Black Box Warning Added to the Cancer Drug Tamoxifen (NOLVADEX)

The strongest cautionary language that the Food and Drug Administration (FDA) can require, a so-called “black box warning,” was added to the professional product labeling, or “package insert,” for the cancer drug tamoxifen (NOLVADEX) in June 2002. The warning concerns increased risk of sometimes fatal uterine cancers, stroke and blood clots in the lungs (pulmonary embolism) in women at high risk of breast cancer who use the drug to reduce the incidence of breast cancer and in women with a form of breast cancer called ductal carcinoma in situ (DCIS).

The new black box warning is reprinted in full at the end of this article.

DCIS is characterized by abnormal cells that involve only the lining of a duct. Such cells have not yet spread outside the duct to other breast tissues. It is a noninvasive cancer that can become invasive in some cases.

Endometrial cancer, involving the lining of the uterus, is the most common form of cancer in this organ, accounting for approximately 95 percent of all uterine cancers. Uterine sarcoma is a rare cancer of the body of the uterus, accounting for 2 to 5 percent of all uterine cancers. Because it is usually diagnosed at a more advanced stage than other uterine tumors, women diagnosed usually have a poorer outcome and shorter survival than others.

The labeling change is aimed at women who are considering tamoxifen as a way to reduce the incidence of breast cancer or those with DCIS for whom a survival benefit of the drug has not been demonstrated. At this time, the known benefits of tamoxifen outweigh its risks in women already diagnosed with other kinds of breast cancer.

Evidence of the risk of uterine sarcoma with tamoxifen use, leading to the FDA’s black box warning decision, came in a letter in the June 6, 2002 New England Journal of Medicine from FDA staff. The FDA found that between 1978, when tamoxifen was first approved in the U.S., and April 2001, there were 43 cases of uterine sarcoma reported to the agency or published in the medical literature. In addition, this cancer was reported to have developed in 116 women in other countries who had used tamoxifen for breast cancer.

When tamoxifen was approved to reduce the incidence of breast cancer in October 1998—not for the prevention of breast cancer—in women at high risk of the disease, we were concerned about the amount of misleading information being spread about the drug. For example, National Public Radio’s News Hour with Jim Lehrer presented a segment on February 18, 1999 asserting that tamoxifen prevented breast cancer. On-air and on the Public Broadcasting System Web site corrections were made March 22, 1999 in response to Public Citizen letters to Jim Lehrer. On January 22, 1999, the FDA issued a warning letter to AstraZeneca, tamoxifen’s manufacturer, concerning an advertising brochure it had circulated among physicians that contained repeated references to a “Breast Cancer Prevention Trial” which had misleadingly promoted tamoxifen for “prevention.” The FDA letter also objected to misuse of the word “uncommon” to describe the incidence of endometrial cancer, lack of adequate information on adverse effects, promotion of tamoxifen’s use in an unapproved patient population (women over 60 years of age not at high risk), misleading efficacy data, and misleading fracture data, among other things.

Because of the extent of confusing information surrounding the use of tamoxifen and the fact that existing FDA approved labeling regarding reduction in breast cancer incidence provided inadequate information and was difficult for both patients and physicians to interpret, the Health Research Group and the National Women’s Health Network petitioned the FDA on May 4, 1999 to revise the drug’s professional labeling and require the distribution by pharmacists of FDA approved information written for patients that would clearly inform women of the risks of this drug. This type of written information is known as a Medication Guide.

We noted in our petition that tamoxifen is a known human carcinogen (cancer causing agent). When it is prescribed for healthy women to reduce the incidence of breast cancer there must be compelling evidence of great benefit. We are still not convinced that the benefits of tamoxifen outweigh its risks in this population of women and we stated that it was imperative that information be clearly presented and the risks and benefits clearly stated.

The table below is from a large clinical trial (over 13,000 women) that was used to gain approval for tamoxifen in reducing breast cancer incidence in high risk women. The trial compared tamoxifen to a placebo over a period of five years.

The incidence of breast cancer was reduced by 2.9 cases per year out of 1,000 women using tamoxifen. However, there was an excess of 1.4 cases of endometrial cancer per year out of 1,000 women taking tamoxifen. For blood clot in the lungs, blood clot in the veins, and stroke the number of excess cases of these serious adverse drug reactions with tamoxifen compared to placebo was 0.5, 0.5, and 0.4 cases per year out of 1,000 women taking tamoxifen, respectively. Overall, there was an excess of 2.8 cases of a potentially life-threatening adverse drug reaction per year out of 1,000 women on tamoxifen. Said another way, for each reduction of one case in the incidence of breast cancer, there was about one case of a potentially life-threatening drug reaction with the use of tamoxifen.

In this study, the benefit of tamoxifen equaled its serious risks—it was a wash. However, there was also an increased risk of cataracts and cataract surgery in women using tamoxifen.

Tamoxifen’s new labeling is somewhat better than it was, but still does not meet the level of clarity that we asked for in our May 4, 1999 petition to the FDA. There is FDA approved information written for patients that now accompanies the drug to the pharmacy.

However, it is not known to what extent this information is distributed to patients. The sheet that most prescription drug consumers receive at the pharmacy is produced by unregulated commercial information vendors. In a recent national survey of the drug information distributed by pharmacists, not a single piece of this information met minimum quality guidelines. See the article in this issue of the newsletter about the quality of information being distributed by pharmacists.

What You Can Do

If you are taking tamoxifen or have ever taken it, you should contact your doctor immediately if you experience any unusual vaginal discharge, vaginal bleeding, menstrual irregularities, or pain or pressure in the pelvis. In addition, you should have annual gynecological examinations.