1. Loss of Bone Mineral Density

Use of Depo-Provera CI 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 Depo-Provera CI 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 Depo-Provera CI is discontinued and ovarian estrogen production increases. A study to assess the reversibility of loss of BMD in adolescents is ongoing.

Depo-Provera CI 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 evaluated 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.

BMD Changes in Adult Women

In a controlled, clinical study, adult women using Depo-Provera CI 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 Depo-Provera CI (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.

Table 2. Mean Percent Change from Baseline in BMD in Adults by Skeletal Site and Cohort

Time in Study	Spine		Total Hip		Femoral Neck
	Depo-Provera*	Control**	Depo-Provera*	Control**	Depo-Provera*	Control**
5 years	n=33 -5.38%	n=105 0.43%	n=21 -5.16%	n=65 0.19%	n=34 -6.12%	n=106 -0.27%
7 years	n=12 -3.13%	n=60 0.53%	n=7 -1.34%	n=39 0.94%	n=13 -5.38%	n=63 -0.11%
*The treatment group consisted of women who received Depo-Provera Contraceptive Injection for 5 years and were then followed for 2 years post-use. **The control group consisted of women who did not use hormonal contraception and were followed for 7 years.

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 Depo-Provera CI 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.

Table 3. Mean Percent Change from Baseline in BMD in Adolescents by Skeletal Site and Cohort

Duration of Treatment		Depo-Provera CI (150 mg IM)		Unmatched, Untreated Cohort
	N	Mean % Change	N	Mean % Change
Total Hip BMD
Week 60 (1.2 years)	103	-2.82	171	1.32
Week 144 (2.8 years)	45	-6.16	111	1.74
Week 240 (4.6 years)	9	-6.92	69	1.12
Femoral Neck BMD
Week 60	103	-3.05	171	1.87
Week 144	45	-6.01	111	2.54
Week 240	9	-6.06	69	1.45
Lumbar Spine BMD
Week 60	104	-2.42	171	3.47
Week 144	46	-2.78	111	5.41
Week 240	9	-4.17	70	5.12

2. Bleeding Irregularities

Most women using DEPO-PROVERA CI 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 DEPO-PROVERA CI, 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 DEPO-PROVERA CI.²

3. Cancer Risks

Long-term case-controlled surveillance of users of DEPO-PROVERA CI found slight or no increased overall risk of breast cancer³ and no overall increased risk of ovarian,⁴ liver,⁵ 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 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 Study³, a component of the pooled analysis¹⁴ 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 only 1.2 (95% CI 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% CI 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% CI 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 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.

4. Thromboembolic Disorders

The physician should be alert to the earliest manifestations of thrombotic disorders (thrombophlebitis, pulmonary embolism, cerebrovascular disorders, and retinal thrombosis). Should any of these occur or be suspected, the drug should not be readministered.

5. Ocular Disorders

Medication should not be readministered 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. If examination reveals papilledema or retinal vascular lesions, medication should not be readministered.

6. Unexpected Pregnancies

To ensure that DEPO-PROVERA CI is not administered inadvertently to a pregnant woman, the first injection must 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 (see DOSAGE AND ADMINISTRATION).

Neonates from unexpected pregnancies that occur 1 to 2 months after injection of DEPO-PROVERA CI may be at an increased risk of low birth weight, which, in turn, is associated with an increased risk of neonatal death. The attributable risk is low because such pregnancies are uncommon.^9,10

A significant increase in incidence of polysyndactyly and chromosomal anomalies was observed among infants of users of DEPO-PROVERA CI, the former being most pronounced in women under 30 years of age. The unrelated nature of these defects, the lack of confirmation from other studies, the distant preconceptual exposure to DEPO-PROVERA CI, and the chance effects due to multiple statistical comparisons, make a causal association unlikely.¹¹

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.

Several reports suggest an association between intrauterine exposure to progestational drugs in the first trimester of pregnancy and genital abnormalities in male and female fetuses. The risk of hypospadias (five to eight per 1,000 male births in the general population) may be approximately doubled with exposure to these drugs. There are insufficient data to quantify the risk to exposed female fetuses, but because some of these drugs induce mild virilization of the external genitalia of the female fetus and because of the increased association of hypospadias in the male fetus, it is prudent to avoid the use of these drugs during the first trimester of pregnancy.

To ensure that DEPO-PROVERA CI is not administered inadvertently to a pregnant woman, it is important that the first injection be given only during the first 5 days after the onset of a normal menstrual period within 5 days postpartum if not breast-feeding and if breast-feeding, at the sixth week postpartum (see DOSAGE AND ADMINISTRATION).

7. Ectopic Pregnancy

Health-care providers should be alert to the possibility of an ectopic pregnancy among women using DEPO-PROVERA CI who become pregnant or complain of severe abdominal pain.

8. Lactation

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.

9. Anaphylaxis and Anaphylactoid Reaction

Anaphylaxis and anaphylactoid reaction have been reported with the use of DEPO-PROVERA CI. If an anaphylactic reaction occurs appropriate therapy should be instituted. Serious anaphylactic reactions require emergency medical treatment.

General

1. Physical Examination

It is good medical practice for all women to have annual history and physical examinations, including women using DEPO-PROVERA CI. The physical examination, however, may be deferred until after initiation of DEPO PROVERA CI if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology and relevant laboratory tests. In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care.

2. Fluid Retention

Because progestational drugs may cause some degree of fluid retention, conditions that might be influenced by this condition, such as epilepsy, migraine, asthma, and cardiac or renal dysfunction, require careful observation.

3. Weight Changes

There is a tendency for women 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.

4. Return of Fertility

DEPO-PROVERA CI has a prolonged contraceptive effect. In a large US study of women who discontinued use of DEPO-PROVERA CI to become pregnant, data are available for 61% of them. 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. CNS Disorders and Convulsions

Patients who have a history of psychic depression should be carefully observed and the drug not be readministered if the depression recurs.

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.

6. Carbohydrate Metabolism

A decrease in glucose tolerance has been observed in some patients on DEPO-PROVERA CI treatment. The mechanism of this decrease is obscure. For this reason, diabetic patients should be carefully observed while receiving such therapy.

7. Liver Function

If jaundice develops, consideration should be given to not readministering the drug.

8. Protection Against Sexually Transmitted Diseases

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

Laboratory Test Interactions

The pathologist should be advised of progestin therapy when relevant specimens are submitted.

The following laboratory tests may be affected by progestins including DEPO-PROVERA CI:

(a)     Plasma and urinary steroid levels are decreased (eg, progesterone, estradiol, pregnanediol, testosterone, cortisol).
(b)     Gonadotropin levels are decreased.
(c)     Sex-hormone-binding-globulin concentrations are decreased.
(d)     Protein-bound iodine and butanol extractable protein-bound iodine may increase. T₃-uptake values may decrease.
(e)     Coagulation test values for prothrombin (Factor II), and Factors VII, VIII, IX, and X may increase.
(f)      Sulfobromophthalein and other liver function test values may be increased.
(g)     The effects of medroxyprogesterone acetate on lipid metabolism are inconsistent. Both increases and decreases in total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol have been observed in studies.

Carcinogenesis

See “WARNINGS” section 3.

Pregnancy

Pregnancy Category X. See “WARNINGS” section 6.

Nursing Mothers

See “WARNINGS” section 8.

Pediatric Use

Depo-Provera CI is not indicated before menarche. Use of Depo-Provera CI is associated with significant loss of BMD. This loss of BMD is of particular concern during adolescence and early adulthood, a critical period of bone accretion. In adolescents, interpretation of BMD results should take into account patient age and skeletal maturity. It is unknown if use of Depo-Provera CI by younger women will reduce peak bone mass and increase the risk of osteoporotic fractures in later life. Other than concerns about loss of BMD, the safety and effectiveness are expected to be the same for postmenarchal adolescents and adult women.

Information for Patients

See Patient Labeling.

Patient labeling is included with each single-dose vial and prefilled syringe of DEPO-PROVERA CI to help describe its characteristics to the patient. It is recommended that prospective users be given this labeling and be informed about the risks and benefits associated with the use of DEPO-PROVERA CI, as compared with other forms of contraception or with no contraception at all. It is recommended that physicians or other health-care providers responsible for those patients advise them at the beginning of treatment that their menstrual cycle may be disrupted and that irregular and unpredictable bleeding or spotting results, and that this usually decreases to the point of amenorrhea as treatment with DEPO-PROVERA CI continues, without other therapy being required.

REFERENCES

2. Schwallie PC, Assenzo JR. Contraceptive use-efficacy study utilizing medroxyprogesterone acetate administered as an intramuscular injection once every 90 days. Fertil Steril. 1973; 24:331-339.

3. WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Breast cancer and depot-medroxyprogesterone acetate: a multi-national study. Lancet. 1991; 338:833-838.

4. WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Depot-medroxyprogesterone acetate (DMPA) and risk of epithelial ovarian cancer. Int J Cancer. 1991; 49:191-195.

5. WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Depot-medroxyprogesterone acetate (DMPA) and risk of liver cancer. Int J Cancer. 1991; 49:182185.

6. WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Depot-medroxyprogesterone acetate (DMPA) and risk of invasive squamous-cell cervical cancer. Contraception. 1992; 45:299-312.

7. WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Depot-medroxyprogesterone acetate (DMPA) and risk of endometrial cancer. Int J Cancer. 1991; 49:186-190.

8. Surveillance, Epidemiology, and End Results: Incidence and Mortality Data, 1973-1977. National Cancer Institute Monograph, 57: June 1981. (NIH publication No. 81-2330).

9. Gray RH, Pardthaisong T. In Utero exposure to steroid contraceptives and survival during infancy. Am J Epidemiol. 1991; 134:804-811.

10. Pardthaisong T, Gray RH. In Utero exposure to steroid contraceptives and outcome of pregnancy. Am J Epidemiol. 1991; 134:795-803.

11. Pardthaisong T, Gray RH, McDaniel EB, Chandacham A. Steroid contraceptive use and pregnancy outcome. Teratology. 1988; 38:51-58.

12. Van Deijk WA, Biljham GH, Mellink WAM, Meulenberg PMM. Influence of aminoglutethimide on plasma levels of medroxyprogesterone acetate: its correlation with serum cortisol. Cancer Treatment Reports. 1985; 69:1, 85-90.

13. Paul C, Skegg DCG, Spears GFS. Depot medroxyprogesterone (Depo-Provera) and risk of breast cancer. Br Med J. 1989; 299:759-762.

14. Skegg DCG, Noonan EA, Paul C, Spears GFS, Meirik O, Thomas DB. Depot Medroxyprogesterone Acetate and Breast Cancer: A Pooled Analysis from the World Health Organization and New Zealand Studies. JAMA. 1995; 273(10):799-804.