Drug Profile

Tamoxifen is listed as a Limited Use drug.

Tamoxifen was approved by the Food and Drug Administration (FDA) in 1977 and is now approved to be used in several different situations involving breast cancer.[2] In 1998, the drug was approved for the reduction of breast cancer incidence in women at high risk of developing the disease. "High" risk was defined as a five-year predicted risk of breast cancer of at least 1.67%.

Confusion soon erupted over whether the FDA approved tamoxifen for all women 60 years of age and older without other risk factors for breast cancer. The news media were initially reporting that regardless of other factors, all women 60 and older were at a five-year predicted risk of 1.67% (the high-risk category) for developing breast cancer and thus were eligible to receive tamoxifen. This is not the case: Not all women older than 60 are at a high risk of developing breast cancer, and not all women older than 60 should be receiving tamoxifen to reduce the risk of breast cancer.

Adverse effects

The most serious adverse effects of tamoxifen include endometrial cancer, uterine sarcoma, deep vein thrombosis (blood clots in large veins, most often in the legs), pulmonary embolism (blood clots in the lungs) and, rarely, liver cancer.[2]

Uterine sarcoma

In 2006, there were three case reports of women who developed a type of cancer known as uterine sarcoma during or following treatment with tamoxifen for breast cancer. Two of these three women died.[3]

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

Evidence of the risk of uterine sarcoma with tamoxifen use — which led to the FDA’s decision to include a black-box warning on its label — came in a letter to The New England Journal of Medicine from FDA staff in June 2002.[4] The FDA found that between 1978, when tamoxifen was first marketed in the United States, and April 2001, there were 43 cases of uterine sarcoma in women who had received the drug that had been reported to the agency or published in the medical literature. In addition, internationally, this cancer was reported to have developed in 116 women who had used tamoxifen for breast cancer.

Diabetes

A study published in 2011 reviewed information to determine if there was an association between tamoxifen use and the occurrence of new diabetes in older breast cancer survivors. Based on the information examined in the study, the authors found that, in this patient population, there was an increased risk of new diabetes.[5]

In 2023, Breast Cancer Research and Treatment published an article showing an increased risk of type 2 diabetes in breast cancer survivor patients who used tamoxifen.[6]

Studies show ...

The large clinical trial (over 13,000 women) that was used to gain approval for tamoxifen in reducing breast cancer incidence in high-risk women compared tamoxifen with a placebo over a period of five years.[7]

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 that occurred with tamoxifen use compared with placebo were 0.5, 0.5 and 0.4, respectively, per year out of 1,000 women taking tamoxifen. Overall, there was an excess of 2.8 cases of potentially life-threatening adverse drug reactions per year out of 1,000 women on tamoxifen. In other words, 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 additional increased risk of cataracts and cataract surgery in women using tamoxifen.

In 2009, The Medical Letter on Drugs and Therapeutics published an article reviewing information on the interaction of tamoxifen and selective serotonin reuptake inhibitors (SSRIs), a class of drugs used to treat depression. The article summarized the results of two observational studies on the effect of SSRIs on tamoxifen and the success rate of tamoxifen in preventing recurrence of breast cancer. One study found a higher two-year recurrence rate, and the other study found no increase in the recurrence rate.[8]

In 2020, PLoS One published an article warning that tamoxifen can increase the risk of developing or worsening fatty liver (a condition in which excess fat builds up in the liver).[9]

In 2023, Cancer Reports published an article showing an increased risk of endometrial cancer in patients using tamoxifen to treat breast cancer.[10]

Regulatory actions surrounding tamoxifen

2002: In June, the FDA required a black-box warning, the strongest type of warning that the agency can require, on the product label for the drug. The warning concerns increased risks of sometimes fatal uterine cancers, stroke and blood clots in the lungs (pulmonary embolism) in women at high risk of breast cancer who use tamoxifen to reduce the incidence of breast cancer and in women with a form of breast cancer called ductal carcinoma in situ (DCIS). 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.

The June labeling change was aimed at women who are considering tamoxifen 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.