Tamoxifen Citrate Tablets

Tamoxifen is the prototype agent of a class of drugs called selective estrogen receptor modulators (SERMs), which have both estrogenic and antiestrogenic effects on various tissues. The structure of tamoxifen is based on the same nucleus as diethylstilbestrol, but tamoxifen’s additional side chain (trans isomer) imparts antiestrogenic activity. It is chemically related to another antiestrogen, clomiphene. Tamoxifen is used as the primary hormonal therapy for metastatic estrogen receptor (ER)-positive breast cancer in both men and postmenopausal women. Adjuvant tamoxifen therapy significantly reduces the risk of breast cancer recurrence and death in women of all age groups. The benefit is greater when tamoxifen is given for 5 years rather than 1—3 years, and when the drug is given to women with ER-positive tumors. Tamoxifen has been shown to decrease the incidence of ER-positive breast cancer in women who are at high risk for developing the disease. It has no effect on the development of ER-negative disease. A new study is underway to examine the benefits of tamoxifen versus raloxifene in the prevention of breast cancer (The Study of Tamoxifen and Raloxifene, STAR); initial results indicate that raloxifene reduces the risk of breast cancer by a similar rate. In the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial, comparing tamoxifen or anastrozole to the combination of anastrozole and tamoxifen in postmenopausal women with early breast cancer, the combination therapy arm was discontinued early as an efficacy benefit over tamoxifen therapy alone was not demonstrated. Furthermore, anastrozole monotherapy, after a median of 5 years, was associated with an increased survival benefit (hazard ratio 0.87, 95% confidence interval 0.78—0.97, p=0.0127) compared to tamoxifen therapy. Patients in the tamoxifen only arm had an increased incidence of vaginal symptoms, thromboembolic events, stroke, and endometrial cancer. However, patients receiving anastrozole had an increased incidence of fractures (including spine, hip, or wrist fractures), joint disorders (e.g., arthralgia, arthritis), and hypercholesterolemia. Similar findings have been found with the other aromatase inhibitors (i.e., exemestane and letrozole) when compared to tamoxifen in postmenopausal women with early breast cancer. Tamoxifen was originally FDA-approved in 1977. An oral solution (Soltamox™) was approved by the FDA on October 29, 2005. A MedGuide is available for tamoxifen and is to be dispensed with every prescription and prescription refill for selected women. The MedGuide discusses ONLY the use of tamoxifen to lower the chance of getting breast cancer in high-risk women and in women treated for ductal carcinoma in situ (DCIS), situations in which the risks and benefits of the medicine should be carefully considered. In October 2006, the Endocrinologic and Metabolic Drugs FDA Advisory Committee recommended that the tamoxifen prescribing information be updated to indicate that patients who are slow-CYP2D6 metabolizers may be at increased risk for breast cancer recurrence; testing for slow CYP2D6 metabolism may be prudent prior to drug initiation, although it is unclear if this will be a requirement for proper prescribing.

Tamoxifen has mixed estrogenic antagonist and agonist properties. Tamoxifen binds to estrogen receptors (ER) and induces conformational changes in the receptor. For example, tamoxifen stimulates ER in bone and may actually prevent postmenopausal osteoporosis and has antiestrogenic effects on breast tissue. The ability of tamoxifen and other drugs to produce both estrogenic and antiestrogenic affects is most likely due to interaction with other coactivators or corepressors in the tissue and binding with different estrogen receptors, ER-alpha or ER-beta. The tissue distribution of ER-alpha and ER-beta suggest different functions for these receptors.

Subsequent to tamoxifen ER binding, the expression of estrogen dependent genes (RNA transcription) is blocked or altered. The binding of tamoxifen to the nuclear chromatin of these tissues is prolonged, resulting in reduced DNA polymerase activity, impaired thymidine utilization, blockade of estradiol uptake, and decreased estrogen response. Most of tamoxifen’s activity occurs in the G2-phase. Cell cycling is slowed by the drug’s activity in the nucleus. Therefore, tamoxifen is cytostatic. Tamoxifen also affects other growth factors. Tamoxifen decreases insulin-like growth factor type 1, a factor that stimulates cancer cell growth and development and induces the secretion of transforming growth factor beta (TGF-beta) which is associated with inhibiting the activity of breast cancer cells. In addition, tamoxifen induces the re-expression of the tumor suppressor gene maspin in breast cancer tissue. In breast cancer, maspin gene expression is diminished or lost, whereas the maspin protein is abundant in normal breast cells. The presence of maspin has been shown to prevent tumor invasion and metastasis; the use of tamoxifen reintroduces maspin into breast cancer cells and may cause the carcinoma to be less invasive.

Tamoxifen also can be used to induce ovulation in anovulatory women. Tamoxifen stimulates the hypothalamus to release gonadotropin-releasing hormone, thereby prompting the release of hormones from the pituitary. The subsequent effect on the ovaries results in ovulation.

Tamoxifen is administered orally as tablets. Tamoxifen is extensively metabolized in the liver by the cytochrome P450 (CYP) system, specifically CYP 3A, 2C9, and 2D6. It also inhibits P-glycoprotein (P-gp). The main metabolite found in plasma is N-desmethyl tamoxifen, which has similar biological activity to tamoxifen and is formed predominantly via CYP3A4/5. Other active metabolites include 4-hydroxytamoxifen, which is predominantly catalyzed by CYP2D6 from tamoxifen, and endoxifen, which is catalyzed predominantly by CYP2D6 from N-desmethyl tamoxifen and to a lesser extent by CYP3A4/5 from 4-hydroxytamoxifen. Endoxifen and 4-hydroxytamoxifen have a 100-fold greater affinity for the estrogen receptor and 30- to 100-fold greater potency in suppressing estrogen-dependent cell proliferation than tamoxifen. Endoxifen concentrations may reach up to 20-fold higher than 4-hydroxytamoxifen. Genetic polymorphisms in CYP2D6 have been shown to result in lower concentrations of endoxifen. Similarly, medications that inhibit CYP2D6 may result in clinically significant reductions in endoxifen formation. Studies have shown poorer clinical outcomes in patients who have genetic polymorphisms that result in a decrease or loss of CYP2D6 function. Tamoxifen and some of its active metabolites are inhibitors of CYP3A4.

Tamoxifen has a biphasic elimination with an initial half-life of 7—14 hours and a terminal elimination half-life of 5—7 days. Steady-state plasma concentrations of N-desmethyl tamoxifen are achieved in 8 weeks, suggesting a half-life for this metabolite of approximately 14 days. Tamoxifen undergoes some enterohepatic circulation. Both the unchanged drug and its metabolites are excreted primarily in the feces, largely as polar conjugates. Unchanged parent compound and unconjugated metabolites account for less than 30% of excretion.

Route-Specific Pharmacokinetics:

Oral Route: Tamoxifen is rapidly absorbed from the GI tract. Bioavailability is comparable between the 10 mg PO twice a day and 20 mg PO once a day dosage regimens and between the tablets and oral solution. Food does not affect the bioavailability of the oral solution. Following a single oral dose of tamoxifen 20 mg, an average peak plasma concentration of 40 ng/ml (range 35—45 ng/ml) occurs in approximately 5 hours. Chronic administration of tamoxifen 10 mg twice daily for 3 months results in average steady-state tamoxifen plasma concentrations of 120 ng/ml (67—183 ng/ml); following 20 mg tamoxifen once daily for 3 months the average steady-state tamoxifen level is 122 ng/ml (range 71—183 ng/ml).

Following chronic administration of tamoxifen 10 mg twice daily or 20 mg once daily for 3 months, the average steady-state levels of N-desmethyl tamoxifen are 336 ng/ml (range 148—654 ng/ml) and 353 ng/ml (range 152—706 ng/ml), respectively. Tamoxifen accumulates after repeated administration and reaches steady-state plasma concentrations in 4 weeks.

Special Populations:

Hepatic Impairment: Patients with biliary stasis may need a lower tamoxifen dose. Specific dosage guidelines based on serum bilirubin or alkaline phosphatase are not available.

Renal Impairment: Dosage adjustment of tamoxifen in patients with renal dysfunction is unnecessary.

Pediatrics: In female pediatric patients, an average steady state peak concentration (Cmax) of 187 ng/ml occurred approximately 8 hours after tamoxifen dosing. Clearance (body weight adjusted) in female pediatric patients was approximately 2.3-fold higher than in adult female breast cancer patients. In the youngest cohort of patients (2—6 years old), the clearance was 2.6-fold higher; in the oldest cohort (7—10.9 years old) the clearance was about 1.9-fold higher. Exposure to N-desmethyl tamoxifen was comparable between pediatric and adult patients.

Tamoxifen Citrate is indicated in the treatment of breast cancer, decreasing the chance of breast cancer recurring, and prevention of breast cancer in women with a high risk for breast cancer.

Your health care provider needs to know if you have any of these conditions: blood clots; blood disease; cataracts or impaired eyesight; endometriosis; high calcium levels; high cholesterol; irregular menstrual cycles; liver disease; stroke; uterine fibroids; an unusual or allergic reaction to tamoxifen or other products; pregnant or trying to get pregnant; breast-feeding. You will need regular exams and blood work while taking this medication.

Because hepatotoxicity can rarely occur in patients treated with tamoxifen, liver function tests should be monitored periodically during tamoxifen therapy.

As with other additive estrogen therapy, there is evidence of an increased risk of thromboembolic events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), during tamoxifen therapy. Concurrent use with chemotherapy further increases the risk of thromboembolism. Tamoxifen for breast cancer prophylaxis is contraindicated in women who require concomitant coumarin-type anticoagulant therapy and in women with a history of thromboembolic disease such as DVT or PE. During the NSABP P-1 trial, women without a history of PE had a statistically significant increase incidence of PE. In this same population there was a non-statistically significant increase in DVT and stroke in the patients randomized to tamoxifen. The majority (87%) of the cases of PE and stroke occurred in women at least 50 years of age at randomization. Women with thromboembolic events were at risk for a second related event and were at risk for complications of the event and its treatment. In addition, screening patients for genetic predisposition to thromboembolic disease (i.e., factor V Leiden, prothrombin mutations G20210A) is probably not helpful for identifying those patients at risk of thromboembolic complications during tamoxifen therapy. In the treatment and prevention of breast cancer, the risk versus benefits of tamoxifen therapy must be carefully considered in women with a history of thromboembolic disease. Some experts feel that the increase in relative risk for venous thromboembolism conferred by tamoxifen for breast cancer prophylaxis does not differ much from that seen with oral contraceptives or hormone replacement therapy.

Tamoxifen is classified as a FDA pregnancy risk category D drug. Women should be advised not to become pregnant while taking or within 2 months of discontinuing tamoxifen. If a woman becomes pregnant while taking or within 2 months of stopping tamoxifen, she should be counseled regarding the potential risks to the fetus, including the potential long-term risk of a DES-like syndrome. Sexually active premenopausal females should use barrier or non-hormonal contraceptive measures during treatment and for 2 months after discontinuing therapy. Tamoxifen does not cause infertility, even in the presence of menstrual irregularity. Effects on reproductive functions are expected from the antiestrogenic properties of the drug; it can induce ovulation and increase the chance of pregnancy. Tamoxifen can cause harm to the fetus if administered to pregnant women and is therefore should not be used during the first 4 months of pregnancy. There are reports of teratogenesis, including abnormal reproductive anatomy, fetal death, spontaneous abortion and vaginal bleeding in infants of those mothers exposed to tamoxifen during early pregnancy. In animal studies with doses 2-fold the maximum human dose on a mg/m2 basis during organogenesis or during the last half of pregnancy, no deformations were seen and, although the dose was high enough to terminate pregnancy in some animals, those that did maintain pregnancy showed no evidence of teratogenic malformations. For breast cancer prophylaxis in sexually active females of childbearing potential, initiate therapy during menstruation. In women with menstrual irregularity, document a negative beta-HCG test prior to initiating tamoxifen therapy.

It is uncertain if tamoxifen is distributed into breast milk. The potential for serious adverse effects on the infant indicates that breast-feeding should be discontinued during tamoxifen therapy. If excreted, there are no data regarding the effects of tamoxifen in breast milk on the breastfed infant or breastfed animals. Direct neonatal exposure of tamoxifen to mice and rats (not via breast milk) produced reproductive tract lesions in female rodents (similar to those seen in humans after intrauterine exposure to diethylstilbestrol) and functional defects of the reproductive tract in male rodents. Tamoxifen has also been reported to inhibit early postpartum milk production. The effect of tamoxifen on established milk production is not known.

An increased risk of endometrial cancer, endometrial changes (including hyperplasia and polyps), and uterine sarcoma has been reported in association with tamoxifen treatment for any indication (see Adverse Reactions). The underlying mechanism is unknown, but may be related to the estrogen-like effect of tamoxifen. Most uterine malignancies seen in association with tamoxifen therapy are classified as adenocarcinoma of the endometrium. However, rare uterine sarcomas, including malignant mixed mullerian tumors, have been reported. Uterine sarcoma has been reported to occur more frequently among long-term tamoxifen users (> 2 years) versus non-users. Some of the uterine malignancies (endometrial carcinoma or uterine sarcoma) have been fatal. In general, patients with preexisting endometrial hyperplasia should not receive long-term tamoxifen therapy. Health care providers should discuss the potential benefits versus risks of these serious events with women at high risk of breast cancer and also those women with ductal carcinoma in situ (DCIS) considering tamoxifen therapy to decrease their risk of developing breast cancer. The benefits of tamoxifen therapy in the adjuvant treatment of breast cancer (improved disease-free and overall survival) or for advanced breast cancer (response and palliation) outweigh the risks. Patients receiving or having previously received tamoxifen should have routine gynecological care and should promptly inform their health care professional if they experience any abnormal gynecological symptoms (e.g., menstrual irregularities, abnormal vaginal bleeding, changes in vaginal discharge, or pelvic pain or pressure). In the P-1 study, endometrial sampling in women with an intact uterus 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). There are no data to suggest that routine endometrial sampling would be beneficial in asymptomatic women taking tamoxifen for breast cancer prevention.

Tamoxifen should be used with caution in patients with preexisting bone marrow suppression (i.e., neutropenia, leukopenia, or thrombocytopenia). Periodically, platelet counts and complete blood counts should be determined in patients receiving tamoxifen. Tamoxifen decreases platelet counts and rare hemorrhagic episodes have occurred in patients with significant thrombocytopenia.

Intramuscular injections should be avoided in patients receiving tamoxifen with platelet counts < 50,000/mm3. Since tamoxifen has been associated with thrombocytopenia, IM injections may cause bleeding, bruising, or hematomas.

Marked hyperlipoproteinemia and other lipoprotein abnormalities can occur in patients receiving tamoxifen, so lipid profiles and cholesterol should be monitored during tamoxifen therapy in patients who have a preexisting lipoprotein abnormalities, including hypercholesterolemia.

Patients with cataracts or visual disturbance should use tamoxifen with caution. Tamoxifen can cause visual disturbances including corneal changes, cataracts, and retinopathy. During the NSABP P-1 breast cancer prevention trial, an increased risk of borderline significance of developing cataracts was observed among those tamoxifen-treated women without cataracts at baseline. In addition, tamoxifen therapy was associated with an increased risk of having cataract surgery.

Use tamoxifen cautiously in patients with preexisting hypercalcemia. As with other antiestrogens, hypercalcemia and tumor flare have been reported in some breast cancer patients with bone metastases during the first weeks of treatment with tamoxifen. Patients with bone metastases should be monitored closely for hypercalcemia during the first weeks of treatment. If hypercalcemia occurs, appropriate measures should be instituted, and if hypercalcemia is severe, tamoxifen therapy should be discontinued.

The safety and effectiveness of tamoxifen in children have not been established. The safety and efficacy of tamoxifen for girls aged 2—10 years with McCune-Albright Syndrome and precocious puberty have not been studied beyond one year of treatment. The long-term effects of tamoxifen therapy in girls have not been established. In girls treated with tamoxifen, mean uterine volume increased after 6 months of treatment and doubled at the end of the one-year study. A causal relationship has not been established; however, an increase in the incidence of endometrial adenocarcinoma and uterine sarcoma has been noted in adults treated with tamoxifen. Continued monitoring of McCune-Albright patients treated with tamoxifen for long-term uterine effects is recommended.

This list may not include all possible contraindications.

Tamoxifen is classified as a FDA pregnancy risk category D drug. Women should be advised not to become pregnant while taking or within 2 months of discontinuing tamoxifen. If a woman becomes pregnant while taking or within 2 months of stopping tamoxifen, she should be counseled regarding the potential risks to the fetus, including the potential long-term risk of a DES-like syndrome. Sexually active premenopausal females should use barrier or non-hormonal contraceptive measures during treatment and for 2 months after discontinuing therapy. Tamoxifen does not cause infertility, even in the presence of menstrual irregularity. Effects on reproductive functions are expected from the antiestrogenic properties of the drug; it can induce ovulation and increase the chance of pregnancy. Tamoxifen can cause harm to the fetus if administered to pregnant women and is therefore should not be used during the first 4 months of pregnancy. There are reports of teratogenesis, including abnormal reproductive anatomy, fetal death, spontaneous abortion and vaginal bleeding in infants of those mothers exposed to tamoxifen during early pregnancy. In animal studies with doses 2-fold the maximum human dose on a mg/m2 basis during organogenesis or during the last half of pregnancy, no deformations were seen and, although the dose was high enough to terminate pregnancy in some animals, those that did maintain pregnancy showed no evidence of teratogenic malformations. For breast cancer prophylaxis in sexually active females of childbearing potential, initiate therapy during menstruation. In women with menstrual irregularity, document a negative beta-HCG test prior to initiating tamoxifen therapy.

It is uncertain if tamoxifen is distributed into breast milk. The potential for serious adverse effects on the infant indicates that breast-feeding should be discontinued during tamoxifen therapy. If excreted, there are no data regarding the effects of tamoxifen in breast milk on the breastfed infant or breastfed animals. Direct neonatal exposure of tamoxifen to mice and rats (not via breast milk) produced reproductive tract lesions in female rodents (similar to those seen in humans after intrauterine exposure to diethylstilbestrol) and functional defects of the reproductive tract in male rodents. Tamoxifen has also been reported to inhibit early postpartum milk production. The effect of tamoxifen on established milk production is not known.

Tamoxifen Citrate interacts with a substantial number of medications from myriad classes; give your healthcare provider a detailed list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine.

Additionally, in vitro studies showed that erythromycin, cyclosporine, nifedipine, and diltiazem competitively inhibited formation of N-desmethyl tamoxifen with apparent K_1of 20, 1, 45, and 30 µM, respectively. The clinical significance of these in vitro studies is unknown.

Tamoxifen reduced the plasma concentration of letrozole by 37% when these drugs were co-administered. Rifampin, a cytochrome P-450 3A4 inducer reduced tamoxifen AUC and Cmax by 86% and 55% respectively. Aminoglutethimide reduces tamoxifen and N-desmethyl tamoxifen plasma concentration. Medroxyprogesterone reduces plasma concentrations of N-desmethyl, but not tamoxifen.

What are some possible side effects of this medicine? Fatigue; hair loss, although uncommon and is usually mild; headache; hot flashes; impotence; nausea, vomiting (mild); vaginal discharge. This list may not describe all possible side effects. Call your health care provider immediately if you are experiencing any changes in vision (blurred vision); changes in your menstrual cycle; difficulty breathing or shortness of breath; difficulty walking or talking; new breast lumps; numbness; pelvic pain or pressure; redness, blistering, peeling or loosening of the skin, including inside the mouth; skin rash or itching (hives); sudden chest pain; swelling of lips, face, or tongue; swelling, pain or tenderness in your calf or leg; unusual bruising or bleeding; vaginal discharge that is bloody, brown, or rust; weakness; yellowing of the whites of the eyes or skin.

Pain was reported in 16% of postmenopausal women with operable breast cancer who received adjuvant tamoxifen therapy (n = 3094) in the ATAC trial.

Accidental injury was reported in 10% of postmenopausal women with operable breast cancer who received adjuvant tamoxifen therapy (n = 3094) in the ATAC trial.

Increased creatinine levels occurred in 2% of women with axillary node-negative, estrogen-receptor positive breast cancer who received adjuvant tamoxifen (n = 1422) compared with 1% of women who received placebo (n = 1437) following primary surgery in a randomized, double-blind study (the NSABP B-14 study).

Neoplasm (5%) and cyst (5%) were reported in postmenopausal women with operable breast cancer who received adjuvant tamoxifen therapy (n = 3094) in the ATAC trial.

In a pooled analysis of 3 randomized trials, amenorrhea (16%), altered menses (13%), oligomenorrhea (9%), menstrual disorder (menstrual irregularity) (6%), and ovarian cyst (3%) were reported in premenopausal women with metastatic breast cancer (MBC) who received tamoxifen therapy (n = 104). Vaginal dryness has been reported infrequently with tamoxifen use in MBC patients. Vaginal discharge (30% vs 15%) and menstrual irregularity (25% vs 19%) occurred more often in women with axillary node-negative, estrogen-receptor positive breast cancer who received adjuvant tamoxifen (n = 1422) compared with placebo (n = 1437) following primary surgery in a randomized, double-blind study (the NSABP B-14 study). Vaginal bleeding occurred in 2% of women who received tamoxifen in another adjuvant breast cancer trial. Urogenital adverse events that occurred in postmenopausal women with operable breast cancer who received adjuvant tamoxifen therapy (n = 3094) in the ATAC trial include vaginal discharge (13%), leukorrhea (9%), breast pain/mastalgia (6%), breast neoplasm (5%), vaginitis (5%), vaginal bleeding without further diagnosis (6%), vaginal bleeding (10%), and vulvovaginitis (5%). In a randomized, double-blind, breast cancer prevention trial (NSABP P-1 trial), vaginal discharge (any severity, 55% vs 35%; severe, 12.3% vs 4.5%) and vaginal bleeding (23% vs 22%) were reported more often in women at high risk for developing breast cancer who received 5 years of tamoxifen therapy (n = 6441) compared with placebo (n = 6469). The mean uterine volume was increased after 6 months of tamoxifen and doubled after 1 year of tamoxifen in female pediatric patients (age range, 2—10 years) with McCune-Albright syndrome (off-label use) in a 1-year study. The long-term effects of tamoxifen have not been established in this patient population; therefore, close monitoring for long-term adverse events is recommended. In post-marketing surveillance, vaginal bleeding, vaginal discharge, and menstrual irregularity have been reported in patients who received tamoxifen. Patients should have gynecological examinations annually and be counseled to contact their healthcare provider if they experience any abnormal gynecological symptoms such as menstrual irregularities, abnormal vaginal bleeding, changes in vaginal discharge, or pelvic pain or pressure. Promptly evaluate patients who report abnormal vaginal bleeding.

Secondary malignancy has been reported with tamoxifen use, specifically uterine malignancies such as endometrial adenocarcinoma (incidence rate per 1000 women-years of 2.2 for tamoxifen vs 0.71 for placebo) and uterine sarcoma (incidence rate per 1000 women-years of 0.17 for tamoxifen vs 0.4 for placebo) including malignant mixed mullerian tumors (MMMT) in women with ductal carcinoma in situ or at high risk for breast cancer in a randomized, double-blind, breast cancer prevention trial (NSABP P-1 trial); some cases were fatal. The average time to development of endometrial cancer was 32 months (range, 1—61 months). In this study, endometrial cancer (0.5% vs 0.2%; relative risk = 2.48, 95% CI, 1.27—4.92) occurred more often in women at high risk for developing breast cancer who received 5 years of tamoxifen therapy (n = 6681) compared with placebo (n = 6707). Of the 33 tamoxifen-treated patients who developed endometrial cancer, all cases were FICO stage I (IA, n = 20; IB, n = 12; IC, n = 1), 5 patients had received postoperative radiation, and 26 patients were at least 50 years old (RR = 4.5; 95% CI, 1.78—13.16). At a median follow-up time of 6.9 years, endometrial cancer was identified in 36 tamoxifen-treated patients during the blinded follow-up period (FIGO stage: IA, n = 22; IB, n = 13; IC, n = 1) and 53 tamoxifen-treated patients during the total follow-up period (FIGO stage : IA, n = 30; IB, n = 20; IC, n = 1; IIIC, n = 2). Additionally, endometrial cancer occurred in 0.6% of postmenopausal women with operable breast cancer who received adjuvant tamoxifen therapy (n = 3094) in the ATAC trial. Uterine sarcomas developed in 4 patients in the tamoxifen arm (FIGO stage: IA, n = 1; IB, n = 1; IIA, n = 1; IIIC, n = 1) compared with 1 patient in the placebo arm in the NSABP P-1 trial. Patients who develop uterine sarcoma typically have a higher stage disease (FIGO stage III or IV) at diagnosis, poorer prognosis, and shorter survival; long-term tamoxifen use (> 2 years) may increase the risk of uterine sarcoma. Endometrial adenocarcinoma and uterine sarcoma were observed at a similar incidence in 5 other NSABP clinical trials. Patients should have gynecological examinations annually and be counseled to contact their healthcare provider if they experience any abnormal gynecological symptoms such as menstrual irregularities, abnormal vaginal bleeding, changes in vaginal discharge, or pelvic pain or pressure. Promptly evaluate patients who report abnormal vaginal bleeding. There have been rare reports of liver cancer in tamoxifen-treated patients. Endometrial hyperplasia and polyps have been reported in women who received tamoxifen; endometriosis and uterine fibroids have also been reported with tamoxifen use.

There are reports of teratogenesis, including abnormal reproductive anatomy, fetal death, spontaneous fetal abortion, and vaginal bleeding in pregnant women exposed to tamoxifen during early pregnancy. In addition, there is a long-term risk of a DES-like syndrome to the fetus.

Thromboembolic events including stroke, deep vein thrombosis (DVT) and pulmonary embolism (PE) have been reported with tamoxifen use. The risk of thromboembolic events may increase when tamoxifen is used in combination with chemotherapy. Stroke (incidence rate per 1000 women-years was 1.43 for tamoxifen vs 1 for placebo) and PE (incidence rate per 1000 women-years was 0.75 for tamoxifen vs 0.25 for placebo) have been reported with tamoxifen use in women with ductal carcinoma in situ or at high risk for breast cancer in a randomized, double-blind, breast cancer prevention trial (NSABP P-1 trial); some cases were fatal. In this study, PE (0.27% vs 0.09%; relative risk (RR) = 3.01; 95% CI, 1.15—9.27), DVT (0.45% vs 0.28%; RR = 1.59; 95% CI: 0.86—2.98), and stroke (0.5% vs 0.36%; RR = 1.42; 95% CI, 0.82—2.51) were reported more often in women at high risk for developing breast cancer who received 5 years of tamoxifen therapy (n = 6681) compared with placebo (n = 6707). Of the 34 tamoxifen-treated patients who had a stroke, 10 were hemorrhagic, 17 were occlusive, and 7 were of unknown etiology. The average times to PE, DVT, and stroke development after beginning tamoxifen therapy were 27 months (range, 2—60 months), 19 months (range, 2—57 months), and 30 months (range, 1—63 months), respectively. There appeared to be no benefit in screening women for factor V Leiden and prothrombin mutations G20210A to identify patients who may not be appropriate candidates for tamoxifen therapy in a subgroup of patients in the NSABP P-1 trial (n = 81). Additionally, thrombotic events specifically DVT (0.8% vs 0.2%), PE (0.5% vs 0.2%), and superficial phlebitis (0.4% vs 0%) occurred more often in women with axillary node-negative, estrogen-receptor positive breast cancer who received adjuvant tamoxifen (n = 1422) compared with placebo (n = 1437) following primary surgery in a randomized, double-blind study (the NSABP B-14 study). Thromboembolism events reported in postmenopausal women with operable breast cancer who received adjuvant tamoxifen therapy (n = 3094) in the ATAC trial venous thromboembolic events (5%), DVT (2%), and ischemic cerebrovascular event (3%).

Leukopenia, neutropenia, anemia, pancytopenia, and thrombocytopenia have been reported in patients taking tamoxifen for breast cancer. Rarely, bleeding has occurred in patients with severe thrombocytopenia. Platelet counts less than 100,000/mm3 occurred in 2% of women with axillary node-negative, estrogen-receptor positive breast cancer who received adjuvant tamoxifen (n = 1422) compared with 1% of women who received placebo (n = 1437) following primary surgery in a randomized, double-blind study (the NSABP B-14 study). In another adjuvant breast cancer trial (the ECOG-1178 trial), thrombocytopenia was reported in 10% of women who received 2 years of tamoxifen compared with 3% of women who received placebo following a mastectomy. Anemia was reported in 5% of postmenopausal women with operable breast cancer who received adjuvant tamoxifen therapy (n = 3094) in the ATAC trial. In a randomized, double-blind, breast cancer prevention trial (NSABP P-1 trial), decreased platelets (0.7% vs 0.3%) occurred more often in women at high risk for developing breast cancer who received 5 years of tamoxifen therapy (n = 6520) compared with placebo (n = 6535). Grade 3 or 4 thrombocytopenia (platelet count <= 50,000/mm3) was reported in 0.09% of tamoxifen-treated patients in this study. Monitor complete blood counts, including platelets, periodically during therapy.

Increased tumor and bone pain and local tumor flare have occurred with tamoxifen therapy in patients with metastatic breast cancer (MBC); these effects typically start soon after starting therapy, subside rapidly, and are sometimes associated with a favorable response. Some patients may require additional analgesics to treat symptoms. In MBC patients with soft tissue disease, increased size or marked erythema within and around preexisting lesions and/or the development of new lesions have been reported with tamoxifen use. In a pooled analysis of 3 randomized trials, bone pain (6%), pain (3%), and musculoskeletal pain (3%) were reported in premenopausal MBC patients who received tamoxifen therapy (n = 104). Musculoskeletal adverse events were reported in 29% of postmenopausal women with operable breast cancer who received adjuvant tamoxifen therapy (n = 3094) in the ATAC trial and included arthritis (14%), arthralgia (11%), back pain (10%), osteoporosis (7%), bone pain (6%), arthrosis (5%), joint disorder (5%), and myalgia (5%). In this study, bone fractures were reported in 7% of tamoxifen-treated patients including spine, hip, or wrist fractures (3%), wrist/Colles’ fractures (2%), spine fractures (1%), and hip fractures (1%); patients who received tamoxifen had mean increases in both lumbar spine and total hip bone mineral density compared to baseline. Hypercalcemia has been reported infrequently with tamoxifen use in patients with metastatic breast cancer. Discontinue tamoxifen in patients who develop severe hypercalcemia.

Ophthalmic adverse events such as corneal changes, decrement in color vision perception (visual impairment), retinal thrombosis, and retinopathy have been reported with tamoxifen use. Cataracts occurred in 7% of postmenopausal women with operable breast cancer who received adjuvant tamoxifen therapy (n = 3094) in the ATAC trial. In a randomized, double-blind, breast cancer prevention trial (NSABP P-1 trial), cataracts (8.1% vs 7.2%; relative risk (RR) = 1.13; 95% CI, 1—1.28) occurred more often in women at high risk for developing breast cancer who received 5 years of tamoxifen therapy (n = 6681) compared with placebo (n = 6707); additionally, cataract surgery was performed in 1.5% of patients in the tamoxifen arm compared with 0.93% of patients in the placebo arm (RR = 1.51; 95% CI, 1.21—1.89).

Hepatotoxicity (e.g., fatty liver, cholestasis, hepatitis, and hepatic necrosis) has been reported with tamoxifen use; fatalities have been reported. Tamoxifen-related hepatotoxicity was possible based upon drug rechallenge or dechallenge in some cases. Elevated hepatic enzymes, specifically increased AST levels (5% vs 3%), and hyperbilirubinemia (2% vs 1%) occurred more often in women with axillary node-negative, estrogen-receptor positive breast cancer who received adjuvant tamoxifen (n = 1422) compared with placebo (n = 1437) following primary surgery in a randomized, double-blind study (the NSABP B-14 study). Monitor liver function tests periodically during therapy. Grade 3 or 4 liver function changes (increased AST, ALT, bilirubin, alkaline phosphatase levels) were reported in 6 women at high risk for developing breast cancer who received 5 years of tamoxifen therapy (n = 6681) compared with 10 women who received placebo (n =6707) in a randomized double-blind, breast cancer prevention trial (NSABP P-1 trial).

Elevated LH, FSH, testosterone, and estrogen levels have been reported in oligospermic male patients with breast cancer who received tamoxifen therapy. Impotence (erectile dysfunction) and libido decrease have occurred in male patients when tamoxifen was discontinued.

Infectious events reported in postmenopausal women with operable breast cancer who received adjuvant tamoxifen therapy (n = 3094) in the ATAC trial include infection (9%), urinary tract infection (10%), sinusitis (5%), and bronchitis (5%). In a randomized, double-blind, breast cancer prevention trial (NSABP P-1 trial), infection/sepsis (6% vs 5.1%) occurred more often in women at high risk for developing breast cancer who received 5 years of tamoxifen therapy (n = 6492) compared with placebo (n = 6484).

Influenza syndrome was reported in 6% of postmenopausal women with operable breast cancer who received adjuvant tamoxifen therapy (n = 3094) in the ATAC trial.

Cardiovascular adverse events reported in postmenopausal women with operable breast cancer who received adjuvant tamoxifen therapy (n = 3094) in the ATAC trial include peripheral vasodilation (41%), hypertension (11%), chest pain (unspecified) (5%), ischemic cardiovascular disease (3%), angina pectoris (1.6%), and myocardial infarction (1.1%).

Weight gain was reported in 9% of postmenopausal women with operable breast cancer who received adjuvant tamoxifen therapy (n = 3094) in the ATAC trial.

Weight loss (of greater than 5% of body weight) occurred in 23% of women with axillary node-negative, estrogen-receptor positive breast cancer who received adjuvant tamoxifen (n = 1422) compared with 18% of women who received placebo (n = 1437) following primary surgery in a randomized, double-blind study (the NSABP B-14 study).

In a pooled analysis of 3 randomized trials, fatigue was reported in 4% of premenopausal women with metastatic breast cancer who received tamoxifen therapy (n = 104). Fatigue/asthenia was reported in 18% of postmenopausal women with operable breast cancer who received adjuvant tamoxifen therapy (n = 3094) in the ATAC trial.

In a pooled analysis of 3 randomized trials, edema was reported in 4% of premenopausal women with metastatic breast cancer (MBC) who received tamoxifen therapy (n = 104). Peripheral edema has been reported infrequently with tamoxifen use in MBC patients. Fluid retention occurred in 32% of women with axillary node-negative, estrogen-receptor positive breast cancer who received adjuvant tamoxifen (n = 1422) compared with 30% of women who received placebo (n = 1437) following primary surgery in a randomized, double-blind study (the NSABP B-14 study). Lymphoedema (11%) and peripheral edema (11%) occurred in postmenopausal women with operable breast cancer who received adjuvant tamoxifen therapy (n = 3094) in the ATAC trial.

Gastrointestinal (GI) adverse events such as nausea (5—26%) have been reported with tamoxifen use. In a pooled analysis of 3 randomized trials, nausea (5%), anorexia (1%), and abdominal pain/cramps (1%) were reported in premenopausal women with metastatic breast cancer (MBC) who received tamoxifen therapy (n = 104). Additionally, distaste for food has been reported infrequently with tamoxifen use in MBC patients. Nausea occurred in 26% of women with axillary node-negative, estrogen-receptor positive breast cancer who received adjuvant tamoxifen (n = 1422) compared with 24% of women who received placebo (n = 1437) following primary surgery in a randomized, double-blind study (the NSABP B-14 study). GI adverse events that occurred in postmenopausal women with operable breast cancer who received adjuvant tamoxifen therapy (n = 3094) in the ATAC trial include nausea and vomiting (12%), nausea (11%), abdominal pain (9%), constipation (8%), diarrhea (7%), dyspepsia (6%), and GI disorder (5%). In a randomized, double-blind, breast cancer prevention trial (NSABP P-1 trial), constipation (4.4% vs 3.2%) occurred more often in women at high risk for developing breast cancer who received 5 years of tamoxifen therapy (n = 6492) compared with placebo (n = 6484).

Pruritus vulvae has been reported infrequently with tamoxifen use in patients with metastatic breast cancer.

In a pooled analysis of 3 randomized trials, depression was reported in 2% of premenopausal women with metastatic breast cancer who received tamoxifen therapy (n = 104). Mood disturbance (18%), depression (12%), and anxiety (6%) were reported in postmenopausal women with operable breast cancer who received adjuvant tamoxifen therapy (n = 3094) in the ATAC trial. In a randomized, double-blind, breast cancer prevention trial (NSABP P-1 trial), mood adverse effects (11.6% vs 10.8%) occurred more often in women at high risk for developing breast cancer who received 5 years of tamoxifen therapy (n = 6492) compared with placebo (n = 6484).

Headache, dizziness, and light-headedness have been reported infrequently with tamoxifen use in patients with metastatic breast cancer. Nervous system adverse events reported in postmenopausal women with operable breast cancer who received adjuvant tamoxifen therapy (n = 3094) in the ATAC trial include insomnia (9%), headache (8%), dizziness (8%), and paresthesias (5%).

Hair thinning and partial hair loss (alopecia) have been reported infrequently with tamoxifen use in patients with metastatic breast cancer. Skin changes occurred in 19% of women with axillary node-negative, estrogen-receptor positive breast cancer who received adjuvant tamoxifen (n = 1422) compared with 15% of women who received placebo (n = 1437) following primary surgery in a randomized, double-blind study (the NSABP B-14 study). In post-marketing surveillance, rash including rare cases of erythema multiforme, Stevens-Johnson syndrome, and bullous rash (bullous pemphigoid) have been reported in patients who received tamoxifen. Rash (unspecified) (13%) and hyperhidrosis (6%) were reported in postmenopausal women with operable breast cancer who received adjuvant tamoxifen therapy (n = 3094) in the ATAC trial. In a randomized, double-blind, breast cancer prevention trial (NSABP P-1 trial), alopecia (5.2% vs 4.4%) and skin adverse events (5.6% vs 4.7%) were reported more often in women at high risk for developing breast cancer who received 5 years of tamoxifen therapy (n = 6492) compared with placebo (n = 6484).

In a pooled analysis of 3 randomized trials, cough was reported in 4% of premenopausal women with metastatic breast cancer who received tamoxifen therapy (n = 104). In post-marketing surveillance, interstitial pneumonitis has been reported very rarely in patients who received tamoxifen. Respiratory adverse events reported in postmenopausal women with operable breast cancer who received adjuvant tamoxifen therapy (n = 3094) in the ATAC trial include pharyngitis (14%), cough (9%), and dyspnea (8%).

In post-marketing surveillance, hypersensitivity reactions including rare cases of angioedema have been reported in patients who received tamoxifen; occasionally, the time of reaction onset occurred more than 1 year later. In a randomized, double-blind, breast cancer prevention trial (NSABP P-1 trial), allergy (2.5% vs 2.1%) was reported more often in women at high risk for developing breast cancer who received 5 years of tamoxifen therapy (n = 6492) compared with placebo (n = 6484).

Hypercholesterolemia was reported in 3.5% of postmenopausal women with operable breast cancer who received adjuvant tamoxifen therapy (n = 3094) in the ATAC trial. In post-marketing surveillance, elevated serum triglyceride levels (hypertriglyceridemia), sometimes associated with pancreatitis, have been reported rarely in patients who received tamoxifen.

Hot flashes have been reported commonly (2.8—80%) with tamoxifen use in patients with metastatic breast cancer. In a pooled analysis of 3 randomized trials, flushing was reported in 33% of premenopausal women with metastatic breast cancer who received tamoxifen therapy (n = 104). Hot flashes occurred in 64% of women with axillary node-negative, estrogen-receptor positive breast cancer who received adjuvant tamoxifen (n = 1422) compared with 48% of women who received placebo (n = 1437) following primary surgery in a randomized, double-blind study (the NSABP B-14 study). In another adjuvant breast cancer trial (the ECOG-1178 trial), hot flashes were reported in 19% of women who received 2 years of tamoxifen compared with 8% of women who received placebo following a mastectomy. Hot flashes occurred in 29% and 2.8% of women in 2 other adjuvant breast cancer trials. In a randomized, double-blind, breast cancer prevention trial (NSABP P-1 trial), hot flashes (any severity, 80% vs 68%; severe, 45% vs 28%) were reported more often in women at high risk for developing breast cancer who received 5 years of tamoxifen therapy (n = 6441) compared with placebo (n = 6469).

This list may not include all possible adverse reactions or side effects. Call your health care provider immediately if you are experiencing any signs of an allergic reaction: skin rash, itching or hives, swelling of the face, lips, or tongue, blue tint to skin, chest tightness, pain, difficulty breathing, wheezing, dizziness, red, a swollen painful area/areas on the leg.

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

1.Early Breast Cancer Trialists’ Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998;16:1451-67.
2.Fisher B, Costantino JP, Wickerman L, et al. Tamoxifen for the prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 1998;90:1371-88.
3.Khalkhali-Ellis Z, Christian AL, Kirschmann DA, et al. Regulating the tumor suppressor gene maspin in breast cancer cells. Clinical Cancer Research 2004;10:449-54.
4.Desta Z, Ward BA, Soukhova NV, et al. Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6.
5.Kiyotani K, Mushiroda T, Imamura CK, et al. Significant effects of polymorphisms in CYP2D6 and ABCC2 on clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients. J Clin Oncol 2010;28:1287-1293.
6.Wu X, Hawse JR, Subramaniam M, et al. The tamoxifen metabolite, endoxifen, is a potent antiestrogen that targets estrogen receptor alpha for degradation in breast cancer cells. Cancer Res 2009;69:1722-1727.
7.Sideras K, Ingle JN, Ames MM, et al. Coprescription of tamoxifen and medications that inhibit CYP2D6. J Clin Oncol 2010;28:2768-2776.
8.Schroth W, Goetz MP, Hamann U, et al. Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. JAMA. 2009;302:1429-1436
9.Nolvadex (tamoxifen) package insert. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2006 Mar
10.Zhao XJ, Jones DR, Wang YH, et al. Reversible and irreversible inhibition of CYP3A enzymes by tamoxifen and metabolites. Xenobiotica 2002;32:863-78.
11.Crewe HK, Notley LM, Wunsch RM, et al. Metabolism of tamoxifen by recombinant human cytochrome P450 enzymes: formation of the 4-hydroxy, 4’-hydroxy and N-desmethyl metabolites and isomerization of trans-4-hydroxytamoxifen. Drug Metab Dispos 2002;30:869-74
12.Kinsinger LS, Harris R, Woolf SH, et al. Chemoprevention of breast cancer: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2002;137:59-67.
13.Tewari K, Bonebrake RG, Asrat T, et al. Ambiguous genitalia in an infant exposed to tamoxifen in utero. Lancet 1997;350:183.
14.Tamoxifen package insert. Sellersville, PA: Teva Pharmaceuticals USA; 2008 Aug.
15.Shaaban MM. Suppression of lactation by an antiestrogen, tamoxifen. Eur J Obstet Gynecol Reprod Biol 1975;4:167-9.
16.Tamoxifen tablets package insert. Morgantown, WV: Mylan Pharmaceuticals Inc.; 2013 Apr.
17.Litovitz TL, Klein-Schwartz W, Oderda GM, et al. Ipecac administration in children younger than 1 year of age. Pediatrics 1985;76(5):761-764.