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Ethinyl Estradiol and Etonogestrel

Pronunciation

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

Index Terms

  • Etonogestrel and Ethinyl Estradiol

Dosage Forms

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

Ring, vaginal:

NuvaRing: Ethinyl estradiol 0.015 mg/day and etonogestrel 0.12 mg/day (3s) [3-week duration]

Brand Names: U.S.

  • NuvaRing

Pharmacologic Category

  • Contraceptive
  • Estrogen and Progestin Combination

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.

Contraindications

Hypersensitivity 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.

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; hypertension (uncontrolled); thrombogenic valvular or rhythm diseases of the heart (eg, subacute bacterial endocarditis with valvular disease, atrial fibrillation); women >35 years 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 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 2-5 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 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, 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: Diaphragms may interfere with proper ring placement, and therefore, are not recommended for use as an additional form of contraception.

Dosing: Pediatric

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

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Hepatic Impairment

Use is contraindicated.

Administration

Vaginal: 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. Tampons do not interfere with the effectiveness of the ring; caution should be used when removing tampon not to remove ring. The ring may interfere with correct placement of diaphragms; diaphragms should not be used 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 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

Agomelatine: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Agomelatine. Monitor therapy

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

Antihepaciviral Combination Products: Ethinyl Estradiol may enhance the hepatotoxic effect of Antihepaciviral Combination Products. Avoid combination

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

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

Armodafinil: May decrease the serum concentration of Contraceptives (Estrogens). Management: The manufacturer recommends that patients use nonhormonal contraceptives, in addition to or in place of hormonal contraceptives, during and for one month following treatment with armodafinil. Consider therapy modification

Artemether: May decrease the serum concentration of Contraceptives (Estrogens). 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 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

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 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 (Estrogens). Contraceptive failure is possible. Management: Use of a non-hormonal contraceptive is recommended. 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 (Estrogens). Management: Women of childbearing potential receiving bexarotene should use two reliable forms of contraception (including at least one nonhormonal form). 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 (Estrogens). Management: Administer estrogen-based oral contraceptives at least 1-4 hours prior to or 4-6 hours after administration of a bile acid sequestrant. 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 decrease the serum concentration of Contraceptives (Estrogens). 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. Consider therapy modification

Boceprevir: May increase the serum concentration of Contraceptives (Progestins). This has been seen specifically with drospirenone. Boceprevir may increase the serum concentration of Contraceptives (Progestins). This has been seen specifically with norethindrone. 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 (Estrogens). 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 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

Brigatinib: May decrease the serum concentration of Contraceptives (Estrogens). 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 Contraceptives (Progestins). 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 Contraceptives (Estrogens). Contraceptive failure is possible. Management: Use of a nonhormonal contraceptive is recommended. Consider therapy modification

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

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

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 (Estrogens). Consider therapy modification

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

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

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

Colesevelam: May decrease the serum concentration of Ethinyl Estradiol. Consider therapy modification

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

CYP1A2 Substrates: CYP1A2 Inhibitors (Moderate) may decrease the metabolism of CYP1A2 Substrates. Monitor therapy

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

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

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 (Estrogens). 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 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

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

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

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

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 diminish the therapeutic effect of Etonogestrel. Management: Use a reliable barrier contraceptive if efavirenz is used in combination with etonogestrel. Continue using barrier contraception for 12 weeks after discontinuation of efavirenz. Consider therapy modification

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

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. 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

Eslicarbazepine: May decrease the serum concentration of Contraceptives (Estrogens). 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 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

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

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

Felbamate: May decrease the serum concentration of Contraceptives (Estrogens). Contraceptive failure is possible. Management: Use of a nonhormonal contraceptive is recommended. Consider therapy modification

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 (Estrogens) may increase the serum concentration of Flibanserin. Monitor therapy

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 (Estrogens). 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 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

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

Ixazomib: May decrease the serum concentration of Contraceptives (Progestins). 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

LamoTRIgine: Contraceptives (Estrogens) may decrease the serum concentration of LamoTRIgine. Management: Monitor for increased serum concentrations/effects of lamotrigine in patients in whom a hormonal contraceptive is discontinued/dose decreased (this includes during a pill-free week). A reduced dosage of lamotrigine may be needed. Consider therapy modification

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

Lesinurad: May decrease the serum concentration of Contraceptives (Estrogens). 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 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 (Estrogens). 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 Contraceptives (Progestins). 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 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

Lumacaftor: May decrease the serum concentration of Contraceptives (Estrogens). 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

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

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

MiFEPRIStone: May diminish the therapeutic effect of Contraceptives (Estrogens). MiFEPRIStone may increase the serum concentration of Contraceptives (Estrogens). 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. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Modafinil: May decrease the serum concentration of Contraceptives (Estrogens). Management: The manufacturer recommends that patients use nonhormonal contraceptives, in addition to or in place of hormonal contraceptives, during and for one month following treatment with modafinil. Consider therapy modification

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

Nafcillin: May increase the metabolism of Contraceptives (Estrogens). Management: Use of an alternative, nonhormonal form of contraception during nafcillin therapy is recommended. 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 (Estrogens). 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 (Estrogens). Contraceptive failure is possible. Management: Use of an alternative, nonhormonal contraceptive is recommended. Consider therapy modification

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

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

Pirfenidone: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Pirfenidone. Management: Use any such combination with caution and close monitoring for pirfenidone toxicity. Avoid the use of pirfenidone with moderate CYP1A2 inhibitors whenever CYP2C9, 2C19, 2C6, or 2E1 is also inhibited (either by the CYP1A2 inhibitor or by a third drug). 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 Contraceptives (Progestins). Contraceptive failure is possible. Management: Use of alternative, nonhormonal contraceptives is recommended. Consider therapy modification

Protease Inhibitors: May decrease the serum concentration of Contraceptives (Estrogens). 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. Exceptions: Indinavir. Consider therapy modification

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

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

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

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

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

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

Rufinamide: May decrease the serum concentration of Ethinyl Estradiol. Consider therapy modification

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

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

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

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

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

St John's Wort: May diminish the therapeutic effect of Contraceptives (Estrogens). 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 Contraceptives (Progestins). 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

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

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

Sugammadex: May decrease the serum concentration of Contraceptives (Estrogens). 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 (Estrogens). 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

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

Thalidomide: Contraceptives (Estrogens) may enhance the thrombogenic effect of Thalidomide. 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 (Moderate) may increase the serum concentration of TiZANidine. Management: If combined use cannot be avoided, initiate tizanidine in adults at 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Avoid combination

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

Topiramate: May decrease the serum concentration of Contraceptives (Estrogens). Contraceptive failure is possible. Management: Risk appears greatest for higher topiramate doses (200 mg/day or greater). Some have recommended 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 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

Tranexamic Acid: Contraceptives (Estrogens) 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

Valproate Products: Contraceptives (Estrogens) may decrease the serum concentration of Valproate Products. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Contraceptives (Estrogens) may diminish the anticoagulant effect of Vitamin K Antagonists. In contrast, enhanced anticoagulant effects have also been noted with some products. Consider therapy modification

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 decrease the metabolism of Contraceptives (Estrogens). Contraceptives (Estrogens) may increase the serum concentration of Voriconazole. Monitor therapy

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

Adverse Reactions

The most common adverse reactions associated with NuvaRing (5% to 14%): Headache, mood changes, nausea and vomiting, sinusitis, upper respiratory tract infection, vaginal discharge, vaginitis, and weight gain. The following reactions have been associated with combination hormonal contraceptive use:

Increased risk or evidence of association with use:

Cardiovascular: Arterial thromboembolism, cerebral thrombosis, hypertension, local thrombophlebitis, mesenteric thrombosis, myocardial infarction, pulmonary embolism, retinal thrombosis, venous thrombosis (with or without embolism)

Central nervous system: Cerebral hemorrhage

Endocrine & metabolic: Decreased glucose tolerance, increased corticosteroid-binding globulin, increased sex hormone-binding globulin, increased thyroxine-binding globulin

Gastrointestinal: Gallbladder disease

Hepatic: Hepatic adenomas, hepatic carcinoma (long-term use [>8 years]), hepatic neoplasm (benign)

Adverse reactions considered drug related:

Cardiovascular: Deep vein thrombosis, edema, worsening of varicose veins

Central nervous system: Anxiety, depression, exacerbation of tics, migraine

Dermatologic: Acne vulgaris, allergic skin rash, chloasma

Endocrine & metabolic: Amenorrhea, breast changes (enlargement, pain, secretion, tenderness), change in menstrual flow, decreased libido, decreased serum folate level, exacerbation of porphyria, fluid retention, weight changes

Gastrointestinal: Abdominal cramps, abdominal pain, bloating, change in appetite, cholelithiasis, nausea, vomiting

Genitourinary: Breakthrough bleeding, cervical ectropion, cervical erosion, change in cervical secretions, decreased lactation (with use immediately postpartum), dysmenorrhea, infertility (temporary), spotting, vaginal discomfort, vaginal ulcer, vaginitis, vulvovaginal candidiasis

Hepatic: Cholestatic jaundice

Hypersensitivity: Anaphylactoid reactions (including angioedema, circulatory collapse, respiratory collapse, urticaria), anaphylaxis

Neuromuscular & skeletal: Exacerbation of systemic lupus erythematosus

Ophthalmic: Change in corneal curvature (steepening), contact lens intolerance

Adverse reactions in which association is not confirmed or denied (Limited to important or life-threatening): Budd-Chiari syndrome, cataract, cerebrovascular accident, cervical dysplasia, colitis, cystitis-like syndrome, erythema multiforme, erythema nodosum, hemolytic uremic syndrome, hemorrhagic eruption, hirsutism, hypersensitivity, loss of scalp hair, malignant neoplasm of cervix, optic neuritis (with or without partial or complete loss of vision), pancreatitis, renal insufficiency, toxic shock syndrome

ALERT: U.S. Boxed Warning

Cigarette smoke and serious cardiovascular events:

Cigarette smoking increases the risk of serious cardiovascular events from combination hormonal contraceptive 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 hormonal contraceptives, 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.

• 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:

• 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 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:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• 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 over 35 years 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 a 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. 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.

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).

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).

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, vaginal irritation, weight gain, hair loss, abdominal cramps, bloating, enlarged breasts, decreased libido, menstrual changes, or dark patches on face. Have patient report immediately to prescriber signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), angina, shortness of breath, coughing up blood, severe dizziness, passing out, severe nausea, vomiting, severe headache, depression, severe loss of strength and energy, severe abdominal pain, edema, urinary retention, change in amount of urine passed, blindness, lump in breast, breast soreness or pain, nipple discharge, abnormal vaginal bleeding, vaginitis, vision changes, contact lens discomfort, bulging eyes, or signs of toxic shock syndrome (diarrhea, dizziness, passing out, severe muscle pain, nausea, vomiting, or sunburn like rash) (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 health care 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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