^ 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 (adjuvant breast cancer study in women with axillary node-negative breast cancer) and P-1 studies show no increase in other (non-uterine) cancers among patients receiving tamoxifen [see Clinical Studies (14.2, 14.4)]. Whether an increased risk for other (non-uterine) cancers is associated with tamoxifen is still unknown.
^ Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
^ Description
SOLTAMOX (tamoxifen citrate) oral solution is for oral administration. Tamoxifen citrate is an estrogen agonist/antagonist.
Chemically, tamoxifen is the trans-isomer of a triphenylethylene derivative. The chemical name is (Z)2-[4-(1,2- diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine 2-hydroxy-1,2,3- propanetricarboxylate (1:1). The structural formula, empirical formula, and molecular weight are as follows:
Tamoxifen citrate has a pKa′ of 8.85. The equilibrium solubility in water at 37°C is 0.5 mg/mL, and is 0.2 mg/mL in 0.02 N HCl at 37°C.
Each 10 mL of SOLTAMOX oral solution contains 20 mg tamoxifen, equivalent to 30.4 mg tamoxifen citrate. The oral solution is a sugar-free, clear colorless liquid, with licorice and aniseed odor and taste supplied in a 150 mL bottle with a dosing cup. SOLTAMOX oral solution contains the following inactive ingredients: ethanol, glycerol, propylene glycol, sorbitol solution, licorice flavor, aniseed flavor, purified water.
^ Clinical 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.
^ Overdosage
No specific treatment for SOLTAMOX overdosage is recommended, other than symptomatic treatment.
In a study of advanced metastatic cancer patients to determine the maximum tolerated dose of tamoxifen that could reverse multidrug resistance, the following adverse events were observed: acute neurotoxicity manifested by tremor, hyperreflexia, unsteady gait, and dizziness. These symptoms occurred within 3 to 5 days of beginning tamoxifen and cleared within 2 to 5 days after stopping therapy. No permanent neurologic toxicity was noted. One patient experienced a seizure several days after tamoxifen was discontinued and neurotoxic symptoms had resolved. The causal relationship of the seizure to tamoxifen therapy is unknown. Doses given in these patients were all greater than 400 mg/m2 loading dose (at least 6-fold higher than the recommended dosage), followed by maintenance doses of 150 mg/m2 of tamoxifen given twice a day (at least 6-fold higher than the recommended dosage).
In the same study, prolongation of the QT interval on the electrocardiogram was noted when patients were given doses higher than 250 mg/m2 loading dose (at least 6-fold higher than the recommended dose) , followed by maintenance doses of 80 mg/m2 of tamoxifen given twice a day. For a woman with a body surface area of 1.5 m2, the minimal loading dose and maintenance doses at which neurological symptoms and QT changes occurred were at least 6-fold higher in respect to the maximum recommended dose.
Signs observed at the highest doses following studies to determine LD50 in animals were respiratory difficulties and convulsions.
^ 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 also been reported. Patients should be advised to seek medical attention if they experience any visual disturbance.
In the NSABP P-1 trial, an increased risk of borderline significance of developing cataracts among those women without cataracts at baseline (540 tamoxifen; 483 placebo; RR = 1.13, 95% CI: 1.00 to 1.28) was observed. Among these same women, tamoxifen was associated with an increased risk of having cataract surgery (101 tamoxifen; 63 placebo; RR = 1.62, 95% CI: 1.18 to 2.22) [see Clinical Studies (14.4)]. Among all women on the trial (with or without cataracts at baseline), tamoxifen was associated with an increased risk of having cataract surgery (201 tamoxifen; 129 placebo; RR = 1.58, 95% CI: 1.26 to 1.97).
^ Hematologic Effects
Decreases in platelet counts, usually to 50,000-100,000/mm3, infrequently lower, have been reported in patients taking tamoxifen for breast cancer. In the NSABP P-1 trial, 6 women on tamoxifen and 2 on placebo experienced grade 3 to 4 decreases in platelet counts (≤50,000/mm3). In patients with significant thrombocytopenia, hemorrhagic episodes have occurred, but it is uncertain if these episodes were due to tamoxifen therapy.
Leukopenia has been observed, sometimes in association with anemia and/or thrombocytopenia. There have been reports of neutropenia and pancytopenia, including some severe cases, in patients receiving tamoxifen. Perform periodic complete blood counts, including platelet counts.
^3 Dosage Forms And Strengths
SOLTAMOX oral solution: Each 10 mL of solution contains 20 mg tamoxifen, equivalent to 30.4 mg tamoxifen citrate.
^ Pediatric Use
The safety and effectiveness of SOLTAMOX in pediatric patients have not been established.
^ Hypercalcemia In Patients With Metastatic Breast Cancer
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 occurs, treat as appropriate; if the hypercalcemia is severe, discontinue tamoxifen.
^ Ductal 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)].
^4 Contraindications
^ Strong 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)].
^ Postmarketing Experience
The following adverse reactions have been identified during postapproval use of tamoxifen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Skin and Subcutaneous Disorders: Erythema multiforme, Stevens-Johnson syndrome, bullous pemphigoid
Respiratory, Thoracic, Mediastinal Disorders: Interstitial pneumonitis
Immune System Disorders: Hypersensitivity reactions including angioedema; in some of these cases, the time to onset was more than one year.
Gastrointestinal Disorders: Elevation of serum triglyceride levels, in some cases with pancreatitis
^ How Supplied/storage And Handling
SOLTAMOX oral solution is a sugar-free, clear colorless liquid, with licorice and aniseed odor and taste. It is supplied in a 150 mL bottle with a dosing cup intended for the measurement of SOLTAMOX oral solution only. Each 10 mL of solution contains 20 mg tamoxifen, equivalent to 30.4 mg tamoxifen citrate.
NDC# 51862-682-01
^ Carcinogenesis, Mutagenesis, Impairment Of Fertility
A carcinogenesis study in rats at doses of 5, 20, and 35 mg/kg/day (approximately 1, 3, and 7× higher than the daily maximum recommended human dose on a mg/m2 basis) administered by oral gavage for up to 2 years resulted in 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 (approximately 10× the daily maximum recommended human dose on a mg/m2 basis); hepatocellular neoplasia was exhibited at 3 to 6 months. In addition, granulosa cell ovarian tumors and interstitial cell testicular tumors were observed in two separate mouse studies. The mice were administered the trans and racemic forms of tamoxifen for 13 to 15 months at doses of 5, 20, and 50 mg/kg/day (approximately 0.5, 2, and 5× the daily recommended human dose on a mg/m2 basis).
Tamoxifen has been found to increase levels of micronucleus formation in vitro in the human lymphoblastoid cell line (MCL-5). No genotoxic potential was found in a conventional battery of in vivo and in vitro assays with prokaryotic and eukaryotic test systems with or without drug metabolizing enzymes; however, increased levels of DNA adducts were observed by 32P post-labeling in DNA from rat liver and cultured human lymphocytes. Based on these findings, tamoxifen is genotoxic.
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.
^ Adjuvant Treatment Of Breast Cancer
SOLTAMOX is indicated:
^ Ductal Carcinoma In Situ
NSABP B-24 was a double-blind, randomized trial in women with DCIS that compared the addition of another formulation of tamoxifen or placebo to treatment with lumpectomy and radiation therapy. The primary objective was to determine whether 5 years of tamoxifen therapy (20 mg per day) reduced the incidence of invasive breast cancer in the ipsilateral or contralateral breast. In this trial, 1,804 women were randomized to receive either tamoxifen or placebo for 5 years: 902 women were randomized to tamoxifen 10 mg tablets twice a day and 902 women were randomized to placebo. Follow-up data were available for 1,798 women and the median duration of follow-up was 74 months.
The tamoxifen and placebo groups were balanced for baseline demographic and prognostic factors. Over 80% of the tumors were less than or equal to 1 cm in their maximum dimension, were not palpable, and were detected by mammography alone. Over 60% of the study population was postmenopausal. In 16% of patients, the margin of the resected specimen was reported as being positive after surgery. Approximately half of the tumors were reported to contain comedo necrosis.
The incidence of invasive breast cancer was reduced by 43% among women assigned to tamoxifen (44 cases on tamoxifen, 74 cases on placebo; p = 0.004; RR = 0.57, 95% CI: 0.39 to 0.84). No data are available regarding the ER status of the invasive cancers. The stage distribution of the invasive cancers at diagnosis was similar to that reported annually in the SEER data base.
Results are shown in Table 6. At 5 years from study entry, survival was similar in the placebo and tamoxifen groups.
^ Laboratory Monitoring
Perform periodic complete blood counts, including platelet counts, and periodic liver function tests during therapy with SOLTAMOX. Periodic monitoring of plasma triglycerides and cholesterol may be indicated in patients with preexisting hyperlipidemias.
^ Metastatic Breast Cancer
SOLTAMOX is indicated for the treatment of adult patients with estrogen receptor-positive metastatic breast cancer.
^6 Adverse Reactions
The following serious adverse reactions are discussed below and elsewhere in the labeling:
^Principal Display Panel - Ml Container Carton
NDC 51862-682-01
SUGARFREE
soltamox® (tamoxifen citrate)oral solution
equivalent to20 mg/10 mLTamoxifen
Rx only
150 mL
^ Embryo-fetal Toxicity
Tamoxifen can cause fetal harm when administered to a pregnant woman. There are 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 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 in the offspring. Additionally, rodent models showed reproductive tract changes often associated with diethylstilbestrol (DES) in offspring of both sexes.
Advise pregnant women of the potential risks to a fetus, including the potential long-term risk of a DES-like syndrome. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with tamoxifen and for 2 months following the last dose [see Use in Specific Populations (8.1, 8.3)].
^ . 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)].
^ References
1Cancer.gov [Internet]. Bethesda (MD):National Cancer Institute [updated 2011 May 16]. Available from: http://www.cancer.gov/bcrisktool/.
^ Inducers Of Cyp3a4
Strong CYP3A4 inducers should not be used with tamoxifen. Strong CYP3A4 inducers (e.g., rifampin) reduce tamoxifen AUC and Cmax [see Clinical Pharmacology (12.3)].
^ Pharmacogenomics
The impact of CYP2D6 polymorphisms on the efficacy of tamoxifen is not well established.
CYP2D6 poor metabolizers carrying two non-functional alleles exhibit significantly lower endoxifen plasma concentrations compared to patients carrying one or more fully functional alleles of CYP2D6.
In patients with estrogen receptor-positive breast cancer who were participating in the WHEL (Women's Health Eating and Living) Study (NCT00003787), the mean (SD) serum concentration of endoxifen was 22.8 (11.3), 15.9 (9.2), 8.1 (4.9) and 5.6 (3.8) ng/mL in 27 ultrarapid, 1,097 normal, 164 intermediate and 82 poor metabolizers (p<0.001), respectively. This finding is consistent with other published studies that report lower endoxifen concentrations in poor metabolizers compared to normal metabolizers.
^ Thromboembolic 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. 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.
^ Drug-laboratory Test Interactions
There are postmarketing reports of T4 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.
^ Mechanism Of Action
Tamoxifen is an estrogen agonist/antagonist. Tamoxifen competes with estrogen for binding to the estrogen receptor, which can result in a decrease in estrogen receptor signaling-dependent growth in breast tissue. Tamoxifen has demonstrated antitumor activity against human breast cancer cell lines xenografted in mice. The drug has been shown to inhibit the induction of rat mammary carcinoma induced by dimethylbenzanthracene (DMBA) and to cause the regression of already established DMBA-induced tumors.
^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 (14.4)]:
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 (5)]. For most patients already diagnosed with breast cancer, the benefits of tamoxifen outweigh its risks.
^ Reduction 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)].
^Medication Guidesoltamox® (sol-ta-mox)(tamoxifen Citrate)oral Solution
Before taking SOLTAMOX, you and your healthcare provider should talk about the possible benefits and risks.
What is the most important information I should know about SOLTAMOX?
SOLTAMOX can cause serious side effects, including:
What is SOLTAMOX?
SOLTAMOX is a prescription medicine used:
It is not known if SOLTAMOX is safe and effective in children.
Do not take SOLTAMOX if you:
Before taking SOLTAMOX, tell your healthcare provider about all of your medical conditions, including if you:
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
Know the medicines you take. Keep a list of them to show to your healthcare provider and pharmacist when you get a new medicine.
How should I take SOLTAMOX?
What are the possible side effects of SOLTAMOX?
SOLTAMOX can cause serious side effects, including:
The most common side effects of SOLTAMOX include:
Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
These are not all the possible side effects of SOLTAMOX.
Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store SOLTAMOX?
Keep SOLTAMOX and all medicines out of the reach of children.
General information about the safe and effective use of SOLTAMOX.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use SOLTAMOX for a condition for which it was not prescribed. Do not give SOLTAMOX to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about SOLTAMOX that is written for health professionals.
What are the ingredients in SOLTAMOX?
Active ingredient: tamoxifen citrate
Inactive ingredients: ethanol, glycerol, propylene glycol, sorbitol solution, licorice flavor, aniseed flavor, purified water.
Distributed by: Mayne Pharma Greenville, NC 27834
The brands listed (other than SOLTAMOX®) are registered trademarks of their respective owners.
For more information, call 1-844-825-8500.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Revised: 11/2020
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