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Ethinyl Estradiol and Levonorgestrel

Pronunciation

(ETH in il es tra DYE ole & LEE voe nor jes trel)

Index Terms

  • Levonorgestrel and Ethinyl Estradiol
  • Triphasil

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Tablet, oral [low-dose formulation]:

Aubra: Ethinyl estradiol 0.02 mg and levonorgestrel 0.1 mg [21 light yellow tablets and 7 brown inactive tablets] (28s)

Aviane: Ethinyl estradiol 0.02 mg and levonorgestrel 0.1 mg [21 orange tablets and 7 light green inactive tablets] (28s)

Delyla: Ethinyl estradiol 0.02 mg and levonorgestrel 0.1 mg [21 white tablets and 7 yellow inactive tablets] (28s)

FaLessa Kit: Ethinyl estradiol 0.02 mg and levonorgestrel 0.1 mg [21 orange tablets and 7 white inactive tablets] (28s) [contains soya lecithin, tartrazine; packaged with Quatrefolic folate tablets]

Falmina: Ethinyl estradiol 0.02 mg and levonorgestrel 0.1 mg [21 orange tablets and 7 white inactive tablets] (28s) [contains soya lecithin, tartrazine]

Larissia: Ethinyl estradiol 0.02 mg and levonorgestrel 0.1 mg [21 white tablets and 7 yellow inactive tablets] (28s)

Lessina: Ethinyl estradiol 0.02 mg and levonorgestrel 0.1 mg [21 pink tablets and 7 white inactive tablets] (28s)

Lutera: Ethinyl estradiol 0.02 mg and levonorgestrel 0.1 mg [21 white tablets and 7 peach inactive tablets] (28s)

Orsythia: Ethinyl estradiol 0.02 mg and levonorgestrel 0.1 mg [21 pink tablets and 7 light green inactive tablets] (28s)

Sronyx: Ethinyl estradiol 0.02 mg and levonorgestrel 0.1 mg [21 white tablets and 7 peach inactive tablets] (28s)

Vienva: Ethinyl estradiol 0.02 mg and levonorgestrel 0.1 mg [21 white tablets and 7 peach inactive tablets] (28s)

Generic: Ethinyl estradiol 0.02 mg and levonorgestrel 0.1 mg [21 tablets and 7 inactive tablets] (28s)

Tablet, oral [monophasic formulation]:

Altavera: Ethinyl estradiol 0.03 mg and levonorgestrel 0.15 mg [21 peach tablets and 7 white inactive tablets] (28s)

Chateal: Ethinyl estradiol 0.03 mg and levonorgestrel 0.15 mg [21 white tablets and 7 green inactive tablets] (28s)

Kurvelo: Ethinyl estradiol 0.03 mg and levonorgestrel 0.15 mg [21 light orange tablets and 7 pink inactive tablets] (28s)

Levora: Ethinyl estradiol 0.03 mg and levonorgestrel 0.15 mg [21 white tablets and 7 peach inactive tablets] (28s)

Marlissa: Ethinyl estradiol 0.03 mg and levonorgestrel 0.15 mg [21 light orange tablets and 7 pink inactive tablets] (28s)

Portia 28: Ethinyl estradiol 0.03 mg and levonorgestrel 0.15 mg [21 pink tablets and 7 white inactive tablets] (28s)

Generic: Ethinyl estradiol 0.03 mg and levonorgestrel 0.15 mg [21 tablets and 7 inactive tablets] (28s)

Tablet, oral [extended cycle regimen]:

Amethia: Ethinyl estradiol 0.03 mg and levonorgestrel 0.15 mg [84 white tablets] and ethinyl estradiol 0.01 mg [7 light blue tablets] (91s)

Amethia Lo: Ethinyl estradiol 0.02 mg and levonorgestrel 0.1 mg [84 white tablets] and ethinyl estradiol 0.01 mg [7 blue tablets] (91s)

Ashlyna: Ethinyl estradiol 0.03 mg and levonorgestrel 0.15 mg [84 blue tablets] and ethinyl estradiol 0.01 mg [7 yellow tablets] (91s)

camrese: Ethinyl estradiol 0.03 mg and levonorgestrel 0.15 mg [84 light blue-green tablets] and ethinyl estradiol 0.01 mg [7 yellow tablets] (91s)

camrese lo: Ethinyl estradiol 0.02 mg and levonorgestrel 0.1 mg [84 orange tablets] and ethinyl estradiol 0.01 mg [7 yellow tablets] (91s)

Daysee: Ethinyl estradiol 0.03 mg and levonorgestrel 0.15 mg [84 light blue tablets] and ethinyl estradiol 0.01 mg [7 mustard tablets] (91s)

Introvale: Ethinyl estradiol 0.03 mg and levonorgestrel 0.15 mg [84 peach tablets and 7 white inactive tablets] (91s)

Jolessa: Ethinyl estradiol 0.03 mg and levonorgestrel 0.15 mg [84 pink tablets and 7 white inactive tablets] (91s)

LoSeasonique: Ethinyl estradiol 0.02 mg and levonorgestrel 0.1 mg [84 orange tablets] and ethinyl estradiol 0.01 mg [7 yellow tablets] (91s)

Quartette:

Day 1-42: Ethinyl estradiol 0.02 mg and levonorgestrel 0.15 mg [42 light pink tablets]

Day 43-63: Ethinyl estradiol 0.025 mg and levonorgestrel 0.15 mg [21 pink tablets]

Day 64-84: Ethinyl estradiol 0.03 mg and levonorgestrel 0.15 mg [21 purple tablets]

Day 85-91: Ethinyl estradiol 0.01 mg [7 yellow tablets] (91s)

Quasense: Ethinyl estradiol 0.03 mg and levonorgestrel 0.15 mg [84 white tablets and 7 peach inactive tablets] (91s)

Seasonique: Ethinyl estradiol 0.03 mg and levonorgestrel 0.15 mg [84 light blue-green tablets] and ethinyl estradiol 0.01 mg [7 yellow tablets] (91s)

Setlakin: Ethinyl estradiol 0.03 mg and levonorgestrel 0.15 mg [84 pink tablets and 7 white inactive tablets] (91s)

Generic: Ethinyl estradiol 0.02 mg and levonorgestrel 0.1 mg [84 tablets] and ethinyl estradiol 0.01 mg [7 tablets] (91s); Ethinyl estradiol 0.03 mg and levonorgestrel 0.15 mg [84 tablets] and ethinyl estradiol 0.01 mg [7 tablets] (91s); Ethinyl estradiol 0.03 mg and levonorgestrel 0.15 mg [84 tablets and 7 inactive tablets] (91s)

Tablet, oral [noncyclic regimen]:

Amethyst: Ethinyl estradiol 0.02 mg and levonorgestrel 0.09 mg [28 white tablets] (28s)

Tablet, oral [triphasic formulation]:

Enpresse:

Day 1-6: Ethinyl estradiol 0.03 mg and levonorgestrel 0.05 mg [6 pink tablets]

Day 7-11: Ethinyl estradiol 0.04 mg and levonorgestrel 0.075 mg [5 white tablets]

Day 12-21: Ethinyl estradiol 0.03 mg and levonorgestrel 0.125 mg [10 orange tablets]

Day 22-28: 7 light green inactive tablets (28s)

Levonest:

Day 1-6: Ethinyl estradiol 0.03 mg and levonorgestrel 0.05 mg [6 yellow tablets]

Day 7-11: Ethinyl estradiol 0.04 mg and levonorgestrel 0.075 mg [5 green tablets]

Day 12-21: Ethinyl estradiol 0.03 mg and levonorgestrel 0.125 mg [10 light brown tablets]

Day 22-28: 7 white inactive tablets (28s)

Myzilra

Day 1-6: Ethinyl estradiol 0.03 mg and levonorgestrel 0.05 mg [6 beige tablets]

Day 7-11: Ethinyl estradiol 0.04 mg and levonorgestrel 0.075 mg [5 white tablets]

Day 12-21: Ethinyl estradiol 0.03 mg and levonorgestrel 0.125 mg [10 light yellow tablets]

Day 22-28: 7 light green inactive tablets (28s)

Trivora:

Day 1-6: Ethinyl estradiol 0.03 mg and levonorgestrel 0.05 mg [6 blue tablets]

Day 7-11: Ethinyl estradiol 0.04 mg and levonorgestrel 0.075 mg [5 white tablets]

Day 12-21: Ethinyl estradiol 0.03 mg and levonorgestrel 0.125 mg [10 pink tablets]

Day 22-28: 7 peach inactive tablets (28s)

Generic:

Day 1-6: Ethinyl estradiol 0.03 mg and levonorgestrel 0.05 mg [6 tablets]

Day 7-11: Ethinyl estradiol 0.04 mg and levonorgestrel 0.075 mg [5 tablets]

Day 12-21: Ethinyl estradiol 0.03 mg and levonorgestrel 0.125 mg [10 tablets]

Day 22-28: 7 inactive tablets (28s)

Brand Names: U.S.

  • Altavera
  • Amethia
  • Amethia Lo
  • Amethyst
  • Ashlyna
  • Aubra
  • Aviane
  • camrese
  • camrese lo
  • Chateal
  • Daysee
  • Delyla
  • Enpresse
  • FaLessa Kit
  • Falmina
  • Introvale
  • Jolessa
  • Kurvelo
  • Larissia
  • Lessina
  • Levonest
  • Levora
  • LoSeasonique
  • Lutera
  • Marlissa
  • Myzilra
  • Orsythia
  • Portia
  • Quartette
  • Quasense
  • Seasonique
  • Setlakin
  • Sronyx
  • Trivora
  • Vienva

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.

Absorption

Rapid

Distribution

Ethinyl estradiol: 4.3 L/kg; Levonorgestrel: 1.8 L/kg

Metabolism

Ethinyl estradiol: Hepatic via CYP3A4; undergoes first-pass metabolism; forms metabolites

Levonorgestrel: Forms conjugated in unconjugated metabolites

Excretion

Ethinyl estradiol: Urine and feces

Levonorgestrel: Urine (40% to 68%, parent drug and metabolites); feces (16% to 48% as metabolites)

Half-Life Elimination

Ethinyl estradiol: 12-23 hours; Levonorgestrel: 22-49 hours

Protein Binding

Ethinyl estradiol: 95% to 97% to albumin

Levonorgestrel: 97% to 99% primarily to sex hormone binding globulin (SHBG), lesser amounts to albumin

Use: Labeled Indications

Prevention of pregnancy; postcoital contraception

Use: Unlabeled

Treatment of hypermenorrhea (menorrhagia); pain associated with endometriosis; dysmenorrhea; dysfunctional uterine bleeding; treatment of polycystic ovary syndrome (PCOS) in women with menstrual irregularities and hirsutism/acne

Contraindications

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

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

Canadian-labeling: Additional contraindication: Ocular lesions due to ophthalmic vascular disease including partial or complete loss of vision or defect in visual fields; severe dyslipoproteinemia; hereditary or acquired predisposition for venous or arterial thrombosis

Dosing: Adult

Females:

Contraception, 28-day cycle: Oral:

Schedule 1 (Sunday starter): Dose begins on first Sunday after onset of menstruation; if the menstrual period starts on Sunday, take first tablet that very same day. With a Sunday start, an additional method of contraception should be used until after the first 7 days of consecutive administration:

For 21-tablet package: 1 tablet/day for 21 consecutive days, followed by 7 days off of the medication; a new course begins on the 8th day after the last tablet is taken

For 28-tablet package: 1 tablet/day without interruption

Schedule 2 (Day-1 starter): Dose starts on first day of menstrual cycle taking 1 tablet/day:

For 21-tablet package: 1 tablet/day for 21 consecutive days, followed by 7 days off of the medication; a new course begins on the 8th day after the last tablet is taken

For 28-tablet package: 1 tablet/day without interruption

If all doses have been taken on schedule and one menstrual period is missed, continue dosing cycle. If two consecutive menstrual periods are missed, pregnancy test is required before new dosing cycle is started.

Missed doses monophasic formulations (refer to package insert for complete information):

One dose missed: Take as soon as remembered or take 2 tablets next day

Two consecutive doses missed in the first 2 weeks: Take 2 tablets as soon as remembered or 2 tablets next 2 days. An additional method of contraception should be used for 7 days after missed dose.

Two consecutive doses missed in week 3 or three consecutive doses missed at any time: An additional method of contraception must be used for 7 days after a missed dose:

Schedule 1 (Sunday starter): Continue dose of 1 tablet daily until Sunday, then discard the rest of the pack, and a new pack should be started that same day.

Schedule 2 (Day-1 starter): Current pack should be discarded, and a new pack should be started that same day.

Missed doses biphasic/triphasic formulations (refer to package insert for complete information):

One dose missed: Take as soon as remembered or take 2 tablets next day.

Two consecutive doses missed in week 1 or week 2 of the pack: Take 2 tablets as soon as remembered and 2 tablets the next day. Resume taking 1 tablet daily until the pack is empty. An additional method of contraception should be used for 7 days after a missed dose.

Two consecutive doses missed in week 3 of the pack: An additional method of contraception must be used for 7 days after a missed dose.

Schedule 1 (Sunday starter): Take 1 tablet every day until Sunday. Discard the remaining pack and start a new pack of pills on the same day.

Schedule 2 (Day-1 starter): Discard the remaining pack and start a new pack the same day.

Three or more consecutive doses missed: An additional method of contraception must be used for 7 days after a missed dose.

Schedule 1 (Sunday starter): Take 1 tablet every day until Sunday; on Sunday, discard the pack and start a new pack.

Schedule 2 (Day-1 starter): Discard the remaining pack and begin new pack of tablets starting on the same day.

Contraception, 91-day cycle (extended cycle regimen): Dose begins on first Sunday after onset of menstruation; if the menstrual period starts on Sunday, take first tablet that very same day. An additional method of contraception should be used until after the first 7 days of consecutive administration:

Introvale, Jolessa, Quasense, Seasonale [Canadian product]: One active tablet/day for 84 consecutive days, followed by 1 inactive tablet/day for 7 days; if all doses have been taken on schedule and one menstrual period is missed, pregnancy should be ruled out prior to continuing therapy.

Seasonique, LoSeasonique, Quartette: One active tablet/day for 84 consecutive days, followed by 1 low dose estrogen tablet/day for 7 days; if all doses have been taken on schedule and one menstrual period is missed, pregnancy should be ruled out prior to continuing therapy.

Missed doses:

One dose missed: Take as soon as remembered or take 2 tablets the next day

Two consecutive doses missed: Take 2 tablets as soon as remembered or 2 tablets the next 2 days. An additional nonhormonal method of contraception should be used for 7 consecutive days after the missed dose.

Three or more consecutive doses missed: Do not take the missed doses; continue taking 1 tablet/day until pack is complete. Bleeding may occur during the following week. An additional nonhormonal method of contraception should be used for 7 consecutive days after the missed dose.

Any number of pills during week 13: Throw away the missed pills and keep taking scheduled pills until the pack is finished. A back-up method of contraception is not needed

Dosing: Pediatric

Females: Contraception or emergency contraception: Oral: Refer to adult dosing; not to be used prior to menarche.

Dosing: Renal Impairment

Specific guidelines not available; use with caution and monitor blood pressure closely. Consider other forms of contraception.

Dosing: Hepatic Impairment

Contraindicated in patients with hepatic impairment.

Administration

Administer at the same time each day.

Quartette: If severe diarrhea or vomiting occur within 3-4 hours after taking a light pink, pink, or purple tablet, it should be considered a missed dose; additional contraceptive measures are recommended.

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

Dietary Considerations

Should be taken at the same time each day.

Storage

Store at controlled room temperature of 20°C to 25°C (68°F to 77°F).

Drug Interactions

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

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

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

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

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

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

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

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

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

C1 inhibitors: Estrogen Derivatives 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

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

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

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

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

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

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

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

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

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

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

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

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

Griseofulvin: May increase the metabolism of Contraceptives (Estrogens). Contraceptive failure is possible. Management: Use an alternative, nonhormonal form of contraception, or use an alternative to griseofulvin. Consider therapy modification

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

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

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

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

LamoTRIgine: 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

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

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

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

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

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

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

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

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

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

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

Retinoic Acid Derivatives: May diminish the therapeutic effect of Contraceptives (Estrogens). Two forms of contraception are recommended in females of child-bearing potential during retinoic acid derivative therapy. Exceptions: Adapalene; Bexarotene (Topical); Tretinoin (Topical). Monitor therapy

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

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

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

Selegiline: Contraceptives (Estrogens) 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 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 (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

Thalidomide: Contraceptives (Estrogens) 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

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

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

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

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

Adverse Reactions

The following reactions have been associated with oral contraceptive use:

Increased risk or evidence of association with use:

Cardiovascular: Arterial thromboembolism, cerebral hemorrhage, cerebral thrombosis, hypertension, mesenteric thrombosis, MI, venous thrombosis (with or without embolism)

Gastrointestinal: Gallbladder disease

Hepatic: Hepatic adenomas, liver tumors (benign)

Local: Thrombophlebitis

Ocular: Retinal thrombosis

Respiratory: Pulmonary embolism

Adverse reactions considered drug related:

Cardiovascular: Edema, varicose vein aggravation

Central nervous system: Depression, migraine, mood changes

Dermatologic: Chloasma, melasma, rash (allergic)

Endocrine & metabolic: Amenorrhea, breakthrough bleeding, breast changes (enlargement, pain, secretion, tenderness), carbohydrate tolerance decreased, fluid retention, infertility (temporary), lactation decreased (with use immediately postpartum), menstrual flow changes, spotting

Gastrointestinal: Abdominal bloating, abdominal cramps, abdominal pain, appetite changes, nausea, weight changes, vomiting

Genitourinary: Cervical ectropion, cervical secretion/erosion, endocervical hyperplasia, fibroid enlargement, vaginal candidiasis, vaginitis

Hematologic: Folate decreased, porphyria exacerbation

Hepatic: Cholestatic jaundice, focal nodular hyperplasia

Neuromuscular & skeletal: Chorea exacerbation

Ocular: Contact lens intolerance, corneal curvature changes (steepening)

Respiratory: Rhinitis

Miscellaneous: Anaphylactic/anaphylactoid reactions (including angioedema, circulatory collapse, respiratory collapse, urticaria), SLE exacerbation

Adverse reactions in which association is not confirmed or denied: Acne, auditory disturbances, Budd-Chiari syndrome, cataracts, cervical smear abnormal, colitis, cystitis-like syndrome, dizziness, dysmenorrhea, erythema multiforme, erythema nodosum, headache, hemolytic uremic syndrome, hemorrhagic eruption, hirsutism, libido changes, nervousness, optic neuritis (with or without partial or complete loss of vision), pancreatitis, premenstrual syndrome, renal function impaired, scalp hair loss

ALERT: U.S. Boxed Warning

Cigarette smoke and serious cardiovascular events:

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

Warnings/Precautions

Concerns related to adverse effects:

• Angioedema: Estrogens may induce or exacerbate symptoms in women with hereditary angioedema.

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

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

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

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

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

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

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

• Vaginal bleeding: Presentation of irregular, unresolving vaginal bleeding warrants further evaluation including endometrial sampling, if indicated, to rule out malignancy; evaluate hypothalamic-pituitary-function in women with persistent (≥6 months) amenorrhea (especially associated with breast secretion) following discontinuation of therapy.

Disease-related concerns:

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

• Depression: Use with caution in patients with depression.

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

• Fibroids: Discontinue use with the onset of sudden enlargement, pain, or tenderness of fibroids (leiomyomata).

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

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

• Hepatic impairment: Combination hormonal contraceptives may be poorly metabolized in women with hepatic impairment. Discontinue if jaundice develops during therapy or if liver function becomes abnormal. Use is contraindicated with preexisting hepatic disease.

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

• Renal impairment: Women with renal disease should be encouraged to use a nonhormonal form of contraception.

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:

• Pediatric: Not for use prior to menarche.

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

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

Dosage form specific issues:

• Tartrazine: Some products may contain tartrazine, which may cause allergic reactions in certain individuals.

Special handling:

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

Other warnings/precautions:

• Extended cycle regimen: Contraceptives with an extended cycle regimen provide more hormonal exposure per year than conventional monthly contraceptives.

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

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

• Minimum effective dosage: The minimum dosage combination of estrogen/progestin that will effectively treat the individual patient should be used. New patients should be started on products containing ≤0.035 mg of estrogen per tablet.

Monitoring Parameters

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

Pregnancy Risk Factor

X

Pregnancy Considerations

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

Due to increased risk of venous thromboembolism (VTE) postpartum, combination hormonal contraceptives should not be started in any woman <21 days following delivery. Women without risk factors for VTE and who are not breast-feeding may start combination hormonal contraceptives during 21-42 days postpartum. After 42 days postpartum, restrictions for use are not related to postpartum status and should be based on other medical conditions (CDC, 2011). Some manufacturers recommend waiting ≥4 weeks postpartum before starting this combination.

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 lack of appetite, more hungry, weight gain, cramps, bloating, menstrual irregularities, enlarged breasts, hair loss, acne, decreased libido, 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, edema, shortness of breath, coughing up blood, severe dizziness, passing out, severe nausea, severe vomiting, severe headache, depression, severe loss of strength and energy, severe abdominal pain, urinary retention, change in amount of urine passed, lump in breast, breast soreness and pain, nipple discharge, vaginal bleeding, vaginitis, vision changes, vision loss, bulging eyes, or contact lens discomfort (HCAHPS).

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

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for 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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