| PROVERAŽ |
|Pharmacia & Upjohn |
|Medroxyprogesterone Acetate |
|Action And Clinical Pharmacology: Medroxyprogesterone, an orally active progestational steroid (progestin) derived from a natural source (soy beans), when administered to women with adequate levels of estrogen (endogenous or exogenous), transforms a proliferative endometrium into a secretory endometrium. Furthermore, the anticancer activity of medroxyprogesterone at pharmacologic doses, may be dependent on its effect on the hypothalamic/pituitary/gonadal axis, estrogen receptors and metabolism of steroids at the tissue level.
Bioavailability: In a randomized cross-over study using 22 healthy male volunteers, the bioavailability of Provera 2.5 mg and Provera 10 mg tablets was studied following 10 mg single oral doses in the following regimens: (a) four 2.5 mg tablets or; (b) one 10 mg tablet as a single dose during a fasting period which began 9 hours before and lasted until 4 hours after the dose. Treatment phases were separated by a 14 day washout period. Blood samples were collected prior to and at the following times after drug administration: 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, 72, 96 and 120 hours. The resulting serum samples were analyzed for medroxyprogesterone using a radioimmunoassay procedure.
The bioavailability of Provera 100 mg tablets was assessed in a clinical study using 16 healthy, male volunteers. A single dose of medroxyprogesterone 100 mg was administered orally to subjects who fasted overnight and for 2 hours after the dose was administered. Blood samples were collected prior to, and at the following times, after drug administration: 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 26, 32, 50, 74, 98, and 170 hours. Serum samples were analyzed for medroxyprogesterone using a radioimmunoassay procedure.
Medroxyprogesterone has an apparent half-life of about 30 hours.
Medroxyprogesterone is rapidly absorbed from the gastrointestinal tract and 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.
Medroxyprogesterone 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 that has been isolated and unequivocally identified is 6a-methyl-6b,17a,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 an glucuronide conjugate.
Indications And Clinical Uses: For hormonal replacement therapy, to oppose the effects of estrogen on the endometrium and significantly reduce the risk of hyperplasia and carcinoma.
For functional menstrual disorders due to hormonal imbalance in non-pregnant women, in the absence of organic pathology.
As adjunctive and/or palliative treatment of recurrent and/or metastatic endometrial carcinoma.
As adjunctive and/or palliative treatment of hormonally-dependent, recurrent metastatic breast cancer in post-menopausal women.
Contra-Indications: Thrombophlebitis, thromboembolic disorders, cerebral apoplexy or patients with a past history of these conditions. Known sensitivity to medroxyprogesterone, or to any of the tablet's excipients (see Supplied). Undiagnosed vaginal bleeding. Undiagnosed urinary tract bleeding. Undiagnosed breast pathology.
Pregnancy: Pregnancy (either for diagnosis or therapy) (see Warnings).
Manufacturers' Warnings In Clinical States: Liver function tests should be performed periodically in patients who have or are suspected of having hepatic disease. The physician should be alert to the earliest manifestations of impaired liver function. Should these occur or be suspected, the drug should be discontinued and the patient's status re-evaluated.
Although medroxyprogesterone has not been causally associated with the induction of thromboembolic disorders, the physician should be alert to the earliest manifestations of these disorders. Should any occur, or be suspected, while the patient is undergoing therapy with medroxyprogesterone, the drug should be discontinued immediately. The patient's status and need for treatment should be carefully assessed before continuing therapy.
Pregnancy: Usage in pregnancy is not recommended. Progestational agents are also not recommended as a diagnostic test for pregnancy. If the patient is exposed to medroxyprogesterone during pregnancy or if she becomes pregnant while taking the drug, she should be apprised of the potential risk to the fetus.
Discontinue medication pending examination, if there is 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, the drug should not be continued.
Clinical suppression of adrenocortical function has not been observed at low dose levels. However, the high doses of medroxyprogesterone 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).
Lactation: 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.
Anaphylactic and anaphylactoid reactions have occasionally been reported in patients treated with medroxyprogesterone.
Precautions: Prior to administering medroxyprogesterone, a thorough examination should be conducted with special reference to breast and pelvic organs, and include a Papanicolaou smear. This evaluation should exclude the presence of genital or breast neoplasia before considering the use of this drug. For those patients who will be receiving this drug for the treatment of endometrial or breast cancer, the caution expressed by the preceding sentence does not apply.
Because this drug may cause some degree of fluid retention, conditions which might be influenced by this factor, such as epilepsy, migraine, asthma, cardiac or renal dysfunction require careful observation.
In cases of breakthrough bleeding, as in all cases of irregular bleeding per vagina, organic causes should be considered. In cases of undiagnosed vaginal bleeding, adequate diagnostic measures are indicated.
Patients should be advised of the menstrual bleeding patterns expected with the sequential regimen (see Dosage).
Upon sequential administration of medroxyprogesterone to women with adequate levels of estrogen (endogenous or exogenous), withdrawal bleeding usually occurs within 7 days after stopping this drug. Bleeding that occurs during medroxyprogesterone administration period indicates a need for a longer duration, or a higher dose.
Patients who have a history of mental depression should be carefully monitored while receiving therapy with medroxyprogesterone. Some patients may complain of premenstrual like depression while taking this medication.
A decrease in glucose tolerance has been observed in some patients on progestins. The mechanism of this decrease is obscure. For this reason, diabetic patients should be carefully observed while receiving medroxyprogesterone therapy.
The age of the patient constitutes no absolute limiting factor although treatment with progestins may mask the onset of the climacteric.
The pathologist should be advised of progestin therapy when relevant specimens are submitted.
Aminoglutethimide administered concomitantly with medroxyprogesterone may significantly depress the bioavailability of this drug.
Rifampin can increase the metabolism of exogenously administered progestational agents. The extent to which rifampin may alter the metabolism of medroxyprogesterone remains to be determined; the possibility of an interaction should be considered.
Adverse Reactions: The following adverse reactions have been associated with the use of medroxyprogesterone: Breast: tenderness, galactorrhea.
Reproductive System: breakthrough bleeding, spotting, change in menstrual flow, amenorrhea, changes in cervical erosion and cervical secretions.
CNS: headache, nervousness, dizziness, depression, insomnia, somnolence, fatigue, premenstrual syndrome-like symptoms.
Thromboembolic Phenomena: including thrombophlebitis and pulmonary embolism.
Skin and Mucous Membranes: sensitivity reactions ranging from pruritus, urticaria, angioneurotic edema to generalized rash and anaphylaxis; acne, alopecia, hirsutism.
Gastrointestinal: abdominal discomfort, nausea, bloating.
Miscellaneous: pyrexia, increase in weight, peripheral edema, "moon" facies.
The following laboratoy tests may be affected by the use of medroxyprogesterone: 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, metyrapone test.
Symptoms And Treatment Of Overdose: Symptoms: 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.
Treatment: There is no known therapy for overdosage of medroxyprogesterone. Doses as high as 1 000 mg for the therapy of endometrial carcinoma have been used without adverse effect.
Dosage And Administration: Hormone Replacement Therapy: Progestin Challenge Test: Subsequent to the diagnosis of menopause, the progestin challenge test is recommended for amenorrheic women with an intact uterus. Medroxyprogesterone 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. In these women, hormone replacement therapy consisting of estrogen therapy, and concurrent medroxyprogesterone, should be considered.
A positive test is indicated by the presence of withdrawal bleeding which occurs within 7 days after stopping medroxyprogesterone treatment. Withdrawal bleeding implies the presence of sufficient endogenous estrogen to stimulate the endometrium. Medroxyprogesterone therapy should be administered, as above, until withdrawal bleeding no longer occurs. This cessation of withdrawal bleeding indicates the absence of endometrial stimulation due to a decline in estrogen secretion. In these women, hormone replacement therapy consisting of estrogen therapy, and concurrent medroxyprogesterone should be considered.
In women with an intact uterus receiving estrogen replacement therapy, medroxyprogesterone may be given in a dosage of 5 to 10 mg daily for 12 to 14 days. The recommended starting dose should be 10 mg/day, administered for 12 to 14 days. A dose of 5 mg/day for 12 to 14 days may be appropriate for some women.
Note: The lowest dose required to protect the endometrium from estrogenic-hyperstimulation should be used. A good indicator is the lowest dose that will consistently result in withdrawal bleeding within 7 days after stopping medroxyprogesterone treatment. Bleeding that occurs during treatment indicates a need for a longer duration, or higher dose.
Functional Menstrual Disorders: Secondary Amenorrhea: After ruling out pregnancy, medroxyprogesterone may be administered in doses ranging from 5 to 10 mg daily depending upon the degree of progestational effect desired. The dose should be given daily for 12 to 14 days every month.
Note: In patients with poorly developed endometria, conventional estrogen therapy should be given in conjunction with medroxyprogesterone.
Dysfunctional Uterine Bleeding: In dysfunctional uterine bleeding, medroxyprogesterone may be given in doses ranging from 5 to 10 mg/day, for 10 to 14 days, beginning on the assumed or calculated 12th to 16th 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 medroxyprogesterone. 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.
Endometrial Cancer: 200 to 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.
Breast Cancer: 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 2 400 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.
Medroxyprogesterone 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 medroxyprogesterone.
Availability And Storage: Provera Pak: 5 mg: Each blue tablet embossed "U 286" contains: medroxyprogesterone acetate 5 mg. Nonmedicinal ingredients: cornstarch, FD&C, lactose, starch and sucrose. Blisters of 14, cartons of 10.
10 mg: Each white tablet embossed "Upjohn 50" contains: medroxyprogesterone acetate 10 mg. Nonmedicinal ingredients: cornstarch, FD&C, lactose, starch and sucrose. Blisters of 10, cartons of 10.
Tablets: 2.5 mg: Each orange, round compressed tablet embossed "U 64", contains: medroxyprogesterone acetate 2.5 mg. Nonmedicinal ingredients: calcium stearate, cornstarch, FD&C Yellow #6, lactose, mineral oil, sucrose and talc. Gluten-free. Bottles of 100 and 500. Blisters of 30, cartons of 3.
5 mg: Each blue, round, scored, compressed tablet embossed "U 286", contains: medroxyprogesterone acetate 5 mg. Nonmedicinal ingredients: calcium stearate, cornstarch, FD&C Blue #2, lactose, mineral oil, sucrose and talc. Gluten-free. Bottles of 100 and 500.
10 mg: Each white, round, scored, compressed tablet, embossed "Upjohn 50", contains: medroxyprogesterone acetate 10 mg. Nonmedicinal ingredients: calcium stearate, cornstarch, lactose, mineral oil, sucrose and talc. Gluten-free. Bottles of 100 and 500.
100 mg: Each white, round, scored, compressed tablet embossed "U 467", contains: medroxyprogesterone acetate 100 mg. Nonmedicinal ingredients: calcium stearate, cornstarch, lactose, mineral oil, sodium laurylsulfate, sucrose and talc. Gluten-free. Bottles of 100.
Store at controlled room temperature (15 to 30°C).
(Shown in Product Recognition Section)