Medroxyprogesterone
Acetate Tablets, USP

Medroxyprogesterone acetate tablets contain medroxyprogesterone acetate, which is a derivative of progesterone. It is a white to off-white, odorless crystalline powder, stable in air, melting between 200 and 210°C. It is freely soluble in chloroform, soluble in acetone and in dioxane, sparingly soluble in alcohol and in 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-, (6a)-. The structural formula is:

Each tablet for oral administration contains 2.5 mg, 5 mg or 10 mg of medroxyprogesterone acetate. Inactive ingredients: calcium stearate, corn starch, lactose, mineral oil, sorbic acid, sucrose, talc. The 2.5 mg tablet contains FD&C Yellow No. 6.

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.

The pharmacokinetics of medroxyprogesterone acetate were determined in 20 postmenopausal women following a single-dose administration of eight medroxyprogesterone acetate tablets 2.5 mg or a single administration of two medroxyprogesterone acetate tablets 10 mg under fasting conditions. In another study, the steady-state pharmacokinetics of medroxyprogesterone acetate were determined under fasting conditions in 30 postmenopausal women following daily administration of one medroxyprogesterone acetate tablet 10 mg for 7 days. In both studies, medroxyprogesterone acetate was quantitated in serum using a validated gas chromatography-mass spectrometry (GC-MS) method. Estimates of the pharmacokinetic parameters of medroxyprogesterone acetate after single and multiple doses of medroxyprogesterone acetate tablets were highly variable and are summarized in Table 1.

No formal pharmacokinetic drug-drug interaction studies have been conducted with medroxyprogesterone acetate. However, published literature indicates that coadministration of conjugated estrogens with medroxyprogesterone acetate does not affect the pharmacokinetic profile of medroxyprogesterone acetate; similarly, medroxyprogesterone acetate does not affect the pharmacokinetic profile of the conjugated or unconjugated estrogens. Literature data also indicate that concomitant administration with aminoglutethimide would significantly reduce serum concentrations of medroxyprogesterone acetate, likely by increasing the clearance of the drug.

The use of unopposed estrogen therapy has been associated with an increased risk of endometrial hyperplasia, a possible precursor of endometrial carcinoma.¹ The incidence of estrogen-associated endometrial hyperplasia and endometrial cancer was assessed in two large, long-term, randomized clinical trials. The histological results of the clinical studies indicate that the addition of medroxyprogesterone acetate to an estrogen replacement regimen for 12 to 14 days per cycle reduces the incidence of endometrial hyperplasia in women with intact uteri. The addition of a progestin to 0.625 mg conjugated estrogen has not been shown to interfere with the efficacy of 0.625 mg conjugated estrogen for its approved indications.^1–3

A 3-year, double-blind, placebo-controlled study of nonhysterectomized, postmenopausal women between the ages of 45 and 64 years were randomized to receive placebo, conjugated estrogen only, or conjugated estrogen plus cyclic medroxyprogesterone acetate. The treatment group receiving 10 mg medroxyprogesterone acetate plus 0.625 mg conjugated estrogens showed a significantly lower rate of hyperplasia in comparison to the group given 0.625 mg conjugated estrogens only. The 3-year histological results are summarized in Table 2.

In a second study, postmenopausal women between the ages of 45 and 65 years were enrolled in a 1-year, double-blind study. All patients received conjugated estrogen 0.625 mg every day of a 28-day cycle, and were randomized to receive cyclic medroxyprogesterone acetate 5 mg, cyclic medroxyprogesterone acetate 10 mg, or conjugated estrogen only. The treatment groups receiving medroxyprogesterone acetate 5 or 10 mg plus conjugated estrogens showed a significantly lower rate of hyperplasia in comparison to the group given conjugated estrogens only. The incidence of endometrial hyperplasia is shown in Table 3.

Medroxyprogesterone acetate tablets are indicated for secondary amenorrhea and for abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology, such as fibroids or uterine cancer. Medroxyprogesterone acetate tablets are also indicated to reduce the incidence of endometrial hyperplasia in nonhysterectomized postmenopausal women receiving 0.625 mg conjugated estrogen.

• Thrombophlebitis, thromboembolic disorders, cerebral apoplexy or patients with a past history of these conditions.
• Liver dysfunction or disease.
• Known or suspected malignancy of breast or genital organs.
• Undiagnosed vaginal bleeding.
• Missed abortion.
• As a diagnostic test for pregnancy.
• Known sensitivity to medroxyprogesterone acetate tablets.
• Known or suspected pregnancy.

• The physician should be alert to the earliest manifestations of thrombotic disorders (thrombophlebitis, cerebrovascular disorders, pulmonary embolism, and retinal thrombosis). Should any of these occur or be suspected, the drug should be discontinued immediately.
• Beagle dogs treated with medroxyprogesterone acetate developed mammary nodules some of which were malignant. Although nodules occasionally appeared in control animals, they were intermittent in nature, whereas the nodules in the drug-treated animals were larger, more numerous, persistent, and there were some breast malignancies with metastases. Their significance with respect to humans has not been established.
• 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, medication should be withdrawn.
• Detectable amounts of progestin have been identified in the milk of mothers receiving the drug. The effect of this on the nursing infant has not been determined.
• Usage in pregnancy is contraindicated.
• Retrospective studies of morbidity and mortality in Great Britain and studies of morbidity in the United States have shown a statistically significant association between thrombophlebitis, pulmonary embolism, and cerebral thrombosis and embolism and the use of oral contraceptives.^4–7 The estimate of the relative risk of thromboembolism in the study by Vessey and Doll⁶ was about sevenfold, while Sartwell and associates⁷ in the United States found a relative risk of 4.4, meaning that the users are several times as likely to undergo thromboembolic disease without evident cause as nonusers. The American study also indicated that the risk did not persist after discontinuation of administration, and that it was not enhanced by long continued administration. The American study was not designed to evaluate a difference between products.

• The pretreatment physical examination should include special reference to breast and pelvic organs, as well as Papanicolaou smear.
• Because progestogens 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  vaginum, nonfunctional causes should be borne in mind. In cases of undiagnosed vaginal bleeding, adequate diagnostic measures are indicated.
• Patients who have a history of psychic depression should be carefully observed and the drug discontinued if the depression recurs to a serious degree.
• Any possible influence of prolonged progestin therapy on pituitary, ovarian,  adrenal, hepatic or uterine functions awaits further study.
• Diabetic patients should be carefully observed while receiving progestin 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.
• Because of the occasional occurrence of thrombotic disorders, (thrombophlebitis, pulmonary embolism, retinal thrombosis, and cerebrovascular disorders) in patients taking estrogen-progestin combinations and since the mechanism is obscure, the physician should be alert to the earliest manifestation of these disorders.

Long-term intramuscular administration of medroxyprogesterone acetate has been shown to produce mammary tumors in beagle dogs. There was no evidence of a carcinogenic effect associated with the oral administration of medroxyprogesterone acetate tablets 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.

See Patient Information at end of insert.

The administration of any drug to nursing mothers should be done only when clearly necessary since many drugs are excreted in human milk. Detectable amounts of progestin have been identified in the milk of nursing mothers receiving progestins. The effect of this on the nursing infant has not been determined.

The safety and effectiveness of medroxyprogesterone acetate tablets in pediatric patients has not been established.

Breast tenderness or galactorrhea has been reported.

Sensitivity reactions consisting of urticaria, pruritus, edema and generalized rash have occurred. Acne, alopecia and hirsutism have been reported.

Thromboembolic phenomena including thrombophlebitis and pulmonary embolism have been reported.

The following adverse reactions have been observed in women taking progestins, including medroxyprogesterone acetate tablets:

•   breakthrough bleeding
•   spotting
•   change in menstrual flow
•   amenorrhea
•   edema
•   change in weight (increase or decrease)
•   changes in cervical erosion and cervical secretions
•   cholestatic jaundice
•   anaphylactoid reactions and anaphylaxis
•   rash (allergic) with and without pruritus
•   mental depression
•   pyrexia
•   insomnia
•   nausea
•   somnolence

Although available evidence is suggestive of an association, such a relationship has been neither confirmed nor refuted for the following serious adverse reactions: neuro-ocular lesions, eg, retinal thrombosis and optic neuritis.

The following adverse reactions have been observed in patients receiving estrogen-progestin combination drugs:

•   rise in blood pressure in susceptible individuals
•   premenstrual-like syndrome
•   changes in libido
•   changes in appetite
•   cystitis-like syndrome
    headache
    nervousness
•   fatigue
•   backache
•   hirsutism
•   loss of scalp hair
•   erythema multiforme
•   erythema nodosum 
•   hemorrhagic
    eruption
    itching
    dizziness

The following laboratory results may be altered by the use of estrogen-progestin combination drugs:

Increased sulfobromophthalein retention and other hepatic function tests.
Coagulation tests: increase in prothrombin factors VII, VIII, IX and X.
Metyrapone test.
Pregnanediol determination.

Thyroid function: increase in PBI, and butanol extractable protein bound iodine and decrease in T³ uptake values.

Medroxyprogesterone acetate tablets may be given in dosages of 5 or 10 mg daily for 5 to 10 days. A dose for inducing an optimum secretory transformation of an endometrium that has been adequately primed with either endogenous or exogenous estrogen is 10 mg of medroxyprogesterone acetate daily for 10 days. In cases of secondary amenorrhea, therapy may be started at any time. Progestin withdrawal bleeding usually occurs within three to seven days after discontinuing medroxyprogesterone acetate tablets therapy.

Beginning on the calculated 16th or 21st day of the menstrual cycle, 5 or 10 mg of medroxyprogesterone acetate may be given daily for 5 to 10 days. To produce an optimum secretory transformation of an endometrium that has been adequately primed with either endogenous or exogenous estrogen, 10 mg of medroxyprogesterone acetate daily for 10 days beginning on the 16th day of the cycle is suggested. Progestin withdrawal bleeding usually occurs within three to seven days after discontinuing therapy with medroxyprogesterone acetate tablets. Patients with a past history of recurrent episodes of abnormal uterine bleeding may benefit from planned menstrual cycling with medroxyprogesterone acetate tablets.

Medroxyprogesterone acetate tablets may be given in dosages of 5 or 10 mg daily for 12 to 14 consecutive days per month, either beginning on the 1st day of the cycle or the 16th day of the cycle.

Medroxyprogesterone acetate tablets are available in the following strengths and package sizes:

Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].

• Writing Group for the PEPI Trial: Effects of hormone replacement therapy on endometrial histology in postmenopausal women. JAMA 275:370–375, 1996.
• Woodruff JD, Pickar JH: Incidence of endometrial hyperplasia in postmenopausal women taking conjugated estrogens (Premarin) with medroxyprogesterone acetate or conjugated estrogens alone (The Menopause Study Group). Am J Obstet Gynecol 170:1213–1223, 1994.
• Speroff L, Rowan J, Symons J, et al: The comparative effect on bone density, endometrium, and lipids of continuous hormones as replacement therapy (CHART Study) JAMA 276:1397–1403, 1996.
• Royal College of General Practitioners: Oral contraception and thromboembolic disease. J Coll Gen Pract 13:267–279, 1967.
• Inman WHW, Vessey MP: Investigation of deaths from pulmonary, coronary, and cerebral thrombosis and embolism in women of child-bearing age. Br Med J 2:193–199, 1968.
• Vessey MP, Doll R: Investigation of relation between use of oral contraceptives and thromboembolic disease. A further report. Br Med J 2:651–657, 1969.
• Sartwell PE, Masi AT, Arthes FG, et al: Thromboembolism and oral contraceptives: An epidemiological case-control study. Am J Epidemiol 90:365–380, 1969.

The div of the patient insert for progesterone and progesterone-like drugs is set forth below.

Medroxyprogesterone acetate tablets contain medroxyprogesterone acetate a progesterone. The information below is that which the U.S. Food and Drug Administration requires be provided for all patients taking progesterones. The information below relates only to the risk to the unborn child associated with use of progesterone during pregnancy. For further information on the use, side effects and other risks associated with this product, ask your doctor.

WARNING FOR WOMEN

Progesterone or progesterone-like drugs have been used to prevent miscarriage in the first few months of pregnancy. No adequate evidence is available to show that they are effective for this purpose. Furthermore, most cases of early miscarriage are due to causes which could not be helped by these drugs.

There is an increased risk of minor birth defects in children whose mothers take this drug during the first 4 months of pregnancy. Several reports suggest an association between mothers who take these drugs in the first trimester of pregnancy and genital abnormalities in male and female babies. The risk to the male baby is the possibility of being born with a condition in which the opening of the penis is on the underside rather than the tip of the penis (hypospadias). Hypospadias occurs in about 5 to 8 per 1,000 male births and is about doubled with exposure to these drugs. There is not enough information to quantify the risk to exposed female fetuses, but enlargement of the clitoris and fusion of the labia may occur, although rarely.

Therefore, since drugs of this type may induce mild masculinization of the external genitalia of the female fetus, as well as hypospadias in the male fetus, it is wise to avoid using the drug during the first trimester of pregnancy.

These drugs have been used as a test for pregnancy but such use is no longer considered safe because of possible damage to a developing baby. Also, more rapid methods for testing for pregnancy are now available.

If you take medroxyprogesterone acetate tablets and later find you were pregnant when you took them, be sure to discuss this with your doctor as soon as possible.