Medroxyprogesterone

May cause suppression of hypothalamic-pituitary-adrenal (HPA) axis, resulting in decreased plasma cortisol concentrations, decreased cortisol secretion, and low plasma ACTH concentrations. Cushingoid symptoms may occur.

Anaphylaxis or anaphylactoid reactions have been reported with use of the injection; medication for the treatment of hypersensitivity reactions should be available for immediate use.

Prolonged use of medroxyprogesterone contraceptive injection may result in a loss of bone mineral density (BMD). It is not known if use during adolescence or early adulthood will decrease peak bone mass accretion or increase the risk for osteoporotic fractures later in life. Loss is related to the duration of use, may not be completely reversible on discontinuation of the drug, and incidence is not significantly different between the SubQ and IM dosage forms. The impact on peak bone mass in adolescents should be weighed against the potential for unintended pregnancies in treatment decision. Consider alternative contraceptive methods in patients at risk for osteoporosis (eg, metabolic bone disease, chronic alcohol and/or tobacco use, anorexia nervosa, strong family history of osteoporosis, chronic use of medications associated with osteoporosis such as anticonvulsants or corticosteroids). All patients should have adequate calcium and Vitamin D intake. Consider evaluating bone mineral density in patients receiving high doses of medroxyprogesterone for long term endometrial cancer.

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). Women who used depo-medroxyprogesterone within the previous 5 years and for a duration of 12 months or longer were found to have an increased risk of breast cancer. An increase in abnormal mammogram findings has also been reported with estrogen alone or in combination with progestin therapy. Most products are contraindicated in patients with known or suspected breast cancer. Use of medroxyprogesterone for the treatment of endometrial carcinoma is not recommended in women with known or suspected breast cancer and women with a strong family history of breast cancer should be carefully monitored.

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 in combination with MPA. The risk to younger postmenopausal persons is not known.

When used for contraception, the possibility of ectopic pregnancy should be considered in patients with severe abdominal pain.

MPA is used to reduce the risk of endometrial hyperplasia in nonhysterectomized postmenopausal women receiving conjugated estrogens. 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 is dose and duration dependent; risk appears to be greatest with use ≥5 years and may persist following discontinuation of therapy.

In women using estrogen plus progesterone therapy, triglycerides may be increased in women with preexisting hypertriglyceridemia; discontinue if pancreatitis occurs.

Postmenopausal estrogen therapy and combined estrogen/progesterone therapy 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). Although the risk of ovarian cancer is rare, women who are at an increased risk (eg, family history) should be counseled about the association (NAMS2012).

Discontinue pending examination in cases of sudden partial or complete vision loss, sudden onset of proptosis, diplopia, or migraine; discontinue permanently if papilledema or retinal vascular lesions are observed on examination.

Unscheduled bleeding/spotting may occur. Presentation of irregular, unresolving vaginal bleeding following previously regular cycles warrants further evaluation including endometrial sampling, if indicated, to rule out malignancy.

Contraceptive therapy with medroxyprogesterone commonly results in an average weight gain of ~3.7 kg after 2 years of treatment. Disease-related concerns:

Use estrogen plus progestin therapy with caution in patients with asthma; may exacerbate disease.

Estrogens with 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), pulmonary emboli (PE), and stroke has been reported with CE 0.625 mg with MPA 2.5 mg in postmenopausal women 50 to 79 years. 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 if adverse cardiovascular events occur or are suspected. Use is contraindicated in women with active DVT, PE, arterial thromboembolic disease or a history of these conditions. When used for contraception, use caution in patients with risk factors for cardiovascular disease (Curtis 2016b). If thrombosis develops with contraceptive treatment, discontinue treatment (unless no other acceptable contraceptive alternative).

Use with caution in patients with a history of depression.

Estrogen plus progestin therapy may have adverse effects on glucose tolerance; use caution in women with diabetes mellitus.

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

Use estrogen plus progestin therapy with caution in patients with epilepsy; may exacerbate disease.

Estrogens plus progestins 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. Most products are contraindicated with hepatic impairment or disease. Use of medroxyprogesterone for the treatment of endometrial carcinoma is not recommended in women with significant hepatic dysfunction and should be discontinued if liver dysfunction occurs.

Use estrogen plus progestin therapy with caution in patients with hepatic hemangiomas; may exacerbate disease.

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

Use caution in patients with migraine; may exacerbate disease.

Use estrogen plus progestin therapy with caution in patients with porphyria; may exacerbate disease.

Use estrogen plus progestin therapy with caution in patients with systemic lupus erythematosus (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. Special populations:

Use may mask the onset of menopause in women treated for endometrial cancer.

Not for use prior to menarche.

Whenever possible, progestins in combination with estrogens should be discontinued at least 4 to 6 weeks prior to surgery associated with an increased risk of thromboembolism or during periods of prolonged immobilization. Dosage form specific issues:

Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley, 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling. Other warnings/precautions:

Inform patients that injectable contraceptives do not protect against HIV infection or other sexually transmitted diseases. Women at high risk for HIV infection should be informed that there may be an increased risk of acquiring HIV with use of a progestin-only injection contraceptive. However, available data are inconsistent, and benefits of use may outweigh potential risk; treatment should not be withheld when appropriate. Women should be instructed about HIV prevention measures (Tepper 2017).

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.

Long-term use (ie, >2 years) should be limited to situations where other birth control methods are inadequate. When used for endometrial carcinoma, the effects of long term use on adrenal, hepatic, ovarian, pituitary, and uterine function is not known.

Estrogens with progestin should be used for the shortest duration possible at the lowest effective dose consistent with treatment goals and risks for the individual woman. 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).