MEDROXYPROGESTERONE ACETATE

1.0 PHARMACOLOGIC CATEGORY Progestogen/Sex Hormone 2.0 DESCRIPTION Provera contains medroxyprogesterone acetate, a derivative of progesterone, as its active ingredient. Medroxyprogesterone acetate is active by the parenteral and oral routes of administration. It is a white to off-white, odorless crystalline powder that is stable in air and that melts between 200 C and 210 C. It is freely soluble in chloroform, soluble in acetone and dioxane, sparingly soluble in alcohol and methanol, slightly soluble in ether, and insoluble in water. The chemical name for medroxyprogesterone acetate is pregn-4-ene-3,20-dione. 17-(acetyloxy)-6-methyl-, (6 ). The structural formula is:


Opposition of endometrial effects of estrogen in menopausal women being treated with estrogen (Hormone Therapy)
For women taking 0.625 mg of conjugated estrogen or an equivalent daily dose of another estrogen, medroxyprogesterone acetate can be given in one or two regimens: Continuous regimen of medroxyprogesterone acetate-Oral 2.5 to 5.0 mg daily.Sequential regimen of medroxyprogesterone acetate-Oral 5-10 mg daily for 10 to 14 consecutive days of a 28-day or monthly cycle.
Hepatic Insufficiency [41,42]  No clinical studies have evaluated the effect of hepatic disease on the pharmacokinetics of MPA.However, MPA is almost exclusively eliminated by hepatic metabolism and steroid hormones may be poorly metabolized in patients with sever liver insufficiency.(See Section 4.3 -Contraindications).
Renal Insufficiency [41, 42]  No clinical studies have evaluated the effect of renal disease on the pharmacokinetics of MPA.However, since MPA is almost exclusively eliminated by hepatic metabolism, no dosage adjustment should be necessary in women with renal insufficiency.

Oncology Recurrent and/or Metastatic Breast Cancer
Oral medroxyprogesterone acetate 400 to 1500 mg per day Injectable medroxyprogesterone acetate initial dose 500 to 1000 mg intramuscularly per day for 28 days.The patient should then be placed on a maintenance schedule of 500 mg twice weekly as long as she responds to treatment.

Recurrent and/or Metastatic Endometrial or Renal Cancer
Oral medroxyprogesterone 100 mg to 600 mg per day Injectable medroxyprogesterone 400 to 1000 mg intramuscularly per week is recommended initially.If improvement is noted within a few weeks or month and the disease appears stabilized, it may be possible to maintain improvement with as little as 400mg per month.

Metastatic Prostate Cancer
Oral medroxyprogesterone 100 mg to 500 mg per day

Anorexia and Cachexia Syndrome
Oral medroxyprogesterone 1000 mg per day

Contraindications
Medroxyprogesterone is contraindicated in patients with the following conditions: Known or suspected pregnancy or as a diagnostic test for pregnancy Undiagnosed vaginal bleeding Liver dysfunction or disease Known hypersensitivity to medroxyprogesterone or any component of the drug.Additional Contraindication(s) for Specific Use Contraception/Gynecology: Known or suspected malignancy of the breast

Special Warnings and Special Precautions for Use
Unexpected vaginal bleeding during therapy with medroxyprogesterone should be investigated Medroxyprogesterone may cause some degree of fluid retention; therefore, caution should be exercised in treating any patient with a pre-existing medical condition that might be adversely affected by fluid retention.
Patients with a history of treatment for clinical depression should be carefully monitored while receiving medroxyprogesterone therapy.Some patients receiving medroxyprogesterone may exhibit a decrease in glucose tolerance.Diabetic patients should be carefully observed while receiving such therapy.The pathologist (laboratory) should be informed of the patient's use of medroxyprogesterone if endometrial or endocervical tissue is submitted for examination.The physician/laboratory should be informed that use of medroxyprogesterone may decrease the levels of the following endocrine biomarkers: (i) Plasma/urinary steroids (e.g., cortisol, estrogen, pregnanediol, progesterone, testosterone) (ii) Plasma/urinary gonadotrophins (e.g., LH and FSH) (iii)Sex-hormone-binding-globulin Medication should not be readministered pending examination if there is a sudden partial or complete loss of vision or if there is a sudden onset of proptosis, diplopia, or migraine.If examination reveals papilledema or retinal vascular lesions, medication should not be readministered.

Gynecology
Treatment of menopausal vasomotor symptoms / Opposition of endometrial effects of estrogen in menopausal women being treated with estrogen (Hormone Therapy) -All Formulations: Other doses of oral conjugated estrogens with medroxyprogesterone, and other combinations and dosage forms of HT were not studied in the Women's Health Initiative (WHI) trial (see Section 5.1, Clinical Studies, Women's Health Initiative Study) and, in the absence of comparable data, these risks should be assumed to be similar.

Breast Cancer
The use of combined estrogen/progestin by postmenopausal women has been reported to increase the risk of breast cancer.Results from a randomized placebocontrolled trial, the WHI trial, and epidemiological studies (see Section 5.1, Clinical Studies) have reported an increased risk of breast cancer in women taking estrogen/progestin combinations for HT for several years.In the WHI conjugated equine estrogens (CEE) plus medroxyprogesterone trial and observational studies, the excess risk increased with duration of use (see Section 4.2).The use of estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation.

Cardiovascular Disorders
Estrogens with or without progestins should not be used for the prevention of cardiovascular disease.Several randomized, prospective trials on the long-term effects (see Section 4.2 -Dosage and Method of Administration) of a combined estrogen/progestin regimen in postmenopausal women have reported an increased risk of cardiovascular events such as myocardial infarction, coronary heart disease, and stroke.

Coronary Artery Disease
There is no evidence from randomized controlled trials of cardiovascular benefit with continuous combined conjugated estrogen and medroxyprogesterone.Two large clinical trials [WHI Conjugated Equine Estrogens/ Medroxyprogesterone Acetate and Heart and Estrogen /progestin Replacement Study (HERS) (see Section 5.1, Pharmacodynamic Properties, Clinical Studies)] showed a possible increased risk of cardiovascular morbidity in the first year of use and no overall benefit.
In the Conjugated Equine Estrogens / Medroxyprogesterone Acetate trial, an increased risk of coronary heart disease (CHD) events (defined as nonfatal myocardial infarction and CHD death) was observed in women receiving Conjugated Equine Estrogens/ Medroxyprogesterone Acetate compared to women receiving placebo (37 vs. 30 per 10,000 person years).The increase in VTE risk was observed in year one and persisted over the observation period (see Section 4.2 -Dosage and Method of Administration).

Stroke
In the WHI CEE/MPA trial, an increased risk of stroke was observed in women receiving Conjugated Equine Estrogens /Medroxyprogesterone Acetate compared to women receiving placebo (29 vs. 21 per 10,000 person-years).The increase in risk was observed in year one and persisted over the observation period (see Section 4.2 -Dosage and Method of Administration).

Dementia
The Women's Health Initiative Memory Study (WHIMS) (see Section 5.1-Pharmacodynamic Properties, Clinical Studies), an ancillary study of WHI, for Conjugated Equine Estrogens /Medroxyprogesterone Acetate reported an increased risk of probable dementia in postmenopausal women 65 years of age or older.In addition, CEE/MPA therapy did not prevent mild cognitive impairment (MCI) in these women.Use of hormone therapy (HT) to prevent dementia or MCI in women 65 years or older is not recommended.[38, 42]   Ovarian Cancer Current use of estrogen only or estrogen plus progestin products in postmenopausal women for five or more years, has been associated with an increased risk of ovarian cancer in some epidemiological studies.Past users of estrogen only or estrogen plus progestin products were at no increased risk for ovarian cancer.Other studies did not show a significant association.The WHI CEE/MPA trial reported that estrogen plus progestin increased the risk of ovarian cancer, but this risk was not statistically significant.In one study, women who use HRT are at increased risk of fatal ovarian cancer.

History and Physical Exam Recommendation
A complete medical and family history should be taken before the initiation of any hormone therapy.Pretreatment and periodic physical examination should include special reference to blood pressure, breasts, abdomen, and pelvic organs, including cervical cytology.

Oncology
Medroxyprogesterone may produce cushingoid symptoms.Some patients receiving medroxyprogesterone may exhibit suppressed adrenal function.Medroxyprogesterone may decrease ACTH and hydrocortisone blood levels.The physician/laboratory should be informed that in addition to the endocrine biomarkers listed on Special Warnings and Special Precautions for Use (section 4.4), the use of medroxyprogesterone in oncology indications may also cause partial adrenal insufficiency (decrease in pituitary-adrenal axis response) during metyrapone testing.Thus the ability of adrenal cortex to respond to ACTH should be demonstrated before metyrapone is administered.

Oral Formulations & High Dose Parenteral Formulations (e.g., oncology use in pre-menopausal women) Decrease in Bone Mineral Density
There are no studies on the bone mineral density (BMD) effects of orally administered Medroxyprogesterone Acetate or the high doses of parenteral Medroxyprogesterone Acetate (e.g., for oncology use).
An evaluation of BMD may be appropriate in some patients who use Medroxyprogesterone Acetate long-term.

Interactions with Other Drugs and Other Forms of Interaction
Aminoglutethimide administered concomitantly with high doses Medroxyprogesterone Acetate may significantly depress the serum concentrations of medroxyprogesterone acetate.Users of high-dose Medroxyprogesterone Acetate should be warned of the possibility of decreased efficacy with the use of aminoglutethimide.

Pregnancy
Medroxyprogesterone Acetate is contraindicated in women who are pregnant.
Some reports suggest an association between intrauterine exposure to progestational drugs in the first trimester of pregnancy and genital abnormalities in fetuses.
If the patient becomes pregnant while using this drug, the patient should be apprised of the potential hazard to the fetus.

Lactation
Medroxyprogesterone Acetate and its metabolites are excreted in the breast milk.
There is no evidence to suggest that this presents any hazard to the nursing child.

Effects on Ability to Drive and Use Machines
The effect of medroxyprogesterone acetate on the ability to drive and use machinery has not been systematically evaluated.

Intramuscular Formulations
In postmarketing experience, there have been rare cases of osteoporosis including osteoporotic fractures reported in patients taking medroxyprogesterone acetate IM.

Overdose
Oral doses up to 3 g per day have been well tolerated.
Overdose treatment is symptomatic and supportive.

Mechanism of Action
Medroxyprogesterone acetate is a synthetic progestinic molecule (structurally related to the endogenous hormone progesterone) which has been demonstrated to possess several pharmacologic actions on the endocrine system: Inhibition of Pituitary Gonadotropins (FSH and LH); Decrease circulating testosterone; Decrease of circulating estrogen level (as a result of both FSH inhibition and enzymatic induction of hepatic reductase, resulting in increased clearance of testosterone and consequent decreased conversion of androgens to estrogens).
All of these actions result in a number of pharmacological effects as described below.

Gynecology
Medroxyprogesterone acetate, administered orally or parenterally in the recommended doses to women with adequate endogenous estrogen, transforms proliferative into secretory endometrium.Androgenic and anabolic effects have been noted, but the drug is apparently devoid of significant estrogenic activity.While parenterally administered medroxyprogesterone acetate inhibits gonadotropin production, which in turn 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.

Oncology
Medroxyprogesterone acetate demonstrates antitumor activity.When Medroxyprogesterone Acetate is given to patients at high doses (either by the oral route or by intramuscular injection) it is effective in the palliative treatment of hormone-response, malignant neoplasm.

Bone Mineral Density Studies 36 BMD Changes in Adult Women
In a controlled, clinical study adult women using Medroxyprogesterone Acetate injection (150 mg IM) for up to 5 years showed spine and hip mean BMD decreases of 5-6%, compared to no significant change in BMD in the control group.The decline in BMD was more pronounced during the first two years of use, with smaller declines in subsequent years.Mean changes in lumbar spine BMD of -2.86%, -4.11%, -4.89% and -5.38% after 1,2,3,4 and 5 years respectively, were observed.Mean decreases in BMD of the total hip and femoral neck were similar.
After stopping use of Medroxyprogesterone Acetate injection (150 mg IM), there was progressive recovery of BMD toward baseline values during the 2-year post-therapy period.After 2 years of treatment, the BMD deficit had decreased to approximately 2.1% at the spine and hip.[38,45] BMD Changes in Adolescent Females (12-18 years) 46,47 An open-label non-randomized clinical study of Medroxyprogesterone Acetate injectable (150 mg IM every 3 months for up to 250 weeks [4.6 years]) in adolescent females(12-18 years) also showed a significant decline in BMD from baseline.Among subjects who received ≥4 injections/60-week period, the mean decrease in lumbar spine BMD was 2.1% after 240 weeks; mean decreases for the total hip and femoral neck were -6.4% and -5.4.%, respectively.Post-treatment follow-up showed that lumbar spine BMD recovered to baseline levels approximately one year after treatment was discontinued and that hip BMD recovered to baseline levels approximately 3 years after treatment was discontinued.In contrast, unmatched, untreated subjects showed mean BMD increased at 240 weeks of 5.1%, 1.1% and 1.5% for lumber spine, total hip and femoral neck, respectively.(See Section 4.4-Special Warnings and Precautions for Use -Additonal Warnings and Precautions for Specific Use or Formulation, Contraception/Endometriosis -Injectable Formulations, Loss of Bone Mineral Density)

Women's Health Initiative Study
The WHI Conjugated Equine Estrogens (0.625mg)/ Medroxyprogesterone Acetate (2.5mg) trial 30 enrolled 16,608 postmenopausal women aged 50-79 years with intact uteri at baseline, to assess the risks and benefits of the combined therapy compared with placebo in the prevention of certain chronic diseases.The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome studied.The study was stopped early after an average follow-up of 5.2 years (planned duration 8.5 years) because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the "global index."(See section 4.4-Special Warnings and Precautions for Use, Breast Cancer) The combination Conjugated Equine Estrogens/ Medroxyprogesterone Acetate therapy reported a significant decrease in osteoporotic (23%) and total (24%) fractures.

Million Women Study
The MWS 37 was a prospective cohort study enrolling 1,084,110 women in the UK aged 50-64 years of whom 828,923 with defined time since menopause were included in the main analyses of risk of breast cancer in relation to HT.Overall, 50% of the study population had used HT at some point.Most current users of HT at baseline reported using preparations containing estrogen only (41%) or estrogen-progestin combinations (50%).The average duration of follow-up was 2.6 years for analyses of cancer incidence and 4.1 years for analyses of mortality.(See section 4.4 -Special Warnings and Precautions for Use, Breast Cancer.)Heart and Estrogen/progestin Replacement Studies HERS 31 and HERS II 32  Elimination: Most Medroxyprogesterone Acetate metabolites are excreted in the urine as glucuronide conjugates with only minor amounts excreted as sulfates.
Mean percent dose excreted in the 24-hour urine of patients with fatty liver as intact Medroxyprogesterone Acetate after a 10-mg or 100-mg dose was 7.3% and 6.4%, respectively.Elimination half-life of oral Medroxyprogesterone Acetate is 12 to 17 hours.

Preclinical Safety Data
Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term intramuscular administration of medroxyprogesterone acetate (MPA) has been shown to produce mammary tumors in beagle dogs.There was no evidence of a carcinogenic effect associated with the oral administration of oral Medroxyprogesterone Acetate to rats and mice.Medroxyprogesterone acetate was not mutagenic in a battery of in vitro or in vivo genetic toxicity assays.Medroxyprogesterone acetate at high doses is an antifertility drug and high doses would be expected to impair fertility until the cessation of treatment.

Shelf Life
See outer package for expiration date of the product.

Storage Conditions
Store at temperatures not exceeding 25°C . A longer duration of treatment was associated with a slower rate of BMD recovery.(See Section 4.4 -Special Warnings and Precautions for Use-Additional Warnings and Precautions for 40,39es were two randomized, prospective secondary prevention trials on the long-term effects of oral continuous combined Conjugated Equine Estrogens/ Medroxyprogesterone Acetate (0.625mg Conjugated Equine Estrogens plus 2.5mg Medroxyprogesterone Acetate) regimen in postmenopausal women with CHD.(See section 4.4-Special Warnings and Precautions for Use, Cardiovascular disorders).2, 763 postmenopausal women with a mean age of 66.7 years and with intact uteri were enrolled in this study.The average duration of follow-up was 4.1 years for HERS and 2.7 additional years (for a total of 6.8 years) for HERS II.(See section 4.4 -Special Warnings and Precautions for Use, Cardiovascular Disorders.)Women'sHealthInitiativeMemoryStudyTheWHIMS,asubstudy of WHI,38,39enrolled 4,532 predominantly healthy postmenopausal women age 65 to 79 years to evaluate the effects of Conjugated Equine Estrogens/ Medroxyprogesterone Acetate (0.625 mg Conjugated Equine Estrogens plus 2.5 mg Medroxyprogesterone Acetate) or Conjugated Equine Estrogens-alone (0.625 mg) on the incidence of probable dementia compared with placebo.The average duration of follow-up was 4.05 years for the Conjugated Equine Estrogens/ Medroxyprogesterone Acetate.(Seesection4.4-SpecialWarnings and Precautions for Use, Dementia.)MedroxyprogesteroneAcetate is metabolized in the liver.40Elimination:Theeliminationhalf-lifefollowing single intramuscular injection is about 6 weeks.Medroxyprogesterone acetate is primarily excreted in the feces, via biliary secretion.Approximately 30 % of an intramuscular dose is secreted in the urine after 4 days.Oral medroxyprogesterone acetate (MPA) is rapidly absorbed with maximum concentration obtained between 2 to 4 hours.The half-life of oral Medroxyprogesterone Acetate is approximately 17 hours.It is 90% protein bound, and is mainly excreted in the urine.Administration with food increased the bioavailability of MPA.A 10 mg dose of oral MPA, taken immediately before or after a meal, increased average MPA C max (51 and 77%, respectively) and average AUC 18 and 33% respectively).The half-life of MPA was not changed with food.[47,53]Followingoral dosing, Medroxyprogesterone Acetate is extensively metabolized in the liver via ring A and/or side-chain hydroxylation, with subsequent conjugation and elimination in the urine.At least 16 Medroxyprogesterone Acetate metabolites have been identified.In a study designed to measure the metabolism of medroxyprogesterone acetate (MPA), the results suggest that human cytochrome P450 3A4 is primarily involved in the overall metabolism of Medroxyprogesterone Acetate in human liver microsomes.
Pregnancy and Lactation).Low levels of medroxyprogesterone acetate have been detected in breast milk of lactating women (see Section 4.6 -Pregnancy and Lactation) administered 150 mg of medroxyprogesterone acetate by the IM route.Metabolism: Distribution: Medroxyprogesterone Acetate is approximately 90% protein bound, primarily to albumin; no Medroxyprogesterone Acetate binding occurs with sexhormone binding globulin.The unbound Medroxyprogesterone Acetate modulates pharmacologic responses.Metabolism: Round, white, biconvex tablet, engraved with "PROVERA 10" around the periphery on one side and scored on the other side.Available in blister pack of 10's and box of 100's.Inc.New York, N.Y., U.S.A.
CAUTION: Foods, Drugs, Devices and Cosmetics Act prohibits dispensing without prescription.