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  • CLASSES

    Cytostatic Anti-estrogens
    Selective Estrogen Receptor Modulators/SERMS

    BOXED WARNING

    Anticoagulant therapy, chemotherapy, stroke, thromboembolism

    There is an increased incidence of thromboembolic events, including DVT and PE, during tamoxifen therapy; this risk is increased when tamoxifen is coadministered with chemotherapy. Tamoxifen is contraindicated in patients who require concomitant anticoagulant therapy or have a history of thromboembolism (e.g., deep vein thrombosis (DVT), pulmonary embolus (PE), stroke) if the indication is risk reduction for high-risk patients or risk reduction of invasive breast cancer after ductal carcinoma in situ (DCIS) treatment. For the treatment of breast cancer, carefully consider the risks and benefits of tamoxifen in patients with a history of thromboembolic events. 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 DCIS considering tamoxifen to reduce the risk of developing invasive breast cancer. For most patients already diagnosed with breast cancer, the benefits of tamoxifen outweigh its risks. Advise patients to seek medical attention immediately if signs or symptoms of a thromboembolic event occur. During the NSABP P-1 trial, women without a history of PE had a statistically significant increase in the incidence of PE. In this same population, there was a nonstatistically 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; the relative risk of DVT was not statistically different depending on age. Women with thromboembolic events were at risk for a second related event and were at risk for treatment-related complications. In a small substudy of the NSABP-1 trial (n = 81), 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.[63589]

    Endometrial cancer, endometrial hyperplasia, new primary malignancy, uterine cancer

    An increased risk of endometrial changes (including hyperplasia and polyps) and new primary malignancy (endometrial cancer and uterine cancer) has been reported in association with tamoxifen treatment for any indication. 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 also been reported. Uterine sarcoma has been reported to occur more frequently among long-term tamoxifen users (more than 2 years) versus non-users. Use tamoxifen with caution in patients with preexisting endometrial hyperplasia. Discuss the risks versus benefits of tamoxifen therapy with women at high risk of breast cancer considering tamoxifen preventative therapy, as well as with women who have ductal carcinoma in situ (DCIS) considering tamoxifen to decrease the risk of developing invasive breast cancer. The benefits of tamoxifen therapy for the adjuvant treatment of breast cancer or for advanced breast cancer generally outweigh the risks in most patients. Patients receiving or having previously received tamoxifen should have annual gynecological examinations 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). There are no data to suggest that routine endometrial sampling in asymptomatic women taking tamoxifen is beneficial. Second primary tumors at sites other than the endometrium have been reported following the treatment of breast cancer with tamoxifen in clinical trials; however, data from the NSABP B-14 and P-1 studies show no increase in non-uterine cancers. Whether an increased risk for non-uterine cancers is associated with tamoxifen is still unknown.[63589]

    DEA CLASS

    Rx

    DESCRIPTION

    Selective estrogen receptor modulator; estrogen agonist/antagonist
    Used for the prevention and treatment of specific types of breast cancer
    Discuss benefits vs. serious risks with patients at high risk for breast cancer and patients with DCIS

    COMMON BRAND NAMES

    Nolvadex, Soltamox

    HOW SUPPLIED

    Nolvadex/Tamoxifen/Tamoxifen Citrate Oral Tab: 10mg, 20mg
    Soltamox Oral Sol: 5mL, 10mg

    DOSAGE & INDICATIONS

    For the treatment of breast cancer.
    For the adjuvant treatment of early stage estrogen receptor (ER)-positive breast cancer.
    Oral dosage
    Adult females

    20 mg once daily for 5 to 10 years. Doses greater than 20 mg daily do not provide additional clinical benefit. The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) conducted worldwide overviews of systemic adjuvant therapy for early breast cancer in 1985, 1990, 1995, 1998 and 2011. Women with ER-positive or ER-unknown breast cancer were entered into trials comparing tamoxifen to no adjuvant therapy (n =17,076), or trials comparing tamoxifen plus chemotherapy to chemotherapy alone (n = 12,365). Treatment with tamoxifen for approximately 5 years significantly improved overall survival at 10 years compared to control in both node-positive (n = 15,898; 61.4% vs. 50.5%) and node-negative (n = 13,543; 78.9% vs. 73.3%) disease. The recurrence-free survival rate at 10 years was also significantly improved in both node-positive (59.7% vs. 44.5%) and node-negative (79.2% vs. 64.3%) patients. In women with ER-positive or ER-unknown breast cancer who received 1 year or less, 2 years, or about 5 years of tamoxifen, the proportional reductions in mortality were 12%, 17%, and 26%, respectively; corresponding reductions in breast cancer recurrence were 21%, 29%, and 47%, respectively. The benefit is less clear for women with ER-poor breast cancer, in whom the proportional reduction in recurrence was 10% for all durations taken together, or 9% if contralateral breast cancers are excluded; the reduction in mortality was 6%. These effects were similar regardless of age and concurrent chemotherapy. Continuing tamoxifen for up to 10 years has had conflicting results, with an improved risk of recurrence in one study (ATLAS) and no benefit in two others including NSABP-B14.[63589]

    For the treatment of estrogen receptor (ER)-positive metastatic breast cancer.
    Oral dosage
    Adults

    20 to 40 mg PO daily; doses greater than 20 mg per day should be given in divided doses (morning and evening). In 3 prospective, randomized studies in premenopausal women with advanced breast cancer, the objective response rate, time to treatment failure, and survival were similar with tamoxifen compared to ovarian ablation (oophorectomy or ovarian irradiation); limited patient accrual prevented a demonstration of equivalence. A limited number of patients with disease progression during tamoxifen therapy responded to subsequent ovarian ablation. Published results from 119 evaluable patients and 13 evaluable case reports demonstrated that tamoxifen is effective for the palliative treatment of men with metastatic breast cancer, with a 50% objective response rate.[63589]

    For the treatment of women with ductal carcinoma in situ (DCIS) following breast surgery and radiation, to reduce the risk of invasive breast cancer.
    Oral dosage
    Adult females

    20 mg PO once daily for 5 years. In a randomized, double-blind study (NSABP B-24), the incidence of invasive breast cancer was reduced by 43% in women randomized to receive tamoxifen. Survival was similar for both the placebo and tamoxifen treatment groups. In a randomized, double-blind clinical trial in women with DCIS (NSABP B-24; n = 1,804), treatment with tamoxifen following lumpectomy and radiation significantly reduced the incidence of invasive breast cancer by 43% compared with placebo; no data are available regarding the estrogen receptor (ER) status of the invasive cancers. The stage distribution of the invasive cancers at diagnosis was similar to that reported anually in the SEER database. Fewer deaths occurred in the tamoxifen arm (28 vs. 32 patients); however, patients in the tamoxifen arm experienced more uterine malignancies (9 vs. 4 patients), strokes (7 vs. 2 patients), and thromboembolic events (15 vs. 5 patients).

    For the treatment of hormone receptor (HR)-positive, HER2-negative metastatic breast cancer in postmenopausal women with secondary aromatase inhibitor resistance, in combination with everolimus†.
    Oral dosage
    Postmenopausal females

    20 mg PO once daily plus everolimus 10 mg PO once daily until disease progression or unacceptable toxicity. In a randomized phase 2 study in postmenopausal women with estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer and primary or secondary resistance to aromatase inhibitors (n = 111), treatment with tamoxifen plus everolimus significantly improved clinical benefit rate (61.1% vs. 42.1%), time to progression (TTP) (7.6 months vs. 4.5 months), and overall survival (OS) (16 vs. 31 events) compared with tamoxifen alone. In exploratory analyses, a statistically significant TTP and OS benefit was observed with combination therapy in women with secondary resistance (TTP, 14.8 months vs. 5.5 months; OS, 4 events vs. 16 events) but not primary resistance (TTP, 5.4 months vs. 3.8 months; OS, 12 events vs. 15 events). A higher incidence of grade 3 and 4 stomatitis and anorexia was reported in the combination therapy arm; 22% of patients receiving combination therapy and 7% of patients treated with tamoxifen alone discontinued treatment due to adverse events.

    For the adjuvant treatment of breast cancer, to reduce the occurrence of contralateral breast cancer.
    Oral dosage
    Adults

    20 mg once daily for 5 to 10 years. Doses greater than 20 mg daily do not provide additional clinical benefit. The incidence of contralateral breast cancer was reduced in both premenopausal and postmenopausal breast cancer patients receiving adjuvant tamoxifen compared to placebo in a large overview analysis including 32,422 patients. In this analysis, proportional reductions in the incidence of contralateral breast cancer among women receiving tamoxifen for 1 year or less, 2 years, and about 5 years duration were 13%, 26%, and 47%, respectively, independent of age and estrogen receptor (ER)-status of the primary tumor; the reduction in the incidence of contralateral breast cancer was significant with longer tamoxifen duration. Treatment with about 5 years of tamoxifen reduced the annual incidence of contralateral breast cancer from 7.6 per 1,000 patients in the control group to 3.9 per 1,000 patients in the tamoxifen group. At an increased daily dose of 40 mg in a Sweedish Breast Cancer Cooperative Group trial, the reduction in second primary breast cancers was similar (40%).

    For breast cancer prophylaxis in women who are at high risk for developing breast cancer.
    Oral dosage
    Adult females at risk for breast cancer

    20 mg PO once daily for 5 years. In a double-blind, placebo-controlled clinical trial (the Breast Cancer Prevention Trial), women older than 35 years of age and at high risk for invasive breast cancer were randomized to receive either tamoxifen or placebo for 5 years (n = 13,388); "high risk" was defined as a 5-year predicted risk of breast cancer of 1.67% or higher. Treatment with tamoxifen significantly reduced the incidence of invasive breast cancer by 44% after a median follow-up of 4.2 years; this reduction was significant in each age group (49 years or less, 50 to 59 years, and 60 years or more), in women with or without LCIS, and in each absolute risk level. The decrease was evident in the incidence of small estrogen receptor-positive tumors, but not in the incidence of ER-negative tumors or larger tumors. A nonsignificant decrease in the incidence in DCIS was observed (RR 0.66). There was no significant difference in overall mortality, breast cancer-related mortality, or acute ischemic cardiac events. A subgroup analysis suggested a difference in effect on bone mineral density (BMD) related to menopausal status: there was no evidence of bone loss of the lumbar spine and hip in postmenopausal women, but there was significant bone loss in premenopausal women. Tamoxifen increased the risk for endometrial cancer, DVT, PE, stroke, cataract formation, and cataract surgery.[63589]

    For the treatment of malignant melanoma†.
    For the first-line treatment of metastatic malignant melanoma in combination with dacarbazine, cisplatin, and carmustine†.
    Oral dosage
    Adults

    10 mg PO twice daily or 20 mg PO once daily in combination with carmustine, dacarbazine, and cisplatin (DBCT regimen). First-line treatment with DBCT did not significantly improve the median overall survival (OS) time (7.7 vs 6.3 months), 1-year OS rate (22% vs 27%), or overall response rate (ORR) (16.8% vs 9.9%) compared with single-agent dacarbazine in 240 patients in a multicenter, randomized phase III trial. Additionally, the DBCT regimen did not significantly improve median OS time (202 vs 199 days), 1-year OS rate (22.6% vs 30.6%), or ORR (26.4% vs 17.3%) compared with dacarbazine and interferon alfa-2a in 105 patients in another randomized phase III trial. In this study, treatment with DBCT was associated with significantly longer hospitalization and 2 treatment-related deaths. Serious toxicity that occurred significantly more often with DBCT included grade 3 and 4 hematologic toxicity and increased serum creatinine levels.

    For the treatment of metastatic malignant melanoma in combination with other agents†.
    Oral dosage
    Adults

    Several dosage regimens have been employed. Continuous daily dosing of 20 mg or 20 mg/m2  (rounded to nearest 10 mg) PO daily in conjunction with other chemotherapy agents has been used. In clinical trials, response rates with tamoxifen added to combination therapy range from 14.3—31.9%. Few trials have reported a significant improvement in OS with the addition of tamoxifen.

    For the treatment of malignant glioma†.
    Oral dosage
    Adults

    Multiple dosage regimens have been studied. Salvage tamoxifen 80 mg/m2 PO once daily (or divided twice daily) produced an ORR of 17% in a phase II trial of 24 patients with recurrent anaplastic astrocytomas. Tamoxifen 100 mg PO once daily in combination with procarbazine 100 mg/m2 PO once daily produced an ORR of 29.5% in the second-line treatment of patients with high-grade gliomas. Additionally, tamoxifen 20 mg/m2 PO every 6 hours (escalated 20 mg/day until target reached) was given until disease progression in combination with radiation therapy (30 fractions x 2.0 Gy). Among 75 patients with supratentorial glioblastoma multiforme, combination treatment produced a median overall survival of 9.7 months.

    For the treatment of relapsed or refractory ovarian cancer†.
    Oral dosage
    Adults

    Studies have used 20 mg PO twice daily. Of 105 patients with advanced ovarian cancer treated with tamoxifen, 10% demonstrated a complete response (CR) and 8% a partial response; 38% had disease stabilization. Of the 9 patients with a CR, 8 (89%) had elevated estrogen receptor levels, as compared to patients with stable or progressive disease where only 59% had measurable estrogen receptors. In a reanalysis of this trial, 77 patients with cisplatin-refractory disease had an ORR of 13% with tamoxifen.

    For the treatment of desmoid tumor† or fibromatosis†.
    Oral dosage
    Adults and Adolescents >= 15 years

    Tamoxifen 120 mg PO once daily in combination with sulindac 300 mg PO once daily for the treatment of desmoid tumors. In a study of 25 patients (17 familial adenomatous polyposis-associated, 8 sporadic) with desmoid tumors, among 20 patients administered tamoxifen and sulindac, 3 complete responses, 3 partial responses, and 8 cases of stable disease were observed.]

    Infants >= 11 months and Children

    In a small case series, 6 pediatric patients with desmoid tumors underwent multimodality treatment that included tamoxifen 1 mg/kg PO once daily in combination with diclofenac 2 mg/kg per rectum twice daily. Patients ranged in age from 11 months to 9 years. With varying periods of follow-up, 2 patients achieved no evidence of disease (2.6 years, 3.7 years follow-up), 2 patients had minimal residual tumor (1.1 years, 7.5 years), and 2 patients had stable disease (1 year, 11 years).

    For stimulation of ovulation in the treatment of infertility†.
    Oral dosage
    Adult females

    Limited data suggest 20 to 80 mg/day PO for 5 days may be as effective as clomiphene in ovulation induction. In one study, tamoxifen induced ovulation in 44.2% of patients compared to 45.1% induction with clomiphene (P=NS). Studies have typically started at doses of 20 mg/day PO and titrated up after a lack of ovulation for 1 to 2 cycles. Administering tamoxifen on cycle days 2 thru 6, 3 thru 7, or 5 thru 9 have been studied during clinical trials.

    For the prevention or treatment of mastalgia† and/or gynecomastia†.
    For the treatment of mastalgia†.
    Oral dosage
    Adults

    10 to 20 mg/day PO for 3 to 6 months has been shown to be effective in the treatment of mastalgia. A meta-analysis found significant pain relief with tamoxifen as compared to placebo (RR 1.92, 95% CI 1.52—2.59).

    For the treatment of mastalgia† and or gynecomastia† in men with prostate cancer.
    Oral dosage
    Adult males

    Trials suggest 20 mg/day PO for up to 1 year in men taking bicalutamide is effective in reducing the incidence of gynecomastia and breast pain. Patients randomized to bicalutamide only or tamoxifen plus bicalutamide experienced a rate of gynecomastia of 73% vs. 10%, respectively (p < 0.001), and a rate of breast pain of 39% vs. 6%, respectively (p = 0.006). In another study, lower doses of tamoxifen (1 to 10 mg/day PO) were not as effective as 20 mg/day PO.

    For the treatment of postmenopausal osteoporosis†.
    Oral dosage
    Adults

    In a randomized, double-blind trial of postmenopausal women with breast cancer, tamoxifen 10 mg PO twice daily for 2 years increased bone density of lumbar spine but not radial bone density. The risk or incidence of fractures in this study population was not assessed.

    For the treatment of McCune-Albright Syndrome† and precocious puberty†.
    Oral dosage
    Female Children 2—10 years of age

    A single, uncontrolled trial of tamoxifen 20 mg PO once daily for 12 months was conducted in 28 female patients with McCune-Albright Syndrome and precocious puberty manifested by physical signs of pubertal development, episodes of vaginal bleeding, and/or advanced bone age. Tamoxifen treatment was associated with a 50% reduction in frequency of vaginal bleeding. Not all patients improved on treatment and a few patients not reporting vaginal bleeding in the 6 months prior to enrollment reported menses on treatment. Tamoxifen was associated with a reduction in mean rate of increase of bone age. Linear growth rate was decreased during tamoxifen treatment in the majority of patients. This change was not seen uniformly across all stages of bone maturity; all recorded response failures occurred in patients with bone ages < 7 years at screening. 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, as an increase in the incidence of endometrial adenocarcinoma and uterine sarcoma has been noted in adult females treated with tamoxifen, continued monitoring of McCune-Albright patients treated with tamoxifen for long-term uterine effects is recommended. The safety and efficacy of tamoxifen in these patients beyond one year of treatment has not been studied.

    For the treatment of bipolar disorder† (bipolar I disorder) in patients displaying mania or mixed episodes with or without psychotic features.
    Oral dosage
    Adults

    Limited data suggest that 40 mg PO twice daily may be effective in decreasing the Young Mania Rating Scale (YMRS) and Clinical Global Impression-Mania (CGI-Mania) scores. In a double-blind, placebo-controlled study of 66 patients, tamoxifen (N=35) was compared to placebo (n = 31) for 3 weeks; patients were able to take adjunctive oral lorazepam up to 5 mg/day. The YMRS score decreased from a mean of 38.6 to 20.3 by the end of week 3 in patients treated with tamoxifen and increased from a baseline mean of 37.2 to 40.1 in placebo treated patients; in patients treated with tamoxifen, the weekly YMRS score decreased by an average of 5.85 points while the score increased by 1.5 points per week in patients taking placebo (p < 0.001). Similarly, improvements in the CGI-Mania score were better in patients taking tamoxifen (decrease of 0.73 points/week for tamoxifen vs. an increase of 0.1 points/week for placebo, p < 0.001). The treatment was well-tolerated by all patients. It should be noted that patients were hospitalized for the entire 3 weeks of the study and that the majority of patients in the tamoxifen group (88%) were still symptomatic after 3 weeks of tamoxifen. The authors note that the population studied consisted of patients considered to be difficult to treat (baseline YMRS score higher than similarly designed studies), and patients receiving placebo in other studies have not experienced a worsening of symptoms as they did in the current evaluation. Longer studies are needed to determine the full impact of tamoxifen on bipolar disorder as 3-week studies typically can demonstrate an improvement in symptoms, but not function.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    FDA-approved dosing: 20 mg PO twice daily.
    Off-label dosing: Up to 120 mg PO once daily or 80 mg/m2 PO once daily (or divided twice daily).

    Geriatric

    FDA-approved dosing: 20 mg PO twice daily.
    Off-label dosing: Up to 120 mg PO once daily or 80 mg/m2 PO once daily (or divided twice daily).

    Adolescents

    FDA labelling: Safety and efficacy have not been established.
    Off-label dosing: Up to 120 PO once daily.

    Children

    FDA labelling: Safety and efficacy have not been established.
    Off-label dosing: Up to 1 mg/kg PO once daily or 20 mg PO once daily.

    Infants

    FDA labelling: Safety and efficacy have not been established.
    Off-label dosing: Up to 1 mg/kg PO once daily.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration

    Tamoxifen may be taken with or without food.
    If a dose of tamoxifen is missed, administer the dose as soon as possible. If it is almost time for the next dose, skip the missed dose and administer the next dose at the regularly scheduled time.[63589]

    STORAGE

    Nolvadex:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Soltamox:
    - Do not freeze
    - Do not refrigerate
    - Product should be used within 3 months after opening
    - Protect from light
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    Anticoagulant therapy, chemotherapy, stroke, thromboembolism

    There is an increased incidence of thromboembolic events, including DVT and PE, during tamoxifen therapy; this risk is increased when tamoxifen is coadministered with chemotherapy. Tamoxifen is contraindicated in patients who require concomitant anticoagulant therapy or have a history of thromboembolism (e.g., deep vein thrombosis (DVT), pulmonary embolus (PE), stroke) if the indication is risk reduction for high-risk patients or risk reduction of invasive breast cancer after ductal carcinoma in situ (DCIS) treatment. For the treatment of breast cancer, carefully consider the risks and benefits of tamoxifen in patients with a history of thromboembolic events. 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 DCIS considering tamoxifen to reduce the risk of developing invasive breast cancer. For most patients already diagnosed with breast cancer, the benefits of tamoxifen outweigh its risks. Advise patients to seek medical attention immediately if signs or symptoms of a thromboembolic event occur. During the NSABP P-1 trial, women without a history of PE had a statistically significant increase in the incidence of PE. In this same population, there was a nonstatistically 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; the relative risk of DVT was not statistically different depending on age. Women with thromboembolic events were at risk for a second related event and were at risk for treatment-related complications. In a small substudy of the NSABP-1 trial (n = 81), 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.[63589]

    Endometrial cancer, endometrial hyperplasia, new primary malignancy, uterine cancer

    An increased risk of endometrial changes (including hyperplasia and polyps) and new primary malignancy (endometrial cancer and uterine cancer) has been reported in association with tamoxifen treatment for any indication. 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 also been reported. Uterine sarcoma has been reported to occur more frequently among long-term tamoxifen users (more than 2 years) versus non-users. Use tamoxifen with caution in patients with preexisting endometrial hyperplasia. Discuss the risks versus benefits of tamoxifen therapy with women at high risk of breast cancer considering tamoxifen preventative therapy, as well as with women who have ductal carcinoma in situ (DCIS) considering tamoxifen to decrease the risk of developing invasive breast cancer. The benefits of tamoxifen therapy for the adjuvant treatment of breast cancer or for advanced breast cancer generally outweigh the risks in most patients. Patients receiving or having previously received tamoxifen should have annual gynecological examinations 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). There are no data to suggest that routine endometrial sampling in asymptomatic women taking tamoxifen is beneficial. Second primary tumors at sites other than the endometrium have been reported following the treatment of breast cancer with tamoxifen in clinical trials; however, data from the NSABP B-14 and P-1 studies show no increase in non-uterine cancers. Whether an increased risk for non-uterine cancers is associated with tamoxifen is still unknown.[63589]

    Anemia, bone marrow suppression, leukopenia, neutropenia, thrombocytopenia

    Tamoxifen should be used with caution in patients with pre-existing bone marrow suppression; periodically monitor complete blood counts in patients receiving tamoxifen. Thrombocytopenia, infrequently below 50,000 cells/mm3, has been reported in patients taking tamoxifen for breast cancer. Leukopenia, neutropenia, anemia, and pancytopenia have also been reported.

    Cataracts, visual disturbance, visual impairment

    Use tamoxifen with caution in patients with cataracts or visual impairment at baseline. Advise patients to seek medical attention if they experience any visual disturbance. Tamoxifen can cause visual disturbances including corneal changes, decrement in color vision perception, retinal vein thrombosis, and retinopathy. An increased incidence of cataracts and the need for cataract surgery have also been reported in women without cataracts at baseline.

    Hypercalcemia

    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 hypercalcemia is severe, discontinue tamoxifen.[63589]

    Hepatic disease

    Use tamoxifen with caution in patients with baseline hepatic disease; monitor liver function periodically. Tamoxifen has been associated with changes in liver enzymes; rarely, fatty liver, cholestasis, hepatitis, and hepatic necrosis have also been reported including fatalities. In most reported cases, the relationship to tamoxifen is uncertain; however, positive rechallenges and dechallenges have been reported.[63589]

    Hypercholesterolemia, hyperlipidemia, hypertriglyceridemia

    In patients with preexisting hyperlipidemia (i.e., hypercholesterolemia and hypertriglyceridemia), periodically monitor plasma triglycerides and cholesterol. Hypercholesterolemia has been reported in patients treated with tamoxifen in clinical trials.

    Children

    The safety and effectiveness of tamoxifen in children have not been established. The safety and efficacy of tamoxifen for girls aged 2 to 10 years with McCune-Albright Syndrome and precocious puberty, including long-term effects, have also not been established. Tamoxifen 20 mg daily was administered for up to 12 months in a multicenter, uncontrolled trial, in a heterogeneous group of girls (age, 2 to 10 years) with McCune-Albright syndrome and precocious puberty manifested by physical signs of pubertal development, episodes of vaginal bleeding, and/or advanced bone age (bone age of at least 12 months beyond chronological age) (n = 28). Treatment with tamoxifen was associated with a 50% reduction in frequency of vaginal bleeding episodes by patient or family report (baseline, mean 3.56 episodes per year; tamoxifen, mean 1.73 episodes per year). Among the patients who reported vaginal bleeding during the prestudy period (n = 21), 62% reported no bleeding for a 6-month period and 33% reported no vaginal bleeding for the duration of the trial. Not all patients improved on treatment and a few patients not reporting vaginal bleeding in the 6 months prior to enrollment reported menses on treatment. Tamoxifen therapy was associated with a reduction in mean rate of increase of bone age, but individual responses were highly heterogeneous. Linear growth rate (height velocity) was reduced during the course of tamoxifen treatment in a majority of patients (mean change of 1.68 cm per year relative to baseline); all recorded response failures occurred in patients with bone ages less than 7 years at screening. Mean uterine volume increased after 6 months of treatment and doubled at the end of the one-year study. A causal relationship to tamoxifen has not been established; however, as 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.[63589]

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during tamoxifen treatment and for at least 9 months after the last dose. Although there are no adequately controlled studies in pregnant humans, tamoxifen can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies, including the potential long-term risk of a DES-like syndrome. Women who are pregnant or who become pregnant while receiving tamoxifen should be apprised of the potential hazard to the fetus. 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 the maximum recommended human dose resulted in spontaneous abortion. In rats, a lower incidence of embryo implantation and a higher incidence of fetal death or delayed in utero growth occurred in rats at doses of 0.01 to 0.03 times the recommended human dose on a mg/m2 basis; slower learning behavior in rat pups also occurred. Abortion and premature delivery occurred in rabbits at doses greater than 0.05 times the daily maximum recommended human dose on a mg/m2 basis when administered during organogenesis. 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, approximately 2 times the daily maximum recommended human dose on a mg/m2 basis during organogenesis or in the last half of pregnancy resulted in termination of pregnancy; in pregnancies that continued, there were no malformations or deformations in offspring. Rodent models of fetal reproductive tract development indicated that tamoxifen caused changes in both sexes similar to those caused by estradiol, ethynylestradiol, and diethylstilbestrol at doses 0.002 to 2.4 times the daily maximum recommended human dose on a mg/m2 basis; the clinical relevance of these changes is unknown. Additionally, rodent models showed reproductive tract changes often associated with diethylstilbestrol (DES) in offspring of both sexes.[63589]

    Contraception requirements, infertility, male-mediated teratogenicity, menstrual irregularity, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during tamoxifen treatment. Tamoxifen can cause spontaneous abortions, birth defects, and fetal death if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective non-hormonal contraception during and for at least 9 months after treatment with tamoxifen. Females of reproductive potential should undergo pregnancy testing prior to initiation of tamoxifen. Because of the potential for male-mediated teratogenicity, male patients with female partners of reproductive potential should use effective contraception during treatment with tamoxifen and for 6 months following the last dose. Women who become pregnant while receiving tamoxifen should be apprised of the potential hazard to the fetus. Based on animal studies, tamoxifen may impair embryo implantation in females of reproductive potential, however, may not reliably cause infertility, even in the presence of menstrual irregularity.

    Breast-feeding

    Due to the potential for serious adverse reactions in nursing infants from tamoxifen, advise women to discontinue breast-feeding during treatment and for 3 months after the final dose. It is not known whether tamoxifen is present in human milk, although many drugs are excreted in human milk.

    ADVERSE REACTIONS

    Severe

    hot flashes / Early / 0-45.0
    vaginal discharge / Delayed / 0-12.3
    thromboembolism / Delayed / 0-5.0
    stroke / Early / 0.5-3.0
    new primary malignancy / Delayed / 0-1.0
    endometrial cancer / Delayed / 0-1.0
    thrombocytopenia / Delayed / 0-0.7
    pulmonary embolism / Delayed / 0.3-0.5
    teratogenesis / Delayed / Incidence not known
    fetal death / Delayed / Incidence not known
    spontaneous fetal abortion / Delayed / Incidence not known
    thrombosis / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    retinopathy / Delayed / Incidence not known
    retinal thrombosis / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    hepatic necrosis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    pancreatitis / Delayed / Incidence not known

    Moderate

    peripheral vasodilation / Rapid / 0-41.0
    fluid retention / Delayed / 0-32.0
    vaginal bleeding / Delayed / 6.0-23.0
    depression / Delayed / 2.0-12.0
    hypertension / Early / 11.0-11.0
    peripheral edema / Delayed / 0-11.0
    cataracts / Delayed / 7.0-8.1
    constipation / Delayed / 4.4-8.0
    dyspnea / Early / 0-8.0
    bone pain / Delayed / 0-6.0
    vaginitis / Delayed / 0-5.0
    elevated hepatic enzymes / Delayed / 0-5.0
    chest pain (unspecified) / Early / 5.0-5.0
    edema / Delayed / 0-4.0
    hypercholesterolemia / Delayed / 0-3.0
    hyperbilirubinemia / Delayed / 0-2.0
    phlebitis / Rapid / 0-0.4
    endometrial hyperplasia / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    anemia / Delayed / Incidence not known
    bleeding / Early / Incidence not known
    neutropenia / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    steatosis / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known
    bullous rash / Early / Incidence not known
    pneumonitis / Delayed / Incidence not known
    hypertriglyceridemia / Delayed / Incidence not known
    erythema / Early / Incidence not known
    tumor flare / Delayed / Incidence not known
    hypercalcemia / Delayed / Incidence not known

    Mild

    flushing / Rapid / 0-33.0
    arthralgia / Delayed / 11.0-29.0
    nausea / Early / 5.0-26.0
    menstrual irregularity / Delayed / 6.0-25.0
    weight loss / Delayed / 0-23.0
    fatigue / Early / 0-18.0
    asthenia / Delayed / 0-18.0
    amenorrhea / Delayed / 0-16.0
    pharyngitis / Delayed / 0-14.0
    infection / Delayed / 5.0-14.0
    rash / Early / 0-13.0
    vomiting / Early / 0-12.0
    back pain / Delayed / 0-10.0
    oligomenorrhea / Delayed / 0-9.0
    leukorrhea / Delayed / 0-9.0
    weight gain / Delayed / 0-9.0
    abdominal pain / Early / 0-9.0
    insomnia / Early / 0-9.0
    cough / Delayed / 4.0-9.0
    headache / Early / 0-8.0
    dizziness / Early / 0-8.0
    diarrhea / Early / 0-7.0
    influenza / Delayed / 0-6.0
    dyspepsia / Early / 0-6.0
    anxiety / Delayed / 0-6.0
    hyperhidrosis / Delayed / 0-6.0
    mastalgia / Delayed / 0-6.0
    alopecia / Delayed / 0-5.2
    myalgia / Early / 0-5.0
    sinusitis / Delayed / 0-5.0
    paresthesias / Delayed / 0-5.0
    throat irritation / Early / 5.0-5.0
    musculoskeletal pain / Early / 0-3.0
    anorexia / Delayed / 0-1.0
    pruritus / Rapid / Incidence not known
    libido decrease / Delayed / Incidence not known
    dysgeusia / Early / Incidence not known

    DRUG INTERACTIONS

    Albuterol: (Minor) Caution is advised with the concomitant use of tamoxifen and short-acting beta-agonists due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be lower with short-acting beta-agonists compared with long-acting beta-agonists.
    Albuterol; Ipratropium: (Minor) Caution is advised with the concomitant use of tamoxifen and short-acting beta-agonists due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be lower with short-acting beta-agonists compared with long-acting beta-agonists.
    Alfuzosin: (Major) Caution is advised with the concomitant use of tamoxifen with alfuzosin due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Based on electrophysiology studies performed by the manufacturer, alfuzosin may prolong the QT interval in a dose-dependent manner. Concomitant use may increase the risk of QT prolongation.
    Amiodarone: (Major) Avoid coadministration of amiodarone with tamoxifen if possible due to the risk of QT prolongation. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses.
    Amitriptyline: (Moderate) Caution is advised with the concomitant use of tamoxifen and tricyclic antidepressants (TCAs) due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Amitriptyline; Chlordiazepoxide: (Moderate) Caution is advised with the concomitant use of tamoxifen and tricyclic antidepressants (TCAs) due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Use caution if coadministration of clarithromycin with tamoxifen is necessary due to the risk of QT prolongation. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Use caution if coadministration of clarithromycin with tamoxifen is necessary due to the risk of QT prolongation. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Anagrelide: (Major) Do not use anagrelide with tamoxifen due to the risk of QT prolongation. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses.
    Anastrozole: (Major) Avoid coadministration of tamoxifen with anastrozole, as there is no benefit when compared to tamoxifen alone. Additionally, 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.
    Apalutamide: (Major) Avoid coadministration of apalutamide with tamoxifen due to decreased exposure to tamoxifen which may affect efficacy. Tamoxifen is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of tamoxifen by 86% and 55%, respectively.
    Apomorphine: (Major) Caution is advised with the concomitant use of tamoxifen with apomorphine due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Limited data indicate that QT prolongation is possible with apomorphine administration; the change in QTc interval is not significant in most patients receiving dosages within the manufacturer's guidelines.
    Arformoterol: (Moderate) Caution is advised with the concomitant use of tamoxifen and long-acting beta-agonists due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists compared to short-acting beta-agonists.
    Aripiprazole: (Moderate) Caution is advised with the concomitant use of tamoxifen and aripiprazole due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. QT prolongation has also occurred during therapeutic use of aripiprazole and following overdose. Concomitant use may increase the risk of QT prolongation.
    Arsenic Trioxide: (Major) Avoid coadministration of tamoxifen with aresenic trioxide due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant drug use is unavoidable, frequently monitor electrocardiograms.Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. arsenic trioxide use has been associated wtih TdP, QT interval prolongation, and complete atrioventricular block. Concomitant use may increase the risk of QT prolongation.
    Artemether; Lumefantrine: (Major) Avoid coadministration of tamoxifen with artemether due to an increased risk of QT prolongation. Consider ECG monitoring if tamoxifen must be used with or after artemether treatment. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Artemether; lumefantrine is also associated with prolongation of the QT interval. Concomitant use may increase the risk of QT prolongation.
    Asenapine: (Major) Avoid coadministration of tamoxifen with asenapine due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Asenapine has also been associated with QT prolongation. Concomitant use may increase the risk of QT prolongation.
    Atomoxetine: (Moderate) Caution is advised with the concomitant use of tamoxifen and atomoxetine due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. Concomitant use may increase the risk of QT prolongation.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid coadministration of phenobarbital with tamoxifen due to decreased exposure to tamoxifen which may affect efficacy. Tamoxifen is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of tamoxifen by 86% and 55%, respectively.
    Azithromycin: (Major) Caution is advised with the concomitant use of tamoxifen with azithromycin due to an increased risk of QT prolongation and torsade de pointes (TdP). Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. QT prolongation and TdP have been spontaneously reported during azithromycin postmarketing surveillance.
    Bedaquiline: (Major) Caution is advised with the concomitant use of tamoxifen and bedaquiline due to an increased risk of QT prolongation. Bedaquiline has been reported to prolong the QT interval. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Coadministration may result in additive or synergistic prolongation of the QT interval.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid coadministration of phenobarbital with tamoxifen due to decreased exposure to tamoxifen which may affect efficacy. Tamoxifen is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of tamoxifen by 86% and 55%, respectively.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Caution is advised with the concomitant use of tamoxifen and metronidazole due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Potential QT prolongation has also been reported in limited case reports with metronidazole.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Caution is advised with the concomitant use of tamoxifen and metronidazole due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Potential QT prolongation has also been reported in limited case reports with metronidazole.
    Budesonide; Formoterol: (Moderate) Caution is advised with the concomitant use of tamoxifen and long-acting beta-agonists due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists compared to short-acting beta-agonists.
    Buprenorphine: (Major) Caution is advised with the concomitant use of tamoxifen and buprenorphine due to an increased risk of QT prolongation and torsade de pointes (TdP). If coadministration is necessary, monitor ECG. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Buprenorphine has been associated with QT prolongation and has a possible risk of TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval.
    Buprenorphine; Naloxone: (Major) Caution is advised with the concomitant use of tamoxifen and buprenorphine due to an increased risk of QT prolongation and torsade de pointes (TdP). If coadministration is necessary, monitor ECG. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Buprenorphine has been associated with QT prolongation and has a possible risk of TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval.
    Bupropion: (Moderate) Monitor for decreased efficacy of tamoxifen if coadministration with bupropion is necessary. Tamoxifen is metabolized by CYP2D6 to endoxifen and 4-hydroxytamoxifen, both of which are minor metabolites but have 100-fold greater affinity for the estrogen receptor and 30- to 100-fold greater potency in suppressing estrogen-dependent cell proliferation than tamoxifen. Bupropion is a strong CYP2D6 inhibitor. In one study, the mean steady-state endoxifen plasma concentration was significantly reduced in patients taking CYP2D6 inhibitors compared to those not taking concomitant CYP2D6 inhibitors. In another study, the mean steady-state plasma concentration of endoxifen in CYP2D6 normal metabolizers who were not receiving CYP2D6 inhibitors were 3.6-fold higher compared to normal metabolizers who were receiving strong CYP2D6 inhibitors; plasma levels in CYP2D6 normal metabolizers receiving strong CYP2D6 inhibitors were similar to levels observed in CYP2D6 poor metabolizers taking no CYP2D6 inhibitors. Some studies have shown that the efficacy of tamoxifen may be reduced when concomitant drugs decrease the levels of potent active metabolites; however, others have failed to demonstrate such an effect. The clinical significance is not well established.
    Bupropion; Naltrexone: (Moderate) Monitor for decreased efficacy of tamoxifen if coadministration with bupropion is necessary. Tamoxifen is metabolized by CYP2D6 to endoxifen and 4-hydroxytamoxifen, both of which are minor metabolites but have 100-fold greater affinity for the estrogen receptor and 30- to 100-fold greater potency in suppressing estrogen-dependent cell proliferation than tamoxifen. Bupropion is a strong CYP2D6 inhibitor. In one study, the mean steady-state endoxifen plasma concentration was significantly reduced in patients taking CYP2D6 inhibitors compared to those not taking concomitant CYP2D6 inhibitors. In another study, the mean steady-state plasma concentration of endoxifen in CYP2D6 normal metabolizers who were not receiving CYP2D6 inhibitors were 3.6-fold higher compared to normal metabolizers who were receiving strong CYP2D6 inhibitors; plasma levels in CYP2D6 normal metabolizers receiving strong CYP2D6 inhibitors were similar to levels observed in CYP2D6 poor metabolizers taking no CYP2D6 inhibitors. Some studies have shown that the efficacy of tamoxifen may be reduced when concomitant drugs decrease the levels of potent active metabolites; however, others have failed to demonstrate such an effect. The clinical significance is not well established.
    Carbamazepine: (Major) Avoid coadministration of carbamazepine with tamoxifen due to decreased exposure to tamoxifen which may affect efficacy. Tamoxifen is a CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of tamoxifen by 86% and 55%, respectively.
    Ceritinib: (Major) Periodically monitor electrocardiograms (ECGs) and electrolytes if coadministration of ceritinib with tamoxifen is necessary. An interruption of ceritinib therapy, dose adjustment, or discontinuation of ceritinib therapy may be necessary if QT prolongation occurs. Concentration-dependent QT prolongation has been reported with ceritinib. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Chloroquine: (Major) Use caution if coadministration of chloroquine with tamoxifen is necessary due to the risk of QT prolongation. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); fatalities have been reported. The risk of QT prolongation is increased with higher chloroquine doses. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Chlorpromazine: (Major) Use caution if coadministration of chlorpromazine with tamoxifen is necessary due to the risk of QT prolongation. Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and torsade de pointes (TdP). Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Cinacalcet: (Moderate) Monitor for decreased efficacy of tamoxifen if coadministration with cinacalcet is necessary. Tamoxifen is metabolized by CYP2D6 to endoxifen and 4-hydroxytamoxifen, both of which are minor metabolites but have 100-fold greater affinity for the estrogen receptor and 30- to 100-fold greater potency in suppressing estrogen-dependent cell proliferation than tamoxifen. Cinacalcet is a strong CYP2D6 inhibitor. In one study, the mean steady-state endoxifen plasma concentration was significantly reduced in patients taking CYP2D6 inhibitors compared to those not taking concomitant CYP2D6 inhibitors. In another study, the mean steady-state plasma concentration of endoxifen in CYP2D6 normal metabolizers who were not receiving CYP2D6 inhibitors were 3.6-fold higher compared to normal metabolizers who were receiving strong CYP2D6 inhibitors; plasma levels in CYP2D6 normal metabolizers receiving strong CYP2D6 inhibitors were similar to levels observed in CYP2D6 poor metabolizers taking no CYP2D6 inhibitors. Some studies have shown that the efficacy of tamoxifen may be reduced when concomitant drugs decrease the levels of potent active metabolites; however, others have failed to demonstrate such an effect. The clinical significance is not well established.
    Ciprofloxacin: (Moderate) Caution is advised with the concomitant use of tamoxifen and ciprofloxacin due to an increased risk of QT prolongation and torsade de pointes (TdP). Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Rare cases of QT prolongation and TdP have also been reported with ciprofloxacin during postmarketing surveillance.
    Cisapride: (Severe) Concomitant use of tamoxifen with cisapride is contraindicated due to an increased risk of QT prolongation and torsade de pointes (TdP). Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. QT prolongation and ventricular arrhythmias, including TdP and death, have been reported with cisapride.
    Citalopram: (Major) According to the manufacturer of citalopram, concurrent use with other drugs that prolong the QT interval such as tamoxifen is not recommended. If concurrent therapy is considered essential, ECG monitoring is recommended; consider also monitoring electrolytes. Citalopram causes dose-dependent QT interval prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Clarithromycin: (Major) Use caution if coadministration of clarithromycin with tamoxifen is necessary due to the risk of QT prolongation. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Clomipramine: (Moderate) Caution is advised with the concomitant use of tamoxifen and tricyclic antidepressants (TCAs) due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Clozapine: (Major) Caution is advised with the concomitant use of tamoxifen with clozapine due to an increased risk of QT prolongation and torsade de pointes (TdP). Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death.
    Cocaine: (Major) Monitor for decreased efficacy of tamoxifen if the patient uses cocaine. Tamoxifen is metabolized by CYP2D6 to endoxifen and 4-hydroxytamoxifen, both of which are minor metabolites but have 100-fold greater affinity for the estrogen receptor and 30- to 100-fold greater potency in suppressing estrogen-dependent cell proliferation than tamoxifen. Cocaine is a strong CYP2D6 inhibitor. In one study, the mean steady-state endoxifen plasma concentration was significantly reduced in patients taking CYP2D6 inhibitors compared to those not taking concomitant CYP2D6 inhibitors. In another study, the mean steady-state plasma concentration of endoxifen in CYP2D6 normal metabolizers who were not receiving CYP2D6 inhibitors were 3.6-fold higher compared to normal metabolizers who were receiving strong CYP2D6 inhibitors; plasma levels in CYP2D6 normal metabolizers receiving strong CYP2D6 inhibitors were similar to levels observed in CYP2D6 poor metabolizers taking no CYP2D6 inhibitors. Some studies have shown that the efficacy of tamoxifen may be reduced when concomitant drugs decrease the levels of potent active metabolites; however, others have failed to demonstrate such an effect. The clinical significance is not well established.
    Codeine; Phenylephrine; Promethazine: (Moderate) Use caution if coadministration of promethazine with tamoxifen is necessary due to the risk of QT prolongation. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses.
    Codeine; Promethazine: (Moderate) Use caution if coadministration of promethazine with tamoxifen is necessary due to the risk of QT prolongation. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses.
    Conjugated Estrogens; Medroxyprogesterone: (Minor) Medroxyprogesterone reduces plasma concentrations of N-dimethyltamoxifen, the metabolite of tamoxifen, but not tamoxifen.
    Crizotinib: (Major) Avoid coadministration of crizotinib with tamoxifen due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses; rare case reports of QT prolongation have been described when tamoxifen is used at lower doses.
    Dacomitinib: (Moderate) Monitor for decreased efficacy of tamoxifen if coadministration with dacomitinib is necessary. Tamoxifen is metabolized by CYP2D6 to endoxifen and 4-hydroxytamoxifen, both of which are minor metabolites but have 100-fold greater affinity for the estrogen receptor and 30- to 100-fold greater potency in suppressing estrogen-dependent cell proliferation than tamoxifen. Dacomitinib is a strong CYP2D6 inhibitor. In one study, the mean steady-state endoxifen plasma concentration was significantly reduced in patients taking CYP2D6 inhibitors compared to those not taking concomitant CYP2D6 inhibitors. In another study, the mean steady-state plasma concentration of endoxifen in CYP2D6 normal metabolizers who were not receiving CYP2D6 inhibitors were 3.6-fold higher compared to normal metabolizers who were receiving strong CYP2D6 inhibitors; plasma levels in CYP2D6 normal metabolizers receiving strong CYP2D6 inhibitors were similar to levels observed in CYP2D6 poor metabolizers taking no CYP2D6 inhibitors. Some studies have shown that the efficacy of tamoxifen may be reduced when concomitant drugs decrease the levels of potent active metabolites; however, others have failed to demonstrate such an effect. The clinical significance is not well established.
    Dasatinib: (Major) Caution is advised with the concomitant use of tamoxifen with dasatinib due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. In vitro studies have shown that dasatinib also has the potential to prolong the QT interval.
    Degarelix: (Major) Caution is advised with the concomitant use of tamoxifen with degarelix due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Prolongation of the QTc interval has also been reported with the use of degarelix.
    Desflurane: (Major) Caution is advised with the concomitant use of tamoxifen and halogenated anesthestics due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Halogenated anesthetics can also prolong the QT interval.
    Desipramine: (Moderate) Caution is advised with the concomitant use of tamoxifen and tricyclic antidepressants (TCAs) due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Deutetrabenazine: (Moderate) For patients taking a deutetrabenazine dosage more than 24 mg/day with tamoxifen, assess the QTc interval before and after increasing the dosage of either deutetrabenazine or tamoxifen. Clinically relevant QTc prolongation may occur with deutetrabenazine. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Dextromethorphan; Promethazine: (Moderate) Use caution if coadministration of promethazine with tamoxifen is necessary due to the risk of QT prolongation. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses.
    Dextromethorphan; Quinidine: (Severe) The concomitant use of quinidine, a strong CYP2D6 inhibitor, with drugs that are associated with QT prolongation and are also CYP2D6 substrates, such as tamoxifen, is contraindicated. Quinidine administration is associated with QT prolongation and torsade de pointes (TdP). Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Disopyramide: (Major) Caution is advised with the concomitant use of tamoxifen with disopyramide due to an increased risk of QT prolongation and torsade de pointes (TdP). Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Disopyramide administration is also associated with QT prolongation and TdP.
    Dofetilide: (Severe) Concomitant use of tamoxifen with dofetilide is contraindicated due to an increased risk of QT prolongation and torsade de pointes (TdP). Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP.
    Dolasetron: (Major) Caution is advised with the concomitant use of tamoxifen and dolasetron due to an increased risk of QT prolongation. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Dolutegravir; Rilpivirine: (Major) Use caution if coadministration of rilpivirine with tamoxifen is necessary due to the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses.
    Donepezil: (Major) Caution is advised with the concomitant use of tamoxifen with donepezil due to an increased risk of QT prolongation and torsade de pointes (TdP). Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Case reports indicate that QT prolongation and TdP can also occur during donepezil therapy.
    Donepezil; Memantine: (Major) Caution is advised with the concomitant use of tamoxifen with donepezil due to an increased risk of QT prolongation and torsade de pointes (TdP). Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Case reports indicate that QT prolongation and TdP can also occur during donepezil therapy.
    Doxepin: (Moderate) Caution is advised with the concomitant use of tamoxifen and tricyclic antidepressants (TCAs) due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Dronedarone: (Severe) Concomitant use of tamoxifen with dronedarone is contraindicated due to an increased risk of QT prolongation and torsade de pointes (TdP). Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Droperidol: (Major) Avoid coadministration of tamoxifen with droperidol due to an increased risk of QT prolongation and torsade de pointes (TdP). If coadministration cannot be avoided, use extreme caution; initiate droperidol at a low dose and increase the dose as needed to achieve the desired effect. Droperidol administration is associated with an established risk for QT prolongation and TdP. Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Efavirenz: (Major) Use caution if coadministration of efavirenz with tamoxifen is necessary due to the risk of QT prolongation. Prolongation of the QTc interval has been observed with the use of efavirenz. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Use caution if coadministration of efavirenz with tamoxifen is necessary due to the risk of QT prolongation. Prolongation of the QTc interval has been observed with the use of efavirenz. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Use caution if coadministration of efavirenz with tamoxifen is necessary due to the risk of QT prolongation. Prolongation of the QTc interval has been observed with the use of efavirenz. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Eliglustat: (Major) Use caution in coadministration of eliglustat with tamoxifen is necessary due to the risk of QT prolongation. Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Use caution if coadministration of rilpivirine with tamoxifen is necessary due to the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Use caution if coadministration of rilpivirine with tamoxifen is necessary due to the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses.
    Enflurane: (Major) Caution is advised with the concomitant use of tamoxifen and halogenated anesthestics due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Halogenated anesthetics can also prolong the QT interval.
    Enzalutamide: (Major) Avoid coadministration of enzalutamide with tamoxifen due to decreased exposure to tamoxifen which may affect efficacy. Tamoxifen is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of tamoxifen by 86% and 55%, respectively.
    Eribulin: (Major) Closely monitor ECGs for QT prolongation if coadministration of tamoxifen with eribulin is necessary. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Eribulin has also been associated with QT prolongation.
    Erythromycin: (Major) Use caution if coadministration of tamoxifen with erythromycin is necessary due to the risk of QT prolongation. Erythromycin is associated with QT prolongation and torsade de pointes (TdP). Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Erythromycin; Sulfisoxazole: (Major) Use caution if coadministration of tamoxifen with erythromycin is necessary due to the risk of QT prolongation. Erythromycin is associated with QT prolongation and torsade de pointes (TdP). Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Escitalopram: (Moderate) Caution is advised with the concomitant use of tamoxifen and escitalopram due to an increased risk of QT prolongation and torsade de pointes (TdP). Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Escitalopram has also been associated with a risk of QT prolongation and TdP.
    Estradiol Cypionate; Medroxyprogesterone: (Minor) Medroxyprogesterone reduces plasma concentrations of N-dimethyltamoxifen, the metabolite of tamoxifen, but not tamoxifen.
    Ezogabine: (Major) Caution is advised with the concomitant use of tamoxifen and ezogabine due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Ezogabine has also been associated with QT prolongation.
    Fingolimod: (Major) Caution is advised with the concomitant use of tamoxifen and fingolimod due to an increased risk of QT prolongation and torsade de pointes (TdP). If coadministration is necessary, overnight monitoring with continuous ECG in a medical facility is advised after the first fingolimod dose. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
    Flecainide: (Major) Caution is advised with the concomitant use of tamoxifen with flecainide due to an increased risk of QT prolongation and torsade de pointes (TdP). Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or TdP; flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs which have the potential for QT prolongation may have an increased risk of developing proarrhythmias. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Fluconazole: (Severe) The concurrent use of fluconazole with drugs that are associated with QT prolongation and are also CYP3A4 substrates, such as tamoxifen, is contraindicated. Fluconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Fluoxetine: (Major) Monitor for decreased efficacy of tamoxifen if coadministration with fluoxetine is necessary; use cautiously due to the risk of QT prolongation. Tamoxifen is metabolized by CYP2D6 to endoxifen and 4-hydroxytamoxifen, both of which are minor metabolites but have 100-fold greater affinity for the estrogen receptor and 30- to 100-fold greater potency in suppressing estrogen-dependent cell proliferation than tamoxifen. Fluoxetine is a strong CYP2D6 inhibitor. In one study, the mean steady-state endoxifen plasma concentration was significantly reduced in patients taking CYP2D6 inhibitors compared to those not taking concomitant CYP2D6 inhibitors. In another study, the mean steady-state plasma concentration of endoxifen in CYP2D6 normal metabolizers who were not receiving CYP2D6 inhibitors were 3.6-fold higher compared to normal metabolizers who were receiving strong CYP2D6 inhibitors (e.g., fluoxetine); plasma levels in CYP2D6 normal metabolizers receiving strong CYP2D6 inhibitors were similar to levels observed in CYP2D6 poor metabolizers taking no CYP2D6 inhibitors. Some studies have shown that the efficacy of tamoxifen may be reduced when concomitant drugs decrease the levels of potent active metabolites; however, others have failed to demonstrate such an effect. The clinical significance is not well established. Additionally, QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Fluoxetine; Olanzapine: (Major) Monitor for decreased efficacy of tamoxifen if coadministration with fluoxetine is necessary; use cautiously due to the risk of QT prolongation. Tamoxifen is metabolized by CYP2D6 to endoxifen and 4-hydroxytamoxifen, both of which are minor metabolites but have 100-fold greater affinity for the estrogen receptor and 30- to 100-fold greater potency in suppressing estrogen-dependent cell proliferation than tamoxifen. Fluoxetine is a strong CYP2D6 inhibitor. In one study, the mean steady-state endoxifen plasma concentration was significantly reduced in patients taking CYP2D6 inhibitors compared to those not taking concomitant CYP2D6 inhibitors. In another study, the mean steady-state plasma concentration of endoxifen in CYP2D6 normal metabolizers who were not receiving CYP2D6 inhibitors were 3.6-fold higher compared to normal metabolizers who were receiving strong CYP2D6 inhibitors (e.g., fluoxetine); plasma levels in CYP2D6 normal metabolizers receiving strong CYP2D6 inhibitors were similar to levels observed in CYP2D6 poor metabolizers taking no CYP2D6 inhibitors. Some studies have shown that the efficacy of tamoxifen may be reduced when concomitant drugs decrease the levels of potent active metabolites; however, others have failed to demonstrate such an effect. The clinical significance is not well established. Additionally, QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. (Moderate) Caution is advised with the concomitant use of tamoxifen and olanzapine due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Fluphenazine: (Minor) Use caution if coadministration of fluphenazine with tamoxifen is necessary due to the risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Fluphenazine is also associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Fluticasone; Salmeterol: (Moderate) Caution is advised with the concomitant use of tamoxifen and long-acting beta-agonists due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists compared to short-acting beta-agonists.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Caution is advised with the concomitant use of tamoxifen and long-acting beta-agonists due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists compared to short-acting beta-agonists.
    Fluticasone; Vilanterol: (Moderate) Caution is advised with the concomitant use of tamoxifen and long-acting beta-agonists due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists compared to short-acting beta-agonists.
    Fluvoxamine: (Moderate) Use caution if coadministration of fluvoxamine with tamoxifen is necessary due to the risk of QT prolongation. Prolongation of the QT interval and torsade de pointes (TdP) has been reported with fluvoxamine during postmarketing use. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Formoterol: (Moderate) Caution is advised with the concomitant use of tamoxifen and long-acting beta-agonists due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists compared to short-acting beta-agonists.
    Formoterol; Mometasone: (Moderate) Caution is advised with the concomitant use of tamoxifen and long-acting beta-agonists due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists compared to short-acting beta-agonists.
    Foscarnet: (Major) Avoid coadministration of foscarnet with tamoxifen due to the risk of QT prolongation. Both QT prolongation and torsade de pointes (TdP) have been reported during postmarketing experience with foscarnet. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Fosphenytoin: (Major) Avoid coadministration of fosphenytoin with tamoxifen due to decreased exposure to tamoxifen which may affect efficacy. Tamoxifen is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of tamoxifen by 86% and 55%, respectively.
    Gemifloxacin: (Major) Caution is advised with the concomitant use of tamoxifen and gemifloxacin due to an increased risk of QT prolongation and torsade de pointes (TdP). Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Gemifloxacin may prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
    Gemtuzumab Ozogamicin: (Moderate) Use gemtuzumab ozogamicin and tamoxifen together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Glasdegib: (Major) Avoid coadministration of glasdegib with tamoxifen due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and tamoxifen as coadministration may increase serum concentrations of glecaprevir and increase the risk of adverse effects. Glecaprevir is a substrate of P-glycoprotein (P-gp); tamoxifen is a P-gp inhibitor.
    Glycopyrrolate; Formoterol: (Moderate) Caution is advised with the concomitant use of tamoxifen and long-acting beta-agonists due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists compared to short-acting beta-agonists.
    Goserelin: (Moderate) Caution is advised with the concomitant use of tamoxifen and goserelin due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Androgen deprivation therapy (e.g., goserelin) also prolongs the QT interval; the risk may be increased with concurrent use of other medications that prolong the QT interval.
    Granisetron: (Major) Caution is advised with the concomitant use of tamoxifen and granisetron due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Granisetron has also been associated with QT prolongation.
    Halogenated Anesthetics: (Major) Caution is advised with the concomitant use of tamoxifen and halogenated anesthestics due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Halogenated anesthetics can also prolong the QT interval.
    Haloperidol: (Major) Use caution if coadministration of haloperidol with tamoxifen is necessary due to the risk of QT prolongation. Prolongation of the QT interval and torsade de pointes (TdP) have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Halothane: (Major) Caution is advised with the concomitant use of tamoxifen and halogenated anesthestics due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Halogenated anesthetics can also prolong the QT interval.
    Histrelin: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and tamoxifen is necessary; correct any electrolyte abnormalities. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Hydroxychloroquine: (Major) Hydroxychloroquine should not be administered with tamoxifen due to the risk of QT prolongation. Hydroxychloroquine prolongs the QT interval. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Hydroxyzine: (Major) Caution is advised with the concomitant use of tamoxifen and hydroxyzine due to an increased risk of QT prolongation and torsade de pointes (TdP). Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Postmarketing data indicate that hydroxyzine also causes QT prolongation and TdP.
    Ibutilide: (Major) Caution is advised with the concomitant use of tamoxifen and ibutilide due to an increased risk of QT prolongation and torsade de pointes (TdP). Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Ibutilide administration can also cause QT prolongation and TdP; proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval.
    Iloperidone: (Major) Avoid coadministration of tamoxifen with iloperidone due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Iloperidone has also been associated with QT prolongation.
    Imipramine: (Moderate) Caution is advised with the concomitant use of tamoxifen and tricyclic antidepressants (TCAs) due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Indacaterol: (Moderate) Caution is advised with the concomitant use of tamoxifen and long-acting beta-agonists due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists compared to short-acting beta-agonists.
    Indacaterol; Glycopyrrolate: (Moderate) Caution is advised with the concomitant use of tamoxifen and long-acting beta-agonists due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists compared to short-acting beta-agonists.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with tamoxifen due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Isoflurane: (Major) Caution is advised with the concomitant use of tamoxifen and halogenated anesthestics due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Halogenated anesthetics can also prolong the QT interval.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of rifampin with tamoxifen due to decreased exposure to tamoxifen which may affect efficacy. Tamoxifen is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the AUC and Cmax of tamoxifen by 86% and 55%, respectively.
    Isoniazid, INH; Rifampin: (Major) Avoid coadministration of rifampin with tamoxifen due to decreased exposure to tamoxifen which may affect efficacy. Tamoxifen is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the AUC and Cmax of tamoxifen by 86% and 55%, respectively.
    Itraconazole: (Major) Use caution if coadministration of itraconazole with tamoxifen is necessary due to the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with tamoxifen due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Ketoconazole: (Major) Use caution if coadministration of ketoconazole with tamoxifen is necessary due to the risk of QT prolongation. Ketoconazole has been associated with prolongation of the QT interval. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Lapatinib: (Major) Consider ECG monitoring for QT prolongation and monitor electrolytes if coadministration of lapatinib with tamoxifen is necessary. Correct hypokalemia or hypomagnesemia prior to lapatinib administration. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Lenvatinib: (Major) Avoid coadministration of lenvatinib with tamoxifen due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses.
    Letrozole: (Major) Coadministration of letrozole with tamoxifen is not recommended because the efficacy of the combination in the treatment of breast cancer has not been established. Additionally, tamoxifen reduced the plasma concentration of letrozole by 38% when the drugs were coadministered.
    Leuprolide: (Moderate) Caution is advised with the concomitant use of tamoxifen and leuprolide due to an increased risk of QT prolongation. Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Leuprolide; Norethindrone: (Moderate) Caution is advised with the concomitant use of tamoxifen and leuprolide due to an increased risk of QT prolongation. Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Levalbuterol: (Minor) Caution is advised with the concomitant use of tamoxifen and short-acting beta-agonists due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be lower with short-acting beta-agonists compared with long-acting beta-agonists.
    Levofloxacin: (Major) Caution is advised with the concomitant use of tamoxifen and levofloxacin due to an increased risk of QT prolongation and torsade de pointes (TdP). Levofloxacin has been associated with a risk of QT prolongation; although extremely rare, TdP has been reported during postmarketing surveillance of levofloxacin. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Lithium: (Moderate) Caution is advised with the concomitant use of tamoxifen and lithium due to an increased risk of QT prolongation. Lithium has been associated with QT prolongation. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Lofexidine: (Moderate) Monitor ECG if lofexidine is coadministered with tamoxifen due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Long-acting beta-agonists: (Moderate) Caution is advised with the concomitant use of tamoxifen and long-acting beta-agonists due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists compared to short-acting beta-agonists.
    Loperamide: (Moderate) Use caution if coadministration of loperamide with tamoxifen is necessary due to the risk of QT prolongation. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Loperamide; Simethicone: (Moderate) Use caution if coadministration of loperamide with tamoxifen is necessary due to the risk of QT prolongation. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Lopinavir; Ritonavir: (Major) Use caution if coadministration of lopinavir with tamoxifen is necessary due to the risk of QT prolongation. Lopinavir; ritonavir is associated with QT prolongation. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Coadministration of lopinavir; ritonavir with other drugs that prolong the QT interval may result in additive QT prolongation.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of lumacaftor; ivacaftor with tamoxifen due to decreased exposure to tamoxifen which may affect efficacy. Tamoxifen is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of tamoxifen by 86% and 55%, respectively.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of lumacaftor; ivacaftor with tamoxifen due to decreased exposure to tamoxifen which may affect efficacy. Tamoxifen is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of tamoxifen by 86% and 55%, respectively.
    Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as tamoxifen. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Maprotiline: (Major) Caution is advised with the concomitant use of tamoxifen with maprotiline due to an increased risk of QT prolongation and torsade de pointes (TdP). Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs, such as tamoxifen.
    Medroxyprogesterone: (Minor) Medroxyprogesterone reduces plasma concentrations of N-dimethyltamoxifen, the metabolite of tamoxifen, but not tamoxifen.
    Meperidine; Promethazine: (Moderate) Use caution if coadministration of promethazine with tamoxifen is necessary due to the risk of QT prolongation. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses.
    Mephobarbital: (Major) Avoid coadministration of mephobarbital with tamoxifen due to decreased exposure to tamoxifen which may affect efficacy. Tamoxifen is a CYP3A4 substrate and mephobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of tamoxifen by 86% and 55%, respectively.
    Metaproterenol: (Minor) Caution is advised with the concomitant use of tamoxifen and short-acting beta-agonists due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be lower with short-acting beta-agonists compared with long-acting beta-agonists.
    Methadone: (Major) Caution is advised with the concomitant use of tamoxifen with methadone due to an increased risk of QT prolongation and torsade de pointes (TdP). Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Methadone is considered to be associated with an increased risk for QT prolongation and TdP, especially at higher doses (more than 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.
    Metronidazole: (Moderate) Caution is advised with the concomitant use of tamoxifen and metronidazole due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Potential QT prolongation has also been reported in limited case reports with metronidazole.
    Midostaurin: (Major) Caution is advised with the concomitant use of tamoxifen and midostaurin due to an increased risk of QT prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Mifepristone: (Moderate) Use caution if coadministration of mifepristone with tamoxifen is necessary due to the risk of QT prolongation; always use the lowest effective dose of mifepristone. Mifepristone has been associated with dose-dependent prolongation of the QT interval. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Mirtazapine: (Moderate) Use caution if coadministration of mirtazapine with tamoxifen is necessary due to the risk of QT prolongation. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing experience, primarily in overdose or in patients with other risk factors for QT prolongation. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Mitotane: (Major) Avoid coadministration of mitotane with tamoxifen due to decreased exposure to tamoxifen which may affect efficacy. Tamoxifen is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of tamoxifen by 86% and 55%, respectively.
    Moxifloxacin: (Major) Caution is advised with the concomitant use of tamoxifen and moxifloxacin due to an increased risk of QT prolongation and torsade de pointes (TdP). Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Quinolones have also been associated with a risk of QT prolongation; although extremely rare, TdP has been reported during postmarketing surveillance of moxifloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Nilotinib: (Major) Avoid coadministration of nilotinib with tamoxifen due to the risk of QT prolongation. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Nortriptyline: (Moderate) Caution is advised with the concomitant use of tamoxifen and tricyclic antidepressants (TCAs) due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Octreotide: (Moderate) Use caution if coadministration of octreotide with tamoxifen is necessary due to the risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy. Since bradycardia is a risk factor for development of torsade de pointes (TdP), the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval.
    Ofloxacin: (Major) Caution is advised with the concomitant use of tamoxifen with ofloxacin due to an increased risk of QT prolongation and torsade de pointes (TdP). Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Quinolones have also been associated with a risk of QT prolongation; although extremely rare, TdP has been reported during postmarketing surveillance of ofloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Olanzapine: (Moderate) Caution is advised with the concomitant use of tamoxifen and olanzapine due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Olodaterol: (Moderate) Caution is advised with the concomitant use of tamoxifen and long-acting beta-agonists due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists compared to short-acting beta-agonists.
    Ondansetron: (Major) Monitor ECGs for QT prolongation if coadministration of ondansetron with tamoxifen is necessary. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Osimertinib: (Major) Avoid coadministration of tamoxifen with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Oxaliplatin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of tamoxifen with oxaliplatin is necessary; correct electrolyte abnormalities prior to administration of oxaliplatin. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses; rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have been reported with oxaliplatin use in postmarketing experience.
    Paliperidone: (Major) Avoid coadministration of tamoxifen with paliperidone due to an increased risk of QT prolongation. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmia, close monitoring is essential. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Paliperidone has been associated with QT prolongation.
    Paroxetine: (Moderate) Monitor for decreased efficacy of tamoxifen if coadministration with paroxetine is necessary. Tamoxifen is metabolized by CYP2D6 to endoxifen and 4-hydroxytamoxifen, both of which are minor metabolites but have 100-fold greater affinity for the estrogen receptor and 30- to 100-fold greater potency in suppressing estrogen-dependent cell proliferation than tamoxifen. Paroxetine is a strong CYP2D6 inhibitor. In one study, the mean steady-state plasma concentration of endoxifen in CYP2D6 normal metabolizers who were not receiving CYP2D6 inhibitors were 3.6-fold higher compared to normal metabolizers who were receiving strong CYP2D6 inhibitors (e.g., paroxetine); plasma levels in CYP2D6 normal metabolizers receiving strong CYP2D6 inhibitors were similar to levels observed in CYP2D6 poor metabolizers taking no CYP2D6 inhibitors. In another study, the mean steady-state endoxifen plasma concentration was significantly reduced in patients taking CYP2D6 inhibitors compared to those not taking concomitant CYP2D6 inhibitors. Some studies have shown that the efficacy of tamoxifen may be reduced when concomitant drugs decrease the levels of potent active metabolites; however, others have failed to demonstrate such an effect. The clinical significance is not well established.
    Pasireotide: (Major) Caution is advised with the concomitant use of tamoxifen and pasireotide due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Pasireotide has also been associated with QT prolongation.
    Pazopanib: (Major) Coadministration of pazopanib with tamoxifen is not advised due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation. Pazopanib has been reported to prolong the QT interval. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses.
    Pentamidine: (Major) Caution is advised with the concomitant use of tamoxifen and pentamidine due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses. Systemic pentamidine has also been associated with QT prolongation.
    Perphenazine: (Minor) Use caution if coadministration of perphenazine with tamoxifen is necessary. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses. Perphenazine is also associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Perphenazine; Amitriptyline: (Moderate) Caution is advised with the concomitant use of tamoxifen and tricyclic antidepressants (TCAs) due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). (Minor) Use caution if coadministration of perphenazine with tamoxifen is necessary. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses. Perphenazine is also associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Phenobarbital: (Major) Avoid coadministration of phenobarbital with tamoxifen due to decreased exposure to tamoxifen which may affect efficacy. Tamoxifen is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of tamoxifen by 86% and 55%, respectively.
    Phenylephrine; Promethazine: (Moderate) Use caution if coadministration of promethazine with tamoxifen is necessary due to the risk of QT prolongation. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses.
    Phenytoin: (Major) Avoid coadministration of phenytoin with tamoxifen due to decreased exposure to tamoxifen which may affect efficacy. Tamoxifen is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of tamoxifen by 86% and 55%, respectively.
    Pimavanserin: (Major) Avoid coadministration of tamoxifen with pimvanserin due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Pimvanserin has also been associated with QT prolongation.
    Pimozide: (Severe) Concomitant use of tamoxifen with pimozide is contraindicated due to an increased risk of QT prolongation and torsade de pointes (TdP). Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Pimozide is associated with a well-established risk of QT prolongation and TdP.
    Pirbuterol: (Minor) Caution is advised with the concomitant use of tamoxifen and short-acting beta-agonists due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be lower with short-acting beta-agonists compared with long-acting beta-agonists.
    Posaconazole: (Severe) Concomitant use of posaconazole with drugs that are associated with QT prolongation and are also CYP3A4 substrates, such as tamoxifen, is contraindicated. Posaconazole has been associated with QT prolongation and torsade de pointes. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Primaquine: (Major) Caution is advised with the concomitant use of tamoxifen and primaquine due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Primaquine has also been associated with QT prolongation.
    Primidone: (Major) Avoid coadministration of primidone with tamoxifen due to decreased exposure to tamoxifen which may affect efficacy. Tamoxifen is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of tamoxifen by 86% and 55%, respectively.
    Procainamide: (Major) Caution is advised with the concomitant use of tamoxifen and procainamide due to an increased risk of QT prolongation and torsade de pointes (TdP). Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Procainamide is associated with a well-established risk of QT prolongation and TdP.
    Prochlorperazine: (Minor) Use caution if coadministration of prochlorperazine with tamoxifen is necessary due to the risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses. Prochlorperazine is also associated with a possible risk for QT prolongation. Theoretically, prochlorperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Promethazine: (Moderate) Use caution if coadministration of promethazine with tamoxifen is necessary due to the risk of QT prolongation. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses.
    Propafenone: (Major) Use caution if coadministration of propafenone with tamoxifen is necessary due to the risk of QT prolongation. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses.
    Protriptyline: (Moderate) Caution is advised with the concomitant use of tamoxifen and tricyclic antidepressants (TCAs) due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Quetiapine: (Major) Avoid coadministration of tamoxifen with quetiapine due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses. Limited data, including some case reports, suggest that quetiapine may also be associated with a significant prolongation of the QTc interval in rare instances.
    Quinidine: (Severe) The concomitant use of quinidine, a strong CYP2D6 inhibitor, with drugs that are associated with QT prolongation and are also CYP2D6 substrates, such as tamoxifen, is contraindicated. Quinidine administration is associated with QT prolongation and torsade de pointes (TdP). Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Quinine: (Major) Avoid coadministration of tamoxifen with quinine due to the risk of QT prolongation. Quinine has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses.
    Ranolazine: (Major) Use caution if coadministration of ranolazine with tamoxifen is necessary due to the risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses. Ranolazine is also associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Ribociclib: (Major) Avoid coadministration of ribociclib with tamoxifen due to the risk of QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner; these ECG changes occurred within the first four weeks of treatment and were reversible with dose interruption. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with tamoxifen due to the risk of QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner; these ECG changes occurred within the first four weeks of treatment and were reversible with dose interruption. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses. (Major) Coadministration of letrozole with tamoxifen is not recommended because the efficacy of the combination in the treatment of breast cancer has not been established. Additionally, tamoxifen reduced the plasma concentration of letrozole by 38% when the drugs were coadministered.
    Rifampin: (Major) Avoid coadministration of rifampin with tamoxifen due to decreased exposure to tamoxifen which may affect efficacy. Tamoxifen is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the AUC and Cmax of tamoxifen by 86% and 55%, respectively.
    Rilpivirine: (Major) Use caution if coadministration of rilpivirine with tamoxifen is necessary due to the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses.
    Risperidone: (Major) Caution is advised with the concomitant use of tamoxifen and risperidone due to an increased risk of QT prolongation and torsade de pointes (TdP). If coadministration is necessary, monitor for evidence of QT prolongation if the patient has known risk factors for cardiac disease or arrhythmias. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Risperidone has been associated with a possible risk for QT prolongation and/or TdP. Reports of QT prolongation and TdP during risperidone therapy have been noted primarily in the overdosage setting.
    Romidepsin: (Major) Monitor ECGs for QT prolongation and monitor electrolytes at baseline and periodically during treatment if coadministration of romidepsin with tamoxifen is necessary. Romidepsin has been reported to prolong the QT interval. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses.
    Salmeterol: (Moderate) Caution is advised with the concomitant use of tamoxifen and long-acting beta-agonists due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists compared to short-acting beta-agonists.
    Saquinavir: (Severe) The concomitant use of tamoxifen and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening arrhythmias, such as torsades de pointes (TdP). Saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; TdP has also been reported rarely. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Additionally, tamoxifen is a CYP3A4 substrate; saquinavir boosted with ritonavir is a strong CYP3A4 inhibitor. The concentrations of saquinavir and/or tamoxifen may be increased, thus increasing the risk of drug toxicity and proarrhythmic effects.
    Sertraline: (Moderate) Use caution if coadministration of sertraline with tamoxifen is necessary due to the risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses. There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline.
    Sevoflurane: (Major) Caution is advised with the concomitant use of tamoxifen and halogenated anesthestics due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Halogenated anesthetics can also prolong the QT interval.
    Short-acting beta-agonists: (Minor) Caution is advised with the concomitant use of tamoxifen and short-acting beta-agonists due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be lower with short-acting beta-agonists compared with long-acting beta-agonists.
    Solifenacin: (Moderate) Caution is advised with the concomitant use of tamoxifen and solifenacin due to an increased risk of QT prolongation and torsade de pointes (TdP). Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Solifenacin has been associated with dose-dependent prolongation of the QT interval; TdP has also been reported with postmarketing use, although causality was not determined.
    Sorafenib: (Major) Closely monitor ECGs for QT prolongation if coadministration of sorafenib with tamoxifen is necessary. Sorafenib has been associated with QT prolongation. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses.
    Sotalol: (Major) Caution is advised with the concomitant use of tamoxifen and sotalol due to an increased risk of QT prolongation and torsade de pointes (TdP). Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Sotalol administration is associated with QT prolongation and TdP. Proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment.
    Soy Isoflavones: (Major) Theoretically, the soy isoflavones may compete with drugs that selectively modulate estrogen receptors. The soy isoflavones have a diphenolic structure similar to that of the potent synthetic and natural estrogens. All isoflavones are competitive ligands of in vitro estrogen receptor assays and appear to function as selective estrogen receptor modifiers (SERMs). Soy isoflavones should be used with caution in patients taking selective estrogen receptor modulators (SERMs, e.g., raloxifene, tamoxifen, or toremifene), as not much is known about how soy might influence side effects or therapeutic efficacy of the SERMs.
    St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of St. Johns Wort with tamoxifen due to decreased exposure to tamoxifen which may affect efficacy. Tamoxifen is a CYP3A4 substrate and St. Johns Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of tamoxifen by 86% and 55%, respectively.
    Sunitinib: (Major) Use caution if coadministration of sunitinib with tamoxifen is necessary due to the risk of QT prolongation. Sunitinib can cause dose-dependent QT prolongation, which may increase the risk for ventricular arrhythmias, including torsades de points (TdP). Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses; rare case reports of QT prolongation have been described when tamoxifen is used at lower doses.
    Tacrolimus: (Major) Caution is advised with the concomitant use of tamoxifen and tacrolimus due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Tacrolimus also causes QT prolongation.
    Telavancin: (Major) Caution is advised with the concomitant use of tamoxifen and telavancin due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Telavancin has also been associated with QT prolongation.
    Telithromycin: (Major) Use caution if coadministration of telithromycin with tamoxifen is necessary due to the risk of QT prolongation. Telithromycin is associated with QT prolongation and torsade de pointes (TdP). Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses.
    Terbinafine: (Moderate) Monitor for decreased efficacy of tamoxifen if coadministration with terbinafine is necessary. Tamoxifen is metabolized by CYP2D6 to endoxifen and 4-hydroxytamoxifen, both of which are minor metabolites but have 100-fold greater affinity for the estrogen receptor and 30- to 100-fold greater potency in suppressing estrogen-dependent cell proliferation than tamoxifen. Terbinafine is a strong CYP2D6 inhibitor. In one study, the mean steady-state endoxifen plasma concentration was significantly reduced in patients taking CYP2D6 inhibitors compared to those not taking concomitant CYP2D6 inhibitors. In another study, the mean steady-state plasma concentration of endoxifen in CYP2D6 normal metabolizers who were not receiving CYP2D6 inhibitors were 3.6-fold higher compared to normal metabolizers who were receiving strong CYP2D6 inhibitors; plasma levels in CYP2D6 normal metabolizers receiving strong CYP2D6 inhibitors were similar to levels observed in CYP2D6 poor metabolizers taking no CYP2D6 inhibitors. Some studies have shown that the efficacy of tamoxifen may be reduced when concomitant drugs decrease the levels of potent active metabolites; however, others have failed to demonstrate such an effect. The clinical significance is not well established.
    Terbutaline: (Minor) Caution is advised with the concomitant use of tamoxifen and short-acting beta-agonists due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be lower with short-acting beta-agonists compared with long-acting beta-agonists.
    Tetrabenazine: (Major) Avoid coadministration of tamoxifen with tetrabenazine due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Tetrabenazine causes a small increase in the corrected QT interval (QTc).
    Thioridazine: (Severe) Concomitant use of tamoxifen with thioridazine is contraindicated due an increased risk of QT prolongation and torsade de pointes (TdP). Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Thioridazine is associated with a well-established risk of QT prolongation and TdP.
    Tiotropium; Olodaterol: (Moderate) Caution is advised with the concomitant use of tamoxifen and long-acting beta-agonists due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists compared to short-acting beta-agonists.
    Tipranavir: (Moderate) Monitor for decreased efficacy of tamoxifen if coadministration with tipranavir is necessary. Tamoxifen is metabolized by CYP2D6 to endoxifen and 4-hydroxytamoxifen, both of which are minor metabolites but have 100-fold greater affinity for the estrogen receptor and 30- to 100-fold greater potency in suppressing estrogen-dependent cell proliferation than tamoxifen. Tipranavir is a strong CYP2D6 inhibitor. In one study, the mean steady-state endoxifen plasma concentration was significantly reduced in patients taking CYP2D6 inhibitors compared to those not taking concomitant CYP2D6 inhibitors. In another study, the mean steady-state plasma concentration of endoxifen in CYP2D6 normal metabolizers who were not receiving CYP2D6 inhibitors were 3.6-fold higher compared to normal metabolizers who were receiving strong CYP2D6 inhibitors; plasma levels in CYP2D6 normal metabolizers receiving strong CYP2D6 inhibitors were similar to levels observed in CYP2D6 poor metabolizers taking no CYP2D6 inhibitors. Some studies have shown that the efficacy of tamoxifen may be reduced when concomitant drugs decrease the levels of potent active metabolites; however, others have failed to demonstrate such an effect. The clinical significance is not well established.
    Tolterodine: (Moderate) Caution is advised with the concomitant use of tamoxifen and tolterodine due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
    Toremifene: (Major) Avoid coadministration of tamoxifen with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Trazodone: (Major) Avoid coadministration of tamoxifen with trazodone due to an increased risk of QT prolongation and torsade de pointes (TdP). Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of TdP.
    Tricyclic antidepressants: (Moderate) Caution is advised with the concomitant use of tamoxifen and tricyclic antidepressants (TCAs) due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Trifluoperazine: (Minor) Caution is advised with the concomitant use of tamoxifen and trifluoperazine due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Trifluoperazine is associated with a possible risk for QT prolongation. Theoretically, trifluoperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Trimipramine: (Moderate) Caution is advised with the concomitant use of tamoxifen and tricyclic antidepressants (TCAs) due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Triptorelin: (Moderate) Caution is advised with the concomitant use of tamoxifen and triptorelin due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Androgen deprivation therapy (e.g., triptorelin) also prolongs the QT interval.
    Umeclidinium; Vilanterol: (Moderate) Caution is advised with the concomitant use of tamoxifen and long-acting beta-agonists due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists compared to short-acting beta-agonists.
    Vandetanib: (Major) Avoid coadministration of vandetanib with tamoxifen due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Vardenafil: (Major) Caution is advised with the concomitant use of tamoxifen and vardenafil due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses. Vardenafil is also associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Vemurafenib: (Major) Closely monitor ECGs for QT prolongation if coadministration of vemurafenib and tamoxifen is necessary. Vemurafenib has been associated with QT prolongation. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses.
    Venlafaxine: (Moderate) Caution is advised with the concomitant use of tamoxifen and venlafaxine due to an increased risk of QT prolongation and torsade de pointes (TdP). Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses. Venlafaxine administration is also associated with a possible risk of QT prolongation; TdP has been reported with postmarketing use.
    Voriconazole: (Major) Use caution if coadministration of voriconazole with tamoxifen is necessary due to the risk of QT prolongation. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses.
    Vorinostat: (Moderate) Caution is advised with the concomitant use of tamoxifen and vorinostat due to an increased risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses. Vorinostat therapy is also associated with a risk of QT prolongation.
    Warfarin: (Major) Closely monitor PT/INR if coadministration of warfarin with tamoxifen for the treatment of metastatic breast cancer or as adjuvant therapy is necessary; a marked increase in anticoagulant effect may occur. Tamoxifen is contraindicated with warfarin therapy if the indication for tamoxifen is reduction of breast cancer incidence in high-risk patients or risk reduction of invasive breast cancer after treatment of DCIS.
    Ziprasidone: (Major) Avoid coadministration of tamoxifen with ziprasidone due to an increased risk of QT prolongation and torsade de pointes (TdP). Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of TdP in patients with multiple confounding factors. Comparative data with other antipsychotics have shown that the mean QTc interval prolongation occurring with ziprasidone exceeds that of haloperidol, quetiapine, olanzapine, and risperidone, but is less than that which occurs with thioridazine.

    PREGNANCY AND LACTATION

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during tamoxifen treatment and for at least 9 months after the last dose. Although there are no adequately controlled studies in pregnant humans, tamoxifen can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies, including the potential long-term risk of a DES-like syndrome. Women who are pregnant or who become pregnant while receiving tamoxifen should be apprised of the potential hazard to the fetus. 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 the maximum recommended human dose resulted in spontaneous abortion. In rats, a lower incidence of embryo implantation and a higher incidence of fetal death or delayed in utero growth occurred in rats at doses of 0.01 to 0.03 times the recommended human dose on a mg/m2 basis; slower learning behavior in rat pups also occurred. Abortion and premature delivery occurred in rabbits at doses greater than 0.05 times the daily maximum recommended human dose on a mg/m2 basis when administered during organogenesis. 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, approximately 2 times the daily maximum recommended human dose on a mg/m2 basis during organogenesis or in the last half of pregnancy resulted in termination of pregnancy; in pregnancies that continued, there were no malformations or deformations in offspring. Rodent models of fetal reproductive tract development indicated that tamoxifen caused changes in both sexes similar to those caused by estradiol, ethynylestradiol, and diethylstilbestrol at doses 0.002 to 2.4 times the daily maximum recommended human dose on a mg/m2 basis; the clinical relevance of these changes is unknown. Additionally, rodent models showed reproductive tract changes often associated with diethylstilbestrol (DES) in offspring of both sexes.[63589]

    Counsel patients about the reproductive risk and contraception requirements during tamoxifen treatment. Tamoxifen can cause spontaneous abortions, birth defects, and fetal death if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective non-hormonal contraception during and for at least 9 months after treatment with tamoxifen. Females of reproductive potential should undergo pregnancy testing prior to initiation of tamoxifen. Because of the potential for male-mediated teratogenicity, male patients with female partners of reproductive potential should use effective contraception during treatment with tamoxifen and for 6 months following the last dose. Women who become pregnant while receiving tamoxifen should be apprised of the potential hazard to the fetus. Based on animal studies, tamoxifen may impair embryo implantation in females of reproductive potential, however, may not reliably cause infertility, even in the presence of menstrual irregularity.

    MECHANISM OF ACTION

    Tamoxifen is an estrogen agonist/antagonist. It competes with estrogen for binding to the estrogen receptor (ER), which can result in a decrease in estrogen receptor signaling-dependent growth in breast tissue.[63589] After tamoxifen binds to the estrogen receptor, the expression of estrogen-dependent genes (RNA transcription) is blocked or altered, 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; it is cytostatic, with cell cycling slowed by its activity in the nucleus. Tamoxifen also decreases insulin-like growth factor type 1 (IGF-1) which 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. It also induces the re-expression of maspin, a tumor suppressor gene, in breast cancer tissue. Maspin gene expression is diminished or lost in breast cancer, whereas it 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.[27874] Tamoxifen has demonstrated antitumor activity against human breast cancer cell lines xenografted in mice. It has also 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.[63589]
     
    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.[34101] [34102]

    PHARMACOKINETICS

    Tamoxifen is administered orally as tablets or a solution. The decline in plasma concentrations of tamoxifen is biphasic, with a terminal elimination half-life of about 5 to 7 days. After initiation of therapy, steady-state for tamoxifen is achieved in approximately 4 weeks; steady-state for N-desmethyl tamoxifen occurs in approximately 8 weeks, suggesting a half-life of approximately 14 days for this metabolite. Studies in women receiving radiolabelled tamoxifen showed that approximately 65% of a radiolabeled dose was excreted from the body over a period of 2 weeks, with fecal excretion as the primary route of elimination. Tamoxifen is excreted mainly as polar conjugates, with unchanged drug and unconjugated metabolites accounting for less than 30% of the total fecal radioactivity.[63589]
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP2D6, CYP2C9, CYP2C19, CYP2B6
    Tamoxifen is extensively metabolized in the liver by the CYP450 system, including CYP3A, CYP2D6, CYP2C9, CYP2C19, and CYP2B6. The main metabolite found in plasma is N-desmethyl tamoxifen, which has similar pharmacological activity to tamoxifen and is formed predominantly via CYP3A. CYP2D6 is involved in the formation of endoxifen and 4-hydroxytamoxifen, both minor metabolites that have 100-fold greater affinity for the estrogen receptor and 30- to 100-fold greater potency in suppressing estrogen-dependent cell proliferation than tamoxifen.[63589] Endoxifen concentrations may be up to 20-fold higher than concentrations of 4-hydroxytamoxifen.[41246] Phase 2 enzymes, such as SULT1A1, UGT2B7, and UGT1A4, are associated with tamoxifen clearance from plasma.[63589]

    Oral Route

    Following a single oral dose of tamoxifen 20 mg, an average peak plasma concentration (Cmax) of 40 ng/mL (range, 35 to 45 ng/mL) occurs in approximately 5 hours; the average Cmax of N-desmethyl tamoxifen, the major metabolite, is 15 ng/mL (range, 10 to 20 ng/mL). Chronic administration of tamoxifen 10 mg twice daily for 3 months results in average steady-state tamoxifen plasma concentrations of 120 ng/mL (range, 67 to 183 ng/mL) for tamoxifen and 336 ng/mL (range, 148 to 654 ng/mL) for N-desmethyl tamoxifen. The average steady-state plasma concentrations of tamoxifen and N-desmethyl tamoxifen after administration of tamoxifen 20 mg once daily for 3 months are similar, at 122 ng/mL (range, 71 to 183 ng/mL) and 353 ng/mL (range, 152 to 706 ng/mL), respectively. Steady-state plasma concentrations of endoxifen and 4-hydroxytamoxifen area 29.1 ng/mL (95% CI, 24.6 to 33.6) and 3.7 ng/mL (95% CI, 3.3 to 4.1), respectively.[63589]
    The rate and extent of tamoxifen citrate oral solution (n = 30) in healthy perimenopausal and postmenopausal female subjects was bioequivalent to tamoxifen citrate tablets (n = 33) under fasting conditions in a pharmacokinetic study. Food did not affect the bioavailability (Cmax and AUC) of tamoxifen oral solution (n = 16); tamoxifen may be given without regard to meals. In a steady-state crossover study, tamoxifen 10 mg tablets given twice daily were bioequivalent to tamoxifen 20 mg tablets given once daily.[63589]