Medroxyprogesterone Acetate Tablets

Generic Name:

Medroxyprogesterone

Brand Name Equivalent:

Provera®

Overview of Medroxyprogesterone Acetate Tablets

Dosage Strength of Medroxyprogesterone Acetate Tablets

10 mg

General Information

Medroxyprogesterone is an oral and parenteral synthetic progestin that is 15 times more potent than progesterone. Medroxyprogesterone can be used for the treatment of amenorrhea, abnormal uterine bleeding, hot flashes, endometriosis secondary to hormonal imbalances, and endometrial and renal cell carcinomas. Medroxyprogesterone may be useful as respiratory stimulants in certain pulmonary disorders such as chronic obstructive pulmonary disease (COPD), Pickwickian syndrome, and other hypercapnic pulmonary conditions. Investigational agents containing medroxyprogesterone are also under development. Medroxyprogesterone was originally approved by the FDA in 1959.

Mechanism of Action

The primary contraceptive effect of progestins involves the inhibition of gonadotropin secretion (suppression of the midcycle surge of luteinizing hormone, or LH), which prevents follicular maturation and ovulation. The exact mechanism of action, however, is unknown. At the cellular level, progestins diffuse freely into target cells and bind to the progesterone receptor. Target cells include the female reproductive tract, the mammary gland, the hypothalamus, and the pituitary. Once bound to the progesterone receptor, progestins slow the frequency of release of gonadotropin releasing hormone (GnRH) from the hypothalamus and blunt the pre-ovulatory LH surge, thereby preventing follicular maturation and ovulation. Additional mechanisms may be involved. Other contraceptive actions of progestins include alterations in the endometrium that can impair implantation and an increase in cervical mucus viscosity which inhibits sperm migration into the uterus.

Medroxyprogesterone converts a proliferative endometrium into a secretory one in women with adequate endogenous estrogen. Restoring adequate progesterone can help pre-menopausal women with secondary amenorrhea or dysfunctional uterine bleeding to re-establish normal menstrual patterns. The drug reduces endometrial growth in menopausal and postmenopausal women with an intact uterus who are receiving estrogen therapy, thus adding a protective effect against endometrial hyperplasia. Medroxyprogesterone decreases endometriosis related pain by suppressing serum estradiol concentrations and possibly by having a direct action on the lesions of endometriosis. Androgenic and anabolic effects have been noted, but the drug is apparently devoid of significant estrogenic activity. The route and dosage of the drug determine pharmacologic effects. While parenterally administered medroxyprogesterone inhibits gonadotropin production and thus prevents follicular maturation and ovulation, available data indicate that this does not occur when the usually recommended oral dosage is given as single daily doses. The mode of action of medroxyprogesterone as palliative therapy against certain cancers has not been determined.12

Progestins are mild, direct stimulants of the respiratory center. During pregnancy and the luteal phase of the menstrual cycle, women can hyperventilate and become hypocapnic due to elevated concentrations of endogenous progestins. Therapeutically, medroxyprogesterone has been used successfully in patients with COPD and hypercapnia, in patients with Pickwickian syndrome, and in patients with sleep apnea.

Pharmacokinetics

Medroxyprogesterone is administered orally or injected intramuscularly or subcutaneously as a depot injection. Greater than 90% of the absorbed drug is protein bound. Medroxyprogesterone acetate is extensively metabolized in the liver via hydroxylation, with subsequent conjugation and elimination in the urine. Most metabolites are excreted in the urine as glucuronide conjugates with only minor amounts excreted as sulfates.2

Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP3A4
CYP3A4 is the principal enzyme responsible for the overall metabolism of medroxyprogesterone.3

Route-Specific Pharmacokinetics:

Oral Route: Peak serum concentrations after oral administration of medroxyprogesterone occur within 2 to 4 hours. The half-life following oral administration of 10 mg for 7 days is variable, but is approximately 16.6 hours to 30 hours. Administration with food increases bioavailability. A 10 mg dose, taken immediately before or after a meal, increased maximum concentration (50 to 70%) and AUC (18 to 33%). The half-life of medroxyprogesterone acetate was not changed with food.2

Indications

For the treatment of secondary amenorrhea:

Oral dosage: Adult and Adolescent females: 5 to 10 mg PO once daily for 5 to 10 days, starting anytime during the cycle; but usually started during the latter half of the cycle (days 16 to 21). If the endometrium has been primed with estrogens, administer 10 mg PO once daily for 10 days starting on the 16th day of the cycle. Progestin withdrawal bleeding usually occurs 3 to 7 days after discontinuation of therapy.2

For the treatment of dysfunctional uterine bleeding due to hormonal imbalance, in the absence of organic pathology such as fibroids or uterine cancer:

Oral dosage: Adult and Adolescent females: 5 to 10 mg PO once daily for 5 to 10 days during the latter half of the cycle (days 16 to 21). If the endometrium has been primed with estrogens, administer 10 mg PO once daily for 10 days starting on the 16th day of the cycle. Progestin withdrawal bleeding usually occurs 3 to 7 days after discontinuation of therapy.2

For the treatment of endometriosis-associated pain:

Oral dosage: Adult and Adolescent females: 10 mg PO once daily for 10 days a month (e.g., from day 16 to 25 of the menstrual cycle) for 3 months.4 Treatment guidelines recommend progestogens, including medroxyprogesterone, as options for reducing endometriosis-associated pain.5 Although many oral progestogen regimens have been studied, current practice is to use regimens with a lower dose and for a shorter duration.4 6

For the prevention of endometrial hyperplasia associated with estrogen replacement therapy in postmenopausal women with an intact uterus:

Oral dosage: Adult females with an intact uterus: 5 to 10 mg PO once daily for 10 to 14 or more days each month for females with an intact uterus in whom estrogen is given in a sequential manner (e.g., withdrawal bleeding is expected). Alternatively, if estrogens are administered continuously each day, take 2.5 to 5 mg PO once daily (when withdrawal bleeding not desirable).2

Contraindications/Precautions

Medroxyprogesterone acetate products are contraindicated in patients with a known hypersensitivity to medroxyprogesterone acetate or any of the product ingredients, including history of anaphylaxis or history of angioedema to medroxyprogesterone acetate. Cases of both anaphylactic reactions and angioedema have been reported in patients receiving medroxyprogesterone acetate.2 1 7 8

Medroxyprogesterone oral tablets are contraindicated in patients with pre-existing breast cancer.2 8 7 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.2 Women with a strong family history of breast cancer should be monitored with particular care.1 Do not use medroxyprogesterone products in patients with undiagnosed abnormal genital or vaginal bleeding.2 8 7 1 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.2 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).9 10 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.9 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. The risk increased with duration of use, and appeared to return to baseline over about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with combined HRT as compared to estrogen-alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration.2 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.2 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.2

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 risk in patients with diabetes receiving hormonal therapy.

Medroxyprogesterone is 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.2 1 8 7 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.2 1 8 7 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.2 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.11 10Estrogens 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 5.10 12 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.13 14 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.15 10 2 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.16 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.16 8 7

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 is contraindicated for use during known pregnancy or suspected pregnancy. Newborns exposed to medroxyprogesterone acetate in-utero and followed to adolescence showed no evidence of any adverse effects on their health including their physical, intellectual, sexual or social development.8 7 There may be an increased risk of minor birth defects in pediatric patients whose mothers are exposed 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.2

Combination estrogen-progestin oral contraceptives are classified as carcinogenic to humans in the development of hepatic cancer by the World Health Organization, International Agency for Research on Cancer (WHO IARC). Because of this association, medroxyprogesterone is contraindicated in patients with hepatic dysfunction or hepatic disease; specifically, the injectable medroxyprogesterone acetate (Depot-Provera) for contraception, is contraindicated for use in patients with severe hepatic disease.8 Medroxyprogesterone for palliative care should not be used by women with significant liver disease and should be discontinued if jaundice or disturbances of liver function occur.1 Use medroxyprogesterone with caution in patients with a past history of cholestasis and jaundice associated with past estrogen use or with pregnancy. If hepatic adverse events recur following medroxyprogesterone administration, consider discontinuation.8 17

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.18 If a patient receiving medroxyprogesterone 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, consider discontinuation of the drug.16

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).19

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.17

Pregnancy

Medroxyprogesterone is contraindicated for use during known pregnancy or suspected pregnancy. Although the drug should not be used during pregnancy, there appears to be little or no increased risk of birth defects in women who have inadvertently been exposed to medroxyprogesterone acetate contraceptive injections in early pregnancy. Newborns exposed to medroxyprogesterone acetate in-utero and followed to adolescence showed no evidence of any adverse effects on their health including their physical, intellectual, sexual or social development.8 7 There may be an increased risk of minor birth defects in pediatric patients whose mothers are exposed 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.2 It is not known whether other forms of medroxyprogesterone acetate (such as the injection dose used for cancer) can cause fetal harm when administered to a pregnant woman; use this cancer treatment during pregnancy only if clearly needed and the benefits to the mother outweigh potential fetal risks.1

Breast-feeding

Medroxyprogesterone contraceptive injections may be used safely during breast-feeding. Detectable amounts of drug have been identified in the milk of mothers receiving contraceptive injections of medroxyprogesterone. However, in nursing mothers, milk composition, quality, and amount are not adversely affected. Neonates and infants exposed to medroxyprogesterone from breast milk have been studied for developmental and behavioral effects through puberty. No adverse effects have been identified.8 7 16Alternatives include other progestin-only contraceptives, such as norethindrone oral contraceptive pills.16 Other dosage forms, such as the medroxyprogesterone suspension injection for cancer treatment, or medroxyprogesterone tablets, are recommended to be avoided during lactation.1 2

Adverse Reactions/Side Effects

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. 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.2 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%.20 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.1 2

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. 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.2 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.2

Dermatologic, vascular, and allergic reactions may occur with medroxyprogesterone therapy. Angioedema, anaphylactoid reactions, and anaphylactic shock have been reported with the use of medroxyprogesterone.

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.1 2 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.1 2

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 8 7; women receiving medroxyprogesterone monotherapy for other indications have also reported these adverse events, but the incidence is not known.2 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.16 Anxiety and irritability have been reported in 1% to 5% of women receiving medroxyprogesterone depot contraceptive injections.7 Drowsiness/somnolence has been reported during postmarketing experience with medroxyprogesterone depot contraceptive injection and with the use of other medroxyprogesterone formulations for various indications.8 1 7 2 Other CNS effects reported postmarketing with the contraceptive injections have included facial palsy, fainting, paralysis, and paresthesias.8 7 Euphoria has been reported in patients receiving medroxyprogesterone depot injection for malignancy.1 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.8 1 7 2 Chorea and mood disturbances have been reported in women receiving combined estrogen plus progestin therapy for hormone replacement.2

Gastrointestinal (GI) effects are fairly common with medroxyprogesterone therapy. 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).2 These effects have also been reported in the use of medroxyprogesterone depot injections for other indications; cholestatic jaundice has included neonatal jaundice and hyperbilirubinemia.1 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.2

Changes in appetite may occur during medroxyprogesterone treatment. Appetite stimulation may occur. 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.1 2

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.2 1 8 7 16 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.10 2 Any patient who develops thrombosis during contraceptive use should discontinue treatment unless she has no other acceptable options for birth control.8 7 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.16 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.1

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.2

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.1 87 2

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.8 7 Backache and arthralgia have been reported in those receiving estrogen-progestin combined hormonal therapy.1 2

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).19 2

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.2 10 21 22 23 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 the 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.2 23 24 10Women 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.2 10 21 22 23

Storage

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

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