Version May 2024
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. Perform adequate diagnostic measures, including directed or random endometrial sampling when indicated, to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.
The Women’s 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 daily oral conjugated estrogens (CE) (0.625 mg) alone, relative to placebo. Do not use estrogen-alone therapy for the prevention of cardiovascular disease.
The WHI estrogen plus progestin substudy reported an increased risk of pulmonary embolism, DVT, stroke, and myocardial infarction in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral CEs (0.625 mg) combined with medroxyprogesterone acetate (MPA) (2.5 mg), relative to placebo. Do not use estrogen plus progestogen therapy for the prevention of cardiovascular disease.
The WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer.
The Women’s Health Initiative Memory Study (WHIMS) estrogen-alone ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women ≥65 years of age during 5.2 years of treatment with daily CE (0.625 mg) alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. Do not use estrogen-alone therapy 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 of age during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. Do not use estrogen plus progestin therapy for the prevention of dementia.
Only daily oral CEs (0.625 mg) and daily oral CE (0.625 mg) and MPA (2.5 mg) were studied in the estrogen-alone and estrogen plus progestin substudies of the WHI, respectively. Therefore, the relevance of the WHI findings regarding the adverse cardiovascular events and dementia to lower CE doses, other routes of administration, or other estrogen-alone products is not known. Likewise, the relevance of the WHI findings regarding the adverse cardiovascular events, dementia, and breast cancer to lower CE plus other MPA doses, other routes of administration, or other estrogen plus progestin products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of the risks for other products. Discuss with your patient the benefits and risks of estrogen-alone or estrogen plus progestin therapy, taking into account her individual risk profile. Prescribe estrogens with or without progestins at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
Vasomotor symptoms associated with menopause: Note: For use in symptomatic patients who are <60 years of age or within 10 years of menopause who do not have contraindications to hormone therapy (eg, breast cancer) (NAMS 2022). Nonoral estrogen preparations are preferred in patients with hypertriglyceridemia, risk factors for venous thromboembolic disease, active gallbladder disease, and/or migraine headache with aura (Martin 2022a; Renoux 2010). Combination products are only indicated for patients with a uterus; the progestogen (ie, a natural progesterone or synthetic progestin) component prevents estrogen therapy-associated endometrial hyperplasia. Use of a combination product offers less dosing flexibility for initiating and tapering estrogen compared to separate estrogen and progestogen products.
Oral: Drospirenone 0.25 mg/estradiol 0.5 mg or drospirenone 0.5 mg/estradiol 1 mg per tablet: 1 tablet daily. Note: Initiate at the lowest dose and increase after ~4 weeks as needed to relieve symptoms (Martin 2022).
Duration of therapy: Not clearly established; continued use may be appropriate in patients ≥60 years of age or >10 years after menopause with a low risk of cardiovascular disease and breast cancer and with persistent vasomotor symptoms after attempted taper/discontinuation of estrogen and trial of alternative therapies. Evaluate routinely for comorbidities and appropriateness of lower doses, nonoral routes of administration (preferred in patients ≥60 years of age), choice of progestogen, and discontinuation of therapy (NAMS 2022).
Vulvar and vaginal atrophy associated with menopause: Oral: Drospirenone 0.5 mg/estradiol 1 mg per tablet: One tablet daily.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Use is contraindicated.
Use is contraindicated.
Note: Duration of use is not clearly established; continued use may be appropriate in patients ≥60 years of age or >10 years after menopause with a low risk of cardiovascular disease and breast cancer with persistent vasomotor symptoms after attempted taper/discontinuation of estrogen and trial of alternative therapies. Evaluate routinely for comorbidities and appropriateness of lower doses, nonoral routes of administration (preferred in patients ≥60 years of age), choice of progestogen, and discontinuation of therapy (NAMS 2022).
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Genitourinary: Mastalgia (6% to 18%), genital bleeding (3% to 14%)
1% to 10%:
Central nervous system: Emotional lability (1%), migraine (≤1%)
Gastrointestinal: Abdominal pain (≤4% to 7%), gastrointestinal pain (≤4% to 7%)
Genitourinary: Cervical polyp (≤1%)
<1%, postmarketing, and/or case reports: Cerebral infarction, cerebrovascular accident, embolism, hypersensitivity reaction, malignant neoplasm of breast, myocardial infarction, pulmonary vascular occlusion, pruritus, skin rash, thromboembolism, urticaria, venous obstruction (peripheral deep vein)
Anaphylactic reaction, angioedema, or hypersensitivity to drospirenone, estradiol, or any component of the formulation; undiagnosed abnormal genital bleeding; deep vein thrombosis or pulmonary embolism (current or history of); active or history of arterial thromboembolic disease (eg, stroke, myocardial infarction); breast cancer (known, suspected, or history of); estrogen-dependent tumor (known or suspected); hepatic impairment or disease; renal impairment; adrenal insufficiency; known protein C, protein S, antithrombin deficiency or other known thrombophilic disorders.
Canadian labeling: Additional contraindications (not in US labeling): Progestin-dependent malignant neoplasia (current or history of); benign or malignant liver tumors (current or history of); endometrial hyperplasia; severe hypertriglyceridemia; classic migraine; partial or complete loss of vision due to ophthalmic vascular disease; pregnancy (confirmed or suspected); breastfeeding.
Concerns related to adverse effects:
• Breast cancer: Based on data from the Women’s Health Initiative (WHI) studies, an increased risk of invasive breast cancer was observed in postmenopausal patients using conjugated estrogens (CE) in combination with medroxyprogesterone acetate (MPA). Observational studies noted this risk declines once therapy is discontinued. The WHI study did not observe an increased risk of invasive breast cancer in patients with a hysterectomy using CE alone. The risk of breast cancer in patients who are postmenopausal receiving hormone therapy may depend upon type of estrogen and/or progestogen, dose, timing of therapy initiation, duration of therapy, route of administration, and individual patient characteristics (AACE/ACE [Cobin 2017]; NAMS 2022). Hormone therapy may be considered for patients who have entered menopause following an oophorectomy if the patient does not have a personal history of breast cancer; individualize treatment for menopausal symptoms (SGO/ASRM [Chen 2019]). Hormone therapy may be associated with increased breast density (NAMS 2022); an increase in abnormal mammogram findings requiring further evaluation has been reported with estrogen alone or in combination with progestogen therapy. Estrogen use may lead to severe hypercalcemia in patients with breast cancer and bone metastases; discontinue estrogen if hypercalcemia occurs.
• Dementia: Do not use estrogens with or without progestogen to prevent dementia. In the Women’s Health Initiative Memory Study (WHIMS), an increased incidence of probable dementia was observed in patients ≥65 years of age taking CE alone or in combination with MPA. Because the WHIMS was conducted in patients ≥65 years of age, it is unknown if these findings apply to younger patients who are postmenopausal. However, hormone therapy is not recommended at any age to prevent or treat cognitive decline or dementia (AACE [Goodman 2011]; NAMS 2022).
• Endometrial cancer: The use of unopposed estrogen in patients 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. Perform adequate diagnostic measures, including endometrial sampling if indicated to rule out malignancy in postmenopausal patients 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, greatest with use ≥5 years, and may persist following discontinuation of therapy (NAMS 2022).
• Endometriosis: Estrogens may exacerbate endometriosis. Malignant transformation of residual endometrial implants has been reported posthysterectomy with unopposed estrogen therapy. Consider adding a progestogen in patients with residual endometriosis posthysterectomy.
• Hyperkalemia: Drospirenone has antimineralocorticoid activity that may lead to hyperkalemia. Use caution with medications that may increase serum potassium.
• Hyponatremia: Drospirenone may increase the possibility of hyponatremia in high risk patients.
• 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 patients with preexisting hypertriglyceridemia; discontinue if pancreatitis occurs. Use with caution in patients with familial defects of lipoprotein metabolism.
• Ovarian cancer: Available information related to the use of menopausal estrogen or estrogen/progestogen therapy and risk of ovarian cancer is inconsistent. If an association is present, the absolute risk is likely rare and may be influenced by duration of therapy (AACE [Goodman 2011]; ES [Stuenkel 2015]; NAMS 2022).
• 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.
• Cardiovascular disease: Do not use estrogens with or without progestogen to prevent cardiovascular disease. The WHI studies reported an increased risk of deep vein thrombosis (DVT) and stroke with CEs, and an increased risk of DVT, stroke, pulmonary emboli (PE), and myocardial infarction (MI) has been reported with CEs with MPA in patients who are postmenopausal 50 to 79 years of age. Additional risk factors include diabetes mellitus, hypercholesterolemia, hypertension, systemic lupus erythematosus (SLE), obesity, tobacco use, and/or history of venous thromboembolism (VTE). Manage risk factors appropriately; discontinue use immediately if adverse cardiovascular events occur or are suspected. Due to possible lower risk of thrombotic events, transdermal administration may be preferred for treating vasomotor symptoms of menopause in patients with risk factors for cardiovascular disease (ACOG 556 2013; AACE/ACE [Cobin 2017]; ES [Stuenkel 2015]).
• Chorea minor: Use caution with chorea minor; may exacerbate disease.
• Diabetes mellitus: May impair glucose tolerance; use caution in patients with diabetes mellitus. Prior to therapy, consider age, cardiovascular and metabolic risk factors in patients previously diagnosed with diabetes (AACE/ACE [Cobin 2017]).
• 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.
• Hepatic hemangiomas: Use with caution in patients with hepatic hemangiomas; may exacerbate disease.
• Hereditary angioedema: Exogenous estrogens may exacerbate angioedema symptoms in patients with hereditary angioedema.
• Hypoparathyroidism: Use caution in patients with hypoparathyroidism; estrogen-induced hypocalcemia may occur.
• Migraine: Use caution with migraine; may exacerbate disease.
• Otosclerosis: Use caution with otosclerosis; 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.
Special populations:
• Surgery: Whenever possible, discontinue estrogens at least 4 to 6 weeks prior to elective surgery associated with an increased risk of thromboembolism or during periods of prolonged immobilization.
Other warnings/precautions:
• Duration of use: Not clearly established; continued use may be appropriate in patients ≥60 years of age or >10 years after menopause with a low risk of cardiovascular disease and breast cancer with persistent vasomotor symptoms after attempted taper/discontinuation of estrogen and trial of alternative therapies. Evaluate routinely for comorbidities and appropriateness of lower doses, nonoral routes of administration (preferred in patients ≥60 years of age), choice of progestogen, and discontinuation of therapy (NAMS 2022).
• Genitourinary syndrome of menopause (GSM): Low-dose vaginal estrogen is preferred over systemic therapy for GSM in the absence of vasomotor symptoms due to increased efficacy and decreased systemic effects (eg, cardiovascular effects, cancer risk) (Crandall 2018; NAMS 2013; NAMS 2022).
• Risks vs benefits: When used for the relief of menopausal symptoms or increased risk of bone fracture/loss, the benefit-risk of hormone therapy is most favorable if started in patients who have no contraindications to therapy, are <60 years of age, within 10 years of menopause onset, have a favorable lipid profile, and do not have the factor V Leiden genotype or metabolic syndrome. Consider cardiovascular disease risk factors for when evaluating therapy and route of administration (AACE/ACE [Cobin 2017]; NAMS 2022). Use for the shortest duration possible at the lowest effective dose consistent with treatment goals and risks for the individual patient. Reevaluate patients 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 patients who are postmenopausal. Other combinations and dosage forms of estrogens and progestogens were not studied. Assume outcomes reported from clinical trials using CE with or without MPA to be similar for other doses and other dosage forms of estrogens and progestins until comparable data becomes available.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Angeliq: Drospirenone 0.5 mg and estradiol 1 mg, Drospirenone 0.25 mg and estradiol 0.5 mg
No
Tablets (Angeliq Oral)
0.25-0.5 mg (per each): $7.98
0.5-1 mg (per each): $7.98
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Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Angeliq: 1-1 MG
Oral: Swallow tablets whole with some liquid with or without food and take at the same time each day. Bleeding may occur if several doses are missed. Start therapy at any time in patients who are not taking estrogen or who are changing from a continuous combination product. Complete the current cycle before switching to this product in patients who are switching from sequential or cyclic hormone therapy. Take a forgotten dose as soon as possible. Do not take the missed tablet if more than 24 hours have passed.
Hazardous agent (NIOSH 2016 [group 2]).
Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage. NIOSH recommends single gloving for administration of intact tablets or capsules (NIOSH 2016).
Vasomotor symptoms associated with menopause: Treatment of moderate to severe vasomotor symptoms associated with menopause in patients with a uterus.
Vulvar and vaginal atrophy associated with menopause: Treatment of moderate to severe vulvar and vaginal atrophy due to menopause in patients with a uterus.
Limitations of use: When used solely for the treatment of vulvar and vaginal atrophy, consider topical vaginal products.
Note: The International Society for the Study of Women’s Sexual Health and The North American Menopause Society have endorsed the term genitourinary syndrome of menopause (GSM) as new terminology for vulvovaginal atrophy. The term GSM encompasses all genital and urinary signs and symptoms associated with a loss of estrogen due to menopause (Ref).
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs that have a heightened risk of causing significant patient harm when used in error.
Substrate of CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP1A2 (weak)
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Ajmaline: Estrogen Derivatives may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased. Risk C: Monitor therapy
Aliskiren: Drospirenone-Containing Products may enhance the hyperkalemic effect of Aliskiren. Risk C: Monitor therapy
Anastrozole: Estrogen Derivatives may diminish the therapeutic effect of Anastrozole. Risk X: Avoid combination
Angiotensin II Receptor Blockers: Drospirenone-Containing Products may enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
Angiotensin-Converting Enzyme Inhibitors: Drospirenone-Containing Products may enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Anthrax Immune Globulin (Human): Estrogen Derivatives may enhance the thrombogenic effect of Anthrax Immune Globulin (Human). Risk C: Monitor therapy
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
C1 inhibitors: Estrogen Derivatives may enhance the thrombogenic effect of C1 inhibitors. Risk C: Monitor therapy
Chenodiol: Estrogen Derivatives may diminish the therapeutic effect of Chenodiol. Risk C: Monitor therapy
Chlorprothixene: Estrogen Derivatives may enhance the adverse/toxic effect of Chlorprothixene. Estrogen Derivatives may enhance the therapeutic effect of Chlorprothixene. Risk C: Monitor therapy
Chlorprothixene: Progestins may enhance the adverse/toxic effect of Chlorprothixene. Progestins may enhance the therapeutic effect of Chlorprothixene. Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CloZAPine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine. Risk C: Monitor therapy
Corticosteroids (Systemic): Estrogen Derivatives may increase the serum concentration of Corticosteroids (Systemic). Risk C: 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. Risk D: Consider therapy modification
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Estrogen Derivatives. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Estrogen Derivatives. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Estrogen Derivatives. Risk C: Monitor therapy
Dantrolene: Estrogen Derivatives may enhance the hepatotoxic effect of Dantrolene. Risk C: Monitor therapy
Dehydroepiandrosterone: May enhance the adverse/toxic effect of Estrogen Derivatives. Risk X: Avoid combination
Exemestane: Estrogen Derivatives may diminish the therapeutic effect of Exemestane. Risk X: Avoid combination
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Fezolinetant: CYP1A2 Inhibitors (Weak) may increase the serum concentration of Fezolinetant. Risk X: Avoid combination
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Growth Hormone Analogs: Estrogen Derivatives may diminish the therapeutic effect of Growth Hormone Analogs. Management: Initiate somapacitan at 2 mg once weekly in patients receiving oral estrogens. Monitor for reduced efficacy of growth hormone analogs; increased doses may be required. Risk D: Consider therapy modification
Hemin: Estrogen Derivatives may diminish the therapeutic effect of Hemin. Risk X: Avoid combination
Heparin: Drospirenone-Containing Products may enhance the hyperkalemic effect of Heparin. Risk C: Monitor therapy
Hyaluronidase: Estrogen Derivatives may diminish the therapeutic effect of Hyaluronidase. Risk C: Monitor therapy
Hydrocortisone (Systemic): Estrogen Derivatives may increase the serum concentration of Hydrocortisone (Systemic). Estrogen Derivatives may decrease the serum concentration of Hydrocortisone (Systemic). Risk C: Monitor therapy
Immune Globulin: Estrogen Derivatives may enhance the thrombogenic effect of Immune Globulin. Risk C: Monitor therapy
Indium 111 Capromab Pendetide: Estrogen Derivatives may diminish the diagnostic effect of Indium 111 Capromab Pendetide. Risk X: Avoid combination
LamoTRIgine: Estrogen Derivatives may decrease the serum concentration of LamoTRIgine. Risk C: Monitor therapy
Lenalidomide: Estrogen Derivatives may enhance the thrombogenic effect of Lenalidomide. Risk C: Monitor therapy
Melatonin: Estrogen Derivatives may increase the serum concentration of Melatonin. Risk C: Monitor therapy
MetyraPONE: Estrogen Derivatives may diminish the diagnostic effect of MetyraPONE. Management: Consider alternatives to the use of the metyrapone test in patients taking estrogen derivatives. Risk D: Consider therapy modification
MetyraPONE: Progestins may diminish the diagnostic effect of MetyraPONE. Management: Consider alternatives to the use of the metyrapone test in patients taking progestins. Risk D: Consider therapy modification
Mivacurium: Estrogen Derivatives may increase the serum concentration of Mivacurium. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: Drospirenone-Containing Products may enhance the hyperkalemic effect of Nonsteroidal Anti-Inflammatory Agents. Risk C: Monitor therapy
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. Risk C: Monitor therapy
Ospemifene: Estrogen Derivatives may enhance the adverse/toxic effect of Ospemifene. Risk X: Avoid combination
Pomalidomide: Estrogen Derivatives may enhance the thrombogenic effect of Pomalidomide. Risk C: Monitor therapy
Potassium Salts: Drospirenone-Containing Products may enhance the hyperkalemic effect of Potassium Salts. Risk C: Monitor therapy
Potassium-Sparing Diuretics: Drospirenone-Containing Products may enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Risk C: Monitor therapy
Protease Inhibitors: May decrease the serum concentration of Estrogen Derivatives. Protease Inhibitors may increase the serum concentration of Estrogen Derivatives. Risk C: Monitor therapy
Raloxifene: Estrogen Derivatives may enhance the adverse/toxic effect of Raloxifene. Risk X: Avoid combination
ROPINIRole: Estrogen Derivatives may increase the serum concentration of ROPINIRole. Risk C: Monitor therapy
Succinylcholine: Estrogen Derivatives may increase the serum concentration of Succinylcholine. Risk C: Monitor therapy
Tacrolimus (Systemic): Estrogen Derivatives may increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Thalidomide: Estrogen Derivatives may enhance the thrombogenic effect of Thalidomide. Risk C: Monitor therapy
Theophylline Derivatives: CYP1A2 Inhibitors (Weak) may increase the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy
Thyroid Products: Estrogen Derivatives may diminish the therapeutic effect of Thyroid Products. Risk C: Monitor therapy
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. Risk D: Consider therapy modification
Tranexamic Acid: Estrogen Derivatives may enhance the thrombogenic effect of Tranexamic Acid. Risk X: Avoid combination
Ulipristal: May diminish the therapeutic effect of Progestins. Progestins may diminish the therapeutic effect of Ulipristal. Risk X: Avoid combination
Ursodiol: Estrogen Derivatives may diminish the therapeutic effect of Ursodiol. Risk C: Monitor therapy
Routine use of ethanol increases estrogen level and risk of breast cancer. Management: Avoid ethanol
This combination product is not indicated for use prior to menopause.
Drospirenone and estrogens are present in breast milk.
Following administration of an oral contraceptive agent containing drospirenone, ~0.02% of the dose was detected in breast milk, resulting in a maximum of ~3 mcg/day drospirenone to the infant. Estrogens may decrease the quality and quantity of breast milk.
Prior to therapy, baseline risk for breast cancer and CVD. During therapy, age-appropriate breast and pelvic exams; blood pressure; unscheduled bleeding lasting >6 months for endometrial pathology (sooner in patients who are obese, diabetic, or have a history of endometrial cancer); serum triglycerides (2 weeks after starting therapy in patients with baseline level >200 mg/dL); TSH (6 to 12 weeks after starting oral therapy in patients taking thyroid replacement). Efficacy beginning 1 to 3 months after starting therapy, then every 6 to 12 months as appropriate. Evaluate duration of treatment at least annually (ES [Stuenkel 2015]).
Serum potassium during the first month of therapy in patients at risk for hyperkalemia and who are on chronic strong CYP3A4 inhibitors
Note: Monitoring of FSH and serum estradiol is not useful when managing vasomotor symptoms or genitourinary symptoms of menopause.
Drospirenone is a synthetic progestin and spironolactone analog with antimineralocorticoid and antiandrogenic activity. Counteracts estrogen effects causing endometrial thinning.
Estrogens are responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Estradiol is the principal intracellular human estrogen and is more potent than estrone and estriol at the receptor level; it is the primary estrogen secreted prior to menopause. Following menopause, estrone and estrone sulfate are more highly produced. Estrogens modulate the pituitary secretion of gonadotropins, luteinizing hormone, and follicle-stimulating hormone through a negative feedback system; estrogen replacement reduces elevated levels of these hormones in patients who are postmenopausal.
Distribution: Drospirenone: 4.2 L/kg
Protein binding:
Drospirenone: 97%; does not bind to sex hormone binding globulin or corticosteroid binding globulin
Estradiol: 37% bound to sex hormone binding globulin; 61% bound to albumin
Metabolism: Hepatic
Drospirenone forms two metabolites (inactive)
Estradiol: Converted to estrone and estriol; also undergoes enterohepatic recirculation; estrone sulfite is the main metabolite in patients who are postmenopausal.
Bioavailability: Drospirenone: 76% to 85%
Half-life elimination: Drospirenone: ~36-42 hours
Time to peak, plasma: Drospirenone: 1 hour; Estradiol: ~2 hours (range: 0.3-10 hours)
Excretion: Drospirenone: Urine and feces; Estradiol: Urine
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