DMPA: Time to repeal black box warning?

The Food and Drug Administration (FDA) added a "black box" warning in 2004 to the contraceptive injection depot medroxyprogesterone acetate (DMPA, Depo-Provera, Pfizer, New York City; Medroxyprogesterone Acetate Injectable Suspension USP, Teva Pharmaceuticals USA, North Wales, PA) advising that prolonged use might result in bone mineral density loss. Has such a warning label been warranted?

No, according to a recently published editorial.1 Guidance contained in the DMPA black box is not based on evidence, and the warning deprives women of long-term use of a safe and effective contraceptive, the authors aver. The warning cautions users that DMPA should be used as a long-term birth control method (longer than two years) only if other birth control methods are inadequate.

The cautionary statement has made its impact on providers, notes Andrew Kaunitz, MD, professor and associate chair in the Obstetrics and Gynecology Department at the University of Florida College of Medicine – Jacksonville. In a 2008 survey of Florida physicians, 46% of those surveyed said they place a time limit on DMPA use, and 66% said the constraint was based on the label warning, notes Kaunitz, a coauthor on the editorial.2 Sixty-five percent of physicians surveyed said they ordered bone mineral density testing solely due to use of DMPA, with 58% indicating that this decision was based on the black box warning.

There is no convincing evidence that links the use of DMPA to fracture, the editorial maintains. Data from studies of menopausal women do not suggest that prior use of DMPA increased their risk of osteoporosis.3-5

Results from two case-control studies indicate that DMPA is associated with an elevated risk of fracture in reproductive-age women.6-7 However, a cohort analysis using one of the same databases suggests the elevated fracture risk observed in women using DMPA occurred before initiation of injectable contraception and was not the result of DMPA use,8 the editorial points out.

The DMPA black box warning is "out of step" with national & international guidance on its use, the editorial points out. A 2008 committee opinion released by the American College of Obstetricians and Gynecologists (ACOG) stated that concerns about the effects of DMPA on bone mineral density should not prevent clinicians from prescribing the method nor should its use be limited to two years.9 The ACOG opinion falls in line with a similar review issued by the World Health Organization (WHO) in 2005.10

In the recently released US Medical Eligibility Criteria for Contraceptive Use, the Centers for Disease Control and Prevention (CDC) rank use of DMPA as 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.11

How might these national and international guidances aid in the argument to remove the black box label? Much depends on the extent to which the FDA uses evidence to guide its decisions, says David Grimes, MD, clinical professor in the Department of Obstetrics and Gynecology at the University of North Carolina at Chapel Hill School of Medicine and a Distinguished Scientist at FHI 360 in Research Triangle Park, NC. The decision to place a black box warning on DMPA was based on studies using an invalid surrogate endpoint for fracture: bone mineral density. That surrogate endpoint was and is scientifically wrong, states Grimes, a co-author of the editorial.

"Whether the FDA will now employ better scientific standards, [such as] clinical studies of fracture showing no association, is unclear," states Grimes. "Poor scientific standards at the FDA caused this problem; the CDC and WHO agree that the black box warning is inappropriate."

References

  1. Kaunitz AM, Grimes DA. Remove the black-box warning for depot medroxyprogesterone acetate! OBG Management 2011; 28:6, 8-9.
  2. Paschall S, Kaunitz AM. Depo-Provera and skeletal health: a survey of Florida obstetrics and gynecologist physicians. Contraception 2008; 78:370-376.
  3. Cundy T, Cornish J, Roberts H, et al. Menopausal bone loss in long-term users of depot medroxyprogesterone acetate contraception. Am J Obstet Gynecol 2002; 186:978-983.
  4. Orr-Walker BJ, Evans MC, Ames RW, et al. The effect of past use of the injectable contraceptive depot medroxyprogesterone acetate on bone mineral density in normal post-menopausal women. Clin Endocrinol (Oxf) 1998; 49:615-618.
  5. Viola AS, Castro S, Marchi NM, et al. Long-term assessment of forearm bone mineral density in postmenopausal former users of depot medroxyprogesterone acetate. Contraception 2011; 84:122-127.
  6. Vestergaard P, Rejnmark L, Mosekilde L. The effects of depot medroxyprogesterone acetate and intrauterine device use on fracture risk in Danish women. Contraception 2008; 78:459-464.
  7. Meier C, Brauchli YB, Jick SS, et al. Use of depot medroxyprogesterone acetate and fracture risk. J Clin Endocrin Metab 2010; 95:4,909-4,916.
  8. Kaunitz AM, Harel Z, Bone H, et al. Retrospective cohort study of DMPA and fractures in reproductive age women. Presented at the Association of Reproductive Health Professional Annual Meeting; Atlanta, September 2010.
  9. ACOG Committee Opinion No. 415: Depot medroxyprogesterone acetate and bone effects. Obstet Gynecol 2008; 112:727-730.
  10. World Health Organization. WHO statement on hormonal contraception and bone health. Wkly Epidemiol Rec 2005; 80:302-304.
  11. Centers for Disease Control and Prevention. US Medical Eligibility Criteria for Contraceptive Use, 2010. MMWR Recomm Rep 2010; 59(RR04):1-6.