Tamoxifen precautions

List of precautions
General Monitoring Hyperlipidemia Carcinogenesis Mutagenesis Impairment of fertility Pregnancy Nursing mothers Pediatric use Geriatric use Effects in metastatic breast cancer patients Effects on the uterus-endometrial cancer and uterine sarcoma Non-malignant effects on the uterus Thromboembolic effects of tamoxifen Effects on the liver Other cancers Effects on the eye

General
Decreases in platelet counts, usually to 50,000-100,000/mm3, infrequently lower, have been occasionally reported in patients taking Tamoxifen for breast cancer. In patients with significant thrombocytopenia, rare hemorrhagic episodes have occurred, but it is uncertain if these episodes are due to Tamoxifen therapy. Leukopenia has been observed, sometimes in association with anemia and/or thrombocytopenia. There have been rare reports of neutropenia and pancytopenia in patients receiving Tamoxifen; this can sometimes be severe. Return to top

Monitoring
Women taking or having previously taken Tamoxifen should be instructed to seek prompt medical attention for new breast lumps, vaginal bleeding, gynecologic symptoms (menstrual irregularities, changes in vaginal discharge, or pelvic pain or pressure), symptoms of leg swelling or tenderness, unexplained shortness of breath, or changes in vision. Women should inform all care providers, regardless of the reason for evaluation, that they take Tamoxifen. Women taking Tamoxifen to reduce the incidence of breast cancer should have a breast examination, a mammogram, and a gynecologic examination prior to the initiation of therapy. These studies should be repeated at regular intervals while on therapy, in keeping with good medical practice. Women taking Tamoxifen as adjuvant breast cancer therapy should follow the same monitoring procedures as for women taking Tamoxifen for the reduction in the incidence of breast cancer. Women taking Tamoxifen as treatment for metastatic breast cancer should review this monitoring plan with their care provider and select the appropriate modalities and schedule of evaluation. Return to top

Hyperlipidemia
In the postmarketing experience with Tamoxifen, infrequent cases of hyperlipidemias have been reported. Periodic monitoring of plasma triglycerides and cholesterol may be indicated in patients with pre-existing hyperlipidemias. Return to top

Carcinogenesis
A conventional carcinogenesis study in rats at doses of 5, 20, and 35 mg/kg/day (about one, three and seven-fold the daily maximum recommended human dose on a mg/m2 basis) administered by oral gavage for up to 2 years revealed a significant increase in hepatocellular carcinoma at all doses. The incidence of these tumors was significantly greater among rats administered 20 or 35 mg/kg/day (69%) compared to those administered 5 mg/kg/day (14%). In a separate study, rats were administered Tamoxifen at 45 mg/kg/day (about nine-fold the daily maximum recommended human dose on a mg/m2 basis); hepatocellular neoplasia was exhibited at 3 to 6 months. Return to top

Mutagenesis
No genotoxic potential was found in a conventional battery of in vivo and in vitro tests with pro- and eukaryotic test systems with drug metabolizing systems. However, increased levels of DNA adducts were observed by 32P post-labeling in DNA from rat liver and cultured human lymphocytes. Tamoxifen also has been found to increase levels of micronucleus formation in vitro in human lymphoblastoid cell line (MCL-5). Based on these findings, Tamoxifen is genotoxic in rodent and human MCL-5 cells. Return to top

Impairment of fertility
Tamoxifen produced impairment of fertility and conception in female rats at doses of 0.04 mg/kg/day (about 0.01-fold the daily maximum recommended human dose on a mg/m2 basis) when dosed for two weeks prior to mating through day 7 of pregnancy. At this dose, fertility and reproductive indices were markedly reduced with total fetal mortality. Fetal mortality was also increased at doses of 0.16 mg/kg/day (about 0.03-fold the daily maximum recommended human dose on a mg/m2 basis) when female rats were dosed from days 7-17 of pregnancy. Tamoxifen produced abortion, premature delivery and fetal death in rabbits administered doses equal to or greater than 0.125 mg/kg/day (about 0.05-fold the daily maximum recommended human dose on a mg/m2 basis). There were no teratogenic changes in either rats or rabbits. Return to top

Pregnancy
Teratogenic Effects Return to top
 * Pregnancy category D.

Nursing mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Tamoxifen, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Return to top

Pediatric use
Approved labeling describing pediatric safety and efficacy information regarding Tamoxifen use in patients with McCune-Albright syndrome is available for AstraZeneca's Tamoxifen citrate tablets. However, due to AstraZeneca's marketing exclusivity rights, this drug product is not labeled for pediatric use. The long-term effects of Tamoxifen therapy for girls have not been established. In adults treated with Tamoxifen, an increase in incidence of endometrial adenocarcinoma and uterine sarcoma has been noted. Return to top

Geriatric use
In the NSABP P-1 trial, the percentage of women at least 65 years of age was 16%. Women at least 70 years of age accounted for 6% of the participants. A reduction in breast cancer incidence was seen among participants in each of the subsets: A total of 28 and 10 invasive breast cancers were seen among participants 65 and older in the placebo and Tamoxifen groups, respectively. Across all other outcomes, the results in this subset reflect the results observed in the subset of women at least 50 years of age. No overall differences in tolerability were observed between older and younger patients. Return to top

Effects in metastatic breast cancer patients
As with other additive hormonal therapy (estrogens and androgens), hypercalcemia has been reported in some breast cancer patients with bone metastases within a few weeks of starting treatment with Tamoxifen. If hypercalcemia does occur, appropriate measures should be taken and, if severe, Tamoxifen should be discontinued. Return to top

Effects on the uterus-endometrial cancer and uterine sarcoma
An increased incidence of uterine malignancies has been reported in association with Tamoxifen treatment. The underlying mechanism is unknown, but may be related to the estrogen-like effect of Tamoxifen. Most uterine malignancies seen in association with Tamoxifen are classified as adenocarcinoma of the endometrium. However, rare uterine sarcomas, including malignant mixed mullerian tumors, have also been reported. Uterine sarcoma is generally associated with a higher FIGO stage (III/IV) at diagnosis, poorer prognosis, and shorter survival. Uterine sarcoma has been reported to occur more frequently among long-term users (≥ 2 years) of Tamoxifen than non-users. Some of the uterine malignancies (endometrial carcinoma or uterine sarcoma) have been fatal. Return to top

Non-malignant effects on the uterus
An increased incidence of endometrial changes including hyperplasia and polyps have been reported in association with Tamoxifen treatment. The incidence and pattern of this increase suggest that the underlying mechanism is related to the estrogenic properties of Tamoxifen.Return to top

Thromboembolic effects of tamoxifen
There is evidence of an increased incidence of thromboembolic events, including deep vein thrombosis and pulmonary embolism, during Tamoxifen therapy. When Tamoxifen is coadministered with chemotherapy, there may be a further increase in the incidence of thromboembolic effects. For treatment of breast cancer, the risks and benefits of Tamoxifen should be carefully considered in women with a history of thromboembolic events. Return to top

Effects on the liver
Tamoxifen has been associated with changes in liver enzyme levels, and on rare occasions, a spectrum of more severe liver abnormalities including fatty liver, cholestasis, hepatitis and hepatic necrosis. A few of these serious cases included fatalities. In most reported cases the relationship to Tamoxifen is uncertain. However, some positive rechallenges and dechallenges have been reported. Return to top

Other cancers
A number of second primary tumors, occurring at sites other than the endometrium, have been reported following the treatment of breast cancer with Tamoxifen in clinical trials. Data from the NSABP B-14 and P-1 studies show no increase in other (non-uterine) cancers among patients receiving Tamoxifen. Whether an increased risk for other (non-uterine) cancers is associated with Tamoxifen is still uncertain and continues to be evaluated. Return to top

Effects on the eye
Ocular disturbances, including corneal changes, decrement in color vision perception, retinal vein thrombosis, and retinopathy have been reported in patients receiving Tamoxifen. An increased incidence of cataracts and the need for cataract surgery have been reported in patients receiving Tamoxifen. Return to top