Segesterone Acetate and Ethinyl Estradiol

Dosage Forms

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

Ring, Vaginal:

Annovera: Ethinyl estradiol 0.013 mg/day and segesterone acetate 0.15 mg/day [3-week duration] (1 ea)

Pharmacology

Mechanism of Action

Combination hormonal contraceptives lower the risk of pregnancy primarily by suppressing ovulation.

Pharmacokinetics/Pharmacodynamics

Distribution

Segesterone acetate: V_d 19.6 L/kg

Metabolism

Ethinyl estradiol and segesterone acetate: Hepatic via CYP 3A4 to metabolites

Excretion

Ethinyl estradiol: Urine and feces

Onset of Action

Effective on the day of insertion when inserted between days 2 and 5 of menstrual period

Time to Peak

Ethinyl estradiol and segesterone acetate: 2 hours (median) following cycle 1; peak concentrations decline over subsequent dosing cycles

Half-Life Elimination

Ethinyl estradiol: 15.1 ± 7.5 hours

Segesterone acetate: 4.5 ± 3.4 hours

Protein Binding

Ethinyl estradiol: 98.5%; increases sex hormone binding globulin (SHBG)

Segesterone acetate: 95% to human serum; negligible to SHBG

Use in Specific Populations

Special Populations Note

Obesity: Systemic exposure (AUC _{0-21 day}) of ethinyl estradiol is decreased by 33% and systemic exposure of segesterone acetate is decreased by 16% in patients with a BMI >25 kg/m² when compared to patients with a BMI <25 kg/m²

Use: Labeled Indications

Contraceptive: To prevent pregnancy in females of reproductive potential

Contraindications

Hypersensitivity to segesterone, ethinyl estradiol, or any component of the formulation; breast cancer or other estrogen- or progestin-sensitive cancer (current or a history of), hepatic tumors, acute hepatitis, severe (decompensated) cirrhosis, undiagnosed abnormal uterine bleeding; concomitant use of hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir

Use is also contraindicated in females at high risk of arterial or venous thrombotic diseases, for example, females with: Cerebrovascular disease, coronary artery disease, diabetes mellitus with hypertension or vascular disease (or other end organ damage), diabetes mellitus and >35 years of age, diabetes mellitus >20 years duration, DVT or PE (current or history of), hypercoagulopathies (inherited or acquired), headaches with focal neurological symptoms, migraine headaches with aura, migraine headaches if >35 years of age, hypertension (uncontrolled or with concomitant vascular disease), thrombogenic valvular or rhythm diseases of the heart (eg, subacute bacterial endocarditis with valvular disease or atrial fibrillation), females >35 years of age who smoke.

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

Dosage and Administration

Dosing: Adult

Contraception: Females: Vaginal: Insert 1 ring vaginally. Following insertion, ring should remain in place for 21 continuous days (3 weeks), then removed for 7 days (1 week). This pattern (3 weeks in and 1 week out) is one cycle; one ring provides contraception for 13 cycles (1 year).

Initiation of therapy:

No hormonal contraceptive use in preceding cycle and after copper IUD removal:

Insert between days 2 and 5 of menstrual cycle. Back-up barrier contraception should be used for the first 7 days of therapy if menstrual cycles are irregular or if start is >5 days from last menstrual bleeding

Switching from a combination hormonal contraceptive (CHC):

Insert at any time during the 28-day cycle. Back-up barrier contraception is not needed if CHC was used correctly and consistently and there are ≤7 hormone-free days prior to start.

Switching from a progestin only method (progestin only pill, injection, implant, or intrauterine system):

Insert at the time the next oral pill would be taken, the implant or intrauterine system is removed, or at the time of the next scheduled injection. Back-up barrier contraception should be used for the first 7 days of therapy

Following first trimester abortion or miscarriage:

Insert within 5 days following first trimester abortion or miscarriage; back-up barrier contraception is not needed. If insertion does not occur within 5 days, insert between days 2 and 5 of menstrual cycle. Back-up barrier contraception should be used for the first 7 days of therapy.

Following second trimester abortion or miscarriage:

Do not insert <4 weeks following second trimester abortion or miscarriage.

Following childbirth:

Do not insert <4 weeks following childbirth. When starting therapy ≥4 weeks postpartum in females who have not yet had a menstrual cycle, back-up barrier contraception should be used for the first 7 days of therapy. The manufacturer does not recommend use in females who are breastfeeding.

Additional contraception dosing considerations:

Any deviation from the recommended dosing cycle (3 weeks in and 1 week out is one cycle) that results in the ring being out of the vagina for >7 days requires back-up contraception

Inadvertent removal or expulsion:

If ring is accidently expelled during the 21 days of vaginal use and replaced within 2 hours, back-up contraception is not required. If ring is out of the vagina for >2 hours (or >2 cumulative hours if multiple expulsions occur), back-up contraception (male condom or spermicide) should be used until the vaginal ring has been in place for 7 consecutive days. Use of combined hormonal contraceptives (containing estrogen) for emergency contraception is not recommended.

Prolonged vaginal-free interval:

If vaginal-free interval is prolonged (ring has been removed for >7 days), back-up contraception (male condom or spermicide) should be used until the vaginal ring has been in place for 7 consecutive days. Use of combined hormonal contraceptives (containing estrogen) for emergency contraception is not recommended.

Prolonged insertion:

If ring is left in place for >21 days, remove for 7 days, then restart/resume a 21/7-day cycle

Concomitant use with enzyme inducers (eg, aprepitant, barbiturates, bosentan, carbamazepine, felbamate, griseofulvin, oxcarbazepine, phenytoin, rifampin, rifabutin, furinamide, topiramate, St John's wort, certain protease inhibitors):

Alternate methods of contraception are recommended, otherwise, back-up contraception should be used during therapy with the concomitant medication and for 28 days after the last dose of the enzyme inducer.

Dosing: Pediatric

Contraception: Postmenarche female: Intravaginal: Insert one ring vaginally. Following insertion, ring should remain in place for 21 continuous days (3 weeks), then removed for 7 days (1 week). The pattern of 3 weeks in and 1 week out is one cycle; one ring provides contraception for 13 cycles (1 year).

Initiation of therapy:

No hormonal contraceptive use in preceding cycle and after copper IUD removal: Insert ring between days 2 and 5 of regular menstrual bleeding. Back-up barrier contraception should be used for the first 7 days of therapy if menstrual cycles are irregular or if start is >5 days from last menstrual bleeding.

Switching from a combination hormonal contraceptive (CHC): Insert ring at any time during the 28-day cycle. Back-up barrier contraception is not needed if CHC was used correctly and consistently and there are ≤7 hormone free days prior to start.

Switching from a progestin only method (progestin only pill, injection, implant, or intrauterine system): Insert ring at the time of either: The next oral pill would be taken, the implant or intrauterine system is removed, or at the next scheduled injection. Back-up barrier contraception should be used for the first 7 days of therapy.

Following first trimester abortion or miscarriage: Insert ring within 5 days following a first trimester abortion or miscarriage; back-up barrier contraception is not needed. If insertion does not occur within 5 days, back-up barrier contraception should be used for the first 7 days of therapy.

Following second trimester abortion or miscarriage: Do not insert <4 weeks following second trimester abortion or miscarriage.

Following childbirth in non-breastfeeding individuals: Do not insert <4 weeks following childbirth. Back-up barrier contraception should be used for the first 7 days of therapy. Note: Breastfeeding individuals may begin therapy after weaning.

Additional contraception dosing considerations:

Any deviation from the recommended dosing cycle (3 weeks in and 1 week out is one cycle) that results in the ring being out of the vagina for >7 days requires back-up contraception.

Inadvertent removal or expulsion: If ring is accidently expelled during the 21 days of vaginal use and replaced within 2 hours, back-up contraception is not required. If ring is out of the vagina for >2 hours (or >2 cumulative hours if multiple expulsions occur), back-up contraception (male condom or spermicide) should be used until the vaginal ring has been in place for 7 consecutive days. Use of combined hormonal contraceptives (containing estrogen) used for emergency contraception are not recommended.

Prolonged vaginal free interval: If vaginal free interval is prolonged (ring has been removed for >7 days), back-up contraception (male condom or spermicide) should be used until the vaginal ring has been in place for 7 consecutive days. Use of combined hormonal contraceptives (containing estrogen) used for emergency contraception are not recommended.

Prolonged insertion: If ring is left in place for >21 days, remove for 7 days, then restart/resume a 21/7 day cycle.

Concomitant use with enzyme inducers (eg, aprepitant, barbiturates, bosentan, carbamazepine, felbamate, griseofulvin, oxcarbazepine, phenytoin, rifampin, rifabutin, furinamide, topiramate, St John's wort, certain protease inhibitors): Alternate methods of contraception are recommended, otherwise, back-up contraception should be used during therapy with the concomitant medication and for 28 days after the last dose of the enzyme inducer.

Administration

Intravaginal: Prior to each insertion, wash vaginal ring with mild soap and water, rinse and pat dry. Press sides of ring together and insert folded ring into vagina as far as possible, to a comfortable position completely inside the vagina and behind the pelvic bone. Note day of week and time of day, then remove at the same time/day 3 weeks later. To remove, hook ring with finger and pull downward and forward. Wash ring with mild soap and lukewarm water, dry, and store in provided case until next insertion. Do not discard in toilet.

One vaginal ring can be used for 13 cycles (1 year) when used 3 weeks in and 1 week out per cycle

Storage

Prior to dispensing, store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from direct sunlight. Do not refrigerate or freeze; avoid excessive heat.

Drug Interactions

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Barbiturates: May diminish the therapeutic effect of Estrogen Derivatives (Contraceptive). Contraceptive failure is possible. Management: Use of a non-hormonal contraceptive is recommended. Consider therapy modification

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

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

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

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

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

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

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

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

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

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

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

CarBAMazepine: May diminish the therapeutic effect of Estrogen Derivatives (Contraceptive). Contraceptive failure is possible. Management: Use of a nonhormonal contraceptive is recommended. Consider therapy modification

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

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

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

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

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

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

CloBAZam: May decrease the serum concentration of Estrogen Derivatives (Contraceptive). Consider therapy modification

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

CloZAPine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Monitor therapy

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

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

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

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

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

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

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

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

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

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to 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 Estrogen Derivatives (Contraceptive). Management: Females of reproductive potential should use an alternative, highly effective, non-hormonal means of contraception during and at least 2 weeks (dabrafenib alone) or 4 months (dabrafenib + trametinib) after discontinuation of dabrafenib treatment. Consider therapy modification

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

LamoTRIgine: Estrogen Derivatives (Contraceptive) may decrease the serum concentration of LamoTRIgine. Management: Most patients taking estrogen-containing contraceptives will require lamotrigine dose increases up to 2-fold over the recommended target lamotrigine dose. Increase lamotrigine doses by 50 to 100 mg/day every week based on clinical response. Consider therapy modification

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

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

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

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

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

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

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

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification

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

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

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

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

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

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

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

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

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

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

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

Nelfinavir: May decrease the serum concentration of Progestins (Contraceptive). Management: Use 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

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

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

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

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

Perampanel: May decrease the serum concentration of Progestins (Contraceptive). Management: Patients should use an alternative, nonhormonal-based form of contraception both during the concurrent use of perampanel and for 1 month after discontinuing perampanel. Consider therapy modification

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

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

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

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

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

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

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

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

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

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

Rifamycin Derivatives: May decrease the serum concentration of Progestins (Contraceptive). Contraceptive failure is possible. Management: Contraceptive failure is possible. Use of an alternative, nonhormonal contraceptive is recommended. 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 Progestins (Contraceptive). Management: Use an alternative or additional method of contraception due to possibly decreased contraceptive effectiveness. Injected depot medroxyprogesterone acetate does not appear to participate in this interaction. Consider therapy modification

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Theophylline Derivatives: CYP1A2 Inhibitors (Weak) may increase the serum concentration of Theophylline Derivatives. 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 Progestins (Contraceptive). Management: Use an alternative or additional method of contraception due to possibly decreased contraceptive effectiveness. Injected depot medroxyprogesterone acetate does not appear to participate in this interaction. Consider therapy modification

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use is necessary, initiate tizanidine at an adult dose of 2 mg and increase in 2 to 4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

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

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

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

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

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

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

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

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

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

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

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

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

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

Adverse Reactions

>10%:

Central nervous system: Headache (≤39%), migraine (≤39%)

Gastrointestinal: Nausea (≤25%), vomiting (≤25%), abdominal pain (≤13%), lower abdominal pain (≤13%), upper abdominal pain (≤13%)

Genitourinary: Vulvovaginal candidiasis (15%), dysmenorrhea (13%), vaginal discharge (12%)

1% to 10%:

Cardiovascular: Cerebral thrombosis (≥2%), deep vein thrombosis (≥2%), pulmonary embolism (≥2%)

Central nervous system: Psychiatric disturbance (≥2%)

Dermatologic: Genital pruritus (6%)

Endocrine & metabolic: Heavy menstrual bleeding (≤8%), menstrual disease (≤8%), amenorrhea (≤5%)

Gastrointestinal: Diarrhea (7%)

Genitourinary: Breakthrough bleeding (≤10%), breast tenderness (≤10%), cystitis (≤10%), genitourinary infection (≤10%), mastalgia (≤10%), spotting (≤10%), urinary tract infection (≤10%), spontaneous abortion (≥2%)

Hypersensitivity: Drug-induced hypersensitivity (≥2%)

Renal: Pyelonephritis (≤10%)

Warnings/Precautions

Concerns related to adverse effects:

• Breast cancer: Use of hormonal contraceptives may increase the risk of breast cancer; the absolute risk is small and should be balanced against potential benefits; risk is related to duration of use (Mørch 2017). In females 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 females with a current or recent history of breast cancer may be worse with combination hormonal contraceptive use (Curtis 2016b). Use is contraindicated in females 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; however, studies are not consistent and may be related to additional risk factors (Gierisch 2013). Theoretically, use may affect prognosis of existing disease. Females 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. Females 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 cholestatic jaundice of pregnancy or cholestasis with prior oral contraceptive use. Combination hormonal contraceptives may be considered for use in females with a history of pregnancy related cholestasis but should be avoided in patients who have a history of cholestasis with prior oral contraceptive use (Curtis 2016b).
• Lipid effects: Combination hormonal contraceptives may adversely affect lipid levels, including serum triglycerides. Females with hypertriglyceridemia or a family history of hypertriglyceridemia may be at increased risk of pancreatitis when using combination hormonal contraceptives. Consider alternative contraception for females 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. Combination hormonal contraceptives may increase the risk of venous thromboembolic events such as DVT and PE (risk is greatest during first year of use and when restarting after a break of ≥4 weeks; risk is less than the risk associated with pregnancy and postpartum); some studies suggest this risk may be higher in preparations with third- or fourth-generation progestins and/or high dose ethinyl estradiol. Females 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 females 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 females with a history of stroke or ischemic heart disease (Curtis 2016b). Use of combination hormonal contraceptives is contraindicated in females with a high risk of arterial or venous thrombotic disease.
• Toxic shock syndrome: Has been reported following use of vaginal rings and in some cases, concomitant tampon use (causal relationship has not been established).
• Vaginal bleeding: Breakthrough or intracyclic bleeding and spotting may occur, especially during the first month of therapy. Persistent unscheduled bleeding or breakthrough bleeding following previously regular cycles during therapy warrants further evaluation to rule out malignancy or pregnancy. Amenorrhea may occur during therapy. In addition, amenorrhea or oligomenorrhea may occur after discontinuing combination hormonal contraceptives, especially when such a condition was preexistent.

Disease-related concerns:

• Bariatric surgery:

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

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

• Cardiovascular disease: Combination hormonal contraceptives may increase the risk of cardiovascular and cerebrovascular events. Prior to use, consider risk factors for cardiovascular disease (age, diabetes, dyslipidemia, hypertension, obesity, smoking status), especially in females >35 years of age; use may be contraindicated.
• Depression: Use with caution in patients with a history of depression; discontinue if serious depression recurs.
• Diabetes: May impair glucose tolerance; use caution in females 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 females with nonvascular disease. However, use in females 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 females >35 years of age with diabetes mellitus, females with diabetes mellitus >20 years duration, and females with diabetes and vascular disease (including hypertension, retinopathy, neuropathy, nephropathy).
• Endometrial or ovarian cancer: The risk of endometrial or ovarian cancer is decreased in females using combination hormonal contraceptives (ACOG 182 2017; Curtis 2016b). Oral contraceptives may be used for contraception if indicated, and to reduce the risk of ovarian cancer in females with BRCA1 and BRCA2 mutations (ACOG 182 2017). Females awaiting treatment for endometrial or ovarian cancer may use combination hormonal contraceptives (Curtis 2016b).
• Gallbladder disease: Combination hormonal contraceptives may cause a small increased risk of gallbladder disease or may 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 of this product is contraindicated in females with hepatic tumors.
• Hepatic impairment: Combination hormonal contraceptives may be poorly metabolized in females with hepatic impairment. Discontinue if jaundice develops during therapy or if liver function becomes abnormal. Use is contraindicated in females with severe (decompensated) cirrhosis. Use of combination hormonal contraceptives may be considered in females with mild (compensated) cirrhosis (Curtis 2016b).
• Hepatitis: Use is contraindicated in females with acute hepatitis. Continuation of use of combination hormonal contraceptives in females with chronic hepatitis has not been shown to increase the rate or severity of cirrhotic fibrosis or hepatocellular carcinoma. Continuation of use in females 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 females 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 females 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 females 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 females with uncontrolled hypertension, hypertension with vascular disease, or hypertension and diabetes, and recommends monitoring females with well-controlled hypertension; discontinue therapy if blood pressure rises significantly.
• Migraine: Evaluate new, recurrent, severe, or persistent headaches. Use of combination hormonal contraceptives may be considered in females who have migraines without aura (including menstrual migraines) (Curtis 2016b). Use in females with headaches with focal neurological symptoms, migraine headaches with aura, or migraines in females >35 years of age is contraindicated.
• Solid organ transplant: Although data is limited, serious medical complications have been reported in females with complicated organ transplants (eg, graft failure, rejection, cardiac allograft vasculopathy); use of combination hormonal contraceptives is not recommended in females with complicated organ transplants (Curtis 2016b).
• Systemic Lupus Erythematosus (SLE): Females with SLE are at an increased risk for heart disease, stroke, and VTE. Combination hormonal contraceptives should not be used in females 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.

Special populations:

• Obese: This product has not been adequately studied in females with a BMI >29 kg/m². Available evidence suggests efficacy of combination hormonal contraceptives may be decreased in females with a BMI ≥30 kg/m²; however, reductions in effectiveness are considered minimal and information is conflicting. The risk of VTE may be increased in obese females using combination hormonal contraceptives. In general, the benefits of combination hormonal contraceptives may outweigh the risks in obese females who otherwise are eligible for this method (Curtis 2016b). Clinical studies excluded females with a BMI >29 kg/m² after two VTEs occurred in females with a BMI >29 kg/m².
• Pediatric: Not for use prior to menarche.
• Postmenopausal females: Use is not indicated in postmenopausal females.
• Prolonged immobilization: Discontinue during periods of prolonged immobilization. Whenever possible, discontinue at least 4 weeks prior to and for 2 weeks following major surgery or other surgery associated with an increased risk of thromboembolism.
• Smokers: [US Boxed Warning]: Cigarette smoking increases the risk of serious cardiovascular events from combination hormonal contraceptive use. This risk increases with age, particularly in females >35 years of age, and with the number of cigarettes smoked. For this reason, combination hormonal contraceptives should not be used by females who are >35 years of age and smoke.

Dosage form specific issues:

• Vaginal ring: Use may not be appropriate in females with conditions that may increase the risk of vaginal irritation or ulceration. Information related to concomitant use with diaphragms, cervical caps, and female condoms is not available. Water-based vaginal creams, suppositories, or lubricants may be used with the vaginal ring; oil-based (including silicone based) vaginal products should not be used. Use is compatible with male condoms made with natural rubber latex, polyisoprene, and polyurethane. Females and their partners may be aware of the vaginal ring during intercourse.

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). Estrogens may raise serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin, and cortisol-binding globulin. Females on thyroid replacement therapy may require higher doses of thyroid hormone while receiving estrogens.

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 not used on schedule and one menstrual period is missed, the possibility of pregnancy should be considered. If two consecutive menstrual periods are missed, assess pregnancy status before a new dosing cycle is started.

Monitor patient for vision changes; 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

Pregnancy Considerations

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 with adverse fetal or maternal effects (Curtis 2016b).

Due to the increased risk of venous thromboembolism (VTE) postpartum, combination hormonal contraceptives should not be started in females <4 weeks following delivery who are not breastfeeding. The risk decreases to baseline by postpartum day 42. Use of combination hormonal contraceptives in females 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, postpartum hemorrhage, or smoking) (Curtis 2016b).

Patient Education

What is this drug used for?

• It is used to prevent pregnancy.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Vaginal irritation
• Nausea
• Vomiting
• Abdominal pain
• Diarrhea
• Painful periods
• Menstrual changes

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin
• Gallstones like pain in the upper right abdominal area, right shoulder area, or between the shoulder blades; yellow skin; or fever with chills
• Urinary tract infection like blood in the urine, burning or painful urination, passing a lot of urine, fever, lower abdominal pain, or pelvic pain
• Severe cerebrovascular disease like change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or vision changes
• Blood clots like numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; chest pain; shortness of breath; fast heartbeat; or coughing up blood
• Severe headache
• Severe dizziness
• Passing out
• Depression
• Bulging eyes
• Blindness
• Contact lens intolerance
• Breast pain
• Lump in breast
• Breast soreness
• Nipple discharge
• Vaginal pain, itching, and discharge
• Abnormal vaginal bleeding
• Toxic shock syndrome like diarrhea, dizziness, passing out, severe muscle pain, nausea, vomiting, or sunburn like rash
• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.