SOLTAMOX is an estrogen agonist/antagonist indicated: For treatment of adult patients with estrogen receptor-positive metastatic breast cancer ( 1.1 ) For adjuvant treatment of adult patients with early stage estrogen receptor- positive breast cancer ( 1.2 ) To reduce risk of invasive breast cancer following breast surgery and radiation in adult women with ductal carcinoma in situ (DCIS) ( 1.3 ) To reduce the incidence of breast cancer in adult women at high risk ( 1.4 )
1.1Metastatic Breast Cancer
SOLTAMOX is indicated for the treatment of adult patients with estrogen receptor-positive metastatic breast cancer.
1.2Adjuvant Treatment of Breast Cancer
SOLTAMOX is indicated: for the adjuvant treatment of adult patients with early stage estrogen receptor-positive breast cancer to reduce the occurrence of contralateral breast cancer in adult patients when used as adjuvant therapy for the treatment of breast cancer.
1.3Ductal Carcinoma in Situ
In adult women with DCIS, following breast surgery and radiation, SOLTAMOX is indicated to reduce the risk of invasive breast cancer [see Boxed Warning and Clinical Studies (14.3) ] .
1.4Reduction in Breast Cancer Incidence in Women at High Risk
SOLTAMOX is indicated to reduce the incidence of breast cancer in adult women at high risk for breast cancer. [see Boxed Warning and Clinical Studies (14.4) ] .
Contraindications
SOLTAMOX is contraindicated in patients with known hypersensitivity (e.g., angioedema, serious skin reactions) to tamoxifen or any other SOLTAMOX ingredient [see Adverse Reactions (6.2) ] . SOLTAMOX is contraindicated in patients who require concomitant warfarin therapy or have a history of deep vein thrombosis or pulmonary embolus if the indication for treatment is either reduction of breast cancer incidence in high-risk patients or risk reduction of invasive breast cancer after treatment of DCIS [see Warnings and Precautions (5.2) and Drug Interactions (7.2) ].
Known hypersensitivity to tamoxifen or any other SOLTAMOX ingredient ( 4 ) In patients who require concomitant warfarin therapy or have a history of deep vein thrombosis or pulmonary embolus, if the indication for treatment is either reduction of breast cancer incidence in high-risk patients or risk reduction of invasive breast cancer after treatment of DCIS ( 4 )
Uterine malignancies: Promptly evaluate abnormal vaginal bleeding in a woman with current or past tamoxifen use. ( 5.1 ) Thromboembolic events: Risk increases with coadministered chemotherapy. For treatment of breast cancer, consider risks and benefits in patients with a history of thromboembolic events. ( 5.2 ) 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. Tamoxifen has been reported to cause menstrual irregularity or amenorrhea.
5.2Thromboembolic Events
There is an increased incidence of thromboembolic events, including deep vein thrombosis and pulmonary embolism, during tamoxifen therapy. When tamoxifen is coadministered with chemotherapy, there is a further increase in the risk of thromboembolic events. For treatment of breast cancer, carefully consider the risks and benefits of tamoxifen in women with a history of thromboembolic events. For women with DCIS and for the reduction in breast cancer incidence in women at high risk, tamoxifen is contraindicated in women who require concomitant warfarin-type anticoagulant therapy or in women with a history of deep vein thrombosis or pulmonary embolus.
Advise patients to seek medical attention immediately if signs or symptoms of a thromboembolic event occur. Data from the NSABP P-1 trial in women at high risk for breast cancer show that participants receiving tamoxifen without a history of pulmonary emboli (PE) had a statistically significant increase in pulmonary emboli (events: 18 tamoxifen, 6 placebo; incidence rate per 1,000 women-years: 0.75 tamoxifen versus 0.25 placebo; RR = 3.01, 95% CI: 1.15 to 9.27) [see Clinical Studies (14.4) ].
Three of the pulmonary emboli, all in the tamoxifen arm, were fatal. Eighty-seven percent of the cases of pulmonary embolism occurred in women at least 50 years of age at randomization. Among women receiving tamoxifen, PE events occurred between 2 and 60 months (average = 27 months) from the start of treatment. In this same population, a non-statistically significant increase in deep vein thrombosis (DVT) was seen in the tamoxifen group (30 tamoxifen, 19 placebo; relative risk (RR) = 1.59, 95% CI: 0.86 to 2.98).
The same increase in relative risk was seen in women ≤49 and in women ≥50, although fewer events occurred in younger women. Women with thromboembolic events were at risk for a second related event (7 out of 25 women on placebo, 5 out of 48 women on tamoxifen) and were at risk for thromboembolic event and treatment related complications (0/25 on placebo, 4/48 on tamoxifen). Among women receiving tamoxifen, DVT events occurred between 2 and 57 months (average = 19 months) from the start of treatment.
In a small substudy (N = 81) of the NSABP-1 trial, there appeared to be no benefit to screening women for Factor V Leiden and Prothrombin mutations G20210A as a means to identify those who may not be appropriate candidates for tamoxifen therapy. In the NSABP P-1 trial, there was an increase in stroke among women randomized to tamoxifen compared to women randomized to placebo (events: 24 placebo; 34 tamoxifen; incidence rate per 1,000 women-years: 1.43 tamoxifen versus 1.00 placebo; RR = 1.42, 95% CI: 0.82 to 2.51).
Six of the 24 strokes in the placebo group were considered hemorrhagic in origin and 10 of the 34 strokes in the tamoxifen group were categorized as hemorrhagic. Seventeen of the 34 strokes in the tamoxifen group were considered occlusive and 7 were considered to be of unknown etiology. Fourteen of the 24 strokes on the placebo arm were reported to be occlusive and 4 of unknown etiology. Three strokes in the placebo group and 4 strokes in the tamoxifen group were fatal.
5.3Embryo-Fetal Toxicity
Tamoxifen can cause fetal harm when administered to a pregnant woman. There
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Interactions
Anastrozole and letrozole: Should not be used in combination with tamoxifen. ( 7.1 ) Warfarin: Do not use in patients taking tamoxifen for DCIS and for reduction in breast cancer incidence in women at high risk. ( 4 ) Closely monitor coagulation indices for increased anticoagulant effect when used with tamoxifen for metastatic breast cancer or as adjuvant therapy. ( 7.2 )
7.1Aromatase Inhibitors Anastrozole
The combination of anastrozole and tamoxifen did not demonstrate any benefit when compared to tamoxifen alone and should be avoided in all patients [see Clinical Studies (14.2) ] . In the ATAC trial, coadministration of anastrozole and tamoxifen in breast cancer patients reduced the anastrozole plasma concentration by 27% compared to that achieved with anastrozole alone. The tamoxifen concentration was not altered [see Clinical Pharmacology (12.3) ].
Letrozole The concomitant use of letrozole with tamoxifen is not recommended because the efficacy of the combination in the adjuvant treatment of breast cancer has not been established. Tamoxifen reduced the plasma concentration of letrozole by 38% when these drugs were co-administered [see Clinical Pharmacology (12.3) ]. 7.2. Warfarin A marked increase in anticoagulant effect may occur when tamoxifen is used in combination with warfarin.
Closely monitor coagulation indices in patients who are taking tamoxifen for either the treatment of metastatic breast cancer or as adjuvant therapy who require concomitant use of warfarin [see Contraindications (4) ] .
7.3Inducers of CYP3A4 Strong
CYP3A4 inducers should not be used with tamoxifen. Strong CYP3A4 inducers (e.g., rifampin) reduce tamoxifen AUC and C max [see Clinical Pharmacology (12.3) ] .
7.4Strong Inhibitors of CYP2D6
The impact on the efficacy of tamoxifen with co-administration of strong CYP2D6 inhibitors (e.g., paroxetine) is not well established. Some studies have shown that the efficacy of tamoxifen may be reduced when the drugs are co-administered as a result of reduced levels of potent active metabolites of tamoxifen . However, other studies have failed to demonstrate such an effect [see Clinical Pharmacology (12.3) ] .
7.5Drug-Laboratory Test Interactions
There are postmarketing reports of T 4 elevations in postmenopausal patients taking tamoxifen that may be explained by increases in thyroid-binding globulin. These elevations were not accompanied by clinical hyperthyroidism. Variations in the karyopyknotic index on vaginal smears and various degrees of estrogen effect on Pap smears have been seen in postmenopausal patients taking tamoxifen.
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary
SOLTAMOX can cause fetal harm when administered to a pregnant woman . There are no adequate and well- controlled studies of tamoxifen in pregnant women. There are limited postmarketing reports of vaginal bleeding, spontaneous abortions, birth defects, and fetal deaths in pregnant women taking tamoxifen. In a primate model administration of tamoxifen at doses 2 times higher than the maximum recommended human dose resulted in spontaneous abortion.
In rat and rabbit studies, doses of tamoxifen less than or equal to human doses resulted in increased embryotoxicity, abortions, and altered learning behaviors. Additionally, rodent models showed reproductive tract changes often associated with DES in offspring of both sexes [ see Data ]. Advise pregnant women of the potential risk to a fetus, including the potential long-term risk of a DES-like syndrome. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In embryofetal development studies in rats using doses significantly below those used in humans (0.01 to 0.03 times the recommended human dose on a mg/m 2 basis), a lower incidence of embryo implantation and a higher incidence of fetal death or delayed in utero growth occurred, along with slower learning behavior in some rat pups when compared to historical controls.
When pregnant rabbits received tamoxifen during organogenesis, abortion and premature delivery occurred at doses of greater than 0.125 mg/kg/day (about 0.05 times the daily maximum recommended human dose on a mg/m 2 basis). Although reversible nonteratogenic skeletal variations occurred in rat reproductive studies at doses less than or equal to the human dose, there were no teratogenic changes in either rats or rabbits.
In pregnant marmosets, administration of 10 mg/kg/day tamoxifen (about 2 times the daily maximum recommended human dose on a mg/m 2 basis) during organogenesis or in the last half of pregnancy terminated pregnancy in some animals. In pregnancies that continued, there were no malformations or deformations in offspring. In rodent models of fetal reproductive tract development, tamoxifen (at doses 0.002 to 2.4 times the daily maximum recommended human dose on a mg/m 2 basis) caused changes in both sexes that are similar to those caused by estradiol, ethynylestradiol and diethylstilbestrol.
Although the clinical relevance of these changes is unknown, some of these changes, especially vaginal adenosis, are similar to those seen in young women who were exposed to diethylstilbestrol in utero and who have a 1 in 1,000 risk of developing clear-cell adenocarcinoma of the vagina or cervix. To date, in utero exposure to tamoxifen has not been shown to cause vaginal adenosis, or clear-cell adenocarcinoma of the vagina or cervix, in young women; however, only a small number of young women have been exposed to tamoxifen in utero , and a smaller number have been followed long enough (to age 15 to 20) to determine whether vaginal or cervical neoplasia could occur as a result of this exposure.
Adverse reactions
The following serious adverse reactions are discussed below and elsewhere in the labeling: Uterine malignancies [see Boxed Warning , Warnings and Precautions (5.1) , and Clinical Studies (14.4) ] Thromboembolic events [see Boxed Warning , Warnings and Precautions (5.2) , and Clinical Studies (14.4) ] Embryo-Fetal Toxicity [see Warnings and Precautions (5.3) , and Use in Specific Populations (8.1 , 8.3) ] Liver cancer [see Warnings and Precautions (5.4) ] Most common adverse reactions: hot flashes, mood disturbances, vaginal discharge, vaginal bleeding, nausea, and fluid retention ( 6.1 ).
To report SUSPECTED ADVERSE REACTIONS, contact Mayne Pharma at 1-844-825-8500 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Patients with Metastatic Breast Cancer In patients treated with tamoxifen for metastatic breast cancer, the most frequent adverse reaction was hot flashes.
Other adverse reactions which were seen less commonly are hypercalcemia, peripheral edema, distaste for food, pruritus vulvae, depression, dizziness, lightheadedness, headache, hair thinning and/or partial hair loss, and vaginal dryness. Increased bone, tumor pain and local disease flare have occurred. Patients with soft tissue disease may have sudden increases in the size of preexisting lesions, sometimes associated with marked erythema within and surrounding the lesions and/or the development of new lesions.
When they occurred, the bone pain or disease flares were seen shortly after starting tamoxifen and generally subsided rapidly. Premenopausal Women with Metastatic Breast Cancer Table 1 summarizes the incidence of adverse reactions reported at a frequency of 2% or greater from clinical trials that compared tamoxifen therapy to ovarian ablation in premenopausal patients with metastatic breast cancer. Table 1: Adverse Reactions (frequency ≥2% in either arm) from Trials Comparing Tamoxifen to Ovarian Ablation in Premenopausal Women with Metastatic Breast Cancer % of Women Tamoxifen N=104 Ovarian Ablation N=100 Adverse Reactions Some women had more than one adverse reaction.
Flush 33 46 Amenorrhea 16 69 Altered menses 13 5 Oligomenorrhea 9 1 Bone pain 6 6 Menstrual disorder 6 4 Nausea 5 4 Cough/coughing 4 1 Edema 4 1 Fatigue 4 1 Musculoskeletal pain 3 0 Pain 3 4 Ovarian cyst(s) 3 2 Depression 2 2 Abdominal cramps 1 2 Anorexia 1 2 Adverse Reactions in Adjuvant Breast Cancer In the NSABP B-14 study, women with axillary node-negative breast cancer were randomized to 5 years of tamoxifen 20 mg per day or placebo following primary surgery [see Clinical Studies (14.2) ].
Table 2 presents the most common adverse reactions (mean follow-up of approximately 6.9 years) that were more common on tamoxifen than placebo. Table 2: Most Common Adverse Reactions in Women with Axillary Node-Negative Breast Cancer (Study NSABP B-14) % of Women Tamoxifen N=1,422 Placebo N=1,437 Hot flashes 64 48 Fluid retention 32 30 Vaginal discharge 30 15 Nausea 26 24 Irregular menses 25 19 Weight loss (>5%) 23 18 Skin changes 19 15 Increased SGOT 5 3 Increased bilirubin 2 1 Increased creatinine 2 1 Thrombocytopenia Defined as a platelet count of < 100,000/mm 3 2 1 Thrombotic events Two of the tamoxifen-treated patients who had thrombotic events died.
Deep vein thrombosis 0.8
0.2 Pulmonary embolism 0.5
0.2 Superficial phlebitis 0.4 0 In the Eastern Cooperative Oncology Group (ECOG) adjuvant breast cancer trial [see Clinical Studies (14.2) ] , tamoxifen or placebo was administered for 2 years to women following mastectomy. When compared to placebo, tamoxifen showed a higher incidence of hot flashes (19% vs. 8% for placebo). The incidence of all other adverse reactions was similar in the two treatment groups with the exception of thrombocytopenia, where the incidence for tamoxifen was 10% vs. 3% for placebo.
In other adjuvant studies [the Toronto study and Tamoxifen Adjuvant Trial Organization (NATO)], women received either tamoxifen or no therapy [see Clinical Studies (14.2) ] . In the Toronto study, hot flashes were observed in 29% of patients for tamoxifen vs. 1% in the untreated group. In the NATO trial, hot flashes and vaginal bleeding were reported in 2.8% and 2.0% of women, respectively, for tamoxifen vs. 0.2% for each in the untreated group.
Anastrozole Adjuvant Trial (ATAC: Arimidex, Tamoxifen, Alone or in Combination) – Study of Anastrozole Compared to Tamoxifen for Adjuvant Treatment of Early Breast Cancer At a median follow-up of 33 months, the combination of anastrozole and tamoxifen did not demonstrate an efficacy benefit when compared to tamoxifen monotherapy in all patients as well as in the hormone receptor- positive subpopulation. The combination treatment arm was discontinued from the trial.
The median duration of adjuvant treatment for safety evaluation was 59.8 months and 59.6 months for patients receiving anastrozole 1 mg and tamoxifen 20 mg monotherapy, respectively. Adverse reactions occurring with an incidence of at least 5% in either single-drug treatment group during treatment or within 14 days of the end of treatment are presented in Table 3. Table 3: Adverse Reactions Occurring with an Incidence of at Least 5% in Either Single-Drug Treatment Group During Treatment or Within 14 Days of the End of Treatment in the ATAC Trial % of Women Body system and adverse reactions by COSTART-preferred term COSTART: Coding Symbols for Thesaurus of Adverse Reaction Terms.
A patient may have had more than 1 adverse reaction, including more than 1 adverse reaction in the same body system. Tamoxifen N=3,094 Anastrozole N=3,092 Body as a whole Asthenia 18 19 Pain 16 17 Back pain 10 10 Accidental injury 10 10 Abdominal pain 9 9 Infection 9 9 Headache 8 10 Flu syndrome 6 6 Cyst 5 5 Chest pain 5 7 Neoplasm 5 5 Cardiovascular Vasodilatation 41 36 Hypertension 11 13 Digestive Nausea 11 11 Constipation 8 8 Diarrhea 7 9 Dyspepsia 6 7 Gastrointestinal disorder 5 7 Hemic and lymphatic Lymphedema 11 10 Anemia 5 4 Metabolic and nutritional Peripheral edema 11 10 Weight gain 9 9 Hypercholesterolemia 3 9 Musculoskeletal Arthritis 14 17 Arthralgia 11 15 Osteoporosis 7 11 Fracture 7 10 Bone pain 6 7 Joint disorder 5 6 Myalgia 5 6 Arthrosis 5 7 Nervous system Depression 12 13 Insomnia 9 10 Dizziness 8 8 Anxiety 6 6 Paresthesia 5 7 Respiratory Pharyngitis 14 14 Cough increased 9 8 Dyspnea 8 8 Sinusitis 5 6 Bronchitis 5 5 Skin and appendages Rash 13 11 Sweating 6 5 Special senses Cataract specified 7 6 Urogenital Urinary tract infection 10 8 Leukorrhea 9 3 Vaginal hemorrhage Vaginal hemorrhage without further diagnosis 6 4 Breast pain 6 8 Vaginitis 5 4 Vulvovaginitis 5 6 Breast neoplasm 5 5 Certain adverse reactions and combinations of adverse reactions were prospectively specified for analysis in the ATAC trial, based on the known pharmacologic properties and safety profiles of the two drugs (Table 4).
0.89 Musculoskeletal events Refers to joint symptoms, including joint disorder, arthritis, arthrosis and arthralgia. 29 36 1.32 1.19 to
1.47 Mood disturbances 18 19 1.10 0.97 to
1.25 Fatigue/asthenia 18 19 1.07 0.94 to
1.22 Vaginal discharge 13 4 0.24 0.19 to
0.30Nausea
and vomiting 12 13 1.03 0.88 to
1.19 Vaginal bleeding 10 5 0.50 0.41 to
0.61 Cataracts 7 6 0.85 0.69 to
1.04 All fractures 7 10 1.57 1.30 to
1.88Fractures
of spine, hip, or wrist 3 4 1.48 1.13 to 1
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Composition
Active ingredients
TAMOXIFEN CITRATE EQ 20MG BASE/10ML
Official product information
Drugs@FDA lists the approved labels, letters and reviews for application NDA021807.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
Eighty-eight percent of the strokes occurred in women at least 50 years of age at the time of randomization. Among women receiving tamoxifen, the stroke events occurred between 1 and 63 months (average = 30 months) from the start of treatment.
Table 4: Percentage of Patients with Pre-Specified Adverse Reactions in the ATAC Trial Patients with multiple events in the same category are counted only once in that category. % of Women Odds Ratio The odds ratios <1 favor anastrozole and those >1 favor tamoxifen. 95% CI Tamoxifen N=3,094 Anastrozole N=3,092 Hot flashes 41 36 0.80 0.73 to
