1INDICATIONS AND USAGE

Depo-Provera CI 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 Depo-Provera CI long-term [see Warnings and Precautions (5.1)].

2 DOSAGE AND ADMINISTRATION

2.1Prevention of Pregnancy

Both the 1 mL vial and the 1 mL prefilled syringe of Depo-Provera CI should be vigorously shaken just before use to ensure that the dose being administered represents a uniform suspension.

The recommended dose is 150 mg of Depo-Provera CI every 3 months (13 weeks) administered by deep IM injection in the gluteal or deltoid muscle. Depo-Provera CI should not be used as a long-term birth control method (i.e. longer than 2 years) unless other birth control methods are considered inadequate. Dosage does not need to be adjusted for body weight [See Clinical Studies (14.1)].

To ensure the patient is not pregnant at the time of the first injection, the first injection should be given ONLY during the first 5 days of a normal menstrual period; ONLY within the first 5-days postpartum if not breast-feeding; and if exclusively breast-feeding, ONLY at the sixth postpartum week. If the time interval between injections is greater than 13 weeks, the physician should determine that the patient is not pregnant before administering the drug. The efficacy of Depo-Provera CI depends on adherence to the dosage schedule of administration.

2.2 Switching from other Methods of Contraception

When switching from other contraceptive methods, Depo-Provera CI should be given in a manner that ensures continuous contraceptive coverage based upon the mechanism of action of both methods, (e.g., patients switching from oral contraceptives should have their first injection of Depo-Provera CI on the day after the last active tablet or at the latest, on the day following the final inactive tablet).

3DOSAGE FORMS AND STRENGTHS

Sterile Aqueous suspension: 150mg/ml
Prefilled syringes are available packaged with 22-gauge × 1 1/2 inch BD SafetyGlide™ Needles.

4CONTRAINDICATIONS

The use of Depo-Provera CI is contraindicated in the following conditions:

• Known or suspected pregnancy or as a diagnostic test for pregnancy.
• Active thrombophlebitis, or current or past history of thromboembolic disorders, or cerebral vascular disease [see Warnings and Precautions (5.2)].
• Known or suspected malignancy of breast [see Warnings and Precautions (5.3)].
• Known hypersensitivity to Depo-Provera CI (medroxyprogesterone acetate) or any of its other ingredients [see Warnings and Precautions (5.5)].
• Significant liver disease [see Warnings and Precautions (5.6)].
• Undiagnosed vaginal bleeding [see Warnings and Precautions (5.9)].

5WARNINGS AND PRECAUTIONS

5.1Loss of Bone Mineral Density

Use of Depo-Provera CI reduces serum estrogen levels and is associated with significant loss of bone mineral density (BMD). 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 Depo-Provera CI by younger women will reduce peak bone mass and increase the risk for osteoporotic fracture in later life.

After discontinuing Depo-Provera CI in adolescents, mean BMD loss at total hip and femoral neck did not fully recover by 60 months (240 weeks) post-treatment [see Clinical Studies (14.3)]. Similarly, in adults, there was only partial recovery of mean BMD at total hip, femoral neck and lumbar spine towards baseline by 24 months post-treatment. [See Clinical Studies (14.2).]

Depo-Provera CI should not be used as a long-term birth control method (i.e., longer than 2 years) unless other birth control methods are considered inadequate. BMD should be eva luated when a woman needs to continue to use Depo-Provera CI 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 Depo-Provera CI in women with osteoporosis risk factors. Depo-Provera CI 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 Depo-Provera CI, all patients should have adequate calcium and Vitamin D intake.

5.2 Thromboembolic Disorders

There have been reports of serious thrombotic events in women using Depo-Provera CI (150 mg). However, Depo-Provera CI has not been causally associated with the induction of thrombotic or thromboembolic disorders. Any patient who develops thrombosis while undergoing therapy with Depo-Provera CI should discontinue treatment unless she has no other acceptable options for birth control.

Do not readminister Depo-Provera CI 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. Do not readminister if examination reveals papilledema or retinal vascular lesions.

5.3 Cancer Risks

Breast Cancer

Women who currently have or have had breast cancer should not use hormone contraceptives, including Depo-Provera CI, because breast cancer may be hormonally sensitive. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care.

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

The World Health Organization Study, a component of the pooled analysis described above, showed an increased RR of 2.19 (95% CI 1.23 to 3.89) of breast cancer associated with use of Depo-Provera CI 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 Depo-Provera CI was 1.2 (95% CI 0.96 to 1.52).

The National Cancer Institute reports an average annual incidence rate for breast cancer for US women, all races, age 15 to 34 years of 8.7 per 100,000. A RR of 2.19, thus, increases the possible risk from 8.7 to 19.0 cases per 100,000 women.

Cervical Cancer

A statistically nonsignificant increase in RR estimates of invasive squamous-cell cervical cancer has been associated with the use of Depo-Provera CI in women who were first exposed before the age of 35 years (RR 1.22 to 1.28 and 95% CI 0.93 to 1.70). The overall, nonsignificant relative rate of invasive squamous-cell cervical cancer in women who ever used Depo-Provera CI was estimated to be 1.11 (95% CI 0.96 to 1.29). No trends in risk with duration of use or times since initial or most recent exposure were observed.

Other Cancers

Long-term case-controlled surveillance of users of Depo-Provera CI found no overall increased risk of ovarian or liver cancer.

5.4 Ectopic Pregnancy

Be alert to the possibility of an ectopic pregnancy among women using Depo-Provera CI who become pregnant or complain of severe abdominal pain.

5.5 Anaphylaxis and Anaphylactoid Reaction

Anaphylaxis and anaphylactoid reaction have been reported with the use of Depo-Provera CI. Institute emergency medical treatment if an anaphylactic reaction occurs.

5.6 Liver Function

Discontinue Depo-Provera CI use if jaundice or acute or chronic disturbances of liver function develop. Do not resume use until markers of liver function return to normal and Depo-Provera CI causation has been excluded.

5.7 Convulsions

There have been a few reported cases of convulsions in patients who were treated with Depo-Provera CI. Association with drug use or pre-existing conditions is not clear.

5.8 Depression

Monitor patients who have a history of depression and do not readminister Depo-Provera CI if depression recurs.

5.9 Bleeding Irregularities

Most women using Depo-Provera CI experience disruption of menstrual bleeding patterns. Altered menstrual bleeding patterns include amenorrhea, irregular or unpredictable bleeding or spotting, prolonged spotting or bleeding, and heavy bleeding. Rule out the possibility of organic pathology if abnormal bleeding persists or is severe, and institute appropriate treatment.

As women continue using Depo-Provera CI, fewer experience irregular bleeding and more experience amenorrhea. In clinical studies of Depo-Provera CI, by month 12 amenorrhea was reported by 55% of women, and by month 24, amenorrhea was reported by 68% of women using Depo-Provera CI.

5.10Weight Gain

Women tend to gain weight while on therapy with Depo-Provera CI. From an initial average body weight of 136 lb, women who completed 1 year of therapy with Depo-Provera CI gained an average of 5.4 lb. Women who completed 2 years of therapy gained an average of 8.1 lb. Women who completed 4 years gained an average of 13.8 lb. Women who completed 6 years gained an average of 16.5 lb. Two percent of women withdrew from a large-scale clinical trial because of excessive weight gain.

5.11Carbohydrate Metabolism

A decrease in glucose tolerance has been observed in some patients on Depo-Provera CI treatment. Monitor diabetic patients carefully while receiving Depo-Provera CI.

5.12Lactation

Detectable amounts of drug have been identified in the milk of mothers receiving Depo-Provera CI. In nursing mothers treated with Depo-Provera CI, milk composition, quality, and amount are not adversely affected. Neonates and infants exposed to medroxyprogesterone from breast milk have been studied for developmental and behavioral effects through puberty. No adverse effects have been noted.

5.13Fluid Retention

Because progestational drugs including Depo-Provera CI may cause some degree of fluid retention, monitor patients with conditions that might be influenced by this condition, such as epilepsy, migraine, asthma, and cardiac or renal dysfunction.

5.14Return of Fertility

Return to ovulation and fertility is likely to be delayed after stopping Depo-Provera CI. In a large US study of women who discontinued use of Depo-Provera CI to become pregnant, data are available for 61% of them. Of the 188 women who discontinued the study to become pregnant, 114 became pregnant. Based on Life-Table analysis of these data, it is expected that 68% of women who do become pregnant may conceive within 12 months, 83% may conceive within 15 months, and 93% may conceive within 18 months from the last injection. The median time to conception for those who do conceive is 10 months following the last injection with a range of 4 to 31 months, and is unrelated to the duration of use. No data are available for 39% of the patients who discontinued Depo-Provera CI to become pregnant and who were lost to follow-up or changed their mind.

5.15Sexually Transmitted Diseases

Patients should be counseled that Depo-Provera CI does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

5.16Pregnancy

Although Depo-Provera CI should not be used during pregnancy, there appears to be little or no increased risk of birth defects in women who have inadvertently been exposed to medroxyprogesterone acetate injections in early pregnancy. Neonates exposed to medroxyprogesterone acetate in-utero and followed to adolescence showed no evidence of any adverse effects on their health including their physical, intellectual, sexual or social development.

5.17Monitoring

A woman who is taking hormonal contraceptive should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated healthcare.

5.18Interference with Laboratory Tests

The use of Depo-Provera CI may change the results of some laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins. [See Drug Interactions (7.3)].

6ADVERSE REACTIONS

The following important adverse reactions observed with the use of Depo-Provera CI are discussed in greater detail in the Warnings and Precautions section (5):

• Loss of Bone Mineral Density [see Warnings and Precautions (5.1)]
• Thromboembolic disease [see Warnings and Precautions (5.2)]
• Breast Cancer [see Warnings and Precautions (5.3)]
• Anaphylaxis and Anaphylactoid Reactions [see Warnings and Precautions (5.5)]
• Bleeding Irregularities[see Warnings and Precautions (5.9)]
• Weight Gain [see Warnings and Precautions (5.10)]

6.1Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In the two pivotal clinical trials with Depo-Provera CI, over 3,900 women, who were treated for up to 7 years, reported the following adverse reactions, which may or may not be related to the use of Depo-Provera CI. The population studied ranges in age from 15 to 51 years, of which 46% were White, 50% Non-White, and 4.9% Unknown race. The patients received 150 mg Depo-Provera CI every 3-months (90 days). The median study duration was 13 months with a range of 1–84 months. Fifty eight percent of patients remained in the study after 13 months and 34% after 24 months.