Provera

It was found that some herbal products (e.g., St. John's wort) which are available as over-the-counter (OTC) products might interfere with steroid metabolism, and therefore, alter the efficacy and safety of estrogen/progestin products.

Physicians and other health care providers should made be aware of other non-prescription products concomitantly used by the patient, including herbal and natural products, obtained from the widely spread Health Stores.

Administration with food increases 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. MPA can be taken with or without food.

Concomitant administration of aminoglutethimide with medroxyprogestrone acetate (MPA) may significantly reduce the bioavailability of MPA.

The results of certain endocrine and liver function tests may be affected by estrogen/progestin-containing products:

• increased sulfobromophthalein retention;

  
  

• increased prothrombin time and partial thromboplastin time; increased levels of fibrinogen and fibrinogen activity; increased coagulation factors VII, VIII, IX, X; increased norepinephrine-induced platelet aggregability; decreased antithrombin III;

  
  

• increased thyroxine-binding globulin (TBG), leading to increased circulating total thyroid hormone (T₄) as measured by column or radioimmunoassay; T₃ resin uptake is decreased, reflecting the elevated TBG; free T₄ concentration is unaltered;

  
  

• other binding proteins may be elevated in serum i.e., corticosteroid binding globulin (CBG), sex-hormone binding globulin (SHBG), leading to increased circulating corticosteroids and sex steroids, respectively; free or biologically active hormone concentrations are unchanged;

  
  

• impaired glucose tolerance;

  
  

• reduced serum folate concentration;

  
  

• increased serum triglycerides and phospholipids concentration.

  
  

The following laboratory tests may be affected by the use of PROVERA: gonadotropin levels; plasma progesterone levels; urinary pregnanediol levels; plasma testosterone levels (in the male); plasma estrogen levels (in the female); plasma cortisol levels; glucose tolerance test.

The results of the above laboratory tests should not be considered reliable unless therapy has been discontinued for 2 to 4 weeks. The pathologist should be informed that the patient is receiving HRT therapy when relevant specimens are submitted.

Preparations inducing liver enzymes (e.g., barbiturates, hydantoins, carbamazepine, meprobamates, phenylbutazone or rifampicin) may interfere with the activity of orally administered progestins.

The recommended dose is 400 mg daily, given in divided doses. The patient should be continued on therapy as long as she is responding to treatment. Although doses of up to 2400 mg daily have been reported, controlled studies using 800 mg daily did not demonstrate any appreciable increase in response rates compared to the 400 mg daily dose.

PROVERA is not recommended as primary therapy, but as adjunctive and palliative treatment in advanced, inoperable cases including those with recurrent metastatic disease.

Note: Response to hormonal therapy for endometrial or breast cancer may not be evident until 8 to 10 weeks of therapy. Rapid progression of disease at any time during therapy should result in termination of treatment with PROVERA.

After ruling out pregnancy, PROVERA (medroxyprogesterone acetate) may be administered in doses ranging from 5-10 mg daily depending upon the degree of progestational effect desired. The dose should be given daily for 12-14 days every month.

Note: In patients with poorly developed endometria, conventional estrogen therapy should be given in conjunction with PROVERA.

See Figure 1.

PROVERA (medroxyprogesterone acetate) is administered orally.

If a dose of this medication has been missed, it should be taken as soon as possible. However, if it is almost time for the next dose, skip the missed dose and go back to the regular dosing schedule. Do not double doses.

When estrogen is prescribed for a postmenopausal woman with a uterus, a progestin should also be initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin. Use of estrogen, alone or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be re-evaluated periodically as clinically appropriate (for example, 3-month to 6-month intervals) to determine if treatment is still necessary (see Warnings and Precautions). For women with intact uteri, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding. Patients should be started at the lowest dose. The lowest effective dose of PROVERA has not been determined.

200-400 mg/day is the usual dose. It is suggested that if neither subjective nor objective improvement is noted within 2 to 3 months, therapy should be discontinued. Where improvement is noted and the disease process appears to be stabilized, it may be possible to maintain this improvement with a 200 mg/day dose.

In dysfunctional uterine bleeding, PROVERA may be given in doses ranging from 5-10 mg/day, for 10-14 days, beginning on the assumed or calculated 12-16^th day of the cycle. This regimen should be repeated for 2 subsequent cycles or longer if necessary.

When bleeding is due to a deficiency of both ovarian hormones, as indicated by a poorly developed proliferative endometrium, conventional estrogen therapy should be given in conjunction with PROVERA. If bleeding is controlled satisfactorily, at least 2 subsequent cycles of treatment should be given.

If dysfunctional uterine bleeding is not controlled by hormone therapy, appropriate diagnostic measures should be undertaken to rule out uterine pathology.

The progestin challenge test may be considered for amenorrheic women with intact uteri. PROVERA 10 mg daily should be administered for 10 days.

A negative test is identified by the absence of withdrawal bleeding, and implies the absence of endometrial stimulation due to insufficient estrogen secretion.

A positive test is indicated by the presence of withdrawal bleeding which occurs within 7 days after stopping PROVERA treatment. Withdrawal bleeding implies the presence of sufficient endogenous estrogen to stimulate the endometrium.

In women with intact uteri receiving estrogen replacement therapy, PROVERA tablets may be given in a dosage of 5-10 mg daily for 12-14 days. The recommended starting dose for PROVERA should be 10 mg/day, administered for 12-14 days. A dose of 5 mg/day PROVERA for 12-14 days may be appropriate for some women.

Note: The lowest dose of PROVERA required to protect the endometrium from estrogenic-hyperstimulation should be used. A good indicator is the lowest dose of PROVERA that will consistently result in withdrawal bleeding within 7 days after stopping PROVERA treatment. Bleeding that occurs during the PROVERA treatment indicates a need for a longer duration, or higher dose of PROVERA.

breakthrough bleeding; spotting; change in menstrual flow; dysmenorrhea; vaginal itching/discharge; dyspareunia; endometrial hyperplasia; pre-menstrual-like syndrome; reactivation of endometriosis; changes in cervical erosion and amount of cervical secretion; breast swelling and tenderness.

neuro-ocular lesions (e.g., retinal thrombosis, optic neuritis); visual disturbances; steepening of the corneal curvature; intolerance to contact lenses.

increased blood sugar levels; decreased glucose tolerance.

abdominal discomfort, nausea, bloating.

Adverse events reported during worldwide post-marketing experience, regardless of causality and frequency, are listed below. It should be noted that the nature of post-marketing surveillance makes it difficult to determine if a reported event was actually caused by PROVERA.

The following adverse reactions have been reported with the use of PROVERA (medroxyprogesterone acetate):

fatigue; changes in appetite; changes in body weight; change in libido.

palpitations; increase in blood pressure (see Warnings and Precautions); coronary thrombosis.

dyspnea.

cerebral infarction.

pyrexia, increase in weight, peripheral edema, “moon” facies.

cystitis; dysuria; sodium retention; edema.

The following adverse reactions have been reported with estrogen/progestin combination in general:

chloasma or melasma; which may persist when drug is discontinued; erythema multiform; erythema nodosum; haemorrhagic eruption; loss of scalp hair; hirsutism and acne.

breakthrough bleeding, spotting, change in menstrual flow, amenorrhea, changes in cervical erosion and cervical secretions.

muscle spasms.

gallbladder disorder; asymptomatic impaired liver function; cholestatic jaundice.

hemorrhage.

If adverse symptoms persist, the prescription of the HRT should be re-considered.

abortion spontaneous.

See Warnings and Precautions regarding potential induction of malignant neoplasms and adverse effects similar to those of oral contraceptives.

headache, nervousness, dizziness, depression, insomnia, somnolence, fatigue, premenstrual syndrome-like symptoms.

tenderness, galactorrhea.

altered coagulation tests (see Warnings and Precautions and Drug Interactions, Drug-Laboratory Test Interactions).

sensitivity reactions ranging from pruritus, urticaria, angioneurotic edema to generalized rash and anaphylaxis; acne, alopecia, hirsutism.

including thrombophlebitis and pulmonary embolism.

mental depression; nervousness; irritability.

nausea; vomiting; abdominal discomfort (cramps, pressure, pain); bloating.

PROVERA is not intended for pediatric use and no clinical data has been collected in children.

Progestin (e.g., norethindrone acetate) overdosage has been characterized by depressed mood, tiredness, acne and hirsutism.

In female patients, overdosage may result in a period of amenorrhea of a variable length and may be followed by irregular menses for several cycles.

No cases of overdosage in male patients have been reported. However, such overdosage, if it were to occur, would not likely result in any particular symptomatology.

There is no known therapy for overdosage of medroxyprogesterone. Doses as high as 1000 mg for the therapy of endometrial carcinoma have been used without adverse effect.

Each circular, white tablet, embossed “U 467” on one side and scored on the other, contains: medroxyprogesterone acetate 100 mg. Nonmedicinal ingredients: calcium stearate, corn starch, lactose monohydrate, sodium lauryl sulphate, sucrose and talc. Bottles of 100.

Each circular, orange tablet, embossed with “U 64” on one side and scored on the other, contains: medroxyprogesterone acetate 2.5 mg. Nonmedicinal ingredients: calcium stearate, corn starch, FD&C Yellow No. 6, lactose monohydrate, mineral oil, sucrose and talc. Bottles of 100 and 500. Blisters of 30, cartons of 3.

Each circular, blue tablet, embossed “U 286” on one side and scored on the other, contains: medroxyprogesterone acetate 5 mg. Nonmedicinal ingredients: calcium stearate, corn starch, lactose monohydrate, mineral oil, sucrose and talc. Bottles of 100 and 500.

Each circular, white tablet, embossed “Upjohn 50” on one side and scored on the other, contains: medroxyprogesterone acetate 10 mg. Nonmedicinal ingredients: calcium stearate, corn starch, lactose monohydrate, mineral oil, sucrose and talc. Bottles of 100 and 500.

Available epidemiological data indicate that use of estrogen with or without progestin by postmenopausal women is associated with an increased risk of developing venous thromboembolism (VTE).

In the estrogen plus progestin arm of the WHI trial, among 10 000 women on combined HRT over a one-year period, there were 18 more cases of venous thromboembolism, including 8 more cases of pulmonary embolism.

In the estrogen-alone arm of the WHI trial, among 10 000 women on estrogen therapy over a one-year period, there were 7 more cases of venous thromboembolism, although there was no statistically significant difference in the rate of pulmonary embolism.

Generally recognized risk factors for VTE include a personal history, a family history (the occurrence of VTE in a direct relative at a relatively early age may indicate genetic predisposition) and severe obesity (body mass index >30 kg/m²) and systemic lupus erythematosus. The risk of VTE also increases with age and smoking.

The risk of VTE may be temporarily increased with prolonged immobilization, major surgery or trauma. In women on HRT, attention should be given to prophylactic measures to prevent VTE following surgery. Also, patients with varicose veins should be closely supervised. The physician should be alert to the earliest manifestations of thrombotic disorders (thrombophlebitis, retinal thrombosis, cerebral embolism and pulmonary embolism). If these occur or are suspected, hormone therapy should be discontinued immediately, given the risks of long-term disability or fatality.

If feasible, estrogens with or without progestins should be discontinued at least 4 weeks before major surgery which may be associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

Patients who develop visual disturbances, classical migraine, transient aphasia, paralysis, or loss of consciousness should discontinue medication.

Patients with a previous history of classical migraine and who develop a recurrence or worsening of migraine symptoms should be re-evaluated.

Women using hormone replacement therapy sometimes experience increased blood pressure. Blood pressure should be monitored with HRT use. Elevation of blood pressure in previously normotensive or hypertensive patients should be investigated and HRT may have to be discontinued.

Because the prolonged use of estrogens with or without progestins influences the metabolism of calcium and phosphorus, estrogens with or without progestins should be used with caution in patients with metabolic and malignant bone diseases associated with hypercalcemia and in patients with renal insufficiency.

In the Heart and Estrogen/progestin Replacement Study (HERS) of postmenopausal women with documented heart disease (n=2763, average age 66.7 years), a randomized placebo-controlled clinical trial of secondary prevention of coronary heart disease (CHD), treatment with 0.625 mg/day oral conjugated equine estrogen (CEE) plus 2.5 mg oral medroxyprogesterone acetate (MPA) demonstrated no cardiovascular benefit. Specifically, during an average follow-up of 4.1 years, treatment with CEE plus MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the hormone treated group than in the placebo group in year 1, but not during the subsequent years.

From the original HERS trial, 2321 women consented to participate in an open label extension of HERS known as HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. After 6.8 years, hormone therapy did not reduce the risk of cardiovascular events in women with CHD.

The age of the patient constitutes no absolute limiting factor although treatment with progestins may mask the onset of the climacteric.

Particular caution is indicated in women with epilepsy, as estrogens with or without progestins may cause an exacerbation of this condition.

Usage in pregnancy is not recommended. Progestational agents are also not recommended as a diagnostic test for pregnancy. If the patient is exposed to PROVERA (medroxyprogesterone acetate) during pregnancy or if she becomes pregnant while taking the drug, she should be apprised of the potential risk to the fetus.

Of the total number of subjects in the estrogen plus progestin substudy of the Women’s Health Initiative (WHI), 21.5 percent (n=3576) were 70 to 79 years old at baseline.

No significant differences in relative risks of stroke and invasive breast cancer were observed between subjects 70 years and over compared to younger subjects. However, there was a higher relative risk of stroke and invasive breast cancer in women 75 and over compared to younger subjects.

Some information presented in Warnings and Precautions is provided in light of the fact that a progestin medication is often prescribed concomitantly with an estrogen medication. Information in this section pertaining to combined estrogen-progestin therapy may therefore not apply to progestin-only therapy. Physician discretion is advised.

When PROVERA is used for adjunctive and/or palliative treatment of recurrent and/or metastatic endometrial or hormonally-dependent, recurrent metastatic carcinoma of the breast in post-menopausal women, the risks outlined in Warnings and Precautions (including cardiovascular disorders and breast and ovarian cancer), should be weighed against the potential benefits of this treatment to the patient.

The incidence of estrogen-associated endometrial hyperplasia was assessed in 2 large, long-term, randomized clinical trials. The first study demonstrated that combining conjugated estrogens with medroxyprogesterone acetate or micronized progesterone protected the endometrium from hyperplastic changes associated with estrogen-only therapy. In the second study, the endometrial hyperplasia incidence was significantly lower in women treated with conjugated estrogen and medroxyprogesterone acetate (P<0.001) than in women treated with conjugated estrogen alone.

Pre-existing uterine leiomyomata may increase in size during estrogen use. Growth, pain or tenderness of uterine leiomyomata requires discontinuation of medication and appropriate investigation.

A worsening of glucose tolerance and lipid metabolism have been observed in a significant percentage of peri- and post-menopausal patients. Therefore, diabetic patients or those with a predisposition to diabetes should be observed closely to detect any alterations in carbohydrate or lipid metabolism, especially in triglyceride blood levels.

Women with familial hypertriglyceridemia need special surveillance. Lipid-lowering measures are recommended additionally, before treatment is started.

A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in women receiving postmenopausal estrogens has been reported.

Abnormal vaginal bleeding, due to its prolongation, irregularity or heaviness, occurring during therapy should prompt appropriate diagnostic measures to rule out the possibility of uterine malignancy and the treatment should be re-evaluated.

Clinical suppression of adrenocortical function has not been observed at low dose levels. However, the high doses of PROVERA used in the treatment of certain cancers may, in some cases, produce Cushingoid symptoms (e.g., “moon” facies, fluid retention, glucose intolerance, and blood pressure elevation).

Available epidemiological data indicate that the use of combined estrogen plus progestin by postmenopausal women is associated with an increased risk of invasive breast cancer. In the estrogen plus progestin arm of the WHI trial, among 10 000 women over a one-year period, there were:

• 8 more cases of invasive breast cancer (38 on combined HRT versus 30 on placebo).

  
  

The WHI study also reported that the invasive breast cancers diagnosed in the estrogen plus progestin group were similar in histology but were larger (mean [SD], 1.7 cm [1.1] vs 1.5 cm [0.9], respectively; P=0.04) and were at a more advanced stage compared with those diagnosed in the placebo group. The percentage of women with abnormal mammograms (recommendations for short-interval follow-up, a suspicious abnormality, or highly suggestive of malignancy) was significantly higher in the estrogen plus progestin group versus the placebo group. This difference appeared at year one and persisted in each year thereafter.

In the estrogen-alone arm of the WHI trial, there was no statistically significant difference in the rate of invasive breast cancer in hysterectomized women treated with conjugated equine estrogens versus women treated with placebo.

It is recommended that estrogens with or without progestins not be given to women with existing breast cancer or those with a previous history of the disease (see Contraindications). There is a need for caution in prescribing estrogens with or without progestins for women with known risk factors associated with the development of breast cancer, such as strong family history of breast cancer (first degree relative) or who present a breast condition with an increased risk (abnormal mammograms and/or atypical hyperplasia at breast biopsy). Other known risk factors for the development of breast cancer such as nulliparity, obesity, early menarche, late age at first full term pregnancy and at menopause should also be evaluated.

It is recommended that women undergo a mammography prior to the start of HRT treatment and at regular intervals during treatment, as deemed appropriate by the treating physician and according to the perceived risks for each patient.

The overall benefits and possible risks of hormone replacement therapy should be fully considered and discussed with patients. It is important that the modest increased risk of being diagnosed with breast cancer after 4 years of treatment with combined estrogen plus progestin HRT (as reported in the results of the WHI trial) be discussed with the patient and weighed against its known benefits.

Instructions for regular self-examination of the breasts should be included in this counselling.

Caution is advised in patients with a history of liver and/or biliary disorders. If cholestatic jaundice develops during treatment, the treatment should be discontinued and appropriate investigations carried out.

Available epidemiological data indicate that the use of combined estrogen plus progestin in women age 65 and over may increase the risk of developing probable dementia.

The Women’s Health Initiative Memory Study (WHIMS), a clinical substudy of the WHI, was designed to assess whether postmenopausal hormone replacement therapy (oral estrogen plus progestin or oral estrogen-alone) reduces the risk of dementia in women aged 65 and over (age range 65-79 years) and free of dementia at baseline.

In the estrogen plus progestin arm of the WHIMS (n=4532), women with intact uteri were treated with daily 0.625 mg conjugated equine estrogens (CEE) plus 2.5 mg medroxyprogesterone acetate (MPA) or placebo for an average of 4.05 years. The results, when extrapolated to 10 000 women treated over a one-year period showed:

• 23 more cases of probable dementia (45 on combined HRT versus 22 on placebo).

  
  

In the estrogen-alone arm of the WHIMS (n=2947), women with prior hysterectomy were treated with daily 0.625 mg CEE or placebo for an average of 5.21 years. The results, when extrapolated to 10 000 women treated over a one-year period showed:

• 12 more cases of probable dementia (37 on estrogen-alone versus 25 on placebo), although this difference did not reach statistical significance.

  
  

When data from the estrogen plus progestin arm of the WHIMS and the estrogen alone arm of the WHIMS were combined, as per the original WHIMS protocol, in 10 000 women over a one-year period, there were:

• 18 more cases of probable dementia (41 on estrogen plus progestin or estrogen-alone versus 23 on placebo).

Anaphylactic and anaphylactoid reactions have occasionally been reported in patients treated with PROVERA.

Patients should be advised of the menstrual bleeding patterns expected with the sequential regimen (see Dosage and Administration).

Upon sequential administration of PROVERA to women with adequate levels of estrogen (endogenous or exogenous), withdrawal bleeding usually occurs within 7 days after stopping PROVERA. Bleeding that occurs during PROVERA administration period indicates a need for a longer duration, or a higher dose of PROVERA.

Women with porphyria need special surveillance.

Symptoms and physical findings associated with a previous diagnosis of endometriosis may reappear or become aggravated with estrogen use.

PROVERA is not intended for pediatric use and no clinical data has been collected in children.

Some recent epidemiologic studies have found that the use of hormone replacement therapy (estrogen-alone and estrogen plus progestin therapies), in particular for five or more years, has been associated with an increased risk of ovarian cancer.

Before PROVERA is administered, the patient should have a complete physical examination including a blood pressure determination. Breasts and pelvic organs should be appropriately examined and a Papanicolaou smear should be performed. Endometrial biopsy should be done only when indicated. Baseline tests should include mammography, measurements of blood glucose, calcium, triglycerides and cholesterol, and liver function tests.

The first follow-up examination should be done within 3-6 months after initiation of treatment to assess response to treatment. Thereafter, examinations should be made at intervals at least once a year. Appropriate investigations should be arranged at regular intervals as determined by the physician.

The importance of regular self-examination of the breasts should be discussed with the patient.

Estrogens with or without progestins may cause fluid retention. Therefore, particular caution is indicated in cardiac or renal dysfunction or asthma. If, in any of the above-mentioned conditions, a worsening of the underlying disease is diagnosed or suspected during treatment, the benefits and risks of treatment should be reassessed based on the individual case.

PROVERA contains lactose. In patients with rare hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption, the severity of the condition should be taken into careful consideration before prescribing PROVERA. The patients should be closely monitored.

In the combined estrogen plus progestin arm of the WHI trial, among 10 000 women over a one-year period, there were:

• 8 more cases of stroke (29 on combined HRT versus 21 on placebo)

  
  

• 7 more cases of CHD (37 on combined HRT versus 30 on placebo).

  
  

In the estrogen-alone arm of the WHI trial of women with prior hysterectomy, among 10 000 women over a one-year period, there were/was:

• 12 more cases of stroke (44 on estrogen-alone therapy versus 32 on placebo)

  
  

• no statistically significant difference in the rate of CHD.

Patients who have a history of mental depression should be carefully monitored while receiving therapy with PROVERA. Some patients may complain of premenstrual like depression while on PROVERA.

Detectable amounts of progestin have been identified in the milk of mothers receiving the drug. Infants exposed to medroxyprogesterone via breast milk have been studied for developmental and behavioral effects through puberty. No adverse effects have been noted.

Patients who require thyroid hormone replacement therapy and who are also taking estrogen should have their thyroid function monitored regularly to assure that thyroid hormone levels remain in an acceptable range (see Drug Interactions, Drug-Laboratory Test Interactions).

There are no available studies on the effects of orally administered medroxyprogesterone acetate (MPA) as a single agent, on bone mineral density (BMD).

However, it may be suspected that for specific medical conditions, when MPA is administered over a prolonged period of time at a dose that is high enough to suppress endogenous estrogen production e.g., pre-menopausal women), it could result in a decrease in bone mineral density (BMD). In these circumstances, adequate calcium and vitamin D intake should be considered.

The results of the Heart and Estrogen/progestin Replacement Studies (HERS and HERS II) and the Women’s Health Initiative (WHI) trial indicate that the use of estrogen plus progestin is associated with an increased risk of coronary heart disease (CHD) in postmenopausal women. The results of the WHI trial indicate that the use of estrogen-alone and estrogen plus progestin is associated with an increased risk of stroke in postmenopausal women.

Liver function tests should be done periodically in subjects who are suspected of having hepatic disease. For information on endocrine and liver function tests, see Monitoring and Laboratory Tests.

MPA is approximately 90% protein bound, primarily to albumin; no MPA binding occurs with sex hormone binding globulin.

Medroxyprogesterone acetate is rapidly absorbed from the gastrointestinal tract, and maximum concentrations are obtained between 2 to 4 hours after oral administration.

PROVERA (medroxyprogesterone acetate) is an orally-active progestational steroid (progestin) derived from a natural source (soybeans) and devoid of androgenic and estrogenic activity.

Medroxyprogesterone acetate significantly reduces the risk of endometrial hyperplasia in women with intact uteri. See Pharmacodynamics for specific information on the pharmacology of medroxyprogesterone acetate.

Medroxyprogesterone acetate has an apparent half-life of about 30 hours and is primarily eliminated via fecal excretion, to which biliary secretion may contribute. Approximately 44% of an oral dose is eliminated through urinary excretion in the form of metabolites.

The only metabolite of medroxyprogesterone acetate that has been isolated and unequivocally identified is 6α-methyl-6β,17α,21-trihydroxy-4-pregnene-3,20-dione-17-acetate, and appears to be the primary urinary metabolite. This metabolite accounts for approximately 8% of an oral dose, and is found to be excreted as a glucuronide conjugate.

There is no conclusive evidence that medroxyprogesterone acetate produces adverse coagulation changes in women receiving the progestin alone, or as part of a sequential regimen with estrogen.

Presently there are no conclusive data concerning the mechanism of action of progestins on bone.

Clinically, research to date has shown women treated with medroxyprogesterone acetate to prevent estrogenic hyperstimulation of the endometrium do not lose protection against osteoporosis.

Medroxyprogesterone acetate is metabolized in the liver to several progestin metabolites. The major drug-related material found in circulation following oral administration has been characterized as both free and glucuronide-conjugated metabolites of medroxyprogesterone acetate.

Medroxyprogesterone acetate in appropriate doses, suppresses the secretion of pituitary gonadotropins which in turn, prevents follicular maturation, producing anovulation in the pre-menopausal woman.

The anti-cancer activity of medroxyprogesterone acetate at pharmacologic doses may be dependent upon its effect on the hypothalamic/pituitary/gonadal axis, estrogen receptors and the metabolism of steroids at the tissue level.

Like progesterone, medroxyprogesterone acetate is thermogenic. At the very high dosage levels used in the treatment of certain cancers (500 mg/day or more), corticoid-like activity may be manifest.

Medroxyprogesterone acetate in appropriate doses suppresses the Leydig cell function in the male (ie, suppresses endogenous testosterone production).

Medroxyprogesterone acetate, when administered to women with adequate levels of estrogen (endogenous or exogenous), transforms a proliferative endometrium into a secretory endometrium. Withdrawal bleeding is anticipated within 7 days after stopping medroxyprogesterone acetate.

Microscopically, the secretory change is associated with glycoprotein-rich stromal cells which surround the glands and vessels and assist them in maintaining their integrity during hormonal withdrawal. The result is an orderly regression and remodelling, and preservation of the functional layer of the endometrium.

Medroxyprogesterone acetate decreases both cytoplasmic and nuclear estrogen receptors in endometrial cells. In addition, medroxyprogesterone acetate induces estradiol dehydrogenase (E₂DH) activity, the enzyme mechanism by which endometrial cells metabolize and excrete estrogens.

Oral medroxyprogesterone acetate also produces typical progestational changes in the cervical mucous (inhibits ferning) and increases the intermediate cell count in the maturation index of the vaginal epithelium.