Package Insert

Rx only

Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

DESCRIPTION

Medroxyprogesterone acetate injectable suspension, a contraceptive injection, 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-, (6α)-. he structural formula is as follows:

Medroxyprogesterone acetate injectable suspension, USP for intramuscular (IM) injection is available in vials and prefilled syringes, each containing 1 mL of medroxyprogesterone acetate sterile aqueous suspension 150 mg/mL.

Each mL contains:

When necessary, pH is adjusted with sodium hydroxide or hydrochloric acid, or both.

CLINICAL PHARMACOLOGY

Medroxyprogesterone acetate injectable suspension, when administered at the recommended dose to women every 3 months, inhibits the secretion of gonadotropins which, in turn, prevents follicular maturation and ovulation and results in endometrial thinning. These actions produce its contraceptive effect.

Following a single 150 mg IM dose of medroxyprogesterone acetate injectable suspension, medroxyprogesterone acetate concentrations, measured by an extracted radioimmunoassay procedure, increase for approximately 3 weeks to reach peak plasma concentrations of 1 to 7 ng/mL. The levels then decrease exponentially until they become undetectable (<100 pg/mL) between 120 to 200 days following injection. Using an unextracted radioimmunoassay procedure for the assay of medroxyprogesterone acetate in serum, the apparent half-life for medroxyprogesterone acetate following IM administration of medroxyprogesterone acetate injectable suspension is approximately 50 days.

Women with lower body weights conceive sooner than women with higher body weights after discontinuing medroxyprogesterone acetate injectable suspension.

The effect of hepatic and/or renal disease on the pharmacokinetics of medroxyprogesterone acetate injectable suspension is unknown.

INDICATIONS AND USAGE

Medroxyprogesterone acetate injectable suspension is indicated only for the prevention of pregnancy. The loss of bone mineral density (BMD) in women of all ages and the impact on peak bone mass in adolescents should be considered, along with the decrease in BMD that occurs during pregnancy and/or lactation, in the risk/benefit assessment for women who use medroxyprogesterone acetate injectable suspension long-term (see WARNINGS.) It is a long-term injectable contraceptive in women when administered at 3-month (13-week) intervals. Dosage does not need to be adjusted for body weight.

In five clinical studies using medroxyprogesterone acetate injectable suspension, the 12-month failure rate for the group of women treated with medroxyprogesterone acetate injectable suspension was zero (no pregnancies reported) to 0.7 by Life-Table method. Pregnancy rates with contraceptive measures are typically reported for only the first year of use as shown in Table 1. Except for intrauterine devices (IUD), implants, sterilization, and medroxyprogesterone acetate injectable suspension, the efficacy of these contraceptive measures depends in part on the reliability of use. The effectiveness of medroxyprogesterone acetate injectable suspension is dependent on the patient returning every 3 months (13 weeks) for reinjection.

CONTRAINDICATIONS

1. Known or suspected pregnancy or as a diagnostic test for pregnancy.
2. Undiagnosed vaginal bleeding.
3. Known or suspected malignancy of breast.
4. Active thrombophlebitis, or current or past history of thromboembolic disorders, or cerebral vascular disease.
5. Significant liver disease.
6. Known hypersensitivity to medroxyprogesterone acetate injectable suspension (medroxyprogesterone acetate or any of its other ingredients).

WARNINGS

1. Loss of Bone Mineral Density

Use of medroxyprogesterone acetate injectable suspension reduces serum estrogen levels and is associated with significant loss of bone mineral density (BMD) as bone metabolism accommodates to a lower estrogen level. This loss of BMD is of particular concern during adolescence and early adulthood, a critical period of bone accretion. It is unknown if use of medroxyprogesterone acetate injectable suspension by younger women will reduce peak bone mass and increase the risk for osteoporotic fracture in later life. In both adults and adolescents, the decrease in BMD appears to be at least partially reversible after medroxyprogesterone acetate injectable suspension is discontinued and ovarian estrogen production increases. A study to assess the reversibility of loss of BMD in adolescents is ongoing.

Medroxyprogesterone acetate injectable suspension should be used as a long-term birth control method (e.g. longer than 2 years) only if other birth control methods are inadequate. BMD should be eva luated when a woman needs to continue to use medroxyprogesterone acetate injectable suspension long term. In adolescents, interpretation of BMD results should take into account patient age and skeletal maturity.

Other birth control methods should be considered in the risk/benefit analysis for the use of medroxyprogesterone acetate injectable suspension in women with osteoporosis risk factors. Medroxyprogesterone acetate injectable suspension can pose an additional risk in patients with risk factors for osteoporosis (e.g., metabolic bone disease, chronic alcohol and/or tobacco use, anorexia nervosa, strong family history of osteoporosis or chronic use of drugs that can reduce bone mass such as anticonvulsants or corticosteroids). Although there are no studies addressing whether calcium and Vitamin D may lessen BMD loss in women using medroxyprogesterone acetate injectable suspension, all patients should have adequate calcium and Vitamin D intake.

BMD Changes in Adult Women

In a controlled, clinical study, adult women using medroxyprogesterone acetate injectable suspension for up to 5 years showed spine and hip BMD mean 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%, -4.93% 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 injectable suspension (150 mg), there was partial recovery of BMD toward baseline values during the 2 year post-therapy period. Longer duration of treatment was associated with less complete recovery during this 2 year period following the last injection. Table 2 shows the extent of recovery of BMD for women who completed 5 years of treatment.

BMD Changes in Adolescent Females (12-18 years of age)

Preliminary results from an ongoing, open-label, self-selected, non-randomized clinical study of adolescent females (12-18 years) also showed that medroxyprogesterone acetate injectable suspension use was associated with a significant decline in BMD from baseline (Table 3). In general, adolescents increase bone density during the period of growth following menarche, as seen in the untreated cohort. However, the two cohorts were not matched at baseline for age, gynecologic age, race, BMD and other factors that influence the rate of acquisition of bone mineral density, with the result that they differed with respect to these demographic factors.

Preliminary data from the small number of adolescents participating in the 2 year post-use observation period demonstrated partial recovery of BMD.

2. Bleeding Irregularities

Most women using medroxyprogesterone acetate injectable suspension experience disruption of menstrual bleeding patterns. Altered menstrual bleeding patterns include irregular or unpredictable bleeding or spotting, or rarely, heavy or continuous bleeding. If abnormal bleeding persists or is severe, appropriate investigation should be instituted to rule out the possibility of organic pathology, and appropriate treatment should be instituted when necessary.

As women continue using medroxyprogesterone acetate injectable suspension, fewer experience irregular bleeding and more experience amenorrhea. By month 12 amenorrhea was reported by 55% of women, and by month 24 amenorrhea was reported by 68% of women using medroxyprogesterone acetate injectable suspension2.

3. Cancer Risks

Long-term case-controlled surveillance of users of medroxyprogesterone acetate injectable suspension found slight or no increased overall risk of breast cance3 and no overall increased risk of ovarian4, liver5, or cervical6 cancer and a prolonged, protective effect of reducing the risk of endometrial7 cancer in the population of users.

A pooled analysis14 from two case-control studies, the World Health Organization Study3 and the New Zealand Study13, reported the relative risk (RR) of breast cancer for women who had ever used medroxyprogesterone acetate injectable suspension as 1.1 (95% confidence interval (Cl) 0.97 to 1.4). Overall, there was no increase in risk with increasing duration of use of medroxyprogesterone acetate injectable suspension. The RR of breast cancer for women of all ages who had initiated use of medroxyprogesterone acetate injectable suspension within the previous 5 years was estimated to be 2.0 (95% Cl 1.5 to 2.8).

The World Health Organization Study3, a component of the pooled analysis14 described above, showed an increased RR of 2.19 (95% Cl 1.23 to 3.89) of breast cancer associated with use of medroxyprogesterone acetate injectable suspension in women whose first exposure to drug was within the previous 4 years and who were under 35 years of age. However, the overall RR for ever-users of medroxyprogesterone acetate injectable suspension was only 1.2 (95% Cl 0.96 to 1.52).

[NOTE: A RR of 1.0 indicates neither an increased nor a decreased risk of cancer associated with the use of the drug, relative to no use of the drug. In the case of the subpopulation with a RR of 2.19, the 95% Cl is fairly wide and does not include the value of 1.0, thus inferring an increased risk of breast cancer in the defined subgroup relative to nonusers. The value of 2.19 means that women whose first exposure to drug was within the previous 4 years and who are under 35 years of age have a 2.19 fold (95% Cl 1.23 to 3.89-fold) increased risk of breast cancer relative to nonusers. The National Cancer Institute8 reports an average annual incidence rate for breast cancer for US women, all races, age 30 to 34 years of 26.7 per 100,000. A RR of 2.19, thus, increases the possible risk from 26.7 to 58.5 cases per 100,000 women. The attributable risk, thus, is 31.8 per 100,000 women per year.]

A statistically insignificant increase in RR estimates of invasive squamous-cell cervical cancer has bee