Drospirenone

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.

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 probable dementia was observed in women ≥65 years of age taking CE alone or in combination with MPA.

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. 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. 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 is dose and duration dependent; risk appears to be greatest with use ≥5 years and may persist following discontinuation of therapy.

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.

Drospirenone has antimineralocorticoid activity that may lead to hyperkalemia. Use is contraindicated in patients with conditions which predispose to hyperkalemia (eg, renal insufficiency, hepatic dysfunction, or adrenal insufficiency); use caution with medications that may increase serum potassium.

Drospirenone may increase the possibility of hyponatremia in high risk patients.

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.

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. Use with caution in patients with familial defects of lipoprotein metabolism.

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 (Mørch 2009).

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:

Use caution in patients with asthma; may exacerbate disease.

May impair glucose tolerance; use caution in women with diabetes.

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

Use caution with chorea minor; may exacerbate disease.

Use with caution in patients with diseases which may be exacerbated by fluid retention, including cardiac or renal dysfunction.

Use caution with epilepsy; may exacerbate disease.

Use of postmenopausal estrogen may be associated with an increased risk of gallbladder disease requiring surgery.

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.

Use with caution in patients with hepatic hemangiomas; may exacerbate disease.

Exogenous estrogens may exacerbate angioedema symptoms in women with hereditary angioedema.

Use caution in patients with hypoparathyroidism; estrogen-induced hypocalcemia may occur.

Use caution with migraine; may exacerbate disease.

Use caution with otosclerosis; may exacerbate disease.

Use with caution in patients with porphyria; may exacerbate disease.

Use with caution in patients with SLE; may exacerbate disease. Concurrent drug therapy issues:

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

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:

The benefit-risk of hormone therapy is most favorable if started in women who have no contraindications to therapy, are 60 years of age and may continue in women >65 years of age who have persistent vasomotor symptoms or quality of life issues after discussing the benefits and risks of treatment. Possible adjustments to safer lower-dose and/or route of administration should be evaluated at an annual exam which also considers a review of comorbidities (NAMS 2017)

Not for use prior to menopause.

Whenever possible, estrogens should be discontinued at least 4-6 weeks prior to elective surgery associated with an increased risk of thromboembolism or during periods of prolonged immobilization. Other warnings/precautions:

The use of estrogens and/or progestins may change the results of some laboratory tests (eg, coagulation factors, lipids, glucose tolerance, binding proteins). Drospirenone can also cause an increase in plasma renin activity and plasma aldosterone. 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.

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 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).

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 (NAMS 2017; NAMS 2013; Stuenkel 2015).