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DEPO-subQ PROVERA 104® (medroxyprogesterone acetate) Warnings and Precautions

WARNINGS

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). 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.

A study to assess the reversibility of loss of BMD in adolescents was conducted with Depo-Provera CI (150 mg medroxyprogesterone acetate IM, DMPA). 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. 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.

depo-subQ provera 104 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 evaluated when a woman needs to continue to use depo-subQ provera 104 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-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
Time on Treatment Lumbar Spine Total Hip Femoral Neck
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 change in BMD in women after 5 years of treatment with Depo-Provera CI and in women in a control group, as well as the extent of recovery of BMD for the subset of the women for whom 2-year post treatment data were available.

Table 4. Mean Percent Change from Baseline in BMD in Adults by Skeletal Site and Cohort (5 Years of Treatment and 2 Years of Follow-Up)
Time in Study Spine Total Hip Femoral Neck
Depo-Provera * Control Depo-Provera * Control Depo-Provera * Control
*
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 (total time in study of 7 years).
The control group consisted of women who did not use hormonal contraception and were followed for 7 years.
5 years -5.38% n=33 0.43% n=105 -5.16% n=21 0.19% n=65 -6.12% n=34 -0.27% n=106
7 years -3.13% n=12 0.53% n=60 -1.34% n=7 0.94% n=39 -5.38% n=13 -0.11% n=63

Bone Mineral Density Changes in Adolescent Females (12–18 years of age)

The impact of Depo-Provera CI (150 mg) use for up to 240 weeks (4.6 years) was evaluated in an open-label non-randomized clinical study in 389 adolescent females (12–18 years). Use of Depo-Provera CI was associated with a significant decline from baseline in BMD.

Partway through the trial, drug administration was stopped (at 120 weeks). The mean number of injections per Depo-Provera CI user was 9.3. The decline in BMD at total hip and femoral neck was greater with longer duration of use (see Table 5). The mean decrease in BMD at 240 weeks was more pronounced at total hip (-6.4%) and femoral neck (-5.4%) compared to lumbar spine (-2.1%).

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.

Table 5. Mean Percent Change from Baseline in BMD in Adolescents Receiving ≥4 Injections per 60-week Period, 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) 113 -2.75 166 1.22
Week 120 (2.3 years) 73 -5.40 109 2.19
Week 240 (4.6 years) 28 -6.40 84 1.71
Femoral Neck BMD
  Week 60 113 -2.96 166 1.75
  Week 120 73 -5.30 108 2.83
  Week 240 28 -5.40 84 1.94
Lumbar Spine BMD
  Week 60 114 -2.47 167 3.39
  Week 120 73 -2.74 109 5.28
  Week 240 27 -2.11 84 6.40

BMD recovery post-treatment in adolescent women

Longer duration of treatment and smoking were associated with less recovery of BMD following the last injection of Depo-Provera CI. Table 6 shows the extent of recovery of BMD up to 60 months post-treatment for adolescent women who received Depo-Provera CI for two years or less compared to more than two years. Post-treatment follow-up showed that, in women treated for more than two years, only lumbar spine BMD recovered to baseline levels after treatment was discontinued. Subjects treated with Depo-Provera for more than two years did not recover to their baseline BMD level at femoral neck and total hip even up to 60 months post-treatment. Adolescent women in the untreated cohort gained BMD throughout the trial period (data not shown).

Table 6: Extent of BMD Recovery (Months Post-Treatment) in Adolescents by Years of Depo Provera CI Use (2 Years or Less vs. More than 2 Years)
Duration of Treatment 2 years or less More than 2 years
N Mean % Change from baseline N Mean % Change from baseline
Total Hip BMD
End of Treatment 49 -1.5% 49 -6.2%
12 M post-treatment 33 -1.4% 24 -4.6%
24 M post-treatment 18 0.3% 17 -3.6%
36 M post-treatment 12 2.1% 11 -4.6%
48 M post-treatment 10 1.3% 9 -2.5%
60 M post-treatment 3 0.2% 2 -1.0%
Femoral Neck BMD
End of Treatment 49 -1.6% 49 -5.8%
12 M post-treatment 33 -1.4% 24 -4.3%
24 M post-treatment 18 0.5% 17 -3.8%
36 M post-treatment 12 1.2% 11 -3.8%
48 M post-treatment 10 2.0% 9 -1.7%
60 M post-treatment 3 1.0% 2 -1.9%
Lumbar Spine BMD
End of Treatment 49 -0.9% 49 -3.5%
12 M post-treatment 33 0.4% 23 -1.1%
24 M post-treatment 18 2.6% 17 1.9%
36 M post-treatment 12 2.4% 11 0.6%
48 M post-treatment 10 6.5% 9 3.5%
60 M post-treatment 3 6.2% 2 5.7%

BMD Changes in Adult Women after Six Months of Treatment 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 7).

Table 7. 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
EOT = End of Treatment
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

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)
N = Number of subjects in analysis for indicated month
Figure 3
Figure 4. 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 Contraception Studies
N = Number of subjects with bleeding and/or spotting during indicated month
Figure 4

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)
N = Number of subjects in analysis for indicated month
Figure 5
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
N = Number of subjects with bleeding and/or spotting during indicated month
Figure 6

3. Cancer Risks

Women who have or have had breast cancer should not use hormonal contraceptives, including depo sub-Q provera 104, because breast cancer may be hormonally sensitive [see Contraindications]. Women with a strong family history of breast cancer should be monitored with particular care.

The results of five large case-control studiesii iii iv v vi assessing the association between depo-medroxyprogesterone acetate (DMPA) use and the risk of breast cancer are summarized in Figure 7. Three of the studies suggest a slightly increased risk of breast cancer in the overall population of users; these increased risks were statistically significant in one study. One recent US studyii evaluated the recency and duration of use and found a statistically significant increased risk of breast cancer in recent users (defined as last use within the past five years) who used DMPA for 12 months or longer; this is consistent with results of a previous studyv.

Figure 7. Risk estimates of breast cancer in DMPA users

Figure 7

Odds ratio estimates were adjusted for the following covariates:
Lee et al. (1987): age, parity, and socioeconomic status.
Paul et al. (1989): age, parity, ethnic group, and year of interview.
WHO (1991): age, center, and age at first live birth.
Shapiro et al. (2000): age, ethnic group, socioeconomic status, and any combined estrogen/progestogen oral contraceptive use.
Li et al. (2012): age, year, BMI, duration of OC use, number of full-term pregnancies, family history of breast cancer, and history of screening mammography.

Based on the published SEER-18 2011 incidence rate (age-adjusted to the 2000 US Standard Population ) of breast cancer for US women, all races, age 20 to 49vii years a doubling of risk would increase the incidence of breast cancer in women who use Depo-Provera CI from about 72 to about 144 cases per 100,000 women.

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 reported in women using depo-subQ provera 104. 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 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:

  • Median time to ovulation was 10 months after the last injection
  • Earliest return to ovulation was 6 months after the last injection
  • 12 women (80%) ovulated within 1 year of the last injection

However, ovulation has occurred as early as 14 weeks after a single dose of depo-subQ provera 104, and therefore it is important to follow the recommended dosing schedule.

Return to fertility also is likely to be delayed after stopping therapy. Among 28 women using depo-subQ provera 104 for contraception who stopped treatment to become pregnant, 1 became pregnant within 1 year of her last injection. A second woman became pregnant 443 days after her last injection. Seven women were lost to follow-up.

5. Depression

Patients with a history of treatment for clinical depression should be carefully monitored while receiving depo-subQ provera 104.

6. Injection Site Reactions

In 5 clinical studies of depo-subQ provera 104 involving 2,325 women (282 treated for up to 6 months, 1,780 treated for up to 1 year and 263 women treated for up to 2 years), 5% of women reported injection site reactions, and 1% had persistent skin changes, typically described as small areas of induration or atrophy.

In post-marketing experience, injection site reactions such as persistent atrophy of the injection site, dimpling/indentation and injection site lump/nodule have been reported.

7. Carbohydrate/Metabolism

Some patients receiving progestins may exhibit a decrease in glucose tolerance. Diabetic patients should be carefully observed while receiving such therapy.

8. Liver Function

If jaundice or any other liver abnormality develops in any woman receiving depo-subQ provera 104, treatment should be stopped while the cause is determined. Treatment may be resumed when liver function is acceptable and when the healthcare provider has determined that depo-subQ provera 104 did not cause the abnormality.

9. Drug Interactions

No drug-drug interaction studies have been conducted with depo-subQ provera 104. Aminoglutethimide administered concomitantly with depo-subQ provera 104 may significantly decrease the serum concentrations of MPA.

10. Laboratory Tests

The pathologist should be advised of progestin therapy when relevant specimens are submitted. The physician should be informed that certain endocrine and liver function tests, and blood components may be affected by progestin therapy:

(a)
Plasma and urinary steroid levels are decreased (e.g., progesterone, estradiol, pregnanediol, testosterone, cortisol).
(b)
Plasma and urinary gonadotropin levels are decreased (e.g., LH, FSH).
(c)
SHBG concentrations are decreased.
(d)
T3-uptake values may decrease.
(e)
There may be small changes in coagulation factors.
(f)
Sulfobromophthalein and other liver function test values may be increased slightly.
(g)
There may be small changes in lipid profiles.

11. Carcinogenesis, Mutagenesis, Impairment of Fertility

See WARNINGS, section 3 and PRECAUTIONS, section 4

12. Pregnancy

Although depo-subQ provera 104 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.

13. Nursing Mothers

Although the drug is detectable in the milk of mothers receiving Depo-Provera CI (150 mg), milk composition, quality, and amount are not adversely affected. Neonates and infants exposed to medroxyprogesterone acetate from breast milk have been studied for developmental and behavioral effects through puberty, and no adverse effects have been noted.

14. Pediatric Use

depo-subQ provera 104 is not indicated before menarche. Use of depo-subQ provera 104 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. In adolescents, interpretation of BMD results should take into account patient age and skeletal maturity. It is unknown if use of depo-subQ provera 104 by younger women will reduce peak bone mass and increase the risk for 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.

15. Geriatric Use

depo-subQ provera 104 is intended for use in women with childbearing potential. Studies with depo-subQ provera 104 in geriatric women have not been conducted.

INFORMATION FOR THE PATIENT

See PATIENT LABELING.

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