The types of adverse events that are experienced during medroxyprogesterone use are dependent on the indication for use, and the gender of the recipient. Some of the more common events involve the female genitourinary (GU) system. For the use of medroxyprogesterone depot contraceptive injections, menstrual irregularity predominates, with 57.3% of patients reporting irregular menses during the first 12 months and 32.1% after 24 months of use, respectively. Intermenstrual bleeding was reported in roughly 7% of patients during clinical trials for the subcutaneous contraceptive injection, and amenorrhea in approximately 6%. Amenorrhea is even more common with continued contraceptive injection use (55% at 12 months, 68% at 24 months).[42126] [57649] Other GU events reported with contraceptive injection use in 1% to 5% of women include leukorrhea (2.9%), vaginitis (1.2%), abnormal cervical smears, dysmenorrhea, menometrorrhagia, menorrhagia, uterine hemorrhage, and vaginal hemorrhage.[42126] [57649] Postmarketing, the following events have been reported with the medroxyprogesterone contraceptive injections: oligomenorrhea, delayed return to fertility, prolonged anovulation (temporary infertility), unexpected pregnancy, uterine hyperplasia, genitourinary infections, and vaginal cysts.[42126] [57649] The following GU effects have been reported in the use of medroxyprogesterone tablets as monotherapy (e.g., without estrogens) in females for hormone replacement therapy (HRT): change in menstrual flow; breakthrough bleeding or spotting; changes in cervical erosion; and changes in cervical secretions.[59800] The incidence of amenorrhea during estrogen-medroxyprogesterone HRT in postmenopausal women is determined by the regimens chosen. Amenorrhea accompanies continuous use of combined HRT in many menopausal women; cyclic administration produces amenorrhea in roughly 5%.[59848] When medroxyprogesterone tablets have been used along with estrogens in women for combined hormone replacement therapy (HRT), abnormal uterine postmenopausal bleeding/spotting/flow; breakthrough bleeding or spotting; dysmenorrhea or pelvic pain; increase in size of uterine leiomyomata; vaginitis, including vaginal candidiasis; changes in amount of cervical secretion; changes in cervical ectropion or cervical dysplasia; endometrial growth, and female-related cancers have been reported. The following adverse reactions have also been observed in females receiving estrogen; progestin combination drugs: premenstrual syndrome, cystitis-like syndrome.[57648] [59800]

The types of adverse events that are experienced during medroxyprogesterone use are dependent on the indication for use, and the gender of the recipient. Changes in the breasts and in sexual function have been reported in both females and males. For the use of medroxyprogesterone depot contraceptive injections in females, breast pain (mastalgia) was reported in 2.8%, and libido decrease in up to 5.5%. Breast lumps, changes in breast size, nipple bleeding, galactorrhea, dyspareunia, and libido increase have been reported in post-market reports with contraceptive depot injection use. Lactation suppression is not common with progestin-only contraception, and depot contraceptive medroxyprogesterone injections are often a hormonal agent of choice in the early weeks postpartum [66564]; however, lactation prevention has been reported postmarketing.[42126] [57649] The following breast changes have been reported in the use of medroxyprogesterone tablets as monotherapy (e.g., without estrogens) in females for hormone replacement therapy (HRT): breast tenderness, mastodynia or mastalgia, or galactorrhea.[59800] When medroxyprogesterone tablets have been used along with estrogens in women in combined HRT regimens, breast tenderness, breast enlargement, pain (mastalgia), nipple breast discharge, galactorrhea; fibrocystic breast changes; and breast cancer have been reported.[59800] Changes in libido (decrease or increase) have been reported with the use of medroxyprogesterone-estrogen HRT regimens and with medroxyprogesterone 400 mg/mL depot injection as well.[57648] In males receiving medroxyprogesterone depot injections for palliative reasons or for paraphilia, impotence (erectile dysfunction) may occur when plasma testosterone levels decreased by 25% (one-quarter) or more of the pretreatment concentration.[57648]

Dermatologic, vascular, and allergic reactions may occur with medroxyprogesterone therapy. Angioedema, anaphylactoid reactions, and anaphylactic shock have been reported with the use of medroxyprogesterone. The following common skin reactions occurred in 1—5% of women receiving medroxyprogesterone depot contraceptive injections: hot flashes or flushes and acne vulgaris; increased acne can be a common reason for contraceptive injection discontinuation. No hair growth or alopecia has been reported in approximately 1.1% of contraceptive injection recipients. The following skin disorders have been reported in patients receiving medroxyprogesterone depot contraceptive injections post-marketing: angioedema, dry skin (xerosis), increased body odor and axillary sweating (hyperhidrosis), axillary swelling, melasma, scleroderma, pruritus, rash (unspecified), and urticaria.[42126] [57649] With the use of medroxyprogesterone 400 mg/mL depot injections and medroxyprogesterone tablets as monotherapy (without estrogens), hypersensitivity reactions (anaphylaxis and anaphylactoid reactions, angioedema), urticaria or rash (allergic) with and without pruritus, acne, loss of scalp hair, alopecia, hot flushes, and hirsutism have been reported.[57648] [59800] The following adverse skin reactions have been observed in women receiving combination hormonal therapy (estrogen along with medroxyprogesterone tablets) for hormone replacement therapy (HRT) regimens: chloasma or melasma that may persist when drug is discontinued, erythema multiforme, erythema nodosum, and hemorrhagic eruption, loss of scalp hair, alopecia.[57648] [59800]

Central nervous system (CNS) reactions, including emotional lability, may occur with medroxyprogesterone therapy. Dizziness (less than 5.6%), insomnia (1% to 5%), nervousness (10.8%), depression (1% to 5%), and headache (9% to 16.5%) have been reported in women receiving medroxyprogesterone depot contraceptive injections [42126] [57649]; women receiving medroxyprogesterone monotherapy for other indications have also reported these adverse events, but the incidence is not known.[59800] Changes in headache or migraine pattern during contraceptive or hormonal therapy use may occur; if a headache or migraine has focal features consistent with cerebral ischemia or a potential thrombotic cause, discontinuation of medroxyprogesterone is recommended.[48201] Anxiety and irritability have been reported in 1% to 5% of women receiving medroxyprogesterone depot contraceptive injections.[57649] Drowsiness/somnolence has been reported during postmarketing experience with medroxyprogesterone depot contraceptive injection and with the use of other medroxyprogesterone formulations for various indications.[42126] [57648] [57649] [59800] Other CNS effects reported postmarketing with the contraceptive injections have included facial palsy, fainting, paralysis, and paresthesias.[42126] [57649] Euphoria has been reported in patients receiving medroxyprogesterone depot injection for malignancy.[57648] Patients with a history of seizure disorder should use medroxyprogesterone cautiously since progestins may exacerbate their condition; seizures have been reported in patients receiving medroxyprogesterone for various indications.[42126] [57648] [57649] [59800] Chorea and mood disturbances have been reported in women receiving combined estrogen plus progestin therapy for hormone replacement.[59800]

Gastrointestinal (GI) effects are fairly common with medroxyprogesterone therapy. Abdominal pain/discomfort (11.2%), nausea (3.3%), and bloating (2.3%) are the most common GI effects with medroxyprogesterone IM depot contraceptive injection; abdominal distention, abdominal pain, diarrhea, nausea occurred in approximately 1% to 5% of those receiving depot subcutaneous contraceptive injections in clinical trials. GI side effects reported postmarketing with contraceptive depot injection use include general GI disturbances, jaundice, excessive thirst (polydipsia) and rectal GI bleeding.[42126] [57649] The following adverse reactions have been reported in women taking medroxyprogesterone tablets as monotherapy (without concomitant estrogens): nausea and cholestatic jaundice (jaundice due to cholestasis).[59800] These effects have also been reported in the use of medroxyprogesterone depot injections for other indications; cholestatic jaundice has included neonatal jaundice and hyperbilirubinemia.[57648] Additional adverse events reported in women receiving combined estrogen and progestin treatment include: nausea, vomiting; abdominal pain, cramps, bloating; cholestatic jaundice; increased incidence of gallbladder disease; pancreatitis; and enlargement of hepatic hemangiomas.[59800]

Changes in appetite may occur during medroxyprogesterone treatment. Appetite stimulation may occur. Weight gain iis a common side effects for medroxyprogesterone contraceptive injections in females; increased weight (defined as a more than 10 pound weight gain at 24 months occurs in 37.7% of patients receiving the IM depot contraceptive injection and 6% of those receiving the subcutaneous contraceptive depot injection. Weight gain one of the primary reasons women discontinue the contraceptive (2% or more discontinue due to weight gain).[42126] [57649] A slight amount of weight gain may be due to fluid retention. Edema is reported in 2.2% of contraceptive depot injection recipients.[42126] [57649] Weight gain or weight loss, fluid retention, and/or edema have been reported for medroxyprogesterone tablets for hormone replacement (HRT) in females or in the use of medroxyprogesterone in men or women for palliation of cancer or other indications.[57648] [59800]

During use of medroxyprogesterone, the provider should be alert to possible thrombotic disorders (e.g., cerebrovascular disorder or migraine or headache with focal symptoms that suggest cerebral ischemia, pulmonary embolism or thromboembolism, thromboembolism, heart attack, or unexplained visual disturbance with ocular pain, which might indicate retinal thrombosis). Should any of these occur or be suspected, medroxyprogesterone therapy should be discontinued immediately; with depot-injections, the effects of the hormone may persist for some time after discontinuation.[59800] [57648] [42126] [57649] [48201] HORMONE REPLACEMENT THERAPY: Hormone replacement therapy (HRT) with estrogens and progestins in combination presents a risk for thromboembolism and cardiovascular events in postmenopausal women; these risks are highlighted in the boxed warnings for oral medroxyprogesterone. The Women's Health Initiative (WHI) estrogen plus progestin substudy reported an increased risk of thromboembolism, including deep vein thrombosis (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 oral tablets (MPA) [2.5 mg], relative to placebo. In the absence of comparable data, the risk of such events should be assumed to be similar for other doses of conjugated estrogens/medroxyprogesterone or other estrogen/progestin combinations in postmenopausal women. Should any of these cardiovascular or thrombotic events occur or be suspected, estrogen plus progestin HRT should be discontinued immediately.[27272] [59800] PROGESTIN ONLY CONTRACEPTION: Active thrombophlebitis, or current or past history of thromboembolic disorders, or cerebral vascular disease are contraindications to medroxyprogesterone contraceptive injections. Syncope, sinus tachycardia, chest pain (unspecified), thromboembolism, DVT, PE, thrombo-phlebitis, and varicose veins are cardiovascular effects that have been reported in postmarketing reports from the use of medroxyprogesterone depot contraceptive injections. Although MPA has not been causally associated with the induction of thrombotic or thromboembolic disorders, there have been rare reports of serious thrombotic events in women using MPA contraceptive injections. Any patient who develops thrombosis during contraceptive use should discontinue treatment unless she has no other acceptable options for birth control.[42126] [57649] The use of progestin-only contraception may be acceptable in women without a previous or active history of thromboembolic events, but with certain risk factors for thrombosis, when hormonal contraception is desired. Guidances have been published based on expert review of the literature that can help guide contraceptive product selection in patients with risk factors for thrombosis. Progestin-only contraceptives are generally the hormonal contraceptives of choice in patients with a potential risk for thrombosis when reliable contraception must be ensured and the risks of hormonal therapy are acceptable; advantages of these methods usually outweigh proven or theoretical risks; risk versus benefit must be considered individually. For women who are at an increased risk of thromboembolism and have multiple-risk factors for thrombosis (e.g., tobacco smoking woman age 35 and older, diabetes, hypercoagulopathy, etc.), consider an intra-uterine device (IUD) or other estrogen-free contraceptive if appropriate.[48201] OTHER USES: During clinical use of medroxyprogesterone monotherapy for various indications, effects such as pulmonary embolism (PE) and retinal thrombosis have been rarely reported; when combined with estrogens, various types of thromboembolic events have been reported.[57648]

An injection site reaction can occur with both intramuscular and subcutaneous injections of medroxyprogesterone. Adverse local reactions include residual lump, skin discoloration, pain, tenderness, persistent atrophy, indentation, dimpling, lipodystrophy, and sterile abscess.[42126] [57648] [57649] In women receiving medroxyprogesterone depot contraceptive, injection site reaction was reported in 5% of patients, and 1% had persistent skin changes, typically described as small areas of skin induration or skin atrophy.[57649]

The following adverse reactions have been reported in women taking medroxyprogesterone tablets, without concomitant estrogens treatment: neuro-ocular lesions (e.g., retinal thrombosis) and optic neuritis. The following adverse reactions have been reported with estrogen plus progestin therapy: retinal vascular thrombosis and intolerance to contact lenses. Should retinal thrombosis occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.[59800]

MEDROXYPROGESTERONE CONTRACEPTIVE INJECTIONS: Women using medroxyprogesterone contraceptive injections may lose significant bone mineral density. Bone loss (osteopenia) is greater with increasing duration of use and may not be completely reversible. It is unknown if use of these contraceptive injections during adolescence or early adulthood, a critical period of bone accretion, will reduce peak bone mass and increase the risk for osteoporotic fracture in later life. There have been postmarketing reports of osteopenia and loss of bone mineral density as well as osteoporosis, including osteoporotic bone fractures, in patients using medroxyprogesterone depot contraceptive injections. Women should not use medroxyprogesterone injections as a long-term birth control method (i.e., longer than 2 years) unless other birth control methods are considered inadequate.[42126] [57329] In a controlled clinical study, adult women using medroxyprogesterone depot-injections for up to 5 years showed a 5% to 6% mean decrease in spine and hip bone mineral density (BMD), compared to no significant change in BMD in the control group. The decline in BMD was more pronounced during the first 2 years of use, with smaller declines reported in subsequent years. Observed mean changes in lumbar spine BMD of -2.86%, -4.11%, -4.89%, -4.93%, and -5.38% after 1, 2, 3, 4, and 5 years, respectively. A partial recovery of BMD toward baseline values during a 2-year post-therapy period was seen following the cessation of medroxyprogesterone depot injections; longer duration of treatment was associated with less complete BMD recovery during this 2-year post-treatment period. An open-label, non-randomized, clinical study was preformed to evaluate the impact of treatment for up to 4.6 years in adolescent females (12 to 18 years). Results showed that medroxyprogesterone depot injections were associated with a significant decline in BMD from baseline. The decline in BMD was greater with longer duration of use, with a mean decreases in BMD at 4.6 years of -6.4% at total hip, -5.4% at femoral neck, and -2.1% at lumbar spine. In addition, the extent of BMD recovery was evaluated during post-treatment follow-up for up to 60 months. Data revealed that adolescents treated for more than 2 years did not recover baseline BMD at femoral neck or total hip, but did recover baseline BMD at lumbar spine after treatment discontinuation. In comparison, adolescents in the untreated group gained BMD throughout the trial period. The evidence suggests that the increase in bone density that is normally seen during the period of growth following menarche may be impaired by medroxyprogesterone depot injection use.[42126] [57329] OTHER USES: It is possible that osteoporosis may occur with medroxyprogesterone depot injections used chronically for other purposes. An evaluation of bone mineral density may be appropriate in some patients who use higher doses of medroxyprogesterone acetate depot injection for long-term treatment of cancer.[57648]

Decreased glucose tolerance has been reported with medroxyprogesterone monotherapy, and may occur in either gender and during use of the hormone for a variety of indications. Hyperglycemia may occur, and patients with diabetes should be carefully monitored for changes in blood glucose control during medroxyprogesterone treatment.[57648] [42126] [57649] [59800]

Hypercalcemia has been reported in patients receiving medroxyprogesterone depot injection for malignancy.[57648] Hypocalcemia has been reported in patients receiving estrogen plus progestin therapy, and is due to estrogen-induced hypocalcemia.[59800]

Musculoskeletal adverse reactions reported in >= 1% and < 5% of patients receiving depot medroxyprogesterone for contraception (intramuscularly or subcutaneously) include leg muscle cramps (approximately 3.7%), arthralgia (1%), back pain and limb pain.[42126] [57649] Backache and arthralgia have been reported in those receiving estrogen-progestin combined hormonal therapy.[57648] [59800]

Asthenia and/or fatigue (4.2%) occur in > 1% and < 5% of patients receiving medroxyprogesterone contraceptive injections. Post marketing, fever, chills, asthenia have been reported.[42126] [57649] General adverse reactions reported with hormonal therapy with medroxyprogesterone for cancer or hormone replacement include edema, pyrexia, fatigue, malaise.[57648] [59800]

Anemia and blood dyscrasia reported during post-marketing experience with medroxyprogesterone contraceptive injections.[42126] [57649] Aggravation of porphyria has been reported in the use of medroxyprogesterone for cancer or hormone replacement therapy.[57648] [59800]

Estrogen/progestin combination hormonal replacement therapy (HRT) does not prevent mild impaired cognition (memory loss) and has been found to increase the risk of dementia in women 65 years and older. The WHIMS study, an ancillary study of the WHI trial to assess the effects of estrogen/progestin therapy on cognitive function in geriatric women (65 years of age or older), reported similar rates of developing mild cognitive impairment in those receiving active treatment vs. placebo. Also, patients receiving estrogen/progestin combination therapy were more likely than patients receiving placebo to be diagnosed with dementia. The applicability of this finding to women who use estrogen alone or to the typical user of HRT (i.e., younger, symptomatic adult women taking hormone replacement therapy to relieve menopausal symptoms) is unclear. Administration of estrogen/progestin combination therapy should be avoided in women 65 years of age and older and estrogen/progestin combination therapy should not be used to prevent or treat dementia or preserve cognition (memory).[27451] [59800]

The issue of hormonal influences on the development of cancers (new primary malignancy) has been widely researched for many decades. The risks of various cancers for progestin-only hormonal contraceptive use differ from the risks associated with postmenopausal hormone replacement therapy (HRT) or other hormonal uses. Undiagnosed vaginal bleeding should be evaluated in any patient using medroxyprogesterone as is clinically appropriate, since female genital cancers may be influenced by hormonal therapy. HORMONE REPLACEMENT THERAPY POSTMENOPAUSE: Numerous epidemiologic studies have examined the effects of estrogen and estrogen-progestin hormone replacement therapy (HRT) on the development of new primary malignancy (e.g., breast cancer, endometrial cancer, ovarian cancer) in postmenopausal women. The Women's Health Initiative (WHI) estrogen plus progestin study reported increased risks of invasive breast cancer in patients taking combined estrogen-progestin HRT vs. placebo. The potential risk of breast cancer may increase with longer duration of use. Due to breast cancer and other cancer risks, combined HRT should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.[59800] [27272] [32125] [27273] [50638] There is an association of unopposed estrogen therapy and endometrial cancer in women with an intact uterus. Adding a progestin, such as medroxyprogesterone, to estrogen therapy has been shown to reduce, but not eliminate, the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal vaginal bleeding. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more, and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Among combined estrogen/progestin HRT users, roughly 10% will have some endometrial thickening. Postmarketing reports of endometrial hyperplasia have been reported in women receiving combined estrogen/progestin HRT; however, the incidence of endometrial hyperplasia is estimated to be 1% or less in these patients.[59800] [50638] [23505] [27272] Women who used HRT for menopausal symptoms also had an increased risk for ovarian cancer, but data are still uncertain if risk is associated with a specific duration of use. The contraindications and precautions sections for progesterone HRT product labels more fully discuss the data and what is known about HRT use with respect to risks for various cancers.[59800] [27272] [32125] [27273] [50638] MEDROXYPROGESTERONE CONTRACEPTIVE INJECTIONS: The relative risk of developing breast cancer in patients receiving depot medroxyprogesterone for contraception has been investigated in a number of trials. Among 5 epidemiologic studies assessing the associated risk, 3 of the studies suggested a slightly increased risk of breast cancer in the overall population of users. Data from one study (n = 1,028) of women 20 to 44 years of age, receiving medroxyprogesterone contraceptive injections, showed that recent use (last use within the previous 5 years) for 12 months or longer was associated with a 2.2-fold (95% CI: 1.2 to 4.2) increased risk of invasive breast cancer.[42126] [57649] [58771]

Medroxyprogesterone acetate depot injections are suspensions that are either administered intramuscularly or subcutaneously depending on the formulation. Never administer via intravenous administration; intravenous administration may result in serious adverse reactions.

Medroxyprogesterone contraceptive injections and oral tablets are contraindicated in patients with pre-existing breast cancer.[59800] [42126] [57649] The oral tablets are contraindicated in any other known or suspected estrogen- or progestin-dependent neoplasia, including cervical cancer, endometrial cancer, uterine cancer, or vaginal cancer.[59800] Medroxyprogesterone depot injection suspension for the treatment of endometrial or renal cancer should generally not be used in women with a history of breast cancer, as breast cancer may be hormonally sensitive. Women with a strong family history of breast cancer should be monitored with particular care.[57648] Do not use medroxyprogesterone products in patients with undiagnosed abnormal genital or vaginal bleeding.[59800] [42126] [57649] [57648] HORMONE REPLACEMENT THERAPY (HRT): The WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer (new primary malignancy of the breast) in postmenopausal women receiving HRT. The use of estrogen-alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms, requiring further evaluation. All women taking estrogen with or without a progestin should receive an annual clinical breast examination, perform monthly self-examinations, and have regular mammograms as recommended by their health care professional based on patient age, risk factors, and prior mammogram results.[59800] The most important randomized clinical trial providing information about breast cancer in patients taking combined estrogen-progestin HRT regimens is the WHI substudy of CE (0.625 mg/day) plus MPA (2.5 mg/day).[27530] [27272] After a mean follow-up of 5.6 years, the WHI estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA vs. placebo. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26% of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 vs. 25 cases per 10,000 women-years for CE plus MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 vs. 36 cases per 10,000 women-years for CE plus MPA compared with placebo. In the same WHI substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the combined HRT group compared with the placebo group. Metastatic disease was rare, with no apparent difference between the 2 groups. Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the 2 groups.[27530] Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. Increased risks were dependent on the duration of use and could last up to more than 10 years after stopping treatment. Extension of the WHI Trials also demonstrated increased breast cancer risk associated with estrogen plus progestin therapy. Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen-alone therapy. These studies have not generally found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration.[59800] Adding a progestin such as medroxyprogesterone to estrogen therapy has been shown to reduce, but not completely eliminate, the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Clinical surveillance of all women using estrogen plus progestin therapy is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding.[59800] The WHI estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95% CI, 0.77 to 3.24). The absolute risk for CE plus MPA was 4 versus 3 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen plus progestin and estrogen-only products, in particular for 5 or more years, has been associated with increased risk of ovarian cancer. However, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies and some report no association.[59800] MEDROXYPROGESTERONE CONTRACEPTIVE INJECTIONS: The relative risk of developing breast cancer in patients receiving depot medroxyprogesterone for contraception has been investigated in a number of trials. Among 5 epidemiologic studies assessing the associated risk, three of the studies suggested a slightly increased risk of breast cancer in the overall population of users. Data from one study (n = 1028) of women 20 to 44 years of age, receiving depo-medroxyprogesterone acetate, showed that recent use (last use within the previous 5 years) for 12 months or longer was associated with a 2.2-fold (95% CI: 1.2 to 4.2) increased risk of invasive breast cancer.[42126] [57649] [58771]

Medroxyprogesterone should be used cautiously in patients with diabetes mellitus. Although the effects appear to be minimal during therapy with progestins, altered glucose tolerance secondary to decreased insulin sensitivity has been reported during hormonal contraception and during hormonal replacement therapy (HRT). Monitor blood glucose routinely, and manage risk factors for heart disease to help reduce cardiovascular risks in patients with diabetes receiving hormonal therapy.

Medroxyprogesterone injections are contraindicated in patients with active or a history of thrombophlebitis. Medroxyprogesterone oral and injectable dose forms are contraindicated in patients with active arterial or venous thromboembolic disease (e.g., thromboembolism, deep venous thrombosis, pulmonary embolism, myocardial infarction (MI), cerebrovascular disease and stroke) or a history of these conditions.[59800] [57648] [42126] [57649] Patients with risk factors for heart disease, arterial vascular disease, thromboembolism, and stroke (e.g., hypertension, diabetes mellitus, tobacco smoking, hypercholesterolemia, obesity, etc.) should be monitored closely and managed appropriately. During use of medroxyprogesterone in patients without a history of thrombosis, the provider should be alert to the earliest manifestations of thrombotic disorder (thrombophlebitis, heart attack, cerebrovascular disorder such as stroke or focal headache with symptoms consistent with cerebral ischemia, pulmonary embolism, or unexplained visual disturbance with ocular pain, which might indicate retinal thrombosis). Should any of these occur or be suspected, medroxyprogesterone therapy should be discontinued immediately; with depot-injections, the effects of the hormone may persist for some time after discontinuation.[59800] [57648] [42126] [57649] HORMONAL REPLACEMENT THERAPY: Medroxyprogesterone, when used with estrogen therapy for postmenopausal hormone replacement, is associated with cardiovascular and thromboembolic risks. The Women's Health Initiative (WHI) estrogen plus progestin substudy reported an increased risk of deep vein thrombosis (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 (CE) [0.625 mg] combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo.[59800] In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE was reported in women receiving estrogen (conjugated estrogens) plus progestin (medroxyprogesterone) HRT compared to women receiving placebo (35 vs. 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 vs. 13 per 10,000 women-years) and PE (18 vs. 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted.[17825] [27272] Estrogens with or without a progestin such as medroxyprogesterone should not be used for the prevention of cardiac disease or cardiovascular disease (e.g., coronary artery disease) in postmenopausal women. In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events reported in women receiving daily estrogen plus progestin compared to women receiving placebo (41 vs. 34 per 10,000 women-years). An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5.[27272] [17808] Studies have also shown no cardiovascular benefit to the use of estrogen-progestin therapy for secondary prevention in women with documented cardiac disease or CHD.[25473] [27270] In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving estrogen plus progestin HRT compared to women in the same age group receiving placebo (33 vs. 25 per 10,000 women-years). The increase in risk was demonstrated after the first year and persisted. Women over the age of 65 years were at increased risk for non-fatal stroke.[38488] [27272] [59800] MEDROXYPROGESTERONE CONTRACEPTIVE INJECTIONS: Despite the contraindication against use of medroxyprogesterone injection in patients with known active or history of thrombotic disease, progestin-only contraceptives are generally the hormonal contraceptives of choice in patients with a potential risk for thrombosis when reliable contraception must be ensured and the risks of hormonal therapy are acceptable; advantages of these methods usually outweigh proven or theoretical risks.[48201] When multiple thrombosis risk factors exist, the risk of thromboembolic disease may increase; determine risk vs. benefit for use of the progestin-only contraceptive. The increase in the risk of thrombosis from newer progestin-only contraceptives (e.g., etonorgestrel implants) is still substantially less than with combined oral contraceptives containing both estrogen and progestin.[48201] For women who are at an increased risk of thromboembolism and have multiple-risk factors for thrombosis, consider an IUD or other estrogen-free contraceptive if appropriate. Use with caution in patients with pre-existing hypertension. A woman who is taking a hormonal contraceptive should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated healthcare.[48201] [42126] [57649]

Medroxyprogesterone should be used cautiously in patients with hyperlipidemia. Although hyperlipidemia is associated with estrogen-progestin combinations, the effects of progestin-only oral contraceptives on serum lipids have not been studied. Serum lipoproteins (HDL and LDL) should be monitored during therapy with medroxyprogesterone.

Medroxyprogesterone tablets are contraindicated for use in people with known liver impairment or hepatic disease. Medroxyprogesterone acetate injections for palliative care or contraception are contraindicated in patients with significant liver disease and use of these injections should be discontinued if jaundice or disturbances of liver function occur.[57648] Progestins may be poorly metabolized in people with impaired liver function. Use with caution if the individual has a history of intrahepatic cholestasis of pregnancy or a history of cholestatic jaundice associated with past estrogen use. In the case of recurrence, jaundice, or elevated liver function tests (LFTs) during medroxyprogesterone use, the medication should be discontinued until the health care provider determines the drug was not the cause and the jaundice and/or elevated LFTs have resolved.[42126] [43702]

Estrogen plus progestin therapy should be used with caution in individuals with severe hypocalcemia. In addition, combination hormonal therapy may cause an exacerbation of porphyria and systemic lupus erythematosus (SLE) and should be used with caution in women with these conditions.[43702]

Medroxyprogesterone should be prescribed cautiously in patients with asthma, congestive heart failure, nephrotic syndrome or other renal disease, or cardiac disease. Hormonal contraceptives can cause fluid retention and may exacerbate any of the above conditions.

Medroxyprogesterone should be used cautiously in patients with a history of major depression, migraine, or seizure disorder. Progestins may exacerbate these conditions in some patients.[42126] [57648] [57649] [59800] If a patient receiving medroxyprogesterone (with or without concomitant estrogen therapy) develops changes in migraine patterns, or a focal migraine with symptoms consistent with cerebral ischemia, or a severe headache pattern that may indicate a cerebrovascular disorder, discontinue the drug pending medical evaluation.[59800]

Medroxyprogesterone contraceptive depot-injections carry a boxed warning regarding bone mineral density reductions (osteopenia) in pre-menopausal women. Women using medroxyprogesterone contraceptive injections may lose significant bone mineral density. Bone loss is greater with increasing duration of use and may not be completely reversible. It is unknown if use of these contraceptive injections during adolescence or early adulthood, a critical period of bone accretion, will reduce peak bone mass and increase the risk for osteoporosis and osteoporotic fracture in later life. Women should not use medroxyprogesterone injections as a long-term birth control method (i.e., longer than 2 years) unless other birth control methods are considered inadequate.[42126] [57329] Consider alternative methods of contraception in women with osteoporosis risk factors (e.g., metabolic bone disease, chronic alcohol use, alcoholism, anorexia nervosa, strong family history of osteoporosis, tobacco smoking, or chronic use of drugs that can reduce bone mass, such as anticonvulsants or chronic corticosteroid therapy). While there are no studies available which address the usefulness of calcium and vitamin D to lessen BMD loss in women using medroxyprogesterone depot-injections, all patients should have adequate calcium and vitamin D intake.[42126] [57649] [48201] OTHER USES: BMD evaluation may also be appropriate in patients who use higher doses of depot medroxyprogesterone injections for long-term treatment of endometrial or renal cancers, due to a potential risk for loss of bone mineral density.[57648]

Patients should be counseled that medroxyprogesterone contraceptive injections do not protect against human immunodeficiency virus (HIV) infection or other sexually transmitted disease. Conversely, patients with known HIV infection or acquired immunodeficiency syndrome (AIDS) should be aware that the use of medroxyprogesterone depot-injection will not prevent the transmission of HIV or other diseases to their partner(s).[42126]

There is no use for contraception in pregnancy; therefore, medroxyprogesterone acetate for contraception or endometriosis treatment should be discontinued during pregnancy. However, epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following inadvertent exposure to progestins before conception or during early pregnancy.[42126] [57649] HORMONE REPLACEMENT AND CANCER TREATMENT: Medroxyprogesterone tablets and depot injections for cancer treatment are contraindicated for use during known pregnancy or suspected pregnancy. There may be an increased risk of minor birth defects when there is exposure to medroxyprogesterone tablets during the first 4 months of pregnancy, such as hypospadias, clitoral enlargement and labial fusion; however a clear association between these conditions and the use of the drug has not been established. Cancer treatment with medroxyprogesterone during pregnancy should only be used if the maternal benefits outweigh the potential fetal risks.[59800] [57648]

Estrogen/progestin combination therapy does not prevent mild cognitive impairment (memory loss) and has been found to increase the risk of dementia in women 65 years and older. The WHIMS study, an ancillary study of the WHI trial to assess the effects of estrogen/progestin therapy on cognitive function in geriatric women (65 years of age or older), reported similar rates of developing mild cognitive impairment in those receiving active treatment vs. placebo. Also, patients receiving estrogen/progestin combination therapy were more likely than patients receiving placebo to be diagnosed with dementia. The applicability of this finding to women who use estrogen alone or to the typical user of HRT (i.e., younger, symptomatic adult women taking hormone replacement therapy to relieve menopausal symptoms) is unclear. Administration of estrogen/progestin combination therapy should be avoided in women 65 years of age and older and estrogen/progestin combination therapy should not be used to prevent or treat dementia or preserve cognition (memory).[27451]

Although medroxyprogesterone acetate is detectable in human milk following administration of the medroxyprogesterone contraceptive/endometriosis injections, milk composition, quality, and amount do not appear to be adversely affected during breast-feeding. Effects on milk production and lactation initiation/duration remain unclear when administered before 6 weeks after delivery, therefore, in those who exclusively breastfeed, the prescribing labels recommend to initiate contraception injections during or after the sixth postpartum week, and this recommendation is consistent with recommendations from the World Health Organization. Neonates and infants exposed to medroxyprogesterone acetate contraceptive/endometriosis injections from breast milk have been studied for developmental and behavioral effects through puberty, and no adverse effects have been noted.[42126] [57649] [48204] The U.S. Medical Eligibility Criteria consider medroxyprogesterone contraception injections compatible with breast-feeding and while caution should be used if the individial is less than 30 days postpartum, the benefits of use likely outweigh any potential risk during that time. Alternate contraceptive agents to consider for the breast-feeding individual include non-hormonal contraceptive methods (e.g., copper IUD, barrier methods) and other progestin-only contraceptives (e.g., norgestrel oral contraceptive, levonorgestrel IUDs).[48201] HORMONE REPLACEMENT OR CANCER TREATMENT: Other dosage forms (e.g., medroxyprogesterone suspension injection for cancer treatment or tablets for hormonal indications), are not recommended during lactation due to the fact that detectable amounts of progestin have been identified in the breast milk of nursing individuals receiving progestins, and exposures may be greater than those of the contraceptive injection dosages. Use only when clearly needed, taking into account the clinical need for medroxyprogesterone and the potential for adverse effects to the breastfed child.[57648] [59800]

Medroxyprogesterone depot-contraceptive injections are associated with a significant loss of bone mineral density, which is of particular concern during the critical period of bone accretion of adolescence and early adulthood. It is unknown if use of medroxyprogesterone depot-injections by young menarchal individuals will reduce peak bone mass and increase the risk of osteoporotic fractures in later life. Except for concerns related to bone density, safety and efficacy of hormonal birth control is expected to be the same for postpubertal children less than 16 years and for users 16 years of age and older.[42126] [48201] [57648]