1. Loss of Bone Mineral Density

Use of depo-subQ provera 104 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-subQ provera 104 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-subQ provera 104 is discontinued and ovarian estrogen production increases. A study to assess the reversibility of loss of BMD in adolescents is ongoing.

depo-subQ provera 104 should be used long-term (e.g., longer than 2 years) only if other methods of birth control are inadequate. BMD should be evaluated when a woman needs to use depo-subQ provera 104 long-term. In adolescents, interpretation of BMD results should take into account patient age and skeletal maturity.

Other treatments should be considered in the risk/benefit analysis for the use of depo-subQ provera 104 in women with osteoporosis risk factors. depo-subQ provera 104 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 lessen BMD loss in women using depo-subQ provera 104, all patients should have adequate calcium and Vitamin D intake.

BMD Changes in Adult Women after Long-Term Treatment for Contraception

A study comparing changes in BMD in women using depo-subQ provera 104 with women using Depo-Provera Contraceptive Injection (Depo-Provera CI, 150 mg) showed no significant differences in BMD loss between the two groups after two years of treatment. Mean percent changes in BMD in the depo-subQ provera 104 group are listed in Table 3.

Table 3. Mean Percent Change from Baseline in BMD in Women Using depo-subQ provera 104
	Lumbar Spine		Total Hip		Femoral Neck
Time on Treatment	N	Mean % Change (95% CI)	N	Mean % Change (95% CI)	N	Mean % Change (95% CI)
1 year	166	-2.7 (-3.1 to -2.3)	166	-1.7 (-2.1 to -1.3)	166	-1.9 (-2.5 to -1.4)
2 year	106	- 4.1 (-4.6 to -3.5)	106	-3.5 (-4.2 to -2.7)	106	-3.5 (-4.3 to -2.6)

In another controlled clinical study, adult women using Depo-Provera CI (150 mg) 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 4 shows the extent of recovery of BMD for women who completed 5 years of treatment.

Table 4. Mean Percent Change from Baseline in BMD in Women Using Depo-Provera CI (150 mg) or in Control Subjects
Time in Study	Lumbar Spine		Total Hip		Femoral Neck
	Depo-Provera CI (150 mg)*	Control**	Depo-Provera CI (150 mg)*	Control**	Depo-Provera CI (150 mg)*	Control**
5 years	n=33	n=105	n=21	n=65	n=34	n=106
	-5.38%	0.43%	-5.16%	0.19%	-6.12%	-0.27%
7 years	n=12	n=60	n=7	n=39	n=13	n=63
	-3.13%	0.53%	-1.34%	0.94%	-5.38	-0.11%
*The treatment group consisted of women who received Depo-Provera CI (150 mg) 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) after Long-Term Treatment for Contraception

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 (150 mg) use was associated with a significant decline in BMD from baseline (Table 5). 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 5. Mean Percent Change from Baseline in BMD in Adolescents Using Depo-Provera CI (150 mg) and in Unmatched, Untreated Control Cohort Studies
Duration of Treatment Or Observation Period	Lumbar Spine				Total Hip				FemoralNeck
	Depo-Provera CI (150 mg)		Control (Unmatched/ Untreated)		Depo-Provera CI (150 mg)		Control (Unmatched/ Untreated)		Depo-Provera CI (150 mg)		Control (Unmatched/ Untreated)
	N	Mean % change	N	Mean % change	N	Mean % change	N	Mean % change	N	Mean % change	N	Mean % change
Week 60 (1.2 yrs)	104	-2.42	171	3.47	103	-2.82	171	1.32	103	-3.05	171	1.87
Week 144 (2.8 yrs)	46	-2.78	111	5.41	45	-6.16	111	1.74	45	-6.01	111	2.54
Week 240 (4.6 yrs)	9	-4.17	70	5.12	9	-6.92	69	1.12	9	-6.06	69	1.45

BMD Chan ges in Adult Wom en after Six Mont hs of Treat ment for Endometriosis

In two clinical studies of 573 adult women with endometriosis, the BMD effects of 6 months of depo-subQ provera 104 treatment were compared to 6 months of leuprolide treatment. Subjects were then observed, off therapy, for an additional 12 months (Table 6).

Table 6. Mean Percent Change from Baseline in BMD after 6 Months on Therapy with depo-subQ provera 104 or Leuprolide and 6 and 12 Months after Stopping Therapy (Studies 268 and 270 Combined)
Time of Measurement	Lumbar Spine				Total Hip
	depo-subQ provera 104		Leuprolide		depo-subQ provera 104		Leuprolide
	N	Mean % change	N	Mean % change	N	Mean % change	N	Mean % change
Month 6 of treatment (EOT)	208	-1.20	229	-4.10	207	-0.03	227	-1.83
6 months off treatment	168	-1.06	180	-2.75	169	-0.05	181	-1.59
12 months off treatment	124	-0.54	133	-1.48	125	0.39	134	-1.15
EOT = End of Treatment

2. Bleeding Irregularities

Most women using depo-subQ provera 104 experienced changes in menstrual bleeding patterns, such as amenorrhea, irregular spotting or bleeding, prolonged spotting or bleeding, and heavy bleeding. As women continued using depo-subQ provera 104, fewer experienced irregular bleeding and more experienced amenorrhea. If abnormal bleeding is persistent or severe, appropriate investigation and treatment should be instituted.

In three contraception trials, 39.0 % of women experienced amenorrhea during month six, and 56.5% experienced amenorrhea during month 12. The changes in menstrual bleeding patterns from the three contraception trials are presented in Figures 3 and 4.

Figure 3. Percentages of depo-subQ provera 104 Treated Women with Amenorrhea per 30-Day Month in Contraception Studies (ITT Population, N=2053)

The changes in menstrual patterns in the two endometriosis trials are presented in Figures 5 and 6.

Figure 5. Percentages of depo-subQ provera 104 Treated Women with Amenorrhea per 30-Day Month in Endometriosis Studies (Combined ITT Population, N=289)

Figure 6. Mean (25th, 75th Percentiles) Number of Bleeding and/or Spotting Days in the Subgroup of Women with Bleeding and/or Spotting by Month for Women Treated with depo-subQ provera 104 in Endometriosis Studies Combined

3. Cancer Risks

Long-term, case-controlled surveillance of users of depot medroxyprogesterone acetate IM 150 mg (Depo-Provera CI, 150 mg) found slight or no increased overall risk of breast cancer and no overall increased risk of ovarian, liver, or cervical cancer, and a prolonged, protective effect of reducing the risk of endometrial cancer.

A pooled analysisii from two case-control studiesiii iv reported the relative risk (RR) of breast cancer for women who had ever used Depo-Provera CI (150 mg) 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 (150 mg). The RR of breast cancer for women of all ages who had initiated use of Depo-Provera CI (150 mg) within the previous 5 years was estimated to be 2.0 (95% CI 1.5 to 2.8). A component of the pooled analysisiii 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 (150 mg) 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 (150 mg) was only 1.21 (95% CI 0.96 to 1.52).

[NOTE: The value of 2.19 means that women whose first exposure to drug was within the previous 4 years and who were under 35 years of age had a 2.19-fold (95% CI 1.23 to 3.89-fold) increased risk of breast cancer relative to nonusers. The National Cancer Institutev 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.]

The relative rate of invasive squamous-cell cervical cancer in women who ever used Depo-Provera CI (150 mg) 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

Although MPA has not been causally associated with the induction of thrombotic or thromboembolic disorders, there have been rare reports of serious thrombotic events in women using Depo-Provera CI (150 mg). Any patient who develops thrombosis while undergoing therapy with depo-subQ provera 104 should discontinue treatment unless she has no other acceptable options for birth control (see CONTRAINDICATIONS).

5. Ocular Disorders

Medication should not be re-administered 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 re-administered.

6. Ectopic Pregnancy

Healthcare providers should be alert to the possibility of an ectopic pregnancy among women using depo-subQ provera 104 who become pregnant or complain of severe abdominal pain.

7. Anaphylaxis and Anaphylactoid Reaction

Serious anaphylactic reactions have been infrequently reported in women using Depo-Provera CI (150 mg). If an anaphylactic reaction occurs, appropriate emergency medical treatment should be instituted.

PRECAUTIONS
1. Physical Examination

It is good medical practice for all women to have annual history and physical examinations, including women using depo-subQ provera 104. The physical examination, however, may be deferred until after initiation of depo-subQ provera 104 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 Gain

Weight gain is a common occurrence in women using depo-subQ provera 104. In three large clinical trials using depo-subQ provera 104, the mean weight gain was 3.5 lb in the first year of use. In a small, two-year study comparing depo-subQ provera 104 to Depo-Provera CI (150 mg), the mean weight gain observed for women using depo-subQ provera 104 (7.5 lb) was similar to the mean weight gain for women using Depo-Provera CI, 150 mg (7.6 lb).

Although there are no data related to weight gain beyond 2 years for depo-subQ provera 104, the data on Depo-Provera CI (150 mg) may be relevant. In a clinical study, after five years, 41 women using Depo-Provera CI (150 mg) had a mean weight gain of 11.2 lb, while 114 women using non-hormonal contraception had a mean weight gain of 6.4 lb.

4. Return to Ovulation and Fertility

Return to ovulation is likely to be delayed after stopping therapy. Among 15 women who received multiple doses of depo-subQ provera 104: