Tamoxifen - Warnings and Precautions
The following warnings and precautions are taken directly from the US FDA-approved drug label for Tamoxifen. This is the same information dispensing pharmacists read.
\u26a0\ufe0f Boxed Warning (Highest FDA Alert)
WARNING: UTERINE MALIGNANCIES and THROMBOEMBOLIC EVENTS Serious and life-threatening events from the use of SOLTAMOX include uterine malignancies, stroke, and pulmonary embolism [see Warnings and Precautions (5.1 , 5.2) ] . Fatal cases of each type of event have occurred. Incidence rates per 1000 women-years for these events were estimated from the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial in women at high risk for breast cancer [see Clinical Studies ] : Endometrial adenocarcinoma: 2.20 for tamoxifen vs. 0.71 for placebo Uterine sarcoma: 0.17 for tamoxifen vs. 0.04 for placebo Stroke: 1.43 for tamoxifen vs. 1.00 for placebo. Pulmonary embolism: 0.75 for tamoxifen versus 0.25 for placebo. Discuss the potential benefits of tamoxifen versus the potential risks of these serious events with women at high risk for breast cancer and women with ductal carcinoma in situ (DCIS) considering tamoxifen to reduce the risk of developing breast cancer [see Warnings and Precautions ]. For most patients already diagnosed with breast cancer, the benefits of tamoxifen outweigh its risks. WARNING: UTERINE MALIGNANCIES and THROMBOEMBOLIC EVENTS See full prescribing information for complete boxed warning . Serious, life-threatening, and fatal events from use of tamoxifen include uterine malignancies, stroke, and pulmonary embolism. ( 5.1 , 5.2 ) Discuss risks and benefits of tamoxifen with women at high risk for breast cancer and women with ductal carcinoma in situ (DCIS
5 WARNINGS AND PRECAUTIONS Uterine malignancies: Promptly evaluate abnormal vaginal bleeding in a woman with current or past tamoxifen use.
Thromboembolic events: Risk increases with coadministered chemotherapy.
For treatment of breast cancer, consider risks and benefits in patients with a history of thromboembolic events.
Embryo-fetal toxicity: Can cause fetal harm.
Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.3 , 8.1 , 8.3 ) Effects on the liver: Liver cancer and liver abnormalities, some fatal, have occurred.
Perform periodic liver function testing. ( 5.4 , 5.9 ) 5.1 Endometrial Cancer, Uterine Sarcoma, and Other Effects on the Uterus Endometrial Cancer and Uterine Sarcoma An increased incidence of uterine malignancies (endometrial adenocarcinoma and uterine sarcoma), including fatal cases, has been reported with tamoxifen treatment.
The underlying mechanism is unknown, but may be related to the estrogen-like effect of tamoxifen.
Most uterine malignancies seen with tamoxifen are classified as adenocarcinoma of the endometrium; however, uterine sarcomas, including malignant mixed mullerian tumors (MMMT), have also been reported.
Uterine sarcoma was generally associated with a higher FIGO stage (III/IV) at diagnosis, poor prognosis, and short survival.
Uterine sarcoma has been reported to occur more frequently among long-term users (≥2 years) of tamoxifen than non-users.
Promptly evaluate any patient receiving or who has previously received tamoxifen who reports abnormal vaginal bleeding.
Patients receiving or who have previously received tamoxifen should have annual gynecological examinations.
Advise patients to promptly inform a healthcare provider if they experience any abnormal gynecological symptoms (e.g., menstrual irregularities, abnormal vaginal bleeding, changes in vaginal discharge, or pelvic pain or pressure).
There are no data to suggest that routine endometrial sampling in asymptomatic women taking tamoxifen is beneficial.
In a review of long-term data (median length of total follow-up was 6.9 years, including blinded follow-up) on 8,306 women with an intact uterus at randomization in the NSABP P-1 risk reduction trial, the incidence of both adenocarcinomas and uterine sarcomas was increased in women taking tamoxifen.
During blinded follow-up, there were 36 cases of FIGO Stage I endometrial adenocarcinoma (22 were FIGO Stage IA, 13 IB, and 1 IC) in women receiving tamoxifen and 15 cases in women receiving placebo [14 were FIGO Stage I (9 IA and 5 IB), and 1 case was FIGO Stage IV].
During total follow-up, endometrial adenocarcinoma was reported in 53 women randomized to tamoxifen (30 cases of FIGO Stage IA, 20 were Stage IB, 1 was Stage IC, and 2 were Stage IIIC), and 17 women randomized to placebo (9 cases were FIGO Stage IA, 6 were Stage IB, 1 was Stage IIIC, and 1 was Stage IVB) (incidence per 1,000 women-years of 2.20 and 0.71, respectively).
Uterine sarcomas were reported in 4 women randomized to tamoxifen (1 was FIGO IA, 1 was FIGO IB, 1 was FIGO IIA, and 1 was FIGO IIIC) and 1 patient randomized to placebo (FIGO IA); incidence per 1,000 women-years of 0.17 and 0.04, respectively.
Of the patients randomized to tamoxifen, the FIGO IA and IB cases were a MMMT and sarcoma, respectively; the FIGO II was a MMMT; and the FIGO III was a sarcoma; and the 1 patient randomized to placebo had a MMMT.
A similar increased incidence in endometrial adenocarcinoma and uterine sarcoma was observed among women receiving tamoxifen in 5 other NSABP clinical trials.
In the NSABP P-1 trial, endometrial sampling did not alter the endometrial cancer detection rate compared to women who did not undergo endometrial sampling (0.6% with sampling, 0.5% without sampling) for women who had not undergone hysterectomy.
Non-Malignant Effects on the Uterus An increased incidence of endometrial changes including hyperplasia and polyps has been reported with tamoxifen treatment.
The incidence and pattern of this increase suggest that the underlying mechanism is related to the partial estrogenic effect of tamoxifen.
There have been reports of endometriosis and uterine fibroids in women receiving tamoxifen.
Ovarian cysts have also been observed in premenopausal patients with advanced breast cancer who have been treated with tamoxifen.
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