were unchanged, but there was evidence of substantial patient-to-patient variability in response to this combination. Management: Women of childbearing potential who are receiving mycophenolate mofetil should consider using an alternative and/or additional form of contraception. Consider therapy modification

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

Nafcillin: May increase the metabolism of Estrogen Derivatives (Contraceptive). Management: Use of an alternative, nonhormonal form of contraception during nafcillin therapy is recommended. Consider therapy modification

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

Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective): May enhance the thrombogenic effect of Estrogen Derivatives. Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective) may increase the serum concentration of Estrogen Derivatives. Monitor therapy

Octreotide: May decrease the serum concentration of Hormonal Contraceptives. Management: Women should use an alternative non-hormonal method of contraception or a back-up method when octreotide is combined with hormonal contraceptives. Consider therapy modification

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 Estrogen Derivatives (Contraceptive). Contraceptive failure is possible. Management: Use of an alternative, nonhormonal contraceptive is recommended. Breakthrough bleeding, though an important sign regarding the diminished effect of hormonal contraceptives, might not be present in spite of the occurrence of an interaction. Consider therapy modification

OXcarbazepine: May decrease the serum concentration of Progestins (Contraceptive). 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 Progestins (Contraceptive). Management: Patients should use an alternative, nonhormonal-based form of contraception both during the concurrent use of perampanel and for 1 month after discontinuing perampanel. Oral and non-oral contraceptives likely participate in this interaction. Consider therapy modification

Pexidartinib: May decrease the serum concentration of Hormonal Contraceptives. Management: Use an effective non-hormonal form of contraception. Avoid combination

Phenytoin: May diminish the therapeutic effect of Estrogen Derivatives (Contraceptive). Contraceptive failure is possible. Management: Use of an alternative, nonhormonal means of contraception is recommended. Consider therapy modification

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

Pitolisant: May decrease the serum concentration of Hormonal Contraceptives. Management: Patients using hormonal contraception should be advised to use an alternative non-hormonal contraceptive method during treatment with pitolisant and for at least 21 days after discontinuation of pitolisant treatment. Consider therapy modification

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

Primidone: May diminish the therapeutic effect of Progestins (Contraceptive). Contraceptive failure is possible. Management: Use of alternative, nonhormonal contraceptives is recommended. When using levonorgestrel as emergency contraception, non-US guidelines suggest doubling the dose of levonorgestrel to 3 mg in women who have used enzyme inducing drugs in the past 4 weeks. Consider therapy modification

Proguanil: Ethinyl Estradiol may diminish the therapeutic effect of Proguanil. Monitor therapy

Protease Inhibitors: May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Management: Use oral contraceptives containing at least 35mcg ethinyl estradiol with atazanavir/ritonavir, or no more than 30mcg in patients receiving atazanavir alone. Use of an alternative, non-hormonal contraceptive is recommended with other protease inhibitors. Consider therapy modification

Retinoic Acid Derivatives: May diminish the therapeutic effect of Progestins (Contraceptive). Retinoic Acid Derivatives may decrease the serum concentration of Progestins (Contraceptive). Management: Two forms of effective contraception should be used in patients receiving retinoic acid derivatives. Microdosed progesterone-only preparations (ie, minipills that do not contain estrogen) are considered an inadequate method of contraception. Consider therapy modification

Rifamycin Derivatives: May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Contraceptive failure is possible. Management: Contraceptive failure is possible. Use of an alternative, nonhormonal contraceptive is recommended. Consider therapy modification

Rifamycin Derivatives: May decrease the serum concentration of Progestins (Contraceptive). Contraceptive failure is possible. Management: Contraceptive failure is possible. Use of an alternative, nonhormonal contraceptive is recommended. Recommendations outside the US recommend doubling the levonorgestrel dose to 3 mg if used for emergency contraception. Consider therapy modification

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

Rufinamide: May decrease the serum concentration of Hormonal Contraceptives. Management: Use of rufinamide may reduce the effectiveness of hormonal contraceptives. Advise patients who are using a hormonal contraceptive with rufinamide to use an additional non-hormonal form of contraception during concomitant therapy. Consider therapy modification

Saquinavir: May decrease the serum concentration of Progestins (Contraceptive). 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

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Selegiline: Estrogen Derivatives (Contraceptive) may increase the serum concentration of Selegiline. Monitor therapy

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

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

St John's Wort: May diminish the therapeutic effect of Estrogen Derivatives (Contraceptive). Contraceptive failure is possible. Management: Consider an alternative to St John's wort if possible. If this combination is used, an alternative, nonhormonal contraceptive is recommended. Consider therapy modification

St John's Wort: May diminish the therapeutic effect of Progestins (Contraceptive). Contraceptive failure is possible. Management: Consider using a product other than St John's wort. Contraceptive failure is possible. Use of an alternative, nonhormonal contraceptive is recommended. Consider therapy modification

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

Sugammadex: May decrease the serum concentration of Progestins (Contraceptive). 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

Sugammadex: May decrease the serum concentration of Estrogen Derivatives (Contraceptive). 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

Tazemetostat: May decrease the serum concentration of Hormonal Contraceptives. Management: Women of reproductive potential should use a non-hormonal contraceptive method during treatment with tazemetostat and for 6 months after. Men with female partners should use contraception during treatment and for 3 months after. Consider therapy modification

Tetrahydrocannabinol and Cannabidiol: May decrease the serum concentration of Hormonal Contraceptives. Management: Women using hormonal contraceptives should consider adding a barrier contraceptive due to the potential for tetrahydrocannabinol and cannabidiol to decrease concentrations and effectiveness of hormonal contraceptives. Consider therapy modification

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

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

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

Theophylline Derivatives: CYP1A2 Inhibitors (Weak) may increase the serum concentration of Theophylline Derivatives. 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: Consider alternative, non-hormonal forms of contraception. If used as hormone replacement therapy, monitor for estrogen deficiency. Monitor all patients using tipranavir/ritonavir and ethinyl estradiol/norethindrone for dermatologic adverse effects. Consider therapy modification

Tipranavir: May increase the serum concentration of Progestins (Contraceptive). 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 is necessary, initiate tizanidine at an adult dose of 2 mg and increase in 2 to 4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

Tobacco (Smoked): May enhance the adverse/toxic effect of Estrogen Derivatives (Contraceptive). Specifically, the risk of serious cardiovascular events (eg, stroke, venous thromboembolism, myocardial infarction) may be increased. Management: Avoid cigarette smoking in patients who use estrogen containing contraceptives whenever possible. If combined, monitor for signs and symptoms of serious cardiovascular events (eg, stroke, venous thromboembolism, myocardial infarction). Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Topiramate: May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Contraceptive failure is possible. Management: Risk of contraceptive failure appears greatest for higher topiramate doses (200 mg/day or greater). May consider using at least 50 mcg/day of ethinyl estradiol, but the effectiveness of this is unclear. Consider a nonhormonal form of contraception. Consider therapy modification

Topiramate: May decrease the serum concentration of Progestins (Contraceptive). 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: Progestins (Contraceptive) may enhance the thrombogenic effect of Tranexamic Acid. Avoid combination

Tranexamic Acid: Estrogen Derivatives (Contraceptive) may enhance the thrombogenic effect of Tranexamic Acid. Avoid combination

Triazolam: Hormonal Contraceptives may increase the serum concentration of Triazolam. Monitor therapy

Ulipristal: Progestins may diminish the therapeutic effect of Ulipristal. Ulipristal may diminish the therapeutic effect of Progestins. 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

Valproate Products: Estrogen Derivatives (Contraceptive) may decrease the serum concentration of Valproate Products. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Estrogen Derivatives (Contraceptive) may diminish the anticoagulant effect of Vitamin K Antagonists. In contrast, enhanced anticoagulant effects have also been noted with some products. Management: Avoid coadministration of estrogen-containing contraceptives and vitamin K antagonists. Consider nonhormonal methods of contraception in patients requiring vitamin K antagonists. If combined, monitor for changes in coagulation status. Consider therapy modification

Vitamin K Antagonists (eg, warfarin): Progestins (Contraceptive) 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 decrease the metabolism of Estrogen Derivatives (Contraceptive). Estrogen Derivatives (Contraceptive) may increase the serum concentration of Voriconazole. Monitor therapy

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

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

>10%:

Central nervous system: Headache (11%)

Endocrine & metabolic: Intermenstrual bleeding (7% to 12%)

Genitourinary: Vaginitis (14%)

1% to 10%:

Central nervous system: Mood changes (6%)

Dermatologic: Acne vulgaris (2%)

Endocrine & metabolic: Weight gain (5%), amenorrhea (≤4%), decreased libido (2%)

Gastrointestinal: Nausea (≤6%), vomiting (≤6%), abdominal pain (3%)

Genitourinary: Vaginal discharge (6%), dysmenorrhea (4%), vaginal discomfort (4%), breast tenderness (≤4%), mastalgia (≤4%)

Frequency not defined:

Cardiovascular: Deep vein thrombosis

Central nervous system: Anxiety

Gastrointestinal: Cholelithiasis

<1%, postmarketing, and/or case reports: Acute myocardial infarction, anaphylaxis, angioedema, arterial thromboembolism, cerebrovascular accident, chloasma, galactorrhea not associated with childbirth, hypersensitivity reaction, toxic shock syndrome, urticaria, venous thromboembolism, worsening of varicose veins

ALERT: U.S. Boxed Warning

Cigarette smoke and serious cardiovascular events:

Cigarette smoking increases the risk of serious cardiovascular events from combination hormonal contraceptive (CHC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, CHCs, including ethinyl estradiol/etonogestrel, should not be used by women who are over 35 years of age and smoke.

Warnings/Precautions

Concerns related to adverse effects:

• Breast cancer: In women at risk for breast cancer due to family history or susceptibility genes (BRCA1, BRCA2), the use of combination hormonal contraceptives has not been shown to modify the risk for breast cancer. However, breast cancer is a hormonal sensitive tumor and the prognosis for women with a current or recent history of breast cancer may be worse with combination hormonal contraceptive use (Curtis 2016b). Use is contraindicated in women with (or history of) breast cancer.

• Cervical cancer: The use of combination hormonal contraceptives has been associated with a slight increased risk of cervical cancer or intraepithelial neoplasia; however, studies are not consistent and may be related to additional risk factors (Gierisch 2013). Theoretically, use may affect prognosis of existing disease. Women awaiting treatment for cervical cancer may use combination hormonal contraceptives (Curtis 2016b).

• Chloasma: Combination hormonal contraceptives, as well as sun exposure and pregnancy, are triggers for chloasma. Women with a susceptibility to chloasma or additional risk factors should avoid exposure to sun or ultraviolet radiation during therapy (Handel 2014).

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

• Hypersensitivity reactions: Anaphylaxis and angioedema have been reported.

• Lipid effects: Combination hormonal contraceptives may adversely affect lipid levels, including serum triglycerides. Women with hypertriglyceridemia or a family history of hypertriglyceridemia may be at increased risk of pancreatitis when using combination hormonal contraceptives. Consider alternative contraception for women with uncontrolled dyslipidemia.

• Retinal vascular thrombosis: Discontinue if unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions occur and immediately evaluate for retinal vein thrombosis.

• Thromboembolic disorders: Discontinue use of combination hormonal contraceptives if an arterial or venous thrombotic event occurs. Oral contraceptives may increase the risk of venous thromboembolism (risk is greatest during first year of use and less than the risk associated with pregnancy); some studies suggest this risk may be higher in preparations with third- or fourth-generation progestins and/or high dose ethinyl estradiol. Women with inherited thrombophilias (eg, protein C or S deficiency, factor V Leiden mutation, prothrombin mutation, antithrombin deficiency) may have increased risk of venous thromboembolism. Age >35 years, hypertension, obesity, and tobacco use also increase the risk of thrombotic events in women taking combination hormonal contraceptives (ASRM 2017; Curtis 2016b; DeSancho 2010; van Vlijmen 2011). Combination hormonal contraceptives may also increase the risk of arterial thrombosis (eg, MI, stroke) and should not be used in women with a history of stroke or ischemic heart disease (Curtis 2016b). Use of combination hormonal contraceptives is contraindicated in women with a high risk of arterial or venous thrombotic disease.

• Toxic shock syndrome: Has been reported (causal relationship has not been established); increased risk with tampon use.

• Vaginal bleeding: Breakthrough or intracyclic bleeding and spotting may occur, especially during the first 3 months of therapy. In addition, occasional missed periods may occur. Presentation of irregular, unresolving vaginal bleeding warrants further evaluation to rule out malignancy or pregnancy. Amenorrhea or oligomenorrhea may occur after discontinuing combination hormonal contraceptives, especially when such a condition was preexistent.

Disease-related concerns:

• Bariatric surgery:

- Altered absorption: Consider nonoral contraceptive options in patients who had specific bariatric procedures (Roux-en-Y, biliopancreatic diversion); malabsorptive procedures can potentially decrease absorption of oral contraceptives (Kominiarek 2017; Mechanick 2013; Schlatter 2017). It is difficult to recommend against the use of oral contraceptives in restrictive procedures (sleeve gastrectomy, gastric banding) as the evidence is limited (Merki-Feld 2015).

- Venous thromboembolism risk: Consider discontinuation of estrogen-containing medications 30 days prior to bariatric surgery to reduce risk of venous thromboembolism; however, practice may vary based upon institutional protocols (Mechanick 2013).

• Cardiovascular disease: Use with caution in patients with risk factors for cardiovascular disease (eg, hypertension, low HDL, high LDL, high triglycerides, older age, diabetes, women who smoke); use of combination hormonal contraceptives may increase the risk of cardiovascular disease (Curtis 2016b). Use is contraindicated in women at high risk of arterial or venous thrombotic diseases.

• Depression: Use with caution in patients with a history of depression; discontinue if serious depression recurs.

• Diabetes: May impair glucose tolerance; use caution in women with diabetes or prediabetes. In general, use of combination oral contraceptives has limited effects on daily insulin needs and no long term effects on diabetes control in women with nonvascular disease. However, use in women with concomitant nephropathy, neuropathy, retinopathy, other vascular disease, or diabetes >20 years duration should be evaluated for contraceptive use based on the severity of the condition (Curtis 2016b). Use is contraindicated in women with diabetes mellitus and vascular disease.

• Endometrial or ovarian cancer: The risk of endometrial or ovarian cancer is decreased in women using combination hormonal contraceptives; it is not known if use of the contraceptive ring also decreases this risk (Curtis 2016b; Walker 2015). Women awaiting treatment for endometrial or ovarian cancer may use combination hormonal contraceptives (Curtis 2016b).

• Gallbladder disease: Combination hormonal contraceptives may have a small increased risk of gallbladder disease or worsen existing gallbladder disease (Curtis 2016b).

• Hepatic adenomas or carcinomas: Use of combination hormonal contraceptives is associated with hepatic adenomas (rare); rupture may cause fatal intra-abdominal hemorrhage. Long term use may be associated with an increased risk of hepatocellular carcinoma (rare). Use is contraindicated in women with preexisting hepatic tumors.

• Hepatic impairment: Combination hormonal contraceptives may be poorly metabolized in women with hepatic impairment. Use is contraindicated in hepatic disease. Discontinue if jaundice develops during therapy or if liver function becomes abnormal. Use of combination hormonal contraceptives may be considered in women with mild (compensated) cirrhosis but should not be used in women with severe (decompensated) cirrhosis (Curtis 2016b).

• Hepatitis: Initiation of combination hormonal contraceptives is not recommended in women with acute viral hepatitis or during a flare. Continuation of use in women with chronic hepatitis has not been shown to increase the rate or severity of cirrhotic fibrosis or hepatocellular carcinoma. Continuation of use in women who are carriers has not been shown to trigger liver failure or severe hepatic dysfunction (Curtis 2016b).

• Hereditary angioedema: Estrogens may induce or exacerbate symptoms in women with hereditary angioedema (Geng 2013; Zuraw 2013).

• Hypertension: The risk of hypertension may be increased with age, dose, and duration of use. Combination hormonal contraceptives should not be used in women with hypertension and vascular disease, or persistent blood pressure values ≥160 mm Hg systolic or ≥100 mm Hg diastolic. The risks of use may not outweigh the benefits of treatment in women with less severe hypertension (140 to 159 mm Hg systolic or 90 to 99 mm Hg diastolic) or those with hypertension that is adequately controlled (Curtis 2016a). Other risk factors for cardiovascular disease (eg, older age, smoking, diabetes) should be considered when prescribing contraceptives (Curtis 2016b). The manufacturer contraindicates use in women with uncontrolled hypertension and recommends monitoring women with well-controlled hypertension; discontinue therapy if blood pressure rises significantly.

• Migraine: Evaluate new, recurrent, severe, or persistent headaches and consider discontinuing therapy if appropriate. Use of combination hormonal contraceptives may be considered in women who have migraines without aura (including menstrual migraines) (Curtis 2016b). Use in women with headaches with focal neurological symptoms, or migraine headaches with or without aura if >35 years of age is contraindicated.

• Solid organ transplant: Although data is limited, serious medical complications have been reported in women with complicated organ transplants (eg, graft failure, rejection, cardiac allograft vasculopathy); use of combination hormonal contraceptives is not recommended in women with complicated organ transplants (Curtis 2016b).

• Systemic lupus erythematosus: Women with systemic lupus erythematosus (SLE) are at an increased risk for heart disease, stroke, and VTE. Combination hormonal contraceptives should not be used in women with SLE who have positive (or unknown) antiphospholipid antibodies, due to an increased risk of arterial and venous thrombosis (Curtis 2016b).

Concurrent drug therapy issues:

• 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: In a study using the vaginal ring, ethinyl estradiol serum concentrations were decreased in obese women (BMI 30 to 39.9 kg/m2; n=19) in comparison to women of normal weight (BMI 19 to 24.9 kg/m2; n=18; p=0.004); etonogestrel concentrations did not differ significantly. Bleeding and spotting were more frequent in the obese women. The study was not powered to evaluate contraceptive effectiveness (Westhoff 2012).

• Pediatric: Not for use prior to menarche.

• Postmenopausal women: Use is not indicated in postmenopausal women.

• Smokers:[US Boxed Warning]: 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, and with the number of cigarettes smoked. For this reason, combination oral contraceptives should not be used by women who are >35 years of age and smoke.

• Surgical patients: Whenever possible, discontinue at least 4 weeks prior to and for 2 weeks following major surgery or other surgeries known to have an increased risk of thromboembolism or during periods of prolonged immobilization.

Dosage form specific issues:

• Vaginal preparation: Vaginally administered combination hormonal contraceptive agents may have similar adverse effects associated with oral contraceptive products. In order to reduce some of the possible risks, the minimum dosage combination of estrogen/progestin that will effectively treat the individual patient should be used. May not be appropriate for use in women with conditions that make the vagina susceptible to irritation or ulceration; vaginal/cervical erosion and ulceration has been reported. Ring breakage has been reported including with concomitant use of intravaginal products (eg, antibiotic, antifungal, lubricant) and may cause vaginal injury and associated pain, discomfort, and bleeding. The patients and their sexual partner may feel the ring in the vagina during intercourse. Ensure proper vaginal placement of the ring to avoid inadvertent urinary bladder insertion.

Other warnings/precautions:

• HIV infection protection: Combination hormonal contraceptives do not protect against HIV infection or other sexually transmitted diseases (Curtis 2016a; Curtis 2016b).

• 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).

Monitoring Parameters

Assessment of pregnancy status (prior to therapy); blood pressure (prior to therapy and yearly); weight (optional; BMI at baseline may be helpful to monitor changes during therapy); assess potential health status changes at routine visits (Curtis 2016a).

If vaginal ring was out of the vagina >3 hours, or the ring free interval was extended for >1 week, and 1 menstrual period is missed, the possibility of pregnancy should be considered. If the ring was used as directed and 2 consecutive menstrual periods are missed, assess pregnancy status before a new dosing cycle is started. In addition, assess pregnancy status if ring was in place >4 weeks.

Monitor patient for vision changes; 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. In patients with persistent urinary symptoms, assess for inadvertent urinary bladder insertion if ring is not otherwise located.

Reproductive Considerations

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.

Due to the increased risk of venous thromboembolism (VTE) postpartum, combination hormonal contraceptives should not be started in any woman <21 days following delivery. The risk decreases to baseline by postpartum day 42. Use of combination hormonal contraceptives in women between 21 and 42 days after delivery should take into consideration the individual woman's risk factors for VTE (eg, age ≥35 years, previous VTE, thrombophilia, immobility, preeclampsia, transfusion at delivery, cesarean delivery, peripartum cardiomyopathy, BMI ≥30 kg/m2, postpartum hemorrhage, smoking) (Curtis 2016b).

Pregnancy Considerations

Use is contraindicated in pregnant women. Combination hormonal contraceptives are used to prevent pregnancy; treatment should be discontinued if pregnancy occurs. In general, the use of combination hormonal contraceptives, when inadvertently used early in pregnancy, have not been associated adverse fetal or maternal effects (Curtis 2016b).

Patient Education

What is this drug used for?

• It is used to prevent pregnancy.

• It may be given to you for other reasons. Talk with the doctor.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Acne

• Abdominal pain

• Vaginal irritation

• Weight gain

• Nausea

• Vomiting

• Tender breasts

• Decreased sex drive

• Menstrual changes

• Dark patches on face

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight

• Blood clots like numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; chest pain; shortness of breath; fast heartbeat; or coughing up blood.

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.

• Gallstones like pain in the upper right abdominal area, right shoulder area, or between the shoulder blades; yellow skin; or fever with chills.

• Severe dizziness

• Passing out

• Severe headache

• Depression

• Mood changes

• Blindness

• Lump in breast

• Breast soreness or pain

• Nipple discharge

• Vaginal pain

• Abnormal vaginal bleeding

• Vaginal pain, itching, and discharge

• Vision changes

• Contact lens discomfort

• Bulging eyes

• Toxic shock syndrome like diarrhea, dizziness, passing out, severe muscle pain, nausea, vomiting, or sunburn like rash.

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Frequently asked questions

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.