Expert Commentary

Remove the black-box warning for depot medroxyprogesterone acetate!

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Guidance about DMPA in the black box isn’t evidence-based, and the warning deprives women of long-term use of this safe and effective contraceptive


 

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The Food and Drug Administration (FDA) should remove the black-box warning regarding skeletal health that the agency inserted into labeling for the injectable contraceptive depot medroxyprogesterone acetate (DMPA; Depo-Provera) in 2004. The black box 1) indicates that use of DMPA for longer than 2 years may reduce peak bone mass and place a woman at increased risk of osteoporotic fracture and 2) suggests that ObGyns order bone-density assessment in women who use DMPA long-term.

This warning is not based on scientific evidence. By depriving women of long-term use of a safe, effective contraceptive, the black-box warning damages women’s health and the public health.

The scientific argument for removing the black box

Although DMPA does cause reduced ovarian estradiol production, with a decline in bone mineral density (BMD), complete recovery of BMD occurs approximately 1 or 2 years after discontinuation in adolescent girls1,2 and 3 years after discontinuation in adult women.3,4 BMD trends observed with the use of DMPA parallel those associated with another normal but hypoestrogenic state: breastfeeding. Although BMD declines noted in nursing mothers are similar to those associated with DMPA, breastfeeding one or more infants has not been reported to increase the risk of subsequent osteoporotic fractures.5 The FDA does not warn women against breastfeeding for fear of a theoretical negative impact on skeletal health.

BMD can help predict a risk of osteoporotic fracture in menopausal women, but it is not a valid surrogate endpoint for fracture in women of reproductive age.6 Basing clinical recommendations on invalid surrogate endpoints can cause harm.7-9 Clinical recommendations, including those from the FDA, should be based on sound studies that address important clinical outcomes.

No convincing evidence links the use of DMPA for contraception to fracture. Studies of menopausal women have not suggested that prior use of DMPA increased their risk of osteoporosis.10-12 Two recently published case-control studies, one using a Danish National Patient Registry13 and one based on the United Kingdom Family Practice Research database,14 have demonstrated that DMPA is associated with an elevated risk of fracture in reproductive-age women. However, a cohort analysis using the same British Family Practice database clarifies that the elevated fracture risk observed in women using DMPA occurred before initiation of injectable contraception and was not the result of DMPA use.15


A clearly harmful effect on women’s health

The black-box warning for DMPA has caused clinicians and women to reduce use of this effective method of contraception. The 2008 National Survey of Family Growth shows that the overall percentage of US women, 15 to 44 years of age, who now use DMPA has declined—from 3.3% in 2002 to 2.0% in 2006 to 2008.16

In fact, a survey of ObGyns in Florida found that 1) almost one half of respondents place a time limit on duration of DMPA and 2) two thirds of those respondents base that restriction on the black-box warning.17 Restricting the use of DMPA can lead to more unintended pregnancies and induced abortions.

In the Florida survey, two thirds of respondents order BMD assessment in women who use DMPA, with 58% of those physicians who do so attributing their decision to, again, the black-box warning. Indeed, more than 5% of respondents reported that they selectively prescribe bisphosphonates to women of reproductive age who use DMPA—an expensive practice that is not evidence-based and is potentially dangerous.

FDA guidance is far out of step

The black-box warning for DMPA is not in accord with the guidance provided major medical and public health organizations. The World Health Organization,6 the American College of Obstetricians and Gynecologists,18 the Society for Adolescent Medicine,19 and the Society of Obstetrics and Gynecology of Canada,20 have all stated that skeletal health concerns shouldn’t restrict the use of DMPA, including the duration of use.

In the US Medical Eligibility Criteria for contraceptive use, the Centers for Disease Control and Prevention declared that use of DMPA is Category 1 (no restriction on use) in women 18 to 45 years of age and Category 2 (advantages of the method generally outweigh theoretical or proven risks) in younger women.21 The FDA’s black-box warning is therefore inconsistent with the recommendation of its sister agency.

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