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Osteoporosis prevention (female): Prevention of postmenopausal osteoporosis
Limitations of use: For use only in women at significant risk of postmenopausal osteoporosis; consider use of nonestrogen medications.
Vasomotor symptoms associated with menopause: Treatment of moderate to severe vasomotor symptoms associated with menopause.
Vulvar and vaginal atrophy associated with menopause: Treatment of moderate to severe vulvar and vaginal atrophy associated with menopause.
Limitations of use: When used solely for the treatment of vulvar and vaginal atrophy, topical vaginal products should be considered.
Angioedema or anaphylactic reaction to estrogen, medroxyprogesterone or any component of the formulation; undiagnosed abnormal genital bleeding; DVT or PE (current or history of); active or history of arterial thromboembolic disease (eg, stroke, MI); breast cancer (known, suspected or history of); estrogen-dependent tumor (known or suspected); hepatic impairment or disease; known protein C, protein S, antithrombin deficiency or other known thrombophilic disorders; pregnancy.
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.
There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be taken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal genital bleeding.
Cardiovascular disease:Estrogen-alone therapy should not be used for the prevention of cardiovascular disease. The Womens Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with oral conjugated estrogens 0.625 mg/day, relative to placebo.
Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease. The WHI estrogen plus progestin substudy reported increased risks of DVT, pulmonary embolism (PE), stroke, and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogens (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg), relative to placebo.
Breast Cancer:The Women's Health Initiative (WHI) estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer.
Dementia:Estrogen-alone therapy should not be used for the prevention of dementia. The WHI Memory Study (WHIMS) estrogen-alone ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years and older during 5.2 years of treatment with daily conjugated estrogens (0.625 mg) alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women.
Estrogen plus progestin therapy should not be used for the prevention of dementia. The WHIMS estrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years or older during 4 years of treatment with daily conjugated estrogens (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women.
Risks vs benefits:In the absence of comparable data, these risks should be assumed to be similar for other doses of conjugated estrogens (with or without medroxyprogesterone acetate) and other dosage forms of estrogens (with or without progestins). Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
Female: General dosing considerations: These combination products are indicated for use in women with a uterus. When treating postmenopausal women, use for the shortest duration possible at the lowest effective dose consistent with treatment goals. Reevaluate patients as clinically appropriate to determine if treatment is still necessary. Consider use of an estrogen with a progestin in postmenopausal women with a uterus. Women who have had a hysterectomy generally do not need a progestin; however, one may be needed if there is a history of endometriosis. Dosage needs to be adjusted based upon the patients response.
Osteoporosis prevention, vasomotor symptoms associated with menopause, or vulvar and vaginal atrophy associated with menopause:
Premphase: Oral: One maroon conjugated estrogen 0.625 mg tablet daily on days 1 through 14 and 1 light blue conjugated estrogen 0.625 mg/MPA 5 mg tablet daily on days 15 through 28
Prempro: Oral: One conjugated estrogen/MPA tablet once daily; maximum dose: 1 conjugated estrogen 0.625 mg/MPA 5 mg tablet daily
Refer to adult dosing.
There are no dosage adjustments provided in the manufacturers labeling (has not been studied).
Use is contraindicated with hepatic dysfunction or disease.
Administer at the same time each day.
Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).
Administration with food decreases nausea, administer with food. Ensure adequate calcium and vitamin D intake when used for the prevention of osteoporosis.
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) .
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Premphase [therapy pack contains 2 separate tablet formulations]: Conjugated estrogens 0.625 mg [14 maroon tablets] and conjugated estrogen 0.625 mg/medroxyprogesterone acetate 5 mg [14 light blue tablets] (28s)
Prempro:
0.3/1.5: Conjugated estrogens 0.3 mg and medroxyprogesterone acetate 1.5 mg (28s)
0.45/1.5: Conjugated estrogens 0.45 mg and medroxyprogesterone acetate 1.5 mg (28s)
0.625/2.5: Conjugated estrogens 0.625 mg and medroxyprogesterone acetate 2.5 mg (28s)
0.625/5: Conjugated estrogens 0.625 mg and medroxyprogesterone acetate 5 mg (28s)
Acitretin: May diminish the therapeutic effect of Contraceptives (Progestins). Contraceptive failure is possible. Management: Given the potential for progestin-only preparations to fail to prevent pregnancy during acitretin therapy, such products should not be relied upon. Alternative, nonhormonal forms of contraception must be employed during acitretin therapy. Consider therapy modification
Ajmaline: Estrogen Derivatives may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased. Monitor therapy
Anastrozole: Estrogen Derivatives may diminish the therapeutic effect of Anastrozole. Avoid combination
Anthrax Immune Globulin (Human): Estrogen Derivatives may enhance the thrombogenic effect of Anthrax Immune Globulin (Human). Monitor therapy
Anticoagulants: Estrogen Derivatives may diminish the anticoagulant effect of Anticoagulants. More specifically, the potential prothrombotic effects of some estrogens and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of estrogens against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Consider therapy modification
Anticoagulants: Progestins may diminish the therapeutic effect of Anticoagulants. More specifically, the potential prothrombotic effects of some progestins and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of progestins against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Consider therapy modification
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy
Aprepitant: May decrease the serum concentration of Contraceptives (Progestins). Management: Alternative or additional methods of contraception should be used both during treatment with aprepitant or fosaprepitant and for at least one month following the last aprepitant/fosaprepitant dose. Consider therapy modification
Artemether: May decrease the serum concentration of Contraceptives (Progestins). Management: Consider the use of an alternative (i.e., non-hormonal) means of contraception in all women of childbearing potential who are using artemether. Consider therapy modification
Ascorbic Acid: May increase the serum concentration of Estrogen Derivatives. Monitor therapy
Atazanavir: May increase the serum concentration of Contraceptives (Progestins). However, atazanavir may lead to decreased ethinyl estradiol concentrations and decreased effectiveness of oral contraceptive products. Management: Consider an alternative or additional method of contraception, particularly with combined estrogen/progestin products. Depot medroxyprogesterone acetate may be used without a need for additional contraception. Consider therapy modification
Barbiturates: May diminish the therapeutic effect of Contraceptives (Progestins). Contraceptive failure is possible. Management: Use of alternative, nonhormonal contraceptives is recommended. Consider therapy modification
Bexarotene (Systemic): May decrease the serum concentration of Contraceptives (Progestins). Management: Women of childbearing potential receiving bexarotene should use two reliable forms of contraception (including at least one nonhormonal form). Consider therapy modification
Bile Acid Sequestrants: May decrease the serum concentration of Contraceptives (Progestins). Management: Administer oral progestin-containing contraceptives at least 1-4 hours prior to or 4-6 hours after administration of a bile acid sequestrant. Consider therapy modification
Boceprevir: May increase the serum concentration of Contraceptives (Progestins). This has been seen specifically with norethindrone. Boceprevir may increase the serum concentration of Contraceptives (Progestins). This has been seen specifically with drospirenone. Management: Patients receiving boceprevir, ribavirin, and peginterferon alfa should use two reliable forms of contraception. Norethindrone/ethinyl estradiol may be used for one of these when norethindrone dose is at least 1 mg/day. Avoid drospirenone. Consider therapy modification
Bosentan: May decrease the serum concentration of Contraceptives (Progestins). Management: Use an alternative (i.e., non-hormonal) means of contraception for all women of childbearing potential who are using bosentan, and do not rely on hormonal contraceptives alone. Consider therapy modification
C1 inhibitors: Estrogen Derivatives may enhance the thrombogenic effect of C1 inhibitors. Monitor therapy
C1 inhibitors: Progestins may enhance the thrombogenic effect of C1 inhibitors. Monitor therapy
Cannabis: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy
CarBAMazepine: May diminish the therapeutic effect of Contraceptives (Progestins). Contraceptive failure is possible. Management: Use of alternative, nonhormonal contraceptives is recommended. Consider therapy modification
Carfilzomib: May enhance the thrombogenic effect of Contraceptives (Progestins). Management: Consider alternative, non-hormonal methods of contraception in patients requiring therapy with carfilzomib. Consider therapy modification
Chenodiol: Estrogen Derivatives may diminish the therapeutic effect of Chenodiol. Management: Monitor clinical response to chenodiol closely when used together with any estrogen derivative. Monitor therapy
Choline C 11: Antiandrogens may diminish the therapeutic effect of Choline C 11. Monitor therapy
CloBAZam: May decrease the serum concentration of Contraceptives (Progestins). Consider therapy modification
Cobicistat: May increase the serum concentration of Contraceptives (Progestins). Management: Consider an alternative, non-hormone-based contraceptive in patients receiving cobicistat-containing products. Consider therapy modification
Corticosteroids (Systemic): Estrogen Derivatives may increase the serum concentration of Corticosteroids (Systemic). Monitor therapy
CYP1A2 Inducers (Strong): May increase the metabolism of CYP1A2 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification
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
CYP3A4 Inhibitors (Strong): May increase the serum concentration of MedroxyPROGESTERone. Exceptions: Atazanavir; Boceprevir; Cobicistat; Darunavir; Lopinavir; Nelfinavir; Saquinavir; Telaprevir. Monitor therapy
Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy
Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification
Dabrafenib: May decrease the serum concentration of Contraceptives (Progestins). Management: Females of reproductive potential should use an alternative, highly effective, non-hormonal means of contraception during and at least 2 weeks (dabrafenib alone) or 4 months (dabrafenib + trametinib) after discontinuation of dabrafenib treatment. Consider therapy modification
Darunavir: May decrease the serum concentration of Contraceptives (Progestins). Management: Consider using an alternative or additional means of contraception. Injected depot medroxyprogesterone acetate may be used without a need for additional contraception. Consider therapy modification
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
Dehydroepiandrosterone: May enhance the adverse/toxic effect of Estrogen Derivatives. Avoid combination
Efavirenz: May decrease the serum concentration of Contraceptives (Progestins). Management: Use an alternative or additional method of contraception due to possibly decreased contraceptive effectiveness. Injected depot medroxyprogesterone acetate does not appear to participate in this interaction. Consider therapy modification
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 (Progestins). Management: Alternative, non-hormonal means of birth control should be considered for women of child-bearing potential. Consider therapy modification
Exemestane: Estrogen Derivatives may diminish the therapeutic effect of Exemestane. Avoid combination
Felbamate: May decrease the serum concentration of Contraceptives (Progestins). Management: Contraceptive failure is possible. Use of an alternative, nonhormonal method of contraception is recommended. Consider therapy modification
Flibanserin: Contraceptives (Progestins) may increase the serum concentration of Flibanserin. Monitor therapy
Fosamprenavir: Contraceptives (Progestins) may decrease serum concentrations of the active metabolite(s) of Fosamprenavir. Fosamprenavir may decrease the serum concentration of Contraceptives (Progestins). Management: Consider using an alternative or additional means of contraception. Injected depot medroxyprogesterone acetate may be used without a need for additional contraception. Consider therapy modification
Fosaprepitant: May decrease the serum concentration of Contraceptives (Progestins). The active metabolite aprepitant is likely responsible for this effect. Management: Alternative or additional methods of contraception should be used both during treatment with aprepitant or fosaprepitant and for at least one month following the last aprepitant/fosaprepitant dose. Consider therapy modification
Fosphenytoin: May diminish the therapeutic effect of Contraceptives (Progestins). Contraceptive failure is possible. Management: Contraceptive failure is possible. Use of an alternative, nonhormonal contraceptive is recommended. Consider therapy modification
Griseofulvin: May diminish the therapeutic effect of Contraceptives (Progestins). Contraceptive failure is possible. Avoid combination
Hemin: Estrogen Derivatives may diminish the therapeutic effect of Hemin. Avoid combination
Herbs (Estrogenic Properties): May enhance the adverse/toxic effect of Estrogen Derivatives. Monitor therapy
Herbs (Progestogenic Properties) (eg, Bloodroot, Yucca): May enhance the adverse/toxic effect of Progestins. Monitor therapy
Hyaluronidase: Estrogen Derivatives may diminish the therapeutic effect of Hyaluronidase. Management: Patients receiving estrogens (particularly at larger doses) may not experience the desired clinical response to standard doses of hyaluronidase. Larger doses of hyaluronidase may be required. Consider therapy modification
Immune Globulin: Estrogen Derivatives may enhance the thrombogenic effect of Immune Globulin. Monitor therapy
Indium 111 Capromab Pendetide: Estrogen Derivatives may diminish the diagnostic effect of Indium 111 Capromab Pendetide. Avoid combination
Indium 111 Capromab Pendetide: Antiandrogens may diminish the diagnostic effect of Indium 111 Capromab Pendetide. Avoid combination
LamoTRIgine: May decrease the serum concentration of Contraceptives (Progestins). Management: Women using progestin-only "minipill " � products may be at risk for contraceptive failure; it is unclear if other progestin-containing products would be significantly impacted. Alternative, non-hormonal, means of contraception are recommended. Consider therapy modification
Lenalidomide: Estrogen Derivatives may enhance the thrombogenic effect of Lenalidomide. Monitor therapy
Lesinurad: May decrease the serum concentration of Contraceptives (Progestins). Management: Use of an additional, nonhormonal contraceptive is recommended in patients being treated with lesinurad who desire effective contraception. Consider therapy modification
Lixisenatide: May decrease the serum concentration of Contraceptives (Progestins). Management: Administer oral contraceptives 1 hour before or at least 11 hours after administration of lixisenatide. Consider therapy modification
Lopinavir: May decrease the serum concentration of Contraceptives (Progestins). Lopinavir may increase the serum concentration of Contraceptives (Progestins). Management: Consider using an alternative or additional means of contraception. Injected depot medroxyprogesterone acetate and etonogestrel implants may be used without a need for additional contraception. Consider therapy modification
Lumacaftor: May decrease the serum concentration of Contraceptives (Progestins). Management: Do not rely on hormone-based contraceptives with concurrent use of lumacaftor/ivacaftor; an alternative, non-hormonal, method of contraception should be used if this combination is required. Consider therapy modification
Metreleptin: May decrease the serum concentration of Contraceptives (Progestins). Metreleptin may increase the serum concentration of Contraceptives (Progestins). Monitor therapy
MiFEPRIStone: May diminish the therapeutic effect of Contraceptives (Progestins). MiFEPRIStone may increase the serum concentration of Contraceptives (Progestins). Management: Women of childbearing potential should use an effective, nonhormonal means of contraception during and 4 weeks following mifepristone treatment. Consider therapy modification
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
Mycophenolate: May decrease the serum concentration of Contraceptives (Progestins). Management: Use of an additional or alternative (nonhormonal) method of contraception should be considered. Consider therapy modification
Nalmefene: MedroxyPROGESTERone may increase the serum concentration of Nalmefene. Monitor therapy
Nelfinavir: May decrease the serum concentration of Contraceptives (Progestins). Management: Use an alternative or additional method of contraception due to possibly decreased contraceptive effectiveness. Injected depot medroxyprogesterone acetate does not appear to participate in this interaction. Consider therapy modification
Nevirapine: May decrease the serum concentration of Contraceptives (Progestins). Management: Instruct patients receiving nevirapine to use an alternative or additional nonhormonal contraceptive. Nevirapine product labeling however suggests that depo-medroxyprogesterone acetate may be used as a sole method of contraception. Consider therapy modification
NSAID (COX-2 Inhibitor): May enhance the thrombogenic effect of Estrogen Derivatives. NSAID (COX-2 Inhibitor) may increase the serum concentration of Estrogen Derivatives. Monitor therapy
Osimertinib: May increase the serum concentration of CYP3A4 Substrates. Osimertinib may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
Osimertinib: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy
Ospemifene: Estrogen Derivatives may enhance the adverse/toxic effect of Ospemifene. Estrogen Derivatives may diminish the therapeutic effect of Ospemifene. Avoid combination
OXcarbazepine: May decrease the serum concentration of Contraceptives (Progestins). Management: Contraceptive failure is possible. Use of an additional or alternative, nonhormonal method of contraception is recommended. Consider therapy modification
Perampanel: May decrease the serum concentration of Contraceptives (Progestins). Management: Patients should use an alternative, non-hormonal based form of contraception for the duration of concurrent perampanel. Both oral and non-oral progestin-based contraceptives are likely to be impacted by this interaction. Consider therapy modification
Phenytoin: May diminish the therapeutic effect of Contraceptives (Progestins). Contraceptive failure is possible. Management: Contraceptive failure is possible. Use of an alternative, nonhormonal contraceptive is recommended. Consider therapy modification
Pomalidomide: May enhance the thrombogenic effect of Estrogen Derivatives. Management: Canadian pomalidomide labeling recommends caution with use of hormone replacement therapy and states that hormonal contraceptives are not recommended. US pomalidomide labeling does not contain these specific recommendations. Consider therapy modification
Pomalidomide: Progestins may enhance the thrombogenic effect of Pomalidomide. Management: Canadian pomalidomide labeling recommends caution with use of hormone replacement therapy and states that hormonal contraceptives are not recommended. US pomalidomide labeling does not contain these specific recommendations. Consider therapy modification
Primidone: May diminish the therapeutic effect of Contraceptives (Progestins). Contraceptive failure is possible. Management: Use of alternative, nonhormonal contraceptives is recommended. Consider therapy modification
Prucalopride: May decrease the serum concentration of Contraceptives (Progestins). Consider therapy modification
Retinoic Acid Derivatives: May diminish the therapeutic effect of Contraceptives (Progestins). Retinoic Acid Derivatives may decrease the serum concentration of Contraceptives (Progestins). Management: Two forms of effective contraception should be used in patients receiving retinoic acid derivatives. Particularly, microdosed progesterone-only preparations may be inadequately effective. Exceptions: Adapalene; Bexarotene (Topical); Tretinoin (Topical). Consider therapy modification
Rifamycin Derivatives: May decrease the serum concentration of Contraceptives (Progestins). Contraceptive failure is possible. Management: Contraceptive failure is possible. Use of an alternative, nonhormonal contraceptive is recommended. Consider therapy modification
ROPINIRole: Estrogen Derivatives may increase the serum concentration of ROPINIRole. Monitor therapy
Saquinavir: May decrease the serum concentration of Contraceptives (Progestins). Management: Use an alternative or additional method of contraception due to possibly decreased contraceptive effectiveness. Injected depot medroxyprogesterone acetate does not appear to participate in this interaction. Consider therapy modification
Selegiline: Contraceptives (Progestins) may increase the serum concentration of Selegiline. Monitor therapy
Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
Somatropin: Estrogen Derivatives may diminish the therapeutic effect of Somatropin. Shown to be a concern with oral hormone replacement therapy in postmenopausal women. Management: Monitor for reduced growth hormone efficacy. A larger somatropin dose may be required to reach treatment goal. This interaction does not appear to apply to non-orally administered estrogens (e.g., transdermal, vaginal ring). Consider therapy modification
St Johns Wort: May diminish the therapeutic effect of Contraceptives (Progestins). Contraceptive failure is possible. Management: Consider using a product other than St John's wort. Contraceptive failure is possible. Use of an alternative, nonhormonal contraceptive is recommended. Consider therapy modification
St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification
Sugammadex: May decrease the serum concentration of Contraceptives (Progestins). Management: Patients receiving any hormonal contraceptive (oral or non-oral) should use an additional, nonhormonal contraceptive method during and for 7 days following sugammadex treatment. Consider therapy modification
Telaprevir: May decrease the serum concentration of Contraceptives (Progestins). Management: Two different nonhormonal forms of contraception are required for women of childbearing potential taking telaprevir. Hormonal contraceptives may be less effective during concurrent telaprevir and for up to 2 weeks after telaprevir discontinuation. Consider therapy modification
Teriflunomide: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy
Thalidomide: Contraceptives (Progestins) may enhance the thrombogenic effect of Thalidomide. Monitor therapy
Thalidomide: Estrogen Derivatives may enhance the thrombogenic effect of Thalidomide. Monitor therapy
Theophylline Derivatives: Estrogen Derivatives may increase the serum concentration of Theophylline Derivatives. Exceptions: Dyphylline. Monitor therapy
Thyroid Products: Estrogen Derivatives may diminish the therapeutic effect of Thyroid Products. Monitor therapy
Tipranavir: Estrogen Derivatives may enhance the dermatologic adverse effect of Tipranavir. The combination of tipranavir/ritonavir and ethinyl estradiol/norethindrone was associated with a high incidence of skin rash. Tipranavir may decrease the serum concentration of Estrogen Derivatives. Management: Women using hormonal contraceptives should consider alternative, non-hormonal forms of contraception. Consider therapy modification
Tipranavir: May increase the serum concentration of Contraceptives (Progestins). Management: Use an alternative or additional method of contraception due to possibly decreased contraceptive effectiveness. Injected depot medroxyprogesterone acetate does not appear to participate in this interaction. Consider therapy modification
TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
Topiramate: May decrease the serum concentration of Contraceptives (Progestins). Management: Caution patients that this combination may be associated with reduced contraceptive effectiveness. Consider adding an additional (non-hormonal) contraceptive method. Consider therapy modification
Tranexamic Acid: Contraceptives (Progestins) may enhance the thrombogenic effect of Tranexamic Acid. Avoid combination
Ulipristal: May diminish the therapeutic effect of Progestins. Progestins may diminish the therapeutic effect of Ulipristal. Management: Ulipristal for uterine fibroids (Canadian indication): avoid progestins within 12 days of stopping ulipristal; as emergency contraceptive (U.S. indication): avoid progestins within 5 days of stopping ulipristal. Avoid combination
Ursodiol: Estrogen Derivatives may diminish the therapeutic effect of Ursodiol. Monitor therapy
Vitamin K Antagonists (eg, warfarin): Contraceptives (Progestins) may diminish the anticoagulant effect of Vitamin K Antagonists. In contrast, enhanced anticoagulant effects have also been noted with some products. Management: When possible, concomitant hormonal contraceptives and coumarin derivatives should be avoided in order to eliminate the risk of thromboembolic disorders. Consider using an alternative, nonhormonal contraceptive. Consider therapy modification
Voriconazole: May increase the serum concentration of Contraceptives (Progestins). Contraceptives (Progestins) may increase the serum concentration of Voriconazole. Monitor therapy
Routine physical examination that includes blood pressure and Papanicolaou smear, breast exam, mammogram. Monitor for signs of endometrial cancer. Adequate diagnostic measures, including endometrial sampling, if indicated, should be performed to rule out malignancy in all cases of undiagnosed abnormal genital bleeding. Monitor for loss of vision, sudden onset of proptosis, diplopia, migraine; signs and symptoms of thromboembolic disorders; glycemic control in patients with diabetes; lipid profiles in patients being treated for hyperlipidemias; thyroid function in patients on thyroid hormone replacement therapy.
Menopausal symptoms, vulvar and vaginal atrophy: Assess need for therapy at 3- to 6-month intervals
Prevention of osteoporosis: Bone density measurement
Note: Monitoring of FSH and serum estradiol is not useful when managing vasomotor symptoms associated with menopause or vulvar and vaginal atrophy.
Reduced response to metyrapone test.
Also see individual agents.
>10%:
Central nervous system: Headache (15% to 19%)
Gastrointestinal: Abdominal pain (7% to 17%)
Genitourinary: Mastalgia (13% to 36%), dysmenorrhea (3% to 13%)
1% to 10%:
Cardiovascular: Edema ( ≤4%), peripheral edema (2% to 3%), hypertension (2%), vasodilatation ( ≤2%), chest pain (1%), palpitations ( ≤1%)
Central nervous system: Depression (7% to 8%), pain (5%), emotional lability (3%), dizziness (2% to 3%), migraine (2% to 3%), nervousness (1% to 3%), anxiety (2%), hypertonia (1% to 2%), insomnia (1% to 2%)
Dermatologic: Pruritus (2% to 6%), skin rash (2%), acne vulgaris ( ≤2%), alopecia ( ≤2%), skin discoloration (1% to 2%), diaphoresis ( ≤1%), xeroderma ( ≤1%)
Endocrine & metabolic: Weight gain (3%), decreased glucose tolerance ( ≤1%), hypermenorrhea ( ≤1%)
Gastrointestinal: Nausea (6% to 8%), flatulence (4% to 8%), diarrhea ( ≤6%), constipation (2%), increased appetite ( ≤2%), eructation ( ≤1%)
Genitourinary: Leukorrhea (3% to 8%), breast hypertrophy (2% to 5%), pelvic pain (2% to 5%), vaginal hemorrhage ( ≤5%), vaginitis (2% to 4%), breakthrough bleeding (1% to 4%), uterine spasm (1% to 4%), vulvovaginal candidiasis (1% to 4%), cervical changes (1% to 3%), abnormal Pap smear ( ≤2%), breast engorgement ( ≤1%), urinary incontinence ( ≤1%)
Hematologic & oncologic: Malignant neoplasm of breast ( ≤1%)
Infection: Candidiasis ( ≤2%), infection ( ≤1%)
Neuromuscular & skeletal: Weakness (3% to 6%), back pain (2% to 7%), leg cramps (2% to 4%)
Respiratory: Pharyngitis (>5%), sinusitis (>5%), flu-like symptoms ( ≤1%)
<1% (Limited to important or life-threatening): Abnormal uterine bleeding, amenorrhea, anaphylactoid reaction, anaphylaxis, angioedema, cerebrovascular accident, cholestatic jaundice, contact lens intolerance, deep vein thrombosis, dementia, endometrial carcinoma, endometrial hyperplasia, erythema multiforme, erythema nodosum, exacerbation of asthma, exacerbation of epilepsy, exacerbation of tics, fibrocystic breast changes, galactorrhea, gallbladder disease, hirsutism, hypersensitivity reaction, ischemic colitis, malignant neoplasm of ovary, meningioma (benign; possible growth), myocardial infarction, pancreatitis, pulmonary embolism, retinal thrombosis, superficial venous thrombosis, thrombophlebitis, upper respiratory tract infection, uterine fibroids (increase in size), vulvovaginal candidiasis
Concerns related to adverse effects:
- Anaphylaxis: Anaphylaxis requiring emergency medical management has been reported and may develop at any time during therapy. Angioedema involving the face, feet, hands, larynx, and tongue has also been reported.
- Breast cancer: [US Boxed Warning]: Based on data from the Women 's Health Initiative (WHI) studies, an increased risk of invasive breast cancer was observed in postmenopausal women using conjugated estrogens (CE) in combination with medroxyprogesterone acetate (MPA). This risk may be associated with duration of use and declines once combined therapy is discontinued (Chlebowski, 2009). The risk of invasive breast cancer was decreased in postmenopausal women with a hysterectomy using CE only, regardless of weight. However, the risk was not significantly decreased in women at high risk for breast cancer (family history of breast cancer, personal history of benign breast disease) (Anderson, 2012). An increase in abnormal mammogram findings has also been reported with estrogen alone or in combination with progestin therapy. Estrogen use may also lead to severe hypercalcemia in patients with breast cancer and bone metastases; discontinue estrogen if hypercalcemia occurs. Use is contraindicated in patients with known or suspected breast cancer.
- Dementia: [US Boxed Warning]: Estrogens with or without progestin should not be used to prevent dementia. In the Women 's Health Initiative Memory Study (WHIMS), an increased incidence of dementia was observed in women ≥65 years of age taking CE alone or in combination with MPA.
- Endometrial cancer: [US Boxed Warning]: The use of unopposed estrogen in women with a uterus is associated with an increased risk of endometrial cancer. The addition of a progestin to estrogen therapy may decrease the risk of endometrial hyperplasia, a precursor to endometrial cancer. Adequate diagnostic measures, including endometrial sampling if indicated, should be performed to rule out malignancy in postmenopausal women with undiagnosed abnormal vaginal bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens at equivalent estrogen doses. The risk of endometrial cancer appears to be dose and duration dependent; risk appears to be greatest with use ≥5 years and may persist following discontinuation of therapy.
- Endometriosis: Estrogens may exacerbate endometriosis. Malignant transformation of residual endometrial implants has been reported posthysterectomy with unopposed estrogen therapy. Consider adding a progestin in women with residual endometriosis posthysterectomy.
- Inherited thrombophilia: 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 protein C, protein S, antithrombin deficiency, or other known thrombophilic disorders.
- Lipid effects: Estrogen compounds are generally associated with lipid effects such as increased HDL-cholesterol and decreased LDL-cholesterol. Triglycerides may also be increased in women with preexisting hypertriglyceridemia; discontinue if pancreatitis occurs.
- Ovarian cancer: Postmenopausal estrogens with or without progestins may increase the risk of ovarian cancer; however, the absolute risk to an individual woman is small. Although results from various studies are not consistent, risk does not appear to be significantly associated with the duration, route, or dose of therapy. In one study, the risk decreased after 2 years following discontinuation of therapy (M � �rch, 2009). Although the risk of ovarian cancer is rare, women who are at an increased risk (eg, family history) should be counseled about the association (NAMS, 2012).
- 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.
Disease-related concerns:
- Asthma: Use caution in patients with asthma; may exacerbate disease.
- Carbohydrate intolerance: May have adverse effects on glucose tolerance; use caution in women with diabetes.
- Cardiovascular disease: [US Boxed Warning]: Estrogens with or without progestin should not be used to prevent cardiovascular disease. Using data from the Women 's Health Initiative (WHI) studies, an increased risk of deep vein thrombosis (DVT) and stroke has been reported with CE and an increased risk of DVT, stroke, pulmonary emboli (PE) and myocardial infarction (MI) has been reported with CE with MPA in postmenopausal women 50 to 79 years of age. Additional risk factors include diabetes mellitus, hypercholesterolemia, hypertension, SLE, obesity, tobacco use, and/or history of venous thromboembolism (VTE). Risk factors should be managed appropriately; discontinue use immediately if adverse cardiovascular events occur or are suspected. Use is contraindicated in women with active DVT or PE (or a history of these conditions) or in women with active or recent arterial thromboembolic disease (stroke and MI), or a history of these conditions.
- Diseases exacerbated by fluid retention: Use with caution in patients with diseases which may be exacerbated by fluid retention, including cardiac or renal dysfunction.
- Epilepsy: Use caution with epilepsy; may exacerbate disease.
- Gallbladder disease: Use of postmenopausal estrogen may be associated with an increased risk of gallbladder disease requiring surgery.
- Hepatic dysfunction: Estrogens are poorly metabolized in patients with hepatic dysfunction. Use caution with a history of cholestatic jaundice associated with prior estrogen use or pregnancy. Discontinue if jaundice develops or if acute or chronic hepatic disturbances occur. Use is contraindicated with hepatic impairment or disease.
- Hepatic hemangiomas: Use with caution in patients with hepatic hemangiomas; may exacerbate disease.
- Hereditary angioedema: Exogenous estrogens may exacerbate angioedema symptoms in women with hereditary angioedema.
- Hypoparathyroidism: Use caution with hypoparathyroidism; estrogen-induced hypocalcemia may occur.
- Migraine: Use caution with migraine; may exacerbate disease.
- Porphyria: Use with caution in patients with porphyria; may exacerbate disease.
- SLE: Use with caution in patients with SLE; may exacerbate disease.
Concurrent drug therapy issues:
- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
- Thyroid replacement therapy: Estrogens may increase thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels. Women on thyroid replacement therapy may require higher doses of thyroid hormone while receiving estrogens.
Special populations:
- Elderly: Although hormone therapy is recommended to be initiated in healthy symptomatic women within 10 years of menopause or <60 years of age who do not have contraindications for use, symptoms may continue in women >60 years of age. The continuation of hormone therapy in women >65 years of age should consider the risks and benefits for the individual woman and should not be discontinued only because of the woman 's age (NAMS 2015).
- Surgical patients: Whenever possible, should be discontinued at least 4 to 6 weeks prior to elective surgery associated with an increased risk of thromboembolism or during periods of prolonged immobilization.
Special handling:
- Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).
Other warnings/precautions:
- 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.
- Osteoporosis use: For use only in women at significant risk of osteoporosis and for who other nonestrogen medications are not considered appropriate.
- Risks vs benefits: [US Boxed Warning]: Estrogens with or without progestin should be used for the shortest duration possible at the lowest effective dose consistent with treatment goals and risks for the individual woman. Hormone therapy for menopausal symptoms is generally initiated in healthy symptomatic women within 10 years of menopause or <60 years of age who do not have contraindications for use (Stuenkel 2015). Patients should be reevaluated as clinically appropriate to determine if treatment is still necessary. Available data related to treatment risks are from Women 's Health Initiative (WHI) studies, which evaluated oral CE 0.625 mg with or without MPA 2.5 mg relative to placebo in postmenopausal women. Other combinations and dosage forms of estrogens and progestins were not studied. Outcomes reported from clinical trials using CE with or without MPA should be assumed to be similar for other doses and other dosage forms of estrogens and progestins until comparable data becomes available. Women who are early in menopause, who are in good cardiovascular health, and who are at low risk for adverse cardiovascular events can be considered candidates for estrogen with or without progestin therapy for the relief of menopausal symptoms (ACOG 565 2013). Women at high risk of cardiovascular disease or intermediate to high risk of breast cancer should use nonhormonal therapy to treat vasomotor symptoms of menopause (Stuenkel 2015). Use of a transdermal product should be considered over an oral agent in women requiring systemic therapy who have moderate risk factors for coronary heart disease (ACOG 556 2013; Schenck-Gustafsson 2011; Stuenkel 2015). Nonoral routes of therapy are recommended for women at increased risk for venous thromboembolism (Stuenkel 2015; Tremollieres 2011)
- Vulvar and vaginal atrophy use: Moderate to severe symptoms of vulvar and vaginal atrophy include vaginal dryness, dyspareunia, and atrophic vaginitis. [The combined conditions of vulvovaginal atrophy and urinary tract dysfunction is also referred to as genitourinary syndrome of menopause (GSM) (Portman 2014; Stuenkel 2015)]. When used solely for the treatment of vulvar and vaginal atrophy, topical vaginal products should be considered. Use caution applying topical products to severely atrophic vaginal mucosa. Use of a progestin is normally not required when low-dose estrogen is applied locally and only for this purpose (NAMS 2012; NAMS 2013; Stuenkel 2015).
Use is contraindicated in pregnant women. In general, the use of estrogen and progestin as in combination hormonal contraceptives have not been associated with teratogenic effects when inadvertently taken early in pregnancy.
See individual agents.
- 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 cramps, bloating, enlarged breasts, alopecia, 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, trouble speaking or thinking, change in balance, or change in eyesight), signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), angina, shortness of breath, edema, coughing up blood, severe headache, severe nausea, vomiting, severe dizziness, passing out, bulging eyes, contact lens discomfort, vision changes, eye pain, severe eye irritation, lump in breast, breast soreness or pain, nipple discharge, vaginal bleeding, vaginitis, depression, or memory impairment (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.