Department of Health & Human Services

Office of the Secretary

Assistant Secretary for Health
Office of Public Health and Science
Washington, DC 20201

Date: February 10, 2005

From: Deputy Assistant Secretary for Population Affairs

Subject: OPA Program Instruction Series, OPA 05-01:
Updated Safety Information for Depo-Provera Contraceptive Injection
(medroxyprogesterone acetate injectable suspension)

To: Regional Health Administrators, Regions I-X

On November 17, 2004, the U.S. Food and Drug Administration (FDA) announced that a "black
box" warning would be added to the labeling of Depo-Provera Contraceptive Injection. This
warning highlights that prolonged use of Depo-Provera may result in significant loss of bone
density. The loss of bone density is greater the longer the drug is administered and may not be
completely reversible after discontinuation of the drug. The "black box" warning indicates that
Depo-Provera Contraceptive Injection should be used as a long-term birth control method (e.g.,
longer than two years) only if all other methods are inadequate. In addition, the warning states
that it is unknown if the use of Depo-Provera Contraceptive Injection during adolescence or early
adulthood will reduce peak bone mass and increase the risk of osteoporotic fracture in later life.
On November 18, 2004, U.S. Pharmaceuticals, Pfizer Inc., the pharmaceutical company that
manufactures Depo-Provera, issued letters to Healthcare Professionals and Healthcare
Organization Leaders, informing them of the new "black box" warning, as well as other updated
safety information included in the drug's labeling (copies of these letters are attached).

Although the FDA has indicated that Depo-Provera remains a safe and effective contraceptive
(see attached "FDA Talk Paper"), the "black box" warning was added to the drug's labeling to
"ensure that physicians and patients have access to this important information." The addition of
the "black box" warning came as a result of the FDA's and Pfizer's analysis of data from two
separate studies that showed Depo-Provera's effect on bone density during prolonged use. One
study began in 1994 and enrolled 540 women ages 25 to 38. The other study--which started in
1997 and will continue through 2006--enrolled approximately 400 girls ages 12 to 18 who were
taking the drug and is examining ways to reverse bone mineral density loss. References for these
two studies are attached.

Depo-Provera has been authorized for use in Title X-funded projects since October 29, 1992,
when the FDA announced approval of Depo-Provera for the prevention of pregnancy. Among
females who received services in Title X-funded clinics during calendar year 2003, the Family
Planning Annual Report (FPAR) reflected that 16 percent relied on Depo-Provera as their
primary method of contraception.

As with other prescriptive contraceptive methods, Title X providers should ensure that medical
protocols are developed and followed in accordance with the most current evidence-based
information, accepted standards of care, and current recommendations for use. Title X providers
should ensure that their medical protocols, informed consent and practice related to the use of
Depo-Provera Contraceptive Injection are consistent with the November 17, 2004, "black box"
warning added to the Depo-Provera package insert. Special consideration should be given to the
potential impact of long term use in adolescence and early adulthood. It is incumbent on grantee
agencies to ensure that delegate agencies and clinics have and use protocols that reflect this
updated safety information.

If you have any questions, please contact Susan Moskosky, Director of the Office of Family
Planning, on 301-594-4008.

Alma L. Golden, M.D., F.A.A.P.

Attachments:

1) Depo-Provera Contraceptive Injection package insert, Revised November 2004.

2) "Dear Healthcare Professional Letter" and "Dear Healthcare Organization Leader Letter"
from U.S. Pharmaceuticals Pfizer Inc, dated November 18, 2004.

3) FDA Talk Paper, November 17, 2004.

4) Requested Medical Information from Pfizer Inc., December 09, 2004. This information
contains a summary of 29 studies and a review of 2 unpublished studies (includes references for
the two studies cited in the Program Instruction).

cc: Regional Program Consultants
Regions I-X