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  • CLASSES

    Cytostatic Anti-estrogens
    Selective Estrogen Receptor Modulators/SERMS

    BOXED WARNING

    Anticoagulant therapy, chemotherapy, stroke, thromboembolic disease

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

    Endometrial cancer, endometrial hyperplasia, uterine cancer

    An increased risk of endometrial cancer, endometrial changes (including hyperplasia and polyps), 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 been reported. Uterine sarcoma has been reported to occur more frequently among long-term tamoxifen users (> 2 years) versus non-users. Some of the uterine malignancies (endometrial carcinoma or uterine sarcoma) have been fatal. In general, patients with preexisting endometrial hyperplasia should not receive long-term tamoxifen therapy. Health care providers should discuss the potential benefits versus risks of these serious events with women at high risk of breast cancer and also those women with ductal carcinoma in situ (DCIS) considering tamoxifen therapy to decrease their risk of developing breast cancer. The benefits of tamoxifen therapy in the adjuvant treatment of breast cancer (improved disease-free and overall survival) or for advanced breast cancer (response and palliation) outweigh the risks. Patients receiving or having previously received tamoxifen should have routine gynecological care and should promptly inform their health care professional if they experience any abnormal gynecological symptoms (e.g., menstrual irregularities, abnormal vaginal bleeding, changes in vaginal discharge, or pelvic pain or pressure). In the P-1 study, endometrial sampling in women with an intact uterus did not alter the endometrial cancer detection rate compared to women who did not undergo endometrial sampling (0.6% with sampling; 0.5% without sampling). There are no data to suggest that routine endometrial sampling would be beneficial in asymptomatic women taking tamoxifen for breast cancer prevention.

    DEA CLASS

    Rx

    DESCRIPTION

    Prototype selective estrogen receptor modulator (SERM) with estrogenic and antiestrogenic effects on selected tissues; estrogen-receptor (ER) positive tumors are more likely to respond to tamoxifen therapy; used to treat and prevent breast cancer.

    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.
    NOTE: Evidence indicates that patients whose tumors are estrogen receptor (ER) positive are more likely to benefit from tamoxifen therapy.
    As adjuvant therapy for axillary node-negative breast cancer and axillary node-positive breast cancer in postmenopausal women, following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation to decrease the incidence of contralateral breast cancer.
    Oral dosage
    Adult females

    20—40 mg/day PO in divided doses twice daily. The reduction in recurrence and mortality is greater in women estrogen receptor (ER)-positive breast cancer treated for 5 years than those treated for shorter a duration. There is no evidence that doses > 20 mg/day are more effective. Women with ER-positive tumors may gain a small additional benefit from the combination of tamoxifen and chemotherapy. Adjuvant tamoxifen reduces the occurrence of contralateral breast cancer. Patients with ER-positive and unknown ER status treated with adjuvant tamoxifen for 5 years had a decreased 10-year mortality and all women treated with tamoxifen, regardless of receptor status, have a decreased incidence of contralateral breast cancer following adjuvant tamoxifen therapy. In some tamoxifen adjuvant trials in women who are axillary node positive, most of the benefit has been in the subgroup with >= 4 positive axillary lymph nodes.

    For metastatic breast cancer in men and pre- and post-menopausal women.
    Oral dosage
    Adults

    20—40 mg/day PO in divided doses twice a day. Treatment should continue as long as there is clinical benefit. In premenopausal women, tamoxifen may be used as an alternative to ovarian ablation. Tamoxifen is not usually used as primary treatment of breast cancer in premenopausal women.

    For ductal carcinoma in situ (DCIS) following breast surgery and radiation therapy 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.

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

    20 mg/day PO plus everolimus 10 mg/day PO until disease progression or unacceptable toxicity resulted in significantly improved clinical benefit rate (primary endpoint, 61.1% vs 42.1%; p = 0.045), time to progression (TTP) (7.6 vs 4.5 months; p = 0.0021), and overall survival (OS) (16 vs 31 events; hazard ratio = 0.45; 95% CI, 0.24-0.81; p = 0.007) compared with tamoxifen alone (median follow-up, 24 months) in a randomized, phase II study in 111 postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer and primary or secondary aromatase inhibitor resistance. No crossover was permitted. Primary hormone resistance was defined as relapse during adjuvant aromatase inhibitor (AI) therapy or disease progression within 6 months of starting AI therapy for metastatic disease and secondary hormone resistance was defined as relapse later than 6 months or a previous response and subsequent progression after starting AI therapy for metastatic disease. In exploratory analyses, a statistically significant TTP and OS benefit was observed with combination therapy in women with secondary resistance (TTP: 14.8 vs 5.5 months, p = 0.0087; OS: 4 vs 16 events, p = 0.002) but not primary resistance (TTP: 5.4 vs 3.8 months; OS: 12 vs 15 events). A higher incidence of grade 3 and 4 stomatitis and anorexia was reported in the everolimus plus tamoxifen arm; 22% of patients in the combination therapy arm and 7% of patients in the tamoxifen alone arm discontinued treatment due to adverse events.

    For breast cancer prophylaxis in women who are at high risk (5-year risk >= 1.67%) for developing the disease.
    NOTE: There are no data available regarding the effect of tamoxifen on breast cancer incidence in women with inherited mutations (i.e., BRCA1 or BRCA2).
    NOTE: Clinical guidelines recommend discussing the option of breast cancer chemoprevention only with those women who are at high risk for developing the disease. The potential harm of this therapy outweighs the benefit in women with low or average risk of breast cancer. 
    For women with certain risk factor combinations predicting a 5-year risk >= 1.67% for developing breast cancer.
    NOTE: The Gail Model is to be used to estimate a woman's risk to develop breast cancer. US health care professionals may obtain a Gail Model Risk Assessment Tool by calling (800)—34—LIFE—4.
    Oral dosage
    Adult females >= 35 years

    With a combination of risk factors including one first degree relative with a history of breast cancer, 2 or more benign biopsies and a history of a breast biopsy showing atypical hyperplasia; or, at least 2 first degree relatives with a history of breast cancer, and a personal history of at least one breast biopsy; or, lobular carcinoma in situ (LCIS) may be treated with tamoxifen 20 mg PO once daily for 5 years.

    Adult females >= 40 years

    With a combination of risk factors including one first degree relative with a history of breast cancer, 2 or more benign biopsies, age at first live birth >= 25 years of age and age at menarche <= 11 years or, at least 2 first degree relatives with a history of breast cancer and age at first live birth of <= 19 years; or, one first degree relative with a history of breast cancer and a personal history of a breast biopsy showing atypical hyperplasia may be treated with tamoxifen 20 mg PO once daily for 5 years.

    Adult females >= 45 years

    With a combination of risk factors including at least 2 first degree relatives with a history of breast cancer and age at first live birth of 24 years or younger; or, one first degree relative with a history of breast cancer with a personal history of benign breast biopsy, age at menarche <= 11 years and age at first live birth >= 20 years may be treated with tamoxifen 20 mg PO once daily for 5 years.

    Adult females >= 50 years

    With a combination of risk factors including at least 2 first degree relatives with a history of breast cancer; or, history of one breast biopsy showing atypical hyperplasia and age at first live birth of >= 30 years and age at menarche <= 11 years; or, history of at least 2 breast biopsies with a history of atypical hyperplasia and age at first live birth of >= 30 years may be treated with tamoxifen 20 mg PO once daily for 5 years.

    Adult females >= 55 years

    With a combination of risk factors including one first degree relative with a history of breast cancer with a personal history of benign breast biopsy and age at menarche of <= 11 years; or history of at least 2 breast biopsies with a history of atypical hyperplasia and age at first live birth of >= 20 years may be treated with tamoxifen 20 mg PO once daily for 5 years.

    Oral dosage
    Adult females at risk for breast cancer

    20 mg PO once daily for 5 years. There are no data to support the use of tamoxifen for longer than 5 years. The Breast Cancer Prevention Trial (BCPT, NSABP P-1) was halted early because the incidence of breast cancer was reduced by 44% among women randomized to receive tamoxifen. In this study, there was no impact of tamoxifen on overall or breast cancer-related mortality. Other studies examining the efficacy of tamoxifen for breast cancer prevention have been reported but the interim results of these studies did not show a benefit for tamoxifen therapy, possibly due to inclusion of patients at lower risk and/or patients less likely to respond to tamoxifen therapy (i.e., those more likely to develop ER-negative disease).

    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

    40 mg/day PO for breast cancer treatment; 20 mg/day PO for breast cancer prophylaxis; doses of up to 160 mg/day PO have been used off-label.

    Elderly

    40 mg/day PO for breast cancer treatment; 20 mg/day PO for breast cancer prophylaxis; doses of up to 160 mg/day PO have been used off-label.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established; however, doses of up to 20 mg/day PO have been used off-label in girls for precocious puberty.

    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

    NOTE: A MedGuide is available for tamoxifen and is to be dispensed with every prescription and prescription refill for selected women. The MedGuide discusses ONLY the use of tamoxifen to lower the chance of getting breast cancer in high-risk women and in women treated for ductal carcinoma in situ (DCIS), situations in which the risks and benefits of the medicine should be carefully considered.
     

    Oral Administration

    For sexually active women of childbearing potential, tamoxifen therapy should be initiated during menstruation. In women with menstrual irregularity, a negative pregnancy test should be confirmed prior to beginning therapy.

    Oral Solid Formulations

    Tablets: Tamoxifen may be administered with food or fluids if gastric irritation occurs.

    Oral Liquid Formulations

    Oral solution: Use a calibrated spoon, oral syringe, or container to measure the oral solution for accurate dosing. A 20 mg dose is administered as 10 ml of the oral solution. Doses > 20 mg/day should be given in divided doses (morning and evening). Tamoxifen may be administered with food or fluids if gastric irritation occurs.

    STORAGE

    Nolvadex:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Soltamox:
    - Do not freeze
    - Product should be used within 3 months after opening
    - Protect from light
    - Store below 77 degrees F
    - Store in original package until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

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

    Anticoagulant therapy, chemotherapy, stroke, thromboembolic disease

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

    Menstrual irregularity, pregnancy

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

    Breast-feeding

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

    Endometrial cancer, endometrial hyperplasia, uterine cancer

    An increased risk of endometrial cancer, endometrial changes (including hyperplasia and polyps), 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 been reported. Uterine sarcoma has been reported to occur more frequently among long-term tamoxifen users (> 2 years) versus non-users. Some of the uterine malignancies (endometrial carcinoma or uterine sarcoma) have been fatal. In general, patients with preexisting endometrial hyperplasia should not receive long-term tamoxifen therapy. Health care providers should discuss the potential benefits versus risks of these serious events with women at high risk of breast cancer and also those women with ductal carcinoma in situ (DCIS) considering tamoxifen therapy to decrease their risk of developing breast cancer. The benefits of tamoxifen therapy in the adjuvant treatment of breast cancer (improved disease-free and overall survival) or for advanced breast cancer (response and palliation) outweigh the risks. Patients receiving or having previously received tamoxifen should have routine gynecological care and should promptly inform their health care professional if they experience any abnormal gynecological symptoms (e.g., menstrual irregularities, abnormal vaginal bleeding, changes in vaginal discharge, or pelvic pain or pressure). In the P-1 study, endometrial sampling in women with an intact uterus did not alter the endometrial cancer detection rate compared to women who did not undergo endometrial sampling (0.6% with sampling; 0.5% without sampling). There are no data to suggest that routine endometrial sampling would be beneficial in asymptomatic women taking tamoxifen for breast cancer prevention.

    Bone marrow suppression, leukopenia, neutropenia, thrombocytopenia

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

    Intramuscular injections

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

    Hypercholesterolemia, hyperlipoproteinemia

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

    Cataracts, visual disturbance

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

    Hypercalcemia

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

    Children

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

    ADVERSE REACTIONS

    Severe

    hot flashes / Early / 0-45.0
    vaginal discharge / Delayed / 0-12.3
    bone fractures / Delayed / 7.0-7.0
    stroke / Early / 0.5-3.0
    thrombosis / Delayed / 0.5-2.0
    myocardial infarction / Delayed / 1.1-1.1
    erythema multiforme / Delayed / 0-1.0
    Stevens-Johnson syndrome / Delayed / 0-1.0
    angioedema / Rapid / 0-1.0
    pancreatitis / Delayed / 0-1.0
    pulmonary embolism / Delayed / 0.3-0.5
    thrombocytopenia / Delayed / 0-0.1
    teratogenesis / Delayed / Incidence not known
    fetal abortion / Delayed / Incidence not known
    fetal death / Delayed / Incidence not known
    thromboembolism / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    retinal thrombosis / Delayed / Incidence not known
    retinopathy / Delayed / Incidence not known
    hepatic necrosis / Delayed / Incidence not known

    Moderate

    peripheral vasodilation / Rapid / 41.0-41.0
    fluid retention / Delayed / 32.0-32.0
    vaginal bleeding / Delayed / 2.0-23.0
    depression / Delayed / 2.0-12.0
    hypertension / Early / 11.0-11.0
    peripheral edema / Delayed / 0-11.0
    hypercalcemia / Delayed / 1.0-10.0
    cataracts / Delayed / 7.0-8.1
    constipation / Delayed / 4.4-8.0
    dyspnea / Early / 8.0-8.0
    osteoporosis / Delayed / 7.0-7.0
    bone pain / Delayed / 6.0-6.0
    vaginitis / Delayed / 5.0-5.0
    neutropenia / Delayed / 5.0-5.0
    elevated hepatic enzymes / Delayed / 5.0-5.0
    chest pain (unspecified) / Early / 5.0-5.0
    edema / Delayed / 4.0-4.0
    hypercholesterolemia / Delayed / 3.5-3.5
    hyperbilirubinemia / Delayed / 2.0-2.0
    angina / Early / 1.6-1.6
    bleeding / Early / 0-1.0
    bullous rash / Early / 0-1.0
    pneumonitis / Delayed / 0-1.0
    hypertriglyceridemia / Delayed / 0-1.0
    secondary malignancy / Delayed / 0.5-0.6
    phlebitis / Rapid / 0.4-0.4
    endometrial hyperplasia / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    anemia / Delayed / Incidence not known
    erythema / Early / Incidence not known
    hepatitis / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known

    Mild

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

    DRUG INTERACTIONS

    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors, such as chlorpheniramine. Consider avoiding concomitant use of chlorpheniramine and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors, such as chlorpheniramine. Consider avoiding concomitant use of chlorpheniramine and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Major) Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors, such as chlorpheniramine. Consider avoiding concomitant use of chlorpheniramine and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen.
    Acetaminophen; Diphenhydramine: (Major) Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors, such as diphenhydramine. Consider avoiding concomitant use of diphenhydramine and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen. A trial of 1,298 patients with breast cancer compared the rate of breast cancer recurrence in patients treated with tamoxifen with or without a CYP2D6 inhibitor. Patients who received tamoxifen in combination with a CYP2D6 inhibitor had a significantly higher rate of breast cancer recurrence at 2 years (13.9% v. 7.5%, p < 0.001). A separate observational study of 1,990 patients assessed event free time with adjuvant tamoxifen treatment for breast cancer. Only 215 of these patients were administered a CYP2D6 inhibitor, however no clinically significant differences were observed with the addition of a CYP2D6 inhibitor.
    Acetaminophen; Propoxyphene: (Major) Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors, such as propoxyphene. Consider avoiding concomitant use of propoxyphene and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen.
    Afatinib: (Major) If the concomitant use of tamoxifen and afatinib is necessary, consider reducing the afatinib dose by 10 mg per day if the original dose is not tolerated; resume the previous dose of afatinib as tolerated after discontinuation of tamoxifen. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro, and tamoxifen is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration of another P-gp inhibitor, ritonavir (200 mg twice daily for 3 days), 1 hour before afatinib (single dose) increased the afatinib AUC and Cmax by 48% and 39%, respectively; there was no change in the afatinib AUC when ritonavir was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after afatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise.
    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.
    Aldesleukin, IL-2: (Moderate) Aldesleukin, IL-2 is a mild CYP3A4 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Aldesleukin, IL-2 may inhibit the CYP3A4 metabolism of tamoxifen to these metabolites. Concomitant use of aldesleukin, IL-2 and tamoxifen may result in decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. If it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen.
    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.
    Alogliptin; Pioglitazone: (Major) Pioglitazone is a mild CYP3A4 inducer. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Pioglitazone may induce the CYP3A4 metabolism of tamoxifen to these metabolites; plasma concentrations of tamoxifen and its active metabolites have been reduced when coadministered other CYP3A4 inducers. If coadministration cannot be avoided, monitor for changes to the therapeutic effects of tamoxifen.
    Amiodarone: (Major) Avoid coadministration of tamoxifen with amiodarone due to an increased risk of QT prolongation and torsade de pointes (TdP); reduced tamoxifen efficacy and/or increased tamoxifen toxicity is also possible. Monitor for evidence of QT prolongation, altered tamoxifen efficacy, and increased tamoxifen adverse effects if coadministration cannot be avoided. 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. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and 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. In addition, amiodarone may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP2D6 and CYP3A4. In a clinical trial, there was a significantly higher rate of breast cancer recurrence in patients who had received a CYP2D6 inhibitor with tamoxifen. In another observational study, no clinically significant differences were observed with the addition of a CYP2D6 inhibitor to tamoxifen therapy; however, only 215 patients of 1,990 were administered a CYP2D6 inhibitor.
    Amitriptyline: (Minor) 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: (Minor) 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).
    Amlodipine; Telmisartan: (Moderate) Telmisartan is a weak CYP2C19 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a smaller extent by CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Theoretically, concomitant use of telmisartan and tamoxifen may result in decreased concentrations of the active metabolites of tamoxifen; the clinical significance of this interaction is not known.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Concomitant use of tamoxifen and clarithromycin may cause an increased risk of QT prolongation and torsade de pointes (TdP); reduced tamoxifen efficacy and/or increased tamoxifen toxicity is also possible. If coadministration is unavoidable, monitor for altered tamoxifen efficacy, increased tamoxifen-related adverse effects, and evidence 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. Clarithromycin is associated with an established risk for QT prolongation and TdP. Clarithromycin may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP3A4. (Moderate) Theoretically, concomitant use may result in increased lansoprazole side effects and decreased concentrations of the active metabolites of tamoxifen which can compromise efficacy; the clinical significance of this interaction is not known. In vitro, lansoprazole is a weak CYP2C9 and CYP2C19 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Additionally, lansoprazole is a P-glycoprotein (P-gp) substrate; tamoxifen inhibits P-gp.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Concomitant use of tamoxifen and clarithromycin may cause an increased risk of QT prolongation and torsade de pointes (TdP); reduced tamoxifen efficacy and/or increased tamoxifen toxicity is also possible. If coadministration is unavoidable, monitor for altered tamoxifen efficacy, increased tamoxifen-related adverse effects, and evidence 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. Clarithromycin is associated with an established risk for QT prolongation and TdP. Clarithromycin may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP3A4. (Moderate) Theoretically, concomitant use may result in increased omeprazole side effects and decreased concentrations of the active metabolites of tamoxifen which can compromise efficacy; the clinical significance of this interaction is not known. Omeprazole is a CYP2C19 inhibitor and, in vitro, an inhibitor of CYP2C9. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Additionally, omeprazole is a P-glycoprotein (P-gp) substrate; tamoxifen inhibits P-gp.
    Anagrelide: (Major) Caution is advised with the concomitant use of tamoxifen with anagrelide due to an increased risk of QT prolongation and torsade de pointes (TdP). A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as 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. 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.
    Anastrozole: (Major) Tamoxifen should not be administered with anastrozole. Concurrent administration of anastrozole and tamoxifen resulted in a reduction of anastrozole plasma levels by 27% compared to those achieved with anastrozole alone.
    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.
    Aprepitant, Fosaprepitant: (Moderate) Avoid the concomitant use of tamoxifen with aprepitant, fosaprepitant due to the potential for altered tamoxifen exposure and increased aprepitant exposure. If coadministration cannot be avoided, use caution and monitor for a decrease in tamoxifen efficacy and an increase in aprepitant-related adverse effects for several days after administration of a multi-day aprepitant regimen. Tamoxifen is a moderate CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate. Coadministration of daily oral aprepitant (230 mg, or 1.8 times the recommended single dose) with a moderate CYP3A4 inhibitor, diltiazem, increased the aprepitant AUC 2-fold with a concomitant 1.7-fold increase in the diltiazem AUC; clinically meaningful changes in ECG, heart rate, or blood pressure beyond those induced by diltiazem alone did not occur. Tamoxifen is also metabolized by CYP3A4 and to a lesser extent, by CYP2C9, to other potent active metabolites including endoxifen, which are then inactivated by sulfotransferase 1A1 (SULT1A1). Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer. Aprepitant may inhibit the metabolism of tamoxifen to these active metabolites, which have up to 33 times more affinity for the estrogen receptor than tamoxifen, resulting in decreased efficacy. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. Aprepitant is also a CYP2C9 inducer. Administration of a CYP2C9 substrate, tolbutamide, on days 1, 4, 8, and 15 with a 3-day regimen of oral aprepitant (125 mg/80 mg/80 mg) decreased the tolbutamide AUC by 23% on day 4, 28% on day 8, and 15% on day 15. The AUC of tolbutamide was decreased by 8% on day 2, 16% on day 4, 15% on day 8, and 10% on day 15 when given prior to oral administration of aprepitant 40 mg on day 1, and on days 2, 4, 8, and 15. The effects of aprepitant on tolbutamide were not considered significant.
    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.
    Armodafinil: (Major) In vitro, armodafinil is a CYP3A4 inducer. Tamoxifen and its metabolite, 4-hydroxytamoxifen, are metabolized in part by CYP3A4 to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Armodafinil may induce the CYP3A4 metabolism of tamoxifen to these metabolites; plasma concentrations of tamoxifen and N-desmethyl tamoxifen have been reduced when coadministered other CYP3A4 inducers. If it is not possible to avoid concomitant use, monitor patients for changes in the therapeutic efficacy of tamoxifen.
    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. TdP, QT interval prolongation, and complete atrioventricular block have been reported with arsenic trioxide use. Concomitant use may increase the risk of QT prolongation.
    Artemether; Lumefantrine: (Major) Avoid coadministration of tamoxifen with artemether; lumefantrine due to an increased risk of QT prolongation. Consider ECG monitoring if tamoxifen must be used with or after artemether; lumefantrine 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. (Moderate) Concomitant use may result in decreased concentrations of the active metabolites of tamoxifen, which may compromise efficacy. Monitor patients for changes in the therapeutic effects of tamoxifen. Lumefantrine is a strong CYP2D6 inhibitor. Tamoxifen is metabolized by CYP2D6 to the potent active metabolite 4-hydroxytamoxifen. 4-hydroxytamoxifen is further metabolized to endoxifen by CYP3A4/5. Active metabolite, N-desmethyl-tamoxifen, is also metabolized to endoxifen by CYP2D6. Artemether; lumefantrine may inhibit the CYP2D6 metabolism of tamoxifen to these metabolites, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors. A trial of 1,298 patients with breast cancer compared the rate of breast cancer recurrence in patients treated with tamoxifen with or without a CYP2D6 inhibitor. Patients who received tamoxifen in combination with a CYP2D6 inhibitor had a significantly higher rate of breast cancer recurrence at 2 years (13.9% v. 7.5%, p < 0.001). A separate observational study of 1,990 patients assessed event free time with adjuvant tamoxifen treatment for breast cancer. Only 215 of these patients were administered a CYP2D6 inhibitor, however no clinically significant differences were observed with the addition of a CYP2D6 inhibitor.
    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 been associated with QT prolongation. Concomitant use may increase the risk of QT prolongation.
    Aspirin, ASA; Omeprazole: (Moderate) Theoretically, concomitant use may result in increased omeprazole side effects and decreased concentrations of the active metabolites of tamoxifen which can compromise efficacy; the clinical significance of this interaction is not known. Omeprazole is a CYP2C19 inhibitor and, in vitro, an inhibitor of CYP2C9. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Additionally, omeprazole is a P-glycoprotein (P-gp) substrate; tamoxifen inhibits P-gp.
    Atazanavir: (Major) Atazanavir is a potent CYP3A4 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Atazanavir may inhibit the CYP3A4 metabolism of tamoxifen to these metabolites. Concomitant use of atazanavir and tamoxifen may result in decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. If it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen.
    Atazanavir; Cobicistat: (Major) Atazanavir is a potent CYP3A4 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Atazanavir may inhibit the CYP3A4 metabolism of tamoxifen to these metabolites. Concomitant use of atazanavir and tamoxifen may result in decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. If it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen. (Moderate) Concomitant use may result in decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. If it is not possible to avoid concomitant use, monitor patients for changes in the therapeutic efficacy of tamoxifen. Cobicistat is a strong inhibitor of CYP3A4. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent, CYP2C9 and CYP2C19, to other potent active metabolites including endoxifen, which are then inactivated by sulfotransferase 1A1 (SULT1A1). Cobicistat may inhibit the CYP3A4 metabolism of tamoxifen to these metabolites, which have up to 33 times more affinity for the estrogen receptor than tamoxifen.
    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.
    Axitinib: (Moderate) Use caution if coadministration of axitinib with tamoxifen is necessary, due to the risk of increased axitinib-related adverse reactions. Axitinib is a CYP3A4 substrate and tamoxifen is a moderate CYP3A4 inhibitor. Coadministration with a strong CYP3A4/5 inhibitor, ketoconazole, significantly increased the plasma exposure of axitinib in healthy volunteers. The manufacturer of axitinib recommends a dose reduction in patients receiving strong CYP3A4 inhibitors, but recommendations are not available for moderate or weak CYP3A4 inhibitors.
    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); increased azithromycin exposure is also possible. 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. Tamoxifen may increase exposure to azithromycin via inhibition of P-glycoprotein (P-gp).
    Barbiturates: (Moderate) Tamoxifen and its metabolite, 4-hydroxytamoxifen, are metabolized by the cytochrome P-450 3A4 isoenzyme. Barbiturates may induce the metabolism of tamoxifen, potentially leading to a decrease in clinical effectiveness.
    Basiliximab: (Major) Basiliximab is a mild CYP3A4 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Basiliximab may inhibit the CYP3A4 metabolism of tamoxifen to these metabolites. Concomitant use of basiliximab and tamoxifen may result in decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. If it is not possible to avoid concomitant use, monitor patients for changes in the therapeutic efficacy of tamoxifen.
    Bedaquiline: (Major) Caution is advised with the concomitant use of tamoxifen and bedaquiline due to an increased risk of QT prolongation. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. 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.
    Bexarotene: (Moderate) There is an increased risk of a thromboembolic event occurring when antineoplastic agents are used in combination with tamoxifen. Concomitant administration of bexarotene capsules and tamoxifen has also resulted in a modest decrease in plasma concentrations of tamoxifen, possibly due to an induction of CYP3A4.
    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 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 been reported in limited case reports with metronidazole.
    Boceprevir: (Major) Boceprevir is a potent CYP3A4 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent, CYP2C9 and CYP2C19, to other potent active metabolites including endoxifen, which are then inactivated by sulfotransferase 1A1 (SULT1A1). Boceprevir may inhibit the CYP3A4 metabolism of tamoxifen to these metabolites, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. Additionally, tamoxifen is an inhibitor of the drug efflux transporter P-glycoprotein (P-gp); boceprevir is partially metabolized by P-gp. When used in combination, the plasma concentrations of boceprevir may be elevated and active metabolites of tamoxifen may be decreased, which can compromise efficacy. If it is not possible to avoid concomitant use, monitor patients for changes in the therapeutic efficacy of tamoxifen.
    Bortezomib: (Moderate) There is an increased risk of a thromboembolic event occurring when antineoplastic agents are used in combination with tamoxifen.
    Bosentan: (Major) Bosentan is a CYP3A4 inducer. Tamoxifen and its metabolite, 4-hydroxytamoxifen, are metabolized by CYP3A4 to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Bosentan may induce the CYP3A4 metabolism of tamoxifen to these metabolites, which can compromise efficacy; plasma concentrations of tamoxifen and its active metabolites have been reduced when coadministered other CYP3A4 inducers. If it is not possible to avoid concomitant use, monitor patients for changes in the therapeutic efficacy of tamoxifen.
    Brexpiprazole: (Moderate) Because brexpiprazole is primarily metabolized by CYP3A4 and CYP2D6, systemic exposure of brexpiprazole may be increased during the use of moderate inhibitors of CYP3A4 such as tamoxifen and careful monitoring is recommended. In addition, the manufacturer recommends that the brexpiprazole dose be reduced to one-quarter (25%) of the usual dose in patients receiving a moderate to strong inhibitor of CYP3A4 in combination with a moderate to strong inhibitor of CYP2D6. Therefore, if tamoxifen is used in combination with brexpiprazole and a moderate to strong CYP2D6 inhibitor, the brexpiprazole dose should be adjusted and the patient should be carefully monitored for brexpiprazole-related adverse reactions. If the CYP inhibitor is discontinued, the brexpiprazole dose should be adjusted to the original level.
    Brigatinib: (Moderate) Monitor for decreased efficacy of tamoxifen if coadministration with brigatinib is necessary. Tamoxifen is a CYP3A substrate and brigatinib induces CYP3A in vitro. Plasma concentrations of tamoxifen and active metabolite, N-desmethyl tamoxifen, have been reduced when coadministered with other CYP3A4 inducers. The AUC and Cmax of tamoxifen were decreased by 86% and 55%, respectively, when administered with a strong CYP3A4 inducer; brigatinib may also decrease tamoxifen exposure.
    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.
    Bupivacaine; Lidocaine: (Moderate) Concomitant use of systemic lidocaine and tamoxifen may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; tamoxifen inhibits CYP3A4.
    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. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (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. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (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: (Major) Tamoxifen is converted to endoxifen and other active metabolites by cytochrome P450 (CYP) enzymes (e.g., 2D6, 3A4). Bupropion is considered a moderate to potent inhibitor of CYP2D6; reduced tamoxifen efficacy is possible with concomitant use. If treatment with an antidepressant and tamoxifen is necessary, it may be preferable to use an agent that exhibits mild inhibition of CYP2D6.
    Bupropion; Naltrexone: (Major) Tamoxifen is converted to endoxifen and other active metabolites by cytochrome P450 (CYP) enzymes (e.g., 2D6, 3A4). Bupropion is considered a moderate to potent inhibitor of CYP2D6; reduced tamoxifen efficacy is possible with concomitant use. If treatment with an antidepressant and tamoxifen is necessary, it may be preferable to use an agent that exhibits mild inhibition of CYP2D6.
    Canagliflozin: (Moderate) Canagliflozin is a substrate of drug transporter P glycoprotein (P-gp). Tamoxifen is a PGP inhibitor and may theoretically increase concentrations of canagliflozin. Patients should be monitored for changes in glycemic control.
    Canagliflozin; Metformin: (Moderate) Canagliflozin is a substrate of drug transporter P glycoprotein (P-gp). Tamoxifen is a PGP inhibitor and may theoretically increase concentrations of canagliflozin. Patients should be monitored for changes in glycemic control.
    Capecitabine: (Minor) Use caution if coadministration of capecitabine with tamoxifen is necessary, and monitor for a possible decrease in the efficacy of tamoxifen. Tamoxifen is metabolized in by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Capecitabine and/or its metabolites are thought to be inhibitors of CYP2C9. Capecitabine may inhibit the CYP2C9 metabolism of tamoxifen to its active metabolites, potentially decreasing its efficacy.
    Carbamazepine: (Major) Carbamazepine is a potent CYP3A4 inducer. Tamoxifen and its metabolite, 4-hydroxytamoxifen, are metabolized in part by CYP3A4 to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Carbamazepine may induce the CYP3A4 metabolism of tamoxifen to these metabolites; plasma concentrations of tamoxifen and N-desmethyl tamoxifen have been reduced when coadministered other CYP3A4 inducers. If it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen.
    Carbetapentane; Chlorpheniramine: (Major) Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors, such as chlorpheniramine. Consider avoiding concomitant use of chlorpheniramine and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Major) Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors, such as chlorpheniramine. Consider avoiding concomitant use of chlorpheniramine and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Major) Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors, such as diphenhydramine. Consider avoiding concomitant use of diphenhydramine and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen. A trial of 1,298 patients with breast cancer compared the rate of breast cancer recurrence in patients treated with tamoxifen with or without a CYP2D6 inhibitor. Patients who received tamoxifen in combination with a CYP2D6 inhibitor had a significantly higher rate of breast cancer recurrence at 2 years (13.9% v. 7.5%, p < 0.001). A separate observational study of 1,990 patients assessed event free time with adjuvant tamoxifen treatment for breast cancer. Only 215 of these patients were administered a CYP2D6 inhibitor, however no clinically significant differences were observed with the addition of a CYP2D6 inhibitor.
    Ceritinib: (Major) Avoid coadministration of tamoxifen with ceritinib due to an increased risk of QT prolongation; reduced tamoxifen efficacy and/or increased tamoxifen toxicity is also possible. If coadministration is unavoidable, monitor for altered tamoxifen efficacy, increased tamoxifen-related adverse effects, and evidence of QT prolongation. Periodically monitor electrolytes and ECGs; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Permanently discontinue ceritinib therapy in patients who develop QT prolongation with torsade de pointes, polymorphic ventricular tachycardia, or other serious arrhythmias. Ceritinib causes concentration-dependent prolongation of the QT 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. Ceritinib may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP3A4.
    Cetuximab: (Moderate) There is an increased risk of a thromboembolic event occurring when antineoplastic agents are used in combination with tamoxifen.
    Chloroquine: (Major) Concurrent use of chloroquine and tamoxifen is not recommended as there is an increased risk of retinal toxicity, QT prolongation, and torsade de pointes (TdP). 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 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.
    Chlorpheniramine: (Major) Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors, such as chlorpheniramine. Consider avoiding concomitant use of chlorpheniramine and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen.
    Chlorpheniramine; Codeine: (Major) Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors, such as chlorpheniramine. Consider avoiding concomitant use of chlorpheniramine and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen.
    Chlorpheniramine; Dextromethorphan: (Major) Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors, such as chlorpheniramine. Consider avoiding concomitant use of chlorpheniramine and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors, such as chlorpheniramine. Consider avoiding concomitant use of chlorpheniramine and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors, such as chlorpheniramine. Consider avoiding concomitant use of chlorpheniramine and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Major) Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors, such as chlorpheniramine. Consider avoiding concomitant use of chlorpheniramine and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors, such as chlorpheniramine. Consider avoiding concomitant use of chlorpheniramine and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen.
    Chlorpheniramine; Hydrocodone: (Major) Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors, such as chlorpheniramine. Consider avoiding concomitant use of chlorpheniramine and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors, such as chlorpheniramine. Consider avoiding concomitant use of chlorpheniramine and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Major) Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors, such as chlorpheniramine. Consider avoiding concomitant use of chlorpheniramine and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen.
    Chlorpheniramine; Phenylephrine: (Major) Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors, such as chlorpheniramine. Consider avoiding concomitant use of chlorpheniramine and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen.
    Chlorpheniramine; Pseudoephedrine: (Major) Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors, such as chlorpheniramine. Consider avoiding concomitant use of chlorpheniramine and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen.
    Chlorpromazine: (Major) Caution is advised with the concomitant use of tamoxifen with chlorpromazine due to an increased risk of QT prolongation and torsade de pointes (TdP); reduced tamoxifen efficacy is also possible. Monitor for evidence of QT prolongation and altered tamoxifen efficacy if coadministration is needed. 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. Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and TdP. Chlorpromazine may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP2D6. In a clinical trial, there was a significantly higher rate of breast cancer recurrence in patients who had received a CYP2D6 inhibitor with tamoxifen. In another observational study, no clinically significant differences were observed with the addition of a CYP2D6 inhibitor to tamoxifen therapy; however, only 215 patients of 1,990 were administered a CYP2D6 inhibitor.
    Cimetidine: (Major) Tamoxifen, a selective estrogen receptor modulator (SERM), is converted to endoxifen and other active metabolites by cytochrome P450 (CYP) enzymes (e.g., 2D6, 3A4). Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors. Cimetidine is a weak inhibitor of CYP2D6. A trial of 1,298 patients with breast cancer compared the rate of breast cancer recurrence in patients treated with tamoxifen with or without a CYP2D6 inhibitor. Patients who received tamoxifen in combination with a CYP2D6 inhibitor had a significantly higher rate of breast cancer recurrence at 2 years (13.9% v. 7.5%, p < 0.001). A separate observational study of 1,990 patients assessed event free time with adjuvant tamoxifen treatment for breast cancer. Only 215 of these patients were administered a CYP2D6 inhibitor, however no clinically significant differences were observed with the addition of a CYP2D6 inhibitor. Consider avoiding concomitant use of CYP2D6 inhibitors and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen.
    Cinacalcet: (Major) Concomitant use may result in decreased concentrations of the active metabolites of tamoxifen, which may compromise efficacy. Monitor patients for changes in the therapeutic effects of tamoxifen. Cinacalcet is a potent inhibitor of CYP2D6; tamoxifen is metabolized in part by CYP2D6 to the potent active metabolite 4-hydroxytamoxifen. 4-hydroxytamoxifen is further metabolized to endoxifen by CYP3A4/5. Active metabolite, N-desmethyl-tamoxifen, is also metabolized to endoxifen by CYP2D6. Cinacalcet may inhibit the CYP2D6 metabolism of tamoxifen to these metabolites, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors. A trial of 1,298 patients with breast cancer compared the rate of breast cancer recurrence in patients treated with tamoxifen with or without a CYP2D6 inhibitor. Patients who received tamoxifen in combination with a CYP2D6 inhibitor had a significantly higher rate of breast cancer recurrence at 2 years (13.9% v. 7.5%, p < 0.001). A separate observational study of 1,990 patients assessed event free time with adjuvant tamoxifen treatment for breast cancer. Only 215 of these patients were administered a CYP2D6 inhibitor, however no clinically significant differences were observed with the addition of a CYP2D6 inhibitor.
    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 torsade de pointes (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) Concomitant use of tamoxifen and clarithromycin may cause an increased risk of QT prolongation and torsade de pointes (TdP); reduced tamoxifen efficacy and/or increased tamoxifen toxicity is also possible. If coadministration is unavoidable, monitor for altered tamoxifen efficacy, increased tamoxifen-related adverse effects, and evidence 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. Clarithromycin is associated with an established risk for QT prolongation and TdP. Clarithromycin may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP3A4.
    Clobazam: (Major) Limited in vivo data suggest that clobazam is an inhibitor of CYP2D6. Tamoxifen, a selective estrogen receptor modulator (SERM), is converted to endoxifen and other active metabolites by CYP2D6 and CYP3A4. Some data suggest that the efficacy of tamoxifen is reduced when co-administered with CYP2D6 inhibitors.
    Clomipramine: (Minor) 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).
    Clopidogrel: (Moderate) Clopidogrel may decrease the concentrations of the active metabolites of tamoxifen, which can compromise efficacy. At high concentrations, clopidogrel is a CYP2C9 inhibitor. Tamoxifen is metabolized by CYP3A4 and CYP2D6, and to a lesser extent by CYP2C9, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1).
    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.
    Cobicistat: (Moderate) Concomitant use may result in decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. If it is not possible to avoid concomitant use, monitor patients for changes in the therapeutic efficacy of tamoxifen. Cobicistat is a strong inhibitor of CYP3A4. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent, CYP2C9 and CYP2C19, to other potent active metabolites including endoxifen, which are then inactivated by sulfotransferase 1A1 (SULT1A1). Cobicistat may inhibit the CYP3A4 metabolism of tamoxifen to these metabolites, which have up to 33 times more affinity for the estrogen receptor than tamoxifen.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is warranted when elvitegravir is administered with tamoxifen as there is a potential for decreased tamoxifen concentrations. Tamoxifen is a substrate of CYP2C9, while elvitegravir is an inducer of CYP2C9. (Moderate) Concomitant use may result in decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. If it is not possible to avoid concomitant use, monitor patients for changes in the therapeutic efficacy of tamoxifen. Cobicistat is a strong inhibitor of CYP3A4. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent, CYP2C9 and CYP2C19, to other potent active metabolites including endoxifen, which are then inactivated by sulfotransferase 1A1 (SULT1A1). Cobicistat may inhibit the CYP3A4 metabolism of tamoxifen to these metabolites, which have up to 33 times more affinity for the estrogen receptor than tamoxifen.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as tamoxifen. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. (Moderate) Caution is warranted when elvitegravir is administered with tamoxifen as there is a potential for decreased tamoxifen concentrations. Tamoxifen is a substrate of CYP2C9, while elvitegravir is an inducer of CYP2C9. (Moderate) Concomitant use may result in decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. If it is not possible to avoid concomitant use, monitor patients for changes in the therapeutic efficacy of tamoxifen. Cobicistat is a strong inhibitor of CYP3A4. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent, CYP2C9 and CYP2C19, to other potent active metabolites including endoxifen, which are then inactivated by sulfotransferase 1A1 (SULT1A1). Cobicistat may inhibit the CYP3A4 metabolism of tamoxifen to these metabolites, which have up to 33 times more affinity for the estrogen receptor than tamoxifen.
    Cobimetinib: (Minor) If concurrent use of cobimetinib and tamoxifen is necessary, use caution and monitor for a possible increase in cobimetinib-related adverse effects. Cobimetinib is a P-glycoprotein (P-gp) substrate, and tamoxifen is a P-gp inhibitor; coadministration may result in increased cobimetinib exposure. However, coadministration of cobimetinib with another P-gp inhibitor, vemurafenib (960 mg twice daily), did not result in clinically relevant pharmacokinetic drug interactions.
    Codeine; Phenylephrine; Promethazine: (Major) Avoid coadministration of tamoxifen with promethazine due to the potential for decreased tamoxifen efficacy; additive QT prolongation may also occur. If coadministration is necessary, monitor for altered tamoxifen efficacy and evidence of QT prolongation. Promethazine may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP2D6. 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. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. In a clinical trial, there was a significantly higher rate of breast cancer recurrence in patients who had received a CYP2D6 inhibitor with tamoxifen. In another observational study, no clinically significant differences were observed with the addition of a CYP2D6 inhibitor to tamoxifen therapy; however, only 215 patients of 1,990 were administered a CYP2D6 inhibitor.
    Codeine; Promethazine: (Major) Avoid coadministration of tamoxifen with promethazine due to the potential for decreased tamoxifen efficacy; additive QT prolongation may also occur. If coadministration is necessary, monitor for altered tamoxifen efficacy and evidence of QT prolongation. Promethazine may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP2D6. 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. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. In a clinical trial, there was a significantly higher rate of breast cancer recurrence in patients who had received a CYP2D6 inhibitor with tamoxifen. In another observational study, no clinically significant differences were observed with the addition of a CYP2D6 inhibitor to tamoxifen therapy; however, only 215 patients of 1,990 were administered a CYP2D6 inhibitor.
    Colchicine: (Major) Coadministration of colchicine and should be avoided due to the potential for serious and life-threatening toxicity. Colchicine is a substrate of P-glycoprotein (P-gp) and tamoxifen is an inhibitor of P-gp; increased concentrations of colchicine are expected with concurrent use. Colchicine accumulation may be greater in patients with renal or hepatic impairment; therefore, the manufacturer of Colcrys contraindicates the use of colchicine and P-gp inhibitors in this population. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine either by reducing the daily dose or reducing the dose frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations for coadministration with P-gp inhibitors are provided by the manufacturer of Colcrys.
    Conivaptan: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as tamoxifen, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with tamoxifen. Treatment with tamoxifen may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Conjugated Estrogens: (Major) The use of estrogens, including oral contraceptives and non-oral combination contraceptives, with tamoxifen is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which tamoxifen is prescribed. Tamoxifen exerts its effects by blocking estrogen receptors. Since tamoxifen and estrogens are pharmacological opposites, they are not usually given concurrently.
    Conjugated Estrogens; Bazedoxifene: (Major) The use of estrogens, including oral contraceptives and non-oral combination contraceptives, with tamoxifen is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which tamoxifen is prescribed. Tamoxifen exerts its effects by blocking estrogen receptors. Since tamoxifen and estrogens are pharmacological opposites, they are not usually given concurrently.
    Conjugated Estrogens; Medroxyprogesterone: (Major) The use of estrogens, including oral contraceptives and non-oral combination contraceptives, with tamoxifen is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which tamoxifen is prescribed. Tamoxifen exerts its effects by blocking estrogen receptors. Since tamoxifen and estrogens are pharmacological opposites, they are not usually given concurrently. (Minor) Medroxyprogesterone reduces plasma concentrations of N-dimethyltamoxifen, the metabolite of tamoxifen, but not tamoxifen.
    Crizotinib: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with tamoxifen. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients 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 also been described when tamoxifen is used at lower doses.
    Cyclobenzaprine: (Minor) Caution is advised with the concomitant use of tamoxifen and cyclobenzaprine 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. Cyclobenzaprine is associated with a possible risk of QT prolongation and TdP, particularly in the event of acute overdose.
    Cyclophosphamide: (Moderate) Use caution if cyclophosphamide is used concomitantly with tamoxifen, as there may be an increased risk of thromboembolic events when they are used together.
    Cyclosporine: (Major) Cyclosporine is a CYP3A4 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent, CYP2C9 and CYP2C19, to other potent active metabolites including endoxifen, which are then inactivated by sulfotransferase 1A1 (SULT1A1). Cyclosporine may inhibit the metabolism of tamoxifen to these metabolites, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. Additionally, cyclosporine is a substrate of CYP3A4 and P-glycoprotein (P-gp); tamoxifen inhibits both CYP3A4 and P-gp. Concomitant use of cyclosporine and tamoxifen may result in increased cyclosporine exposure and decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. If it is not possible to avoid concomitant use, monitor patients for increased serum concentrations of cyclosporine and changes in the therapeutic efficacy of tamoxifen.
    Dabigatran: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with tamoxifen, a P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran. When dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE), or prophylaxis of DVT or PE following hip replacement surgery, avoid coadministration with P-gp inhibitors like tamoxifen in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/minute), avoid coadministration with tamoxifen, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Dabrafenib: (Major) Dabrafenib is a CYP3A4 inducer. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Dabrafenib may induce the CYP3A4 metabolism of tamoxifen to these metabolites; plasma concentrations of tamoxifen its active metabolites have been reduced when coadministered other CYP3A4 inducers. The clinical significance of this interaction is not known. If coadministration is necessary, monitor for tamoxifen efficacy.
    Danazol: (Major) Danazol is a CYP3A4 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Danazol may inhibit the CYP3A4 metabolism of tamoxifen to these metabolites. Concomitant use of danazol and tamoxifen may result in decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. If it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen.
    Dapagliflozin; Saxagliptin: (Minor) Monitor patients for hypoglycemia if saxagliptin and tamoxifen are used together. The metabolism of saxagliptin is primarily mediated by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP 3A4/5 inhibitors such as tamoxifen.
    Darunavir: (Major) Darunavir is a potent CYP3A4 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Darunavir may inhibit the CYP3A4 metabolism of tamoxifen to these metabolites. Concomitant use of darunavir and tamoxifen may result in decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. If it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen.
    Darunavir; Cobicistat: (Major) Darunavir is a potent CYP3A4 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Darunavir may inhibit the CYP3A4 metabolism of tamoxifen to these metabolites. Concomitant use of darunavir and tamoxifen may result in decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. If it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen. (Moderate) Concomitant use may result in decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. If it is not possible to avoid concomitant use, monitor patients for changes in the therapeutic efficacy of tamoxifen. Cobicistat is a strong inhibitor of CYP3A4. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent, CYP2C9 and CYP2C19, to other potent active metabolites including endoxifen, which are then inactivated by sulfotransferase 1A1 (SULT1A1). Cobicistat may inhibit the CYP3A4 metabolism of tamoxifen to these metabolites, which have up to 33 times more affinity for the estrogen receptor than tamoxifen.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Caution is advised with the concomitant use of tamoxifen and ritonavir due to an increased risk of QT prolongation; reduced tamoxifen efficacy and/or increased tamoxifen toxicity is also possible. Monitor for evidence of QT prolongation, altered tamoxifen efficacy, and increased tamoxifen adverse effects if coadministration needed. 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. Ritonavir is also associated with QT prolongation. Ritonavir may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP3A4. (Major) Concurrent administration of tamoxifen with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in in increased antiviral exposure and decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. Consider avoiding concomitant use of ritonavir and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for increased antiviral side effects, as well as changes in the therapeutic efficacy of tamoxifen. Both ritonavir and tamoxifen are substrates and inhibitors of the hepatic isoenzyme CYP3A4; paritaprevir and dasabuvir (minor) are CYP3A4 substrates. Tamoxifen is also a substrate for CYP2D6; ritonavir is a CYP2D6 inhibitor. In addition, tamoxifen inhibits the drug transporter P-glycoprotein (P-gp); dasabuvir, ombitasvir, paritaprevir, and ritonavir are all substrates of P-gp. (Major) Concurrent administration of tamoxifen with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in in increased antiviral exposure and decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. Consider avoiding concomitant use of ritonavir and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for increased antiviral side effects, as well as changes in the therapeutic efficacy of tamoxifen. Both ritonavir and tamoxifen are substrates and inhibitors of the hepatic isoenzyme CYP3A4; paritaprevir and dasabuvir (minor) are CYP3A4 substrates. Tamoxifen is also a substrate for CYP2D6; ritonavir is a CYP2D6 inhibitor. In addition, tamoxifen inhibits the drug transporter P-glycoprotein (P-gp); dasabuvir, ombitasvir, paritaprevir, and ritonavir are all substrates of P-gp.
    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 has the potential to prolong the QT interval.
    Daunorubicin: (Moderate) Caution is advised with the concomitant use of tamoxifen and daunorubicin 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. Acute cardiotoxicity can occur during the administration of daunorubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage.
    Deflazacort: (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with tamoxifen. Concurrent use may significantly increase concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in an increased risk of toxicity. Deflazacort is a CYP3A4 substrate; tamoxifen is a moderate inhibitor of CYP3A4. Administration of deflazacort with clarithromycin, a strong CYP3A4 inhibitor, increased total exposure to 21-desDFZ by about 3-fold.
    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. QTc prolongation has been reported with the use of degarelix.
    Delavirdine: (Major) Concomitant use may result in decreased concentrations of the active metabolites of tamoxifen, which may compromise efficacy. Monitor patients for changes in the therapeutic effect of tamoxifen. Delavirdine is a potent inhibitor of CYP3A4 and, in vitro, is also a CYP2D6, CYP2C9, and CYP2C19 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Delavirdine may inhibit both the metabolism of tamoxifen to these metabolites. Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors. A trial of 1,298 patients with breast cancer compared the rate of breast cancer recurrence in patients treated with tamoxifen with or without a CYP2D6 inhibitor. Patients who received tamoxifen in combination with a CYP2D6 inhibitor had a significantly higher rate of breast cancer recurrence at 2 years (13.9% v. 7.5%, p < 0.001). A separate observational study of 1,990 patients assessed event free time with adjuvant tamoxifen treatment for breast cancer. Only 215 of these patients were administered a CYP2D6 inhibitor, however no clinically significant differences were observed with the addition of a CYP2D6 inhibitor.
    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: (Minor) 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 medication. Clinically relevant QTc prolongation may occur with deutetrabenazine. 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.
    Dexamethasone: (Major) Concomitant use of dexamethasone and tamoxifen may result in decreased concentrations of tamoxifen and its active metabolites, which may compromise efficacy. Monitor patients for changes in therapeutic effect of tamoxifen. Dexamethasone is a moderate CYP3A4 inducer. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Plasma concentrations of tamoxifen and its active metabolites have been reduced when coadministered with other CYP3A4 inducers.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Major) Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors, such as diphenhydramine. Consider avoiding concomitant use of diphenhydramine and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen. A trial of 1,298 patients with breast cancer compared the rate of breast cancer recurrence in patients treated with tamoxifen with or without a CYP2D6 inhibitor. Patients who received tamoxifen in combination with a CYP2D6 inhibitor had a significantly higher rate of breast cancer recurrence at 2 years (13.9% v. 7.5%, p < 0.001). A separate observational study of 1,990 patients assessed event free time with adjuvant tamoxifen treatment for breast cancer. Only 215 of these patients were administered a CYP2D6 inhibitor, however no clinically significant differences were observed with the addition of a CYP2D6 inhibitor.
    Dextromethorphan; Promethazine: (Major) Avoid coadministration of tamoxifen with promethazine due to the potential for decreased tamoxifen efficacy; additive QT prolongation may also occur. If coadministration is necessary, monitor for altered tamoxifen efficacy and evidence of QT prolongation. Promethazine may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP2D6. 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. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. In a clinical trial, there was a significantly higher rate of breast cancer recurrence in patients who had received a CYP2D6 inhibitor with tamoxifen. In another observational study, no clinically significant differences were observed with the addition of a CYP2D6 inhibitor to tamoxifen therapy; however, only 215 patients of 1,990 were administered a CYP2D6 inhibitor.
    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.
    Dienogest; Estradiol valerate: (Major) The use of estrogens, including oral contraceptives and non-oral combination contraceptives, with tamoxifen is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which tamoxifen is prescribed. Tamoxifen exerts its effects by blocking estrogen receptors. Since tamoxifen and estrogens are pharmacological opposites, they are not usually given concurrently.
    Diethylstilbestrol, DES: (Major) The use of estrogens, including oral contraceptives and non-oral combination contraceptives, with tamoxifen is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which tamoxifen is prescribed. Tamoxifen exerts its effects by blocking estrogen receptors. Since tamoxifen and estrogens are pharmacological opposites, they are not usually given concurrently.
    Diltiazem: (Major) Concomitant use of diltiazem and tamoxifen may result in increased diltiazem exposure and decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. Monitor patients for side effects of diltiazem and changes in therapeutic efficacy of tamoxifen. Diltiazem is a CYP3A4 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Diltiazem may inhibit the CYP3A4 metabolism of tamoxifen to these metabolites. Additionally, diltiazem is a P-glycoprotein (P-gp) substrate; tamoxifen is an inhibitor of P-gp.
    Diphenhydramine: (Major) Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors, such as diphenhydramine. Consider avoiding concomitant use of diphenhydramine and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen. A trial of 1,298 patients with breast cancer compared the rate of breast cancer recurrence in patients treated with tamoxifen with or without a CYP2D6 inhibitor. Patients who received tamoxifen in combination with a CYP2D6 inhibitor had a significantly higher rate of breast cancer recurrence at 2 years (13.9% v. 7.5%, p < 0.001). A separate observational study of 1,990 patients assessed event free time with adjuvant tamoxifen treatment for breast cancer. Only 215 of these patients were administered a CYP2D6 inhibitor, however no clinically significant differences were observed with the addition of a CYP2D6 inhibitor.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Major) Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors, such as diphenhydramine. Consider avoiding concomitant use of diphenhydramine and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen. A trial of 1,298 patients with breast cancer compared the rate of breast cancer recurrence in patients treated with tamoxifen with or without a CYP2D6 inhibitor. Patients who received tamoxifen in combination with a CYP2D6 inhibitor had a significantly higher rate of breast cancer recurrence at 2 years (13.9% v. 7.5%, p < 0.001). A separate observational study of 1,990 patients assessed event free time with adjuvant tamoxifen treatment for breast cancer. Only 215 of these patients were administered a CYP2D6 inhibitor, however no clinically significant differences were observed with the addition of a CYP2D6 inhibitor.
    Diphenhydramine; Ibuprofen: (Major) Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors, such as diphenhydramine. Consider avoiding concomitant use of diphenhydramine and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen. A trial of 1,298 patients with breast cancer compared the rate of breast cancer recurrence in patients treated with tamoxifen with or without a CYP2D6 inhibitor. Patients who received tamoxifen in combination with a CYP2D6 inhibitor had a significantly higher rate of breast cancer recurrence at 2 years (13.9% v. 7.5%, p < 0.001). A separate observational study of 1,990 patients assessed event free time with adjuvant tamoxifen treatment for breast cancer. Only 215 of these patients were administered a CYP2D6 inhibitor, however no clinically significant differences were observed with the addition of a CYP2D6 inhibitor.
    Diphenhydramine; Naproxen: (Major) Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors, such as diphenhydramine. Consider avoiding concomitant use of diphenhydramine and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen. A trial of 1,298 patients with breast cancer compared the rate of breast cancer recurrence in patients treated with tamoxifen with or without a CYP2D6 inhibitor. Patients who received tamoxifen in combination with a CYP2D6 inhibitor had a significantly higher rate of breast cancer recurrence at 2 years (13.9% v. 7.5%, p < 0.001). A separate observational study of 1,990 patients assessed event free time with adjuvant tamoxifen treatment for breast cancer. Only 215 of these patients were administered a CYP2D6 inhibitor, however no clinically significant differences were observed with the addition of a CYP2D6 inhibitor.
    Diphenhydramine; Phenylephrine: (Major) Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors, such as diphenhydramine. Consider avoiding concomitant use of diphenhydramine and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen. A trial of 1,298 patients with breast cancer compared the rate of breast cancer recurrence in patients treated with tamoxifen with or without a CYP2D6 inhibitor. Patients who received tamoxifen in combination with a CYP2D6 inhibitor had a significantly higher rate of breast cancer recurrence at 2 years (13.9% v. 7.5%, p < 0.001). A separate observational study of 1,990 patients assessed event free time with adjuvant tamoxifen treatment for breast cancer. Only 215 of these patients were administered a CYP2D6 inhibitor, however no clinically significant differences were observed with the addition of a CYP2D6 inhibitor.
    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 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. 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. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
    Dolutegravir; Rilpivirine: (Major) Caution is advised with the concomitant use of tamoxifen and rilpivirine due to an increased risk of QT prolongation; increased rilpivirine exposure may also occur. 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. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    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 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 occur during donepezil therapy.
    Doxepin: (Minor) 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).
    Doxorubicin: (Moderate) Avoid coadministration of tamoxifen and doxorubicin if possible due to the risk for increased doxorubicin concentrations and serious adverse reactions; additive QT prolongation may also occur. If coadministration unavoidable, monitor for increased side effects such as myelosuppression and cardiotoxicity. Tamoxifen is a CYP3A4 and P-glycoprotein (P-gp) inhibitor; doxorubicin is a major substrate of both CYP3A4 and P-gp. 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. Acute cardiotoxicity can occur during the administration of doxorubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage.
    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.
    Drospirenone; Estradiol: (Major) The use of estrogens, including oral contraceptives and non-oral combination contraceptives, with tamoxifen is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which tamoxifen is prescribed. Tamoxifen exerts its effects by blocking estrogen receptors. Since tamoxifen and estrogens are pharmacological opposites, they are not usually given concurrently.
    Drospirenone; Ethinyl Estradiol: (Major) The use of estrogens, including oral contraceptives and non-oral combination contraceptives, with tamoxifen is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which tamoxifen is prescribed. Tamoxifen exerts its effects by blocking estrogen receptors. Since tamoxifen and estrogens are pharmacological opposites, they are not usually given concurrently.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) The use of estrogens, including oral contraceptives and non-oral combination contraceptives, with tamoxifen is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which tamoxifen is prescribed. Tamoxifen exerts its effects by blocking estrogen receptors. Since tamoxifen and estrogens are pharmacological opposites, they are not usually given concurrently.
    Duloxetine: (Major) Tamoxifen, a selective estrogen receptor modulator (SERM), is converted to endoxifen and other active metabolites by cytochrome P450 (CYP) enzymes (e.g., 2D6, 3A4). Several antidepressants are often prescribed to alleviate tamoxifen-associated hot flashes. Many antidepressants are CYP2D6 inhibitors and may reduce plasma endoxifen concentrations. A trial of 1298 patients with breast cancer compared the rate of breast cancer recurrence in patients treated with tamoxifen with or without a CYP2D6 inhibitor. Patients who received tamoxifen in combination with a CYP2D6 inhibitor had a significantly higher rate of breast cancer recurrence at 2 years (13.9% v. 7.5%, p < 0.001). In a retrospective population-based cohort study, 2430 women with breast cancer were identified to have received tamoxifen concomitantly with an SSRI antidepressant. Patients who received paroxetine (n = 630) had a significant increase in the risk of death from breast cancer. No increased risk of breast cancer mortality was observed in patients receiving citalopram, fluoxetine, fluvoxamine, sertraline, or venlafaxine. A separate observational study of 1990 patients assessed event free time with adjuvant tamoxifen treatment for breast cancer; only 215 of these patients were administered a CYP2D6 inhibitor, however no clinically significant differences were observed with the addition of a CYP2D6 inhibitor. Paroxetine, fluoxetine, fluvoxamine, bupropion, and duloxetine are considered moderate to potent inhibitors of CYP2D6. If treatment with an antidepressant and tamoxifen is necessary, it may be preferable to use an agent with less potent or no inhibition of CYP2D6. Sertraline, citalopram, venlafaxine, and escitalopram are considered mild inhibitors, and may be preferable choices. Further, in an analysis of CYP2D6 inhibitors, the following order of inhibitory potency was observed (in descending order): paroxetine, fluoxetine, sertraline, citalopram and venlafaxine.
    Edoxaban: (Moderate) Coadministration of edoxaban and tamoxifen may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and tamoxifen is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of tamoxifen; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Efavirenz: (Major) Caution is advised with the concomitant use of tamoxifen and efavirenz due to an increased risk of QT prolongation; reduced tamoxifen efficacy is also possible. Monitor for evidence of QT prolongation and altered tamoxifen efficacy if coadministration is needed. 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. QTc prolongation has been observed with the use of efavirenz. Concomitant use of efavirenz and tamoxifen may decrease concentrations of the active metabolites of tamoxifen, which can compromise efficacy. Efavirenz is a CYP3A4 inducer, as well as a CYP2C9 and CYP2C19 inhibitor. Efavirenz may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP2C9 and CYP2C19; plasma concentrations of tamoxifen and its active metabolites have also been reduced when coadministered with other CYP3A4 inducers.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Caution is advised with the concomitant use of tamoxifen and efavirenz due to an increased risk of QT prolongation; reduced tamoxifen efficacy is also possible. Monitor for evidence of QT prolongation and altered tamoxifen efficacy if coadministration is needed. 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. QTc prolongation has been observed with the use of efavirenz. Concomitant use of efavirenz and tamoxifen may decrease concentrations of the active metabolites of tamoxifen, which can compromise efficacy. Efavirenz is a CYP3A4 inducer, as well as a CYP2C9 and CYP2C19 inhibitor. Efavirenz may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP2C9 and CYP2C19; plasma concentrations of tamoxifen and its active metabolites have also been reduced when coadministered with other CYP3A4 inducers. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as tamoxifen. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Elbasvir; Grazoprevir: (Moderate) Administering elbasvir; grazoprevir with tamoxifen may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Tamoxifen is a substrate and moderate inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
    Eliglustat: (Major) In intermediate or poor CYP2D6 metabolizers (IMs or PMs), coadministration of tamoxifen and eliglustat is not recommended. In extensive CYP2D6 metabolizers (EMs), coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. The coadministration of eliglustat with both tamoxifen and a moderate or strong CYP2D6 inhibitor is contraindicated in all patients. Tamoxifen is a moderate CYP3A inhibitor and CYP2D6 substrate; eliglustat is a CYP3A and CYP2D6 substrate and CYP2D6 inhibitor. Coadministration of eliglustat with CYP3A inhibitors, such as tamoxifen, may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias); this risk is the highest in CYP2D6 IMs and PMs because a larger portion of the eliglustat dose is metabolized via CYP3A. In addition, eliglustat is a CYP2D6 inhibitor; tamoxifen is metabolized by CYP2D6 to the potent active metabolite 4-hydroxytamoxifen. Active metabolite, N-desmethyl-tamoxifen, is also metabolized to endoxifen by CYP2D6. Eliglustat may inhibit the CYP3A4 metabolism of tamoxifen to these metabolites, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors, while other data have noted no clinically significant effects. Concomitant use of may result in decreased concentrations of the active metabolites of tamoxifen, which might compromise tamoxifen efficacy. Monitor patients closely for adverse events and for tamoxifen efficacy if these drugs must be given together.
    Elvitegravir: (Moderate) Caution is warranted when elvitegravir is administered with tamoxifen as there is a potential for decreased tamoxifen concentrations. Tamoxifen is a substrate of CYP2C9, while elvitegravir is an inducer of CYP2C9.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Caution is advised with the concomitant use of tamoxifen and rilpivirine due to an increased risk of QT prolongation; increased rilpivirine exposure may also occur. 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. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Caution is advised with the concomitant use of tamoxifen and rilpivirine due to an increased risk of QT prolongation; increased rilpivirine exposure may also occur. 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. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as tamoxifen. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as tamoxifen. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    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) Enzalutamide is a potent CYP3A4 inducer, as well as a mild in vitro inhibitor of CYP2D6 and CYP3A4; it also induces CYP2C9 and CYP2C19. Tamoxifen is metabolized in by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Enzalutamide may decrease the metabolism of tamoxifen to these metabolites, which can compromise efficacy; plasma concentrations of tamoxifen and its active metabolites have been reduced when coadministered other CYP3A4 inducers. The clinical significance of this interaction is not known.
    Epirubicin: (Moderate) Caution is advised with the concomitant use of tamoxifen and epirubicin 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. Acute cardiotoxicity can occur during the administration of epirubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage.
    Eplerenone: (Major) Eplerenone is metabolized by the CYP3A4 pathway. Tamoxifen inhibits the hepatic CYP3A4 isoenzyme and therefore may increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension. If these medications are given concurrently in post-myocardial infarction patients with heart failure, do not exceed an eplerenone dose of 25 mg PO once daily. If these medications are given concurrently, and eplerenone is used for hypertension, initiate eplerenone at 25 mg PO once daily. The dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response.
    Eribulin: (Major) Caution is advised with the concomitant use of tamoxifen and eribulin due to an increased risk of QT prolongation. If coadministration is needed, ECG monitoring is recommended; closely monitor the patient for 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. Eribulin has also been associated with QT prolongation.
    Erythromycin: (Major) Concomitant use of tamoxifen and erythromycin may cause an increased risk of QT prolongation and torsade de pointes (TdP); reduced tamoxifen efficacy and/or increased tamoxifen toxicity is also possible. If coadministration is unavoidable, monitor for altered tamoxifen efficacy, increased tamoxifen-related adverse effects, and evidence 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. Erythromycin is associated with QT prolongation and TdP. Erythromycin may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP3A4.
    Erythromycin; Sulfisoxazole: (Major) Concomitant use of tamoxifen and erythromycin may cause an increased risk of QT prolongation and torsade de pointes (TdP); reduced tamoxifen efficacy and/or increased tamoxifen toxicity is also possible. If coadministration is unavoidable, monitor for altered tamoxifen efficacy, increased tamoxifen-related adverse effects, and evidence 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. Erythromycin is associated with QT prolongation and TdP. Erythromycin may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP3A4.
    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 been associated with a risk of QT prolongation and TdP.
    Eslicarbazepine: (Major) Eslicarbazepine is a CYP3A4 inducer and, in vitro, a CYP2C19 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Eslicarbazepine may affect the metabolism of tamoxifen to these metabolites; plasma concentrations of tamoxifen its active metabolites have been reduced when coadministered other CYP3A4 inducers. The clinical significance of this interaction is not known. If coadministration is necessary, monitor for tamoxifen efficacy.
    Esomeprazole: (Moderate) Theoretically, concomitant use may result in decreased concentrations of the active metabolites of tamoxifen which can compromise efficacy; the clinical significance of this interaction is not known. Esomeprazole is a CYP2C19 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1).
    Esomeprazole; Naproxen: (Moderate) Theoretically, concomitant use may result in decreased concentrations of the active metabolites of tamoxifen which can compromise efficacy; the clinical significance of this interaction is not known. Esomeprazole is a CYP2C19 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1).
    Esterified Estrogens: (Major) The use of estrogens, including oral contraceptives and non-oral combination contraceptives, with tamoxifen is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which tamoxifen is prescribed. Tamoxifen exerts its effects by blocking estrogen receptors. Since tamoxifen and estrogens are pharmacological opposites, they are not usually given concurrently.
    Esterified Estrogens; Methyltestosterone: (Major) The use of estrogens, including oral contraceptives and non-oral combination contraceptives, with tamoxifen is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which tamoxifen is prescribed. Tamoxifen exerts its effects by blocking estrogen receptors. Since tamoxifen and estrogens are pharmacological opposites, they are not usually given concurrently.
    Estradiol Cypionate; Medroxyprogesterone: (Major) The use of estrogens, including oral contraceptives and non-oral combination contraceptives, with tamoxifen is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which tamoxifen is prescribed. Tamoxifen exerts its effects by blocking estrogen receptors. Since tamoxifen and estrogens are pharmacological opposites, they are not usually given concurrently. (Minor) Medroxyprogesterone reduces plasma concentrations of N-dimethyltamoxifen, the metabolite of tamoxifen, but not tamoxifen.
    Estradiol: (Major) The use of estrogens, including oral contraceptives and non-oral combination contraceptives, with tamoxifen is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which tamoxifen is prescribed. Tamoxifen exerts its effects by blocking estrogen receptors. Since tamoxifen and estrogens are pharmacological opposites, they are not usually given concurrently.
    Estradiol; Levonorgestrel: (Major) The use of estrogens, including oral contraceptives and non-oral combination contraceptives, with tamoxifen is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which tamoxifen is prescribed. Tamoxifen exerts its effects by blocking estrogen receptors. Since tamoxifen and estrogens are pharmacological opposites, they are not usually given concurrently.
    Estradiol; Norethindrone: (Major) The use of estrogens, including oral contraceptives and non-oral combination contraceptives, with tamoxifen is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which tamoxifen is prescribed. Tamoxifen exerts its effects by blocking estrogen receptors. Since tamoxifen and estrogens are pharmacological opposites, they are not usually given concurrently.
    Estradiol; Norgestimate: (Major) The use of estrogens, including oral contraceptives and non-oral combination contraceptives, with tamoxifen is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which tamoxifen is prescribed. Tamoxifen exerts its effects by blocking estrogen receptors. Since tamoxifen and estrogens are pharmacological opposites, they are not usually given concurrently.
    Estrogens: (Major) The use of estrogens, including oral contraceptives and non-oral combination contraceptives, with tamoxifen is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which tamoxifen is prescribed. Tamoxifen exerts its effects by blocking estrogen receptors. Since tamoxifen and estrogens are pharmacological opposites, they are not usually given concurrently.
    Estropipate: (Major) The use of estrogens, including oral contraceptives and non-oral combination contraceptives, with tamoxifen is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which tamoxifen is prescribed. Tamoxifen exerts its effects by blocking estrogen receptors. Since tamoxifen and estrogens are pharmacological opposites, they are not usually given concurrently.
    Ethinyl Estradiol: (Major) The use of estrogens, including oral contraceptives and non-oral combination contraceptives, with tamoxifen is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which tamoxifen is prescribed. Tamoxifen exerts its effects by blocking estrogen receptors. Since tamoxifen and estrogens are pharmacological opposites, they are not usually given concurrently.
    Ethinyl Estradiol; Desogestrel: (Major) The use of estrogens, including oral contraceptives and non-oral combination contraceptives, with tamoxifen is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which tamoxifen is prescribed. Tamoxifen exerts its effects by blocking estrogen receptors. Since tamoxifen and estrogens are pharmacological opposites, they are not usually given concurrently.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Major) The use of estrogens, including oral contraceptives and non-oral combination contraceptives, with tamoxifen is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which tamoxifen is prescribed. Tamoxifen exerts its effects by blocking estrogen receptors. Since tamoxifen and estrogens are pharmacological opposites, they are not usually given concurrently.
    Ethinyl Estradiol; Etonogestrel: (Major) The use of estrogens, including oral contraceptives and non-oral combination contraceptives, with tamoxifen is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which tamoxifen is prescribed. Tamoxifen exerts its effects by blocking estrogen receptors. Since tamoxifen and estrogens are pharmacological opposites, they are not usually given concurrently.
    Ethinyl Estradiol; Levonorgestrel: (Major) The use of estrogens, including oral contraceptives and non-oral combination contraceptives, with tamoxifen is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which tamoxifen is prescribed. Tamoxifen exerts its effects by blocking estrogen receptors. Since tamoxifen and estrogens are pharmacological opposites, they are not usually given concurrently.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Major) The use of estrogens, including oral contraceptives and non-oral combination contraceptives, with tamoxifen is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which tamoxifen is prescribed. Tamoxifen exerts its effects by blocking estrogen receptors. Since tamoxifen and estrogens are pharmacological opposites, they are not usually given concurrently.
    Ethinyl Estradiol; Norelgestromin: (Major) The use of estrogens, including oral contraceptives and non-oral combination contraceptives, with tamoxifen is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which tamoxifen is prescribed. Tamoxifen exerts its effects by blocking estrogen receptors. Since tamoxifen and estrogens are pharmacological opposites, they are not usually given concurrently.
    Ethinyl Estradiol; Norethindrone Acetate: (Major) The use of estrogens, including oral contraceptives and non-oral combination contraceptives, with tamoxifen is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which tamoxifen is prescribed. Tamoxifen exerts its effects by blocking estrogen receptors. Since tamoxifen and estrogens are pharmacological opposites, they are not usually given concurrently.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Major) The use of estrogens, including oral contraceptives and non-oral combination contraceptives, with tamoxifen is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which tamoxifen is prescribed. Tamoxifen exerts its effects by blocking estrogen receptors. Since tamoxifen and estrogens are pharmacological opposites, they are not usually given concurrently.
    Ethinyl Estradiol; Norethindrone: (Major) The use of estrogens, including oral contraceptives and non-oral combination contraceptives, with tamoxifen is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which tamoxifen is prescribed. Tamoxifen exerts its effects by blocking estrogen receptors. Since tamoxifen and estrogens are pharmacological opposites, they are not usually given concurrently.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Major) The use of estrogens, including oral contraceptives and non-oral combination contraceptives, with tamoxifen is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which tamoxifen is prescribed. Tamoxifen exerts its effects by blocking estrogen receptors. Since tamoxifen and estrogens are pharmacological opposites, they are not usually given concurrently.
    Ethinyl Estradiol; Norgestimate: (Major) The use of estrogens, including oral contraceptives and non-oral combination contraceptives, with tamoxifen is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which tamoxifen is prescribed. Tamoxifen exerts its effects by blocking estrogen receptors. Since tamoxifen and estrogens are pharmacological opposites, they are not usually given concurrently.
    Ethinyl Estradiol; Norgestrel: (Major) The use of estrogens, including oral contraceptives and non-oral combination contraceptives, with tamoxifen is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which tamoxifen is prescribed. Tamoxifen exerts its effects by blocking estrogen receptors. Since tamoxifen and estrogens are pharmacological opposites, they are not usually given concurrently.
    Ethosuximide: (Moderate) Ethosuximide is a CYP3A4 substrate and tamoxifen inhibits CYP3A4. Coadministration may result in increased ethosuximide exposure. If concomitant use is necessary, monitor for increased ethosuximide side effects.
    Etoposide, VP-16: (Major) Monitor for an increased incidence of etoposide-related adverse effects if used concomitantly with tamoxifen. Tamoxifen is an inhibitor of P-glycoprotein (P-gp); etoposide, VP-16 is a P-gp substrate. Coadministration may cause accumulation of etoposide and decreased metabolism, resulting in increased etoposide concentrations.
    Etravirine: (Major) Etravirine is a CYP3A4 inducer and an inhibitor of CYP2C9 and CYP2C19. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Etravirine may affect the metabolism of tamoxifen to these metabolites; plasma concentrations of tamoxifen its active metabolites have been reduced when coadministered other CYP3A4 inducers. The clinical significance of this interaction is not known.
    Everolimus: (Major) Everolimus is an inhibitor and substrate of CYP3A4 and Pgp and an inhibitor of CYP2D6. Coadministration with strong or moderate inhibitors of CYP3A4 or Pgp, such as tamoxifen, is not recommended. Patients may experience an increase in systemic exposure to everolimus if these drugs are coadministered. In addition, tamoxifen is a substrate of CYP3A4 and CYP2D6. The effect of everolimus on tamoxifen pharmacokinetics has not been established; however, pharmacokinetic studies showed no significant impact of the coadministration of everolimus with the CYP3A4 and Pgp substrate atorvastatin.
    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.
    Felbamate: (Major) Felbamate is a mild CYP3A4 inducer and CYP2C19 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Felbamate may decrease the metabolism of tamoxifen to these metabolites, which can compromise efficacy. Plasma concentrations of tamoxifen and its active metabolites have been also reduced when coadministered other CYP3A4 inducers. If coadministration cannot be avoided, monitor for changes to the therapeutic effects of tamoxifen.
    Fenofibrate: (Moderate) Fenofibrate is a moderate CYP2C9 and mild CYP2C19 inhibitor. Tamoxifen is metabolized by CYP3A4 and CYP2D6, and to a smaller extent by CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Theoretically, concomitant use of fenofibrate and tamoxifen may result in decreased concentrations of the active metabolites of tamoxifen; the clinical significance of this interaction is not known.
    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). 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. 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.
    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.
    Fluorouracil, 5-FU: (Moderate) Fluorouracil, 5-FU is a CYP2C9 inhibitor. Tamoxifen is metabolized by CYP3A4 and CYP2D6, and to a lesser extent by CYP2C9, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). By inhibiting CYP2C9, fluorouracil may decrease the concentrations of the active metabolites of tamoxifen. Theoretically, concomitant use of fluorouracil and tamoxifen may result in decreased concentrations of the active metabolites of tamoxifen, which may compromise efficacy. Additionally, there is an increased risk of thromboembolic events occurring when cytotoxic agents are used in combination with tamoxifen.
    Fluoxetine: (Major) Concomitant use of tamoxifen and fluoxetine may cause an increased risk of QT prolongation and torsade de pointes (TdP); reduced tamoxifen efficacy and/or increased tamoxifen toxicity is also possible. If coadministration is unavoidable, monitor for altered tamoxifen efficacy, increased tamoxifen-related adverse effects, and evidence 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 and TdP have been reported in patients treated with fluoxetine. Fluoxetine may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP2D6. In a clinical trial, there was a significantly higher rate of breast cancer recurrence in patients who had received a CYP2D6 inhibitor with tamoxifen. In another observational study, no clinically significant differences were observed with the addition of a CYP2D6 inhibitor to tamoxifen therapy; however, only 215 patients of 1,990 were administered a CYP2D6 inhibitor.
    Fluoxetine; Olanzapine: (Major) Concomitant use of tamoxifen and fluoxetine may cause an increased risk of QT prolongation and torsade de pointes (TdP); reduced tamoxifen efficacy and/or increased tamoxifen toxicity is also possible. If coadministration is unavoidable, monitor for altered tamoxifen efficacy, increased tamoxifen-related adverse effects, and evidence 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 and TdP have been reported in patients treated with fluoxetine. Fluoxetine may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP2D6. In a clinical trial, there was a significantly higher rate of breast cancer recurrence in patients who had received a CYP2D6 inhibitor with tamoxifen. In another observational study, no clinically significant differences were observed with the addition of a CYP2D6 inhibitor to tamoxifen therapy; however, only 215 patients of 1,990 were administered a CYP2D6 inhibitor. (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: (Major) Avoid coadministration of tamoxifen with fluphenazine due to the potential for decreased tamoxifen efficacy and/or increased tamoxifen toxicity; additive QT prolongation may also occur. If coadministration is necessary, monitor for altered tamoxifen efficacy, increased tamoxifen-related adverse effects, and evidence of QT prolongation. Fluphenazine may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP2D6. In a clinical trial, there was a significantly higher rate of breast cancer recurrence in patients who had received a CYP2D6 inhibitor with tamoxifen. In another observational study, no clinically significant differences were observed with the addition of a CYP2D6 inhibitor to tamoxifen therapy; however, only 215 patients of 1,990 were administered a CYP2D6 inhibitor. 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 associated with a possible risk for QT prolongation.
    Flutamide: (Major) In vitro, flutamide is a CYP3A4 inducer. Tamoxifen is metabolized in by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Flutamide may induce the CYP3A4 metabolism of tamoxifen to these metabolites, which can compromise efficacy; plasma concentrations of tamoxifen and its active metabolites have been reduced when coadministered other CYP3A4 inducers. If coadministration cannot be avoided, monitor for changes to the therapeutic effects of tamoxifen.
    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: (Major) There may be an increased risk for QT prolongation, torsade de pointes (TdP), and elevated tamoxifen concentrations during concurrent use of fluvoxamine and tamoxifen. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. 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 addition, tamoxifen is partially converted to active metabolites by CYP3A4 and fluvoxamine is a moderate CYP3A4 inhibitor. It is possible that fluvoxamine could reduce the effectiveness of tamoxifen by reducing the conversion of tamoxifen to certain active metabolites.
    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.
    Fosamprenavir: (Major) Fosamprenavir is a potent inhibitor and moderate inducer of CYP3A4. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Fosamprenavir may affect the CYP3A4 metabolism of tamoxifen to these metabolites. Concomitant use of fosamprenavir and tamoxifen may decrease the concentrations of the active metabolites of tamoxifen; plasma concentrations of tamoxifen and its active metabolites have also been reduced when coadministered other CYP3A4 inducers. Fosamprenavir is also a CYP3A4 and P-glycoprotein (P-gp) substrate; tamoxifen inhibits CYP3A4 and P-gp. If it is not possible to avoid concomitant use, monitor patients for increased fosamprenavir side effects and changes in the therapeutic efficacy of tamoxifen.
    Foscarnet: (Major) Avoid coadministration of tamoxifen with foscarnet due to an increased risk of QT prolongation and torsade de pointes (TdP). If coadministration is necessary, monitor ECG and electrolytes during therapy. 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. Both QT prolongation and TdP have been reported during postmarketing use of foscarnet.
    Fosphenytoin: (Major) Concomitant use of fosphenytoin and tamoxifen may decrease concentrations of the active metabolites of tamoxifen, which can compromise efficacy. Monitor patients for changes in therapeutic efficacy of tamoxifen. Fosphenytoin is a prodrug of phenytoin, a potent CYP3A4 inducer as well as an inducer of CYP2C9 and CYP2C19. Tamoxifen is metabolized in part by CYP3A4 and to a lesser extent, by CYP2C9 and CYP2C19, to other potent active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Phenytoin may induce the metabolism of tamoxifen to these metabolites; plasma concentrations of tamoxifen and its active metabolites have been reduced when coadministered with other CYP3A4 inducers, which can compromise efficacy.
    Gadobenate Dimeglumine: (Moderate) Gadobenate dimeglumine is a substrate for the canalicular multi-specific organic anion transporter (MOAT). Use with other MOAT substrates, such as tamoxifen, may result in prolonged systemic exposure of the coadministered drug. Caution is advised if these drugs are used together.
    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.
    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. (Moderate) Caution is advised with the coadministration of pibrentasvir and tamoxifen as coadministration may increase serum concentrations of pibrentasvir and increase the risk of adverse effects. Pibrentasvir is a substrate of P-glycoprotein (P-gp); tamoxifen is an inhibitor of P-gp.
    Glimepiride; Pioglitazone: (Major) Pioglitazone is a mild CYP3A4 inducer. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Pioglitazone may induce the CYP3A4 metabolism of tamoxifen to these metabolites; plasma concentrations of tamoxifen and its active metabolites have been reduced when coadministered other CYP3A4 inducers. If coadministration cannot be avoided, monitor for changes to the therapeutic effects of tamoxifen.
    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) prolongs 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.
    Grapefruit juice: (Major) Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors, such as grapefruit juice. Consider avoiding concomitant use of grapefruit juice and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen.
    Griseofulvin: (Major) In vitro, griseofulvin is a CYP3A4 inducer. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Griseofulvin may induce the CYP3A4 metabolism of tamoxifen to these metabolites, which can compromise efficacy; plasma concentrations of tamoxifen and its active metabolites have been reduced when coadministered other CYP3A4 inducers. If coadministration cannot be avoided, monitor for changes to the therapeutic effects of tamoxifen.
    Halofantrine: (Major) Concomitant use may result in decreased concentrations of the active metabolites of tamoxifen, which may compromise efficacy. Monitor patients for changes in the therapeutic effects of tamoxifen. Halofantrine is a CYP2D6 inhibitor. Tamoxifen is metabolized by CYP2D6 to the potent active metabolite 4-hydroxytamoxifen. 4-hydroxytamoxifen is further metabolized to endoxifen by CYP3A4/5. Active metabolite, N-desmethyl-tamoxifen, is also metabolized to endoxifen by CYP2D6. Halofantrine may inhibit the metabolism of tamoxifen to these metabolites, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors. A trial of 1,298 patients with breast cancer compared the rate of breast cancer recurrence in patients treated with tamoxifen with or without a CYP2D6 inhibitor. Patients who received tamoxifen in combination with a CYP2D6 inhibitor had a significantly higher rate of breast cancer recurrence at 2 years (13.9% v. 7.5%, p < 0.001). A separate observational study of 1,990 patients assessed event free time with adjuvant tamoxifen treatment for breast cancer. Only 215 of these patients were administered a CYP2D6 inhibitor, however no clinically significant differences were observed with the addition of a CYP2D6 inhibitor.
    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) Concomitant use of tamoxifen and haloperidol may cause an increased risk of QT prolongation and torsade de pointes (TdP); reduced tamoxifen efficacy and/or increased tamoxifen toxicity is also possible. If coadministration is unavoidable, monitor for altered tamoxifen efficacy, increased tamoxifen-related adverse effects, and evidence 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 and 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. Haloperidol may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP2D6. In a clinical trial, there was a significantly higher rate of breast cancer recurrence in patients who had received a CYP2D6 inhibitor with tamoxifen. In another observational study, no clinically significant differences were observed with the addition of a CYP2D6 inhibitor to tamoxifen therapy; however, only 215 patients of 1,990 were administered a CYP2D6 inhibitor.
    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.
    Hydrochlorothiazide, HCTZ; Telmisartan: (Moderate) Telmisartan is a weak CYP2C19 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a smaller extent by CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Theoretically, concomitant use of telmisartan and tamoxifen may result in decreased concentrations of the active metabolites of tamoxifen; the clinical significance of this interaction is not known.
    Hydroxychloroquine: (Major) Avoid coadministration of tamoxifen with hydroxychloroquine due to an increased risk of QT prolongation; reduced tamoxifen efficacy and/or increased tamoxifen toxicity is also possible. Monitor for evidence of QT prolongation, altered tamoxifen efficacy, and increased tamoxifen adverse effects if coadministration is needed. 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. Hydroxychloroquine also prolongs the QT interval. Hydroxychloroquine may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP2D6. In a clinical trial, there was a significantly higher rate of breast cancer recurrence in patients who had received a CYP2D6 inhibitor with tamoxifen. In another observational study, no clinically significant differences were observed with the addition of a CYP2D6 inhibitor to tamoxifen therapy; however, only 215 patients of 1,990 were administered a CYP2D6 inhibitor.
    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 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 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.
    Idarubicin: (Moderate) Caution is advised with the concomitant use of tamoxifen and idarubicin 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. Acute cardiotoxicity can occur during the administration of idarubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage.
    Idelalisib: (Major) Idelalisib is a strong CYP3A4 inhibitor; tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent, CYP2C9 and CYP2C19, to other potent active metabolites including endoxifen, which are then inactivated by sulfotransferase 1A1 (SULT1A1). Idelalisib may inhibit the CYP3A4 metabolism of tamoxifen to these metabolites, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. Concomitant use of idelalisib and tamoxifen may result in decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. If it is not possible to avoid concomitant use, monitor patients for changes in the therapeutic efficacy of tamoxifen.
    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.
    Imatinib: (Major) Concomitant use of imatinib and tamoxifen may result in increased imatinib exposure and decreased concentrations of the active metabolites of tamoxifen, which may compromise efficacy. Monitor patients for increased imatinib side effects and changes in the therapeutic effect of tamoxifen. Imatinib, STI-571 is a CYP2D6 and CYP3A4 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Imatinib may inhibit the metabolism of tamoxifen to these metabolites. Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors. A trial of 1,298 patients with breast cancer compared the rate of breast cancer recurrence in patients treated with tamoxifen with or without a CYP2D6 inhibitor. Patients who received tamoxifen in combination with a CYP2D6 inhibitor had a significantly higher rate of breast cancer recurrence at 2 years (13.9% v. 7.5%, p < 0.001). A separate observational study of 1,990 patients assessed event free time with adjuvant tamoxifen treatment for breast cancer. Only 215 of these patients were administered a CYP2D6 inhibitor, however no clinically significant differences were observed with the addition of a CYP2D6 inhibitor. Additionally, imatinib is a P-glycoprotein (P-gp) substrate; tamoxifen inhibits P-gp.
    Imipramine: (Minor) 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.
    Indinavir: (Major) Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors, such as indinavir. Consider avoiding concomitant use of indinavir and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen.
    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.
    Irinotecan: (Moderate) Coadministration may result in increased irinotecan exposure. Use caution if concomitant use is necessary and monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression. Tamoxifen is a P-glycoprotein (P-gp) inhibitor; irinotecan is a P-gp substrate.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with tamoxifen may result in increased serum concentrations of both drugs. Tamoxifen is a substrate and inhibitor of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate and moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    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: (Major) Isoniazid, INH is a strong CYP3A4 inhibitor, as well as a moderate inhibitor of CYP2C19. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Isoniazid may inhibit the metabolism of tamoxifen to these metabolites, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. Concomitant use of isoniazid and tamoxifen may result in decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. If it is not possible to avoid concomitant use, monitor patients for changes in the therapeutic efficacy of tamoxifen.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) In a pharmacokinetic study in healthy volunteers, administration of a single dose of tamoxifen was given following chronic dosing with rifampin. The AUC of tamoxifen was reduced by 86% and the Cmax was reduced by 55%. The half-life of tamoxifen was reduced from 118 hours to 68 hours following rifampin dosing. The effect rifampin on chronic tamoxifen therapy is unknown but may lead to a loss of tamoxifen's antiestrogen effects. A similar effect may occur with concurrent administration of tamoxifen and rifabutin or rifapentine. (Major) Isoniazid, INH is a strong CYP3A4 inhibitor, as well as a moderate inhibitor of CYP2C19. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Isoniazid may inhibit the metabolism of tamoxifen to these metabolites, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. Concomitant use of isoniazid and tamoxifen may result in decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. If it is not possible to avoid concomitant use, monitor patients for changes in the therapeutic efficacy of tamoxifen.
    Isoniazid, INH; Rifampin: (Major) In a pharmacokinetic study in healthy volunteers, administration of a single dose of tamoxifen was given following chronic dosing with rifampin. The AUC of tamoxifen was reduced by 86% and the Cmax was reduced by 55%. The half-life of tamoxifen was reduced from 118 hours to 68 hours following rifampin dosing. The effect rifampin on chronic tamoxifen therapy is unknown but may lead to a loss of tamoxifen's antiestrogen effects. A similar effect may occur with concurrent administration of tamoxifen and rifabutin or rifapentine. (Major) Isoniazid, INH is a strong CYP3A4 inhibitor, as well as a moderate inhibitor of CYP2C19. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Isoniazid may inhibit the metabolism of tamoxifen to these metabolites, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. Concomitant use of isoniazid and tamoxifen may result in decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. If it is not possible to avoid concomitant use, monitor patients for changes in the therapeutic efficacy of tamoxifen.
    Itraconazole: (Major) Concomitant use of tamoxifen and itraconazole may cause an increased risk of QT prolongation; increased itraconazole/tamoxifen exposure and reduced tamoxifen efficacy are also possible. Monitor for evidence of QT prolongation, increased itraconazole/tamoxifen side effects, and altered tamoxifen efficacy if coadministration needed. 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. Itraconazole has been associated with prolongation of the QT interval. Itraconazole may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP3A4. Tamoxifen may also increase exposure to itraconazole via inhibition of P-glycoprotein (P-gp).
    Ivacaftor: (Major) Use caution when administering ivacaftor and tamoxifen concurrently; monitor for changes in the therapeutic efficacy of tamoxifen. Ivacaftor is a weak CYP3A4 inhibitor, as well as in vitro, a CYP2C9 inhibitor; tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent, CYP2C9 and CYP2C19, to other potent active metabolites including endoxifen, which are then inactivated by sulfotransferase 1A1 (SULT1A1). Ivacaftor may affect the metabolism of tamoxifen to these metabolites, which have up to 33 times more affinity for the estrogen receptor than tamoxifen; the clinical significance of these potential changes is not known.
    Ketoconazole: (Major) Concomitant use of tamoxifen and ketoconazole may cause an increased risk of QT prolongation; reduced tamoxifen efficacy and/or increased tamoxifen toxicity is also possible. If coadministration is unavoidable, monitor for altered tamoxifen efficacy, increased tamoxifen-related adverse effects, and evidence 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. Ketoconazole has also been associated with prolongation of the QT interval. Ketoconazole may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP3A4.
    Lansoprazole: (Moderate) Theoretically, concomitant use may result in increased lansoprazole side effects and decreased concentrations of the active metabolites of tamoxifen which can compromise efficacy; the clinical significance of this interaction is not known. In vitro, lansoprazole is a weak CYP2C9 and CYP2C19 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Additionally, lansoprazole is a P-glycoprotein (P-gp) substrate; tamoxifen inhibits P-gp.
    Lansoprazole; Naproxen: (Moderate) Theoretically, concomitant use may result in increased lansoprazole side effects and decreased concentrations of the active metabolites of tamoxifen which can compromise efficacy; the clinical significance of this interaction is not known. In vitro, lansoprazole is a weak CYP2C9 and CYP2C19 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Additionally, lansoprazole is a P-glycoprotein (P-gp) substrate; tamoxifen inhibits P-gp.
    Lapatinib: (Major) Concomitant use of tamoxifen and lapatinib may cause an increased risk of QT prolongation and torsade de pointes (TdP); reduced tamoxifen efficacy and/or increased tamoxifen toxicity is also possible. If coadministration is necessary, consider ECG monitoring and monitor for altered tamoxifen efficacy and increased tamoxifen-related adverse effects. Correct hypokalemia or hypomagnesemia prior to lapatinib administration. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience. 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. Lapatinib may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP3A4.
    Leflunomide: (Moderate) In vitro, leflunomide is a CYP2C9 inhibitor; tamoxifen is metabolized by CYP3A4, CYP2D6, and to a smaller extent by CYP2C9, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Theoretically, concomitant use of leflunomide and tamoxifen may result in decreased concentrations of the active metabolites of tamoxifen; the clinical significance of this interaction is not known.
    Lenvatinib: (Major) Caution is advised with the concomitant use of tamoxifen and lenvatinib 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 was reported during clinical trials of lenvatinib.
    Letrozole: (Major) Letrozole should not be given concurrently with tamoxifen; when administered together, there is an average 38% reduction in letrozole plasma concentrations. Letrozole therapy after the completion of standard tamoxifen treatment is not associated with impaired effects of letrozole.
    Leuprolide: (Moderate) Caution is advised with the concomitant use of tamoxifen and leuprolide 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., leuprolide) prolongs the QT interval.
    Leuprolide; Norethindrone: (Moderate) Caution is advised with the concomitant use of tamoxifen and leuprolide 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., leuprolide) prolongs the QT interval.
    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). 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. Levofloxacin has been associated with a risk of QT prolongation; although extremely rare, TdP has been reported during postmarketing surveillance of levofloxacin.
    Lidocaine: (Moderate) Concomitant use of systemic lidocaine and tamoxifen may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; tamoxifen inhibits CYP3A4.
    Lithium: (Moderate) Caution is advised with the concomitant use of tamoxifen and lithium 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. Lithium has also been associated with QT prolongation.
    Lomitapide: (Moderate) Caution should be exercised when lomitapide is used with other medications known to have potential for hepatotoxicity, such as tamoxifen. The effect of concomitant administration of lomitapide with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    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) Caution is advised with the concomitant use of tamoxifen with loperamide due to an increased risk of QT prolongation and torsade de pointes (TdP); increased loperamide exposure is also possible. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, TdP, cardiac arrest). 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. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, TdP, and cardiac arrest. Tamoxifen may increase exposure to loperamide via inhibition of P-glycoprotein (P-gp).
    Loperamide; Simethicone: (Moderate) Caution is advised with the concomitant use of tamoxifen with loperamide due to an increased risk of QT prolongation and torsade de pointes (TdP); increased loperamide exposure is also possible. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, TdP, cardiac arrest). 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. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, TdP, and cardiac arrest. Tamoxifen may increase exposure to loperamide via inhibition of P-glycoprotein (P-gp).
    Lopinavir; Ritonavir: (Major) Caution is advised with the concomitant use of tamoxifen and lopinavir due to an increased risk of QT prolongation; reduced tamoxifen efficacy and/or increased tamoxifen toxicity is also possible. Monitor for evidence of QT prolongation, altered tamoxifen efficacy, and increased tamoxifen adverse effects if coadministration needed. 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. Lopinavir; ritonavir is associated with QT prolongation. Lopinavir; ritonavir may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP3A4. (Major) Caution is advised with the concomitant use of tamoxifen and ritonavir due to an increased risk of QT prolongation; reduced tamoxifen efficacy and/or increased tamoxifen toxicity is also possible. Monitor for evidence of QT prolongation, altered tamoxifen efficacy, and increased tamoxifen adverse effects if coadministration needed. 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. Ritonavir is also associated with QT prolongation. Ritonavir may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP3A4.
    Lumacaftor; Ivacaftor: (Major) Use caution when administering ivacaftor and tamoxifen concurrently; monitor for changes in the therapeutic efficacy of tamoxifen. Ivacaftor is a weak CYP3A4 inhibitor, as well as in vitro, a CYP2C9 inhibitor; tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent, CYP2C9 and CYP2C19, to other potent active metabolites including endoxifen, which are then inactivated by sulfotransferase 1A1 (SULT1A1). Ivacaftor may affect the metabolism of tamoxifen to these metabolites, which have up to 33 times more affinity for the estrogen receptor than tamoxifen; the clinical significance of these potential changes is not known.
    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.
    Maraviroc: (Moderate) Use caution if coadministration of maraviroc with tamoxifen is necessary, due to a possible increase in maraviroc exposure. Maraviroc is a CYP3A/P-glycoprotein (P-gp) substrate and tamoxifen is a CYP3A4/P-gp inhibitor. Monitor for an increase in adverse effects with concomitant use.
    Medroxyprogesterone: (Minor) Medroxyprogesterone reduces plasma concentrations of N-dimethyltamoxifen, the metabolite of tamoxifen, but not tamoxifen.
    Mefloquine: (Major) Caution is advised with the concomitant use of tamoxifen with mefloquine 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. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. However, due to the lack of clinical data, mefloquine should be used with caution in patients receiving drugs that prolong the QT interval.
    Melatonin: (Moderate) Based on limited phase-II clinical trials of estrogen-dependent metastatic breast cancer, the addition of melatonin to tamoxifen regimens may enhance the chemotherapeutic effects of tamoxifen through a pharmacodynamic mechanism. Tamoxifen does not appear to exhibit pharmacokinetic interactions with melatonin. Studies suggest that melatonin may alter or enhance immunomodulatory or chemotherapeutic medications in certain types of cancer, such as breast cancer. Further research is needed to determine if the effect of melatonin is beneficial or harmful. Patients who are taking tamoxifen or other chemotherapeutic or immunologic agents are recommended to administer melatonin on the advice of a supervising health professional only.
    Meperidine; Promethazine: (Major) Avoid coadministration of tamoxifen with promethazine due to the potential for decreased tamoxifen efficacy; additive QT prolongation may also occur. If coadministration is necessary, monitor for altered tamoxifen efficacy and evidence of QT prolongation. Promethazine may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP2D6. 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. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. In a clinical trial, there was a significantly higher rate of breast cancer recurrence in patients who had received a CYP2D6 inhibitor with tamoxifen. In another observational study, no clinically significant differences were observed with the addition of a CYP2D6 inhibitor to tamoxifen therapy; however, only 215 patients of 1,990 were administered a CYP2D6 inhibitor.
    Mestranol; Norethindrone: (Major) The use of estrogens, including oral contraceptives and non-oral combination contraceptives, with tamoxifen is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which tamoxifen is prescribed. Tamoxifen exerts its effects by blocking estrogen receptors. Since tamoxifen and estrogens are pharmacological opposites, they are not usually given concurrently.
    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.
    Metformin; Pioglitazone: (Major) Pioglitazone is a mild CYP3A4 inducer. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Pioglitazone may induce the CYP3A4 metabolism of tamoxifen to these metabolites; plasma concentrations of tamoxifen and its active metabolites have been reduced when coadministered other CYP3A4 inducers. If coadministration cannot be avoided, monitor for changes to the therapeutic effects of tamoxifen.
    Metformin; Repaglinide: (Moderate) Repaglinide is partly metabolized by CYP3A4. Drugs that inhibit CYP3A4 may increase plasma concentrations of repaglinide. Tamoxifen has been shown to be an inhibitor of CYP3A4. If these drugs are co-administered, dose adjustment of repaglinide may be necessary.
    Metformin; Saxagliptin: (Minor) Monitor patients for hypoglycemia if saxagliptin and tamoxifen are used together. The metabolism of saxagliptin is primarily mediated by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP 3A4/5 inhibitors such as tamoxifen.
    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.
    Metoclopramide: (Major) Tamoxifen, a selective estrogen receptor modulator (SERM), is converted to endoxifen and other active metabolites by cytochrome P450 (CYP) enzymes (e.g., 2D6, 3A4). Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors. Metoclopramide is an inhibitor of CYP2D6. A trial of 1,298 patients with breast cancer compared the rate of breast cancer recurrence in patients treated with tamoxifen with or without a CYP2D6 inhibitor. Patients who received tamoxifen in combination with a CYP2D6 inhibitor had a significantly higher rate of breast cancer recurrence at 2 years (13.9% v. 7.5%, p < 0.001). A separate observational study of 1,990 patients assessed event free time with adjuvant tamoxifen treatment for breast cancer. Only 215 of these patients were administered a CYP2D6 inhibitor, however no clinically significant differences were observed with the addition of a CYP2D6 inhibitor. Consider avoiding concomitant use of CYP2D6 inhibitors and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen.
    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 been reported in limited case reports with metronidazole.
    Metyrapone: (Major) Metyrapone is a CYP3A4 inducer. Tamoxifen is metabolized in by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Metyrapone may induce the CYP3A4 metabolism of tamoxifen to these metabolites, which can compromise efficacy; plasma concentrations of tamoxifen and its active metabolites have been reduced when coadministered other CYP3A4 inducers. If coadministration cannot be avoided, monitor for changes to the therapeutic effects of tamoxifen.
    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, RU-486: (Major) Avoid coadministration of tamoxifen with mifepristone due to the potential for decreased tamoxifen efficacy and/or increased tamoxifen toxicity; additive QT prolongation may also occur. If coadministration is necessary, monitor for altered tamoxifen efficacy, increased tamoxifen-related adverse effects, and evidence of QT prolongation. Use the lowest effective dose of mifepristone during coadministration to minimize the risk of QT prolongation. Mifepristone may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP3A4. 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 has been associated with dose-dependent prolongation of the QT interval.
    Mipomersen: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as tamoxifen. The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Mirabegron: (Major) Concomitant use of mirabegron and tamoxifen may result in increased mirabegron exposure and decreased concentrations of the active metabolites of tamoxifen, which may compromise efficacy. If it is not possible to avoid concomitant use, monitor patients for increased mirabegron side effects and changes in the therapeutic effects of tamoxifen. Mirabegron is a moderate inhibitor of CYP2D6 and a weak CYP3A4 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Mirabegron may inhibit the metabolism of tamoxifen to these metabolites. Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors. A trial of 1,298 patients with breast cancer compared the rate of breast cancer recurrence in patients treated with tamoxifen with or without a CYP2D6 inhibitor. Patients who received tamoxifen in combination with a CYP2D6 inhibitor had a significantly higher rate of breast cancer recurrence at 2 years (13.9% v. 7.5%, p < 0.001). A separate observational study of 1,990 patients assessed event free time with adjuvant tamoxifen treatment for breast cancer. Only 215 of these patients were administered a CYP2D6 inhibitor, however no clinically significant differences were observed with the addition of a CYP2D6 inhibitor. Additionally, mirabegron is a substrate of P-glycoprotein (P-gp); tamoxifen inhibits P-gp.
    Mirtazapine: (Moderate) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and tamoxifen. Coadminister with caution. 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. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Mitotane: (Major) Use caution if mitotane and tamoxifen are used concomitantly, and monitor for decreased efficacy of tamoxifen. Mitotane is a strong CYP3A4 inducer. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Mitotane can induce the CYP3A4 metabolism of tamoxifen to these metabolites, which may affect efficacy. Rifampin, another strong CYP3A4 inducer, reduced the tamoxifen AUC and Cmax by 86% and 55%, respectively; N-desmethyl tamoxifen plasma concentrations have been shown to be reduced when coadministered with rifampin.
    Modafinil: (Moderate) Modafinil is a CYP3A4 inducer. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Modafinil may induce the CYP3A4 metabolism of tamoxifen to these metabolites, which can compromise efficacy; plasma concentrations of tamoxifen and its active metabolites have been reduced when coadministered other CYP3A4 inducers. If coadministration cannot be avoided, monitor for changes to the therapeutic effects of tamoxifen.
    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 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.
    Nafcillin: (Major) In vitro, nafcillin is a CYP3A4 inducer. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Nafcillin may induce the CYP3A4 metabolism of tamoxifen to these metabolites, which can compromise efficacy; plasma concentrations of tamoxifen and its active metabolites have been reduced when coadministered other CYP3A4 inducers. If coadministration cannot be avoided, monitor for changes to the therapeutic effects of tamoxifen.
    Nefazodone: (Major) Concomitant use may result in decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. Monitor patients for changes in the therapeutic efficacy of tamoxifen. Nefazodone is a strong CYP3A4 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent, CYP2C9 and CYP2C19, to other potent active metabolites including endoxifen, which are then inactivated by sulfotransferase 1A1 (SULT1A1). Nefazodone may inhibit the CYP3A4 metabolism of tamoxifen to these metabolites, which have up to 33 times more affinity for the estrogen receptor than tamoxifen.
    Nelfinavir: (Major) Concomitant use of nelfinavir and tamoxifen may result in increased nelfinavir exposure and decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. Monitor patients for increased nelfinavir side effects and changes in the therapeutic efficacy of tamoxifen. Nelfinavir is a strong CYP3A4 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent, CYP2C9 and CYP2C19, to other potent active metabolites including endoxifen, which are then inactivated by sulfotransferase 1A1 (SULT1A1). Nelfinavir may inhibit the CYP3A4 metabolism of tamoxifen to these metabolites, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. Additionally, nelfinavir is a substrate of P-glycoprotein (P-gp); tamoxifen inhibits P-gp.
    Netupitant; Palonosetron: (Major) Concomitant use of netupitant and tamoxifen may also result in decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. If it is not possible to avoid concomitant use, monitor patients for changes in the therapeutic efficacy of tamoxifen. Netupitant is a moderate CYP3A4 inhibitor; the inhibitory effect can last for many days. Netupitant may inhibit the metabolism of tamoxifen to its active metabolites, which have up to 33 times more affinity for the estrogen receptor than tamoxifen.
    Nevirapine: (Major) Concomitant use of nevirapine and tamoxifen may decrease concentrations of the active metabolites of tamoxifen, which can compromise efficacy. Monitor for changes to the therapeutic effects of tamoxifen. Nevirapine is a CYP3A4 inducer. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Nevirapine may induce the CYP3A4 metabolism of tamoxifen to these metabolites; plasma concentrations of tamoxifen and its active metabolites have been reduced when coadministered with other CYP3A4 inducers.
    Nicardipine: (Major) Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors, such as nicardipine. Consider avoiding concomitant use of nicardipine and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen.
    Nicotine: (Major) Nicotine is a mild CYP3A4 inducer. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Nicotine may induce the CYP3A4 metabolism of tamoxifen to these metabolites; plasma concentrations of tamoxifen and its active metabolites have been reduced when coadministered other CYP3A4 inducers. If coadministration cannot be avoided, monitor for changes to the therapeutic effects of tamoxifen.
    Nilotinib: (Major) Avoid coadministration of tamoxifen with nilotinib due to an increased risk of QT prolongation; increased nilotinib and tamoxifen exposure and reduced tamoxifen efficacy are also possible. If interruption of treatment with nilotinib is not possible, closely monitor for evidence of QT prolongation, increased nilotinib and tamoxifen side effects, and decreased tamoxifen efficacy during concurrent use. Nilotinib prolongs the QT 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. Nilotinib may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP2D6, CYP3A4, and CYP2C9. In a clinical trial, there was a significantly higher rate of breast cancer recurrence in patients who had received a CYP2D6 inhibitor with tamoxifen. In another observational study, no clinically significant differences were observed with the addition of a CYP2D6 inhibitor to tamoxifen therapy; however, only 215 patients of 1,990 were administered a CYP2D6 inhibitor. Tamoxifen may also increase exposure to nilotinib via inhibition of P-glycoprotein (P-gp).
    Nintedanib: (Moderate) Tamoxifen is a moderate inhibitor of both P-glycoprotein (P-gp) and CYP3A4; nintedanib is a P-gp substrate as well as a minor substrate of CYP3A4. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of tamoxifen and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Nortriptyline: (Minor) 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: (Major) Avoid coadministration of tamoxifen with octreotide due to the potential for decreased tamoxifen efficacy and/or increased tamoxifen toxicity; additive QT prolongation may also occur. If coadministration is necessary, monitor for altered tamoxifen efficacy, increased tamoxifen-related adverse effects, and evidence of QT prolongation. Octreotide may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP3A4. 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 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 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.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Caution is advised with the concomitant use of tamoxifen and ritonavir due to an increased risk of QT prolongation; reduced tamoxifen efficacy and/or increased tamoxifen toxicity is also possible. Monitor for evidence of QT prolongation, altered tamoxifen efficacy, and increased tamoxifen adverse effects if coadministration needed. 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. Ritonavir is also associated with QT prolongation. Ritonavir may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP3A4. (Major) Concurrent administration of tamoxifen with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in in increased antiviral exposure and decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. Consider avoiding concomitant use of ritonavir and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for increased antiviral side effects, as well as changes in the therapeutic efficacy of tamoxifen. Both ritonavir and tamoxifen are substrates and inhibitors of the hepatic isoenzyme CYP3A4; paritaprevir and dasabuvir (minor) are CYP3A4 substrates. Tamoxifen is also a substrate for CYP2D6; ritonavir is a CYP2D6 inhibitor. In addition, tamoxifen inhibits the drug transporter P-glycoprotein (P-gp); dasabuvir, ombitasvir, paritaprevir, and ritonavir are all substrates of P-gp. (Major) Concurrent administration of tamoxifen with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in in increased antiviral exposure and decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. Consider avoiding concomitant use of ritonavir and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for increased antiviral side effects, as well as changes in the therapeutic efficacy of tamoxifen. Both ritonavir and tamoxifen are substrates and inhibitors of the hepatic isoenzyme CYP3A4; paritaprevir and dasabuvir (minor) are CYP3A4 substrates. Tamoxifen is also a substrate for CYP2D6; ritonavir is a CYP2D6 inhibitor. In addition, tamoxifen inhibits the drug transporter P-glycoprotein (P-gp); dasabuvir, ombitasvir, paritaprevir, and ritonavir are all substrates of P-gp.
    Omeprazole: (Moderate) Theoretically, concomitant use may result in increased omeprazole side effects and decreased concentrations of the active metabolites of tamoxifen which can compromise efficacy; the clinical significance of this interaction is not known. Omeprazole is a CYP2C19 inhibitor and, in vitro, an inhibitor of CYP2C9. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Additionally, omeprazole is a P-glycoprotein (P-gp) substrate; tamoxifen inhibits P-gp.
    Omeprazole; Sodium Bicarbonate: (Moderate) Theoretically, concomitant use may result in increased omeprazole side effects and decreased concentrations of the active metabolites of tamoxifen which can compromise efficacy; the clinical significance of this interaction is not known. Omeprazole is a CYP2C19 inhibitor and, in vitro, an inhibitor of CYP2C9. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Additionally, omeprazole is a P-glycoprotein (P-gp) substrate; tamoxifen inhibits P-gp.
    Ondansetron: (Major) Caution is advised with the concomitant use of tamoxifen and ondansetron 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. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of TdP.
    Oritavancin: (Moderate) Oritavancin is a weak CYP3A4 and CYP2D6 inducer, as well as a weak inhibitor of CYP2C9 and CYP2C19. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by CYP2C9 and CYP2C19 to other potent active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Oritavancin may affect the metabolism of tamoxifen to these metabolites. Concomitant use of oritavancin and tamoxifen may alter concentrations of the active metabolites of tamoxifen, which can compromise efficacy if oritavancin antimicrobial therapy continues for prolonged periods of time. Monitor patients for changes in the therapeutic efficacy of tamoxifen.
    Osimertinib: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of tamoxifen with osimertinib is necessary; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. 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.
    Ospemifene: (Major) Ospemifene should not be used concomitantly with estrogen agonists/antagonists such as tamoxifen. The safety of concomitant use of ospemifene with estrogen agonists/antagonists has not been studied.
    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.
    Oxcarbazepine: (Major) Oxcarbazepine is a CYP3A4 inducer and at high doses, an inhibitor of CYP2C19. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Oxcarbazepine may affect the metabolism of tamoxifen to these metabolites; plasma concentrations of tamoxifen and its active metabolites have been reduced when coadministered other CYP3A4 inducers. If coadministration cannot be avoided, monitor for changes to the therapeutic effects of tamoxifen.
    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.
    Panobinostat: (Major) Avoid coadministration of tamoxifen with panobinostat due to an increased risk of QT prolongation; reduced tamoxifen efficacy and/or increased tamoxifen toxicity is also possible. If coadministration is necessary, obtain an electrocardiogram at baseline and periodically during treatment; additionally, monitor for altered tamoxifen efficacy and/or increased tamoxifen-related adverse effects. Hold panobinostat if the QTcF increases to 480 milliseconds or more during therapy; permanently discontinue if QT prolongation does not resolve. QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial. 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. Panobinostat may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP2D6. In a clinical trial, there was a significantly higher rate of breast cancer recurrence in patients who had received a CYP2D6 inhibitor with tamoxifen. In another observational study, no clinically significant differences were observed with the addition of a CYP2D6 inhibitor to tamoxifen therapy; however, only 215 patients of 1,990 were administered a CYP2D6 inhibitor.
    Pantoprazole: (Moderate) Concomitant use may result in increased pantoprazole side effects and decreased concentrations of the active metabolites of tamoxifen which can compromise efficacy. Monitor patients for changes in therapeutic efficacy of tamoxifen. Pantoprazole is a CYP2C19 inhibitor and, in vitro, an inhibitor of CYP2C9 and CYP3A4. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Additionally, pantoprazole is a P-glycoprotein (P-gp) substrate; tamoxifen inhibits P-gp.
    Paroxetine: (Major) Tamoxifen is converted to endoxifen and other active metabolites by cytochrome P450 (CYP) enzymes (e.g., 2D6, 3A4). Paroxetine is considered a moderate to potent inhibitor of CYP2D6; reduced tamoxifen efficacy is possible with concomitant use. If treatment with an antidepressant and tamoxifen is necessary, it may be preferable to use an agent that exhibits mild inhibition of CYP2D6.
    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) Avoid coadministration of tamoxifen with pazaopanib due to an increased risk of QT prolongation; increased pazaopanib and tamoxifen exposure and reduced tamoxifen efficacy are also possible. If interruption of treatment with pazaopanib is not possible, closely monitor for evidence of QT prolongation, increased pazaopanib and tamoxifen side effects, and decreased tamoxifen efficacy during concurrent use. Pazopanib prolongs the QT 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. Pazopanib may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP2D6 and CYP3A4. Tamoxifen may also increase exposure to pazopanib via inhibition of P-glycoprotein (P-gp).
    Peginterferon Alfa-2b: (Major) Peginterferon alfa-2b is an inhibitor of CYP2D6. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Peginterferon alfa-2b may inhibit the metabolism of tamoxifen to these metabolites. Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors. A trial of 1,298 patients with breast cancer compared the rate of breast cancer recurrence in patients treated with tamoxifen with or without a CYP2D6 inhibitor. Patients who received tamoxifen in combination with a CYP2D6 inhibitor had a significantly higher rate of breast cancer recurrence at 2 years (13.9% v. 7.5%, p < 0.001). A separate observational study of 1,990 patients assessed event free time with adjuvant tamoxifen treatment for breast cancer. Only 215 of these patients were administered a CYP2D6 inhibitor, however no clinically significant differences were observed with the addition of a CYP2D6 inhibitor.
    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 also been described when tamoxifen is used at lower doses. Systemic pentamidine has been associated with QT prolongation.
    Perampanel: (Major) In vitro, perampanel is a CYP3A4 inducer. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Perampanel may induce the CYP3A4 metabolism of tamoxifen to these metabolites; plasma concentrations of tamoxifen and its active metabolites have been reduced when coadministered with other CYP3A4 inducers. Also, perampanel is a CYP3A4 substrate in vitro, and tamoxifen inhibits CYP3A4. If coadministration cannot be avoided, monitor for increased perampanel side effects and changes to the therapeutic effects of tamoxifen.
    Perphenazine: (Major) Avoid coadministration of tamoxifen with perphenazine due to the potential for decreased tamoxifen efficacy and/or increased tamoxifen toxicity; additive QT prolongation may also occur. If coadministration is necessary, monitor for altered tamoxifen efficacy, increased tamoxifen-related adverse effects, and evidence of QT prolongation. Perphenazine may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP2D6. In a clinical trial, there was a significantly higher rate of breast cancer recurrence in patients who had received a CYP2D6 inhibitor with tamoxifen. In another observational study, no clinically significant differences were observed with the addition of a CYP2D6 inhibitor to tamoxifen therapy; however, only 215 patients of 1,990 were administered a CYP2D6 inhibitor. 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. Perphenazine is associated with a possible risk for QT prolongation.
    Perphenazine; Amitriptyline: (Major) Avoid coadministration of tamoxifen with perphenazine due to the potential for decreased tamoxifen efficacy and/or increased tamoxifen toxicity; additive QT prolongation may also occur. If coadministration is necessary, monitor for altered tamoxifen efficacy, increased tamoxifen-related adverse effects, and evidence of QT prolongation. Perphenazine may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP2D6. In a clinical trial, there was a significantly higher rate of breast cancer recurrence in patients who had received a CYP2D6 inhibitor with tamoxifen. In another observational study, no clinically significant differences were observed with the addition of a CYP2D6 inhibitor to tamoxifen therapy; however, only 215 patients of 1,990 were administered a CYP2D6 inhibitor. 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. Perphenazine is associated with a possible risk for QT prolongation. (Minor) 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).
    Phentermine; Topiramate: (Major) Topiramate is a CYP3A4 inducer and a weak CYP2C19 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Topiramate may affect the metabolism of tamoxifen to these metabolites; plasma concentrations of tamoxifen its active metabolites have been reduced when coadministered other CYP3A4 inducers. The clinical significance of this interaction is not known. If coadministration is necessary, monitor for tamoxifen efficacy.
    Phenylephrine; Promethazine: (Major) Avoid coadministration of tamoxifen with promethazine due to the potential for decreased tamoxifen efficacy; additive QT prolongation may also occur. If coadministration is necessary, monitor for altered tamoxifen efficacy and evidence of QT prolongation. Promethazine may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP2D6. 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. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. In a clinical trial, there was a significantly higher rate of breast cancer recurrence in patients who had received a CYP2D6 inhibitor with tamoxifen. In another observational study, no clinically significant differences were observed with the addition of a CYP2D6 inhibitor to tamoxifen therapy; however, only 215 patients of 1,990 were administered a CYP2D6 inhibitor.
    Phenytoin: (Major) Concomitant use of phenytoin and tamoxifen may decrease concentrations of the active metabolites of tamoxifen, which can compromise efficacy. Monitor patients for changes in therapeutic efficacy of tamoxifen. Phenytoin is a potent CYP3A4 inducer as well as an inducer of CYP2C9 and CYP2C19. Tamoxifen is metabolized in part by CYP3A4 and to a lesser extent, by CYP2C9 and CYP2C19, to other potent active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Phenytoin may induce the metabolism of tamoxifen to these metabolites; plasma concentrations of tamoxifen and its active metabolites have been reduced when coadministered with other CYP3A4 inducers, which can compromise efficacy.
    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.
    Pioglitazone: (Major) Pioglitazone is a mild CYP3A4 inducer. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Pioglitazone may induce the CYP3A4 metabolism of tamoxifen to these metabolites; plasma concentrations of tamoxifen and its active metabolites have been reduced when coadministered other CYP3A4 inducers. If coadministration cannot be avoided, monitor for changes to the therapeutic effects of tamoxifen.
    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.
    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) Caution is advised with the concomitant use of tamoxifen and prochlorperazine 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. Prochlorperazine is associated with a possible risk for QT prolongation.
    Promethazine: (Major) Avoid coadministration of tamoxifen with promethazine due to the potential for decreased tamoxifen efficacy; additive QT prolongation may also occur. If coadministration is necessary, monitor for altered tamoxifen efficacy and evidence of QT prolongation. Promethazine may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP2D6. 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. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. In a clinical trial, there was a significantly higher rate of breast cancer recurrence in patients who had received a CYP2D6 inhibitor with tamoxifen. In another observational study, no clinically significant differences were observed with the addition of a CYP2D6 inhibitor to tamoxifen therapy; however, only 215 patients of 1,990 were administered a CYP2D6 inhibitor.
    Propafenone: (Major) Concomitant use of tamoxifen and propafenone may cause an increased risk of QT prolongation; reduced tamoxifen efficacy and/or increased tamoxifen toxicity is also possible. If coadministration is unavoidable, monitor for altered tamoxifen efficacy, increased tamoxifen-related adverse effects, and evidence 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. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. Propafenone may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP2D6. In a clinical trial, there was a significantly higher rate of breast cancer recurrence in patients who had received a CYP2D6 inhibitor with tamoxifen. In another observational study, no clinically significant differences were observed with the addition of a CYP2D6 inhibitor to tamoxifen therapy; however, only 215 patients of 1,990 were administered a CYP2D6 inhibitor.
    Propoxyphene: (Major) Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors, such as propoxyphene. Consider avoiding concomitant use of propoxyphene and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen.
    Protriptyline: (Minor) 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).
    Purine analogs: (Moderate) There is an increased risk of a thromboembolic event occurring when antineoplastic agents are used in combination with tamoxifen.
    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 also been described when tamoxifen is used at lower doses. Limited data, including some case reports, suggest that quetiapine may 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 an increased risk of QT prolongation and torsade de pointes (TdP); increased quinine exposure and reduced tamoxifen efficacy and/or increased tamoxifen toxicity are also possible. If coadministration is unavoidable, monitor for QT prolongation and other quinine-related adverse effects as well as changes in therapeutic efficacy/toxicity of tamoxifen. Quinine has been associated with QT prolongation and rare cases of 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 may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP2D6. In a clinical trial, there was a significantly higher rate of breast cancer recurrence in patients who had received a CYP2D6 inhibitor with tamoxifen. In another observational study, no clinically significant differences were observed with the addition of a CYP2D6 inhibitor to tamoxifen therapy; however, only 215 patients of 1,990 were administered a CYP2D6 inhibitor. Tamoxifen may also increase exposure to quinine via inhibition of CYP3A4 and P-glycoprotein (P-gp).
    Ranolazine: (Major) Concomitant use of tamoxifen and ranolazine may cause an increased risk of QT prolongation; reduced tamoxifen efficacy and/or increased tamoxifen toxicity is also possible. If coadministration is unavoidable, monitor for altered tamoxifen efficacy, increased tamoxifen-related adverse effects, and evidence 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. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Ranolazine may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP3A4 and CYP2D6. In a clinical trial, there was a significantly higher rate of breast cancer recurrence in patients who had received a CYP2D6 inhibitor with tamoxifen. In another observational study, no clinically significant differences were observed with the addition of a CYP2D6 inhibitor to tamoxifen therapy; however, only 215 patients of 1,990 were administered a CYP2D6 inhibitor.
    Regadenoson: (Moderate) Caution is advised with the concomitant use of tamoxifen and regadenoson 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. Regadenoson has also been associated with QT prolongation.
    Regorafenib: (Major) Concomitant use may result in decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. If it is not possible to avoid concomitant use, monitor patients for changes in the therapeutic efficacy of tamoxifen. In vitro, regorafenib is a weak inhibitor of CYP3A4, CYP2C9, and CYP2C19; active metabolite M-2 is also a weak CYP2D6 inhibitor in vitro. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent, CYP2C9 and CYP2C19, to other potent active metabolites including endoxifen, which are then inactivated by sulfotransferase 1A1 (SULT1A1). Regorafenib may inhibit the CYP3A4, CYP2C9, and CYP2C19 metabolism of tamoxifen to these metabolites, which have up to 33 times more affinity for the estrogen receptor than tamoxifen.
    Repaglinide: (Moderate) Repaglinide is partly metabolized by CYP3A4. Drugs that inhibit CYP3A4 may increase plasma concentrations of repaglinide. Tamoxifen has been shown to be an inhibitor of CYP3A4. If these drugs are co-administered, dose adjustment of repaglinide may be necessary.
    Ribociclib: (Major) Avoid coadministration of tamoxifen with ribociclib due to an increased risk of QT prolongation; reduced tamoxifen efficacy and/or increased tamoxifen toxicity is also possible. If coadministration is unavoidable, monitor for altered tamoxifen efficacy, increased tamoxifen-related adverse effects, and evidence 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. 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. Ribociclib may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP3A4.
    Ribociclib; Letrozole: (Major) Avoid coadministration of tamoxifen with ribociclib due to an increased risk of QT prolongation; reduced tamoxifen efficacy and/or increased tamoxifen toxicity is also possible. If coadministration is unavoidable, monitor for altered tamoxifen efficacy, increased tamoxifen-related adverse effects, and evidence 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. 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. Ribociclib may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP3A4. (Major) Letrozole should not be given concurrently with tamoxifen; when administered together, there is an average 38% reduction in letrozole plasma concentrations. Letrozole therapy after the completion of standard tamoxifen treatment is not associated with impaired effects of letrozole.
    Rifabutin: (Major) Concurrent administration of a rifamycin with tamoxifen may lead to decreased antiestrogen effects due to hepatic enzyme induction by the rifamycin.
    Rifampin: (Major) In a pharmacokinetic study in healthy volunteers, administration of a single dose of tamoxifen was given following chronic dosing with rifampin. The AUC of tamoxifen was reduced by 86% and the Cmax was reduced by 55%. The half-life of tamoxifen was reduced from 118 hours to 68 hours following rifampin dosing. The effect rifampin on chronic tamoxifen therapy is unknown but may lead to a loss of tamoxifen's antiestrogen effects. A similar effect may occur with concurrent administration of tamoxifen and rifabutin or rifapentine.
    Rifapentine: (Moderate) Concurrent administration of rifapentine with tamoxifen may lead to decreased antiestrogen effects due to hepatic enzyme induction by rifapentine.
    Rifaximin: (Major) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and tamoxifen, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin. Additionally, in vitro, rifaximin is a CYP3A4 inducer. Tamoxifen and its metabolite, 4-hydroxytamoxifen, are metabolized in part by CYP3A4 to other potent active metabolites including endoxifen, which are then inactivated by sulfotransferase 1A1 (SULT1A1). Rifaximin may induce the CYP3A4 metabolism of tamoxifen to these metabolites; the clinical significance of this interaction is not known. If it is not possible to avoid concomitant use, monitor patients for changes in therapeutic efficacy of tamoxifen as well as for rifaximin toxicity. In patients with normal liver function and at normal doses, rifaximin is not expected to induce 3A4; oral rifaximin is largely unabsorbed and should not result in any drug interactions.
    Rilpivirine: (Major) Caution is advised with the concomitant use of tamoxifen and rilpivirine due to an increased risk of QT prolongation; increased rilpivirine exposure may also occur. 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. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    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.
    Ritonavir: (Major) Caution is advised with the concomitant use of tamoxifen and ritonavir due to an increased risk of QT prolongation; reduced tamoxifen efficacy and/or increased tamoxifen toxicity is also possible. Monitor for evidence of QT prolongation, altered tamoxifen efficacy, and increased tamoxifen adverse effects if coadministration needed. 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. Ritonavir is also associated with QT prolongation. Ritonavir may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP3A4.
    Rolapitant: (Major) Use caution if tamoxifen and rolapitant are used concurrently, and monitor for possible changes to the efficacy of tamoxifen. Tamoxifen is metabolized by CYP2D6 to the potent active metabolite 4-hydroxytamoxifen. 4-hydroxytamoxifen is further metabolized to endoxifen by CYP3A4/5. Active metabolite, N-desmethyl-tamoxifen, is also metabolized to endoxifen by CYP2D6. These metabolites have up to 33% more affinity for the estrogen receptor than tamoxifen. Rolapitant is an inhibitor of CYP2D6; the inhibitory effect of rolapitant lasts for at least 7 days, and may last longer after single dose administration. The Cmax and AUC of the CYP2D6 substrate, dextromethorphan, were increased by 120% and 160%, respectively, on day 1 with rolapitant, and by 180% and 230%, respectively, on day 8 after rolapitant administration. Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors. A trial of 1,298 patients with breast cancer compared the rate of breast cancer recurrence in patients treated with tamoxifen with or without a CYP2D6 inhibitor. Patients who received tamoxifen in combination with a CYP2D6 inhibitor had a significantly higher rate of breast cancer recurrence at 2 years (13.9% vs. 7.5%, p < 0.001). A separate observational study of 1,990 patients assessed event free time with adjuvant tamoxifen treatment for breast cancer. Only 215 of these patients were administered a CYP2D6 inhibitor, however no clinically significant differences were observed with the addition of a CYP2D6 inhibitor.
    Romidepsin: (Major) Caution is advised with the concomitant use of tamoxifen and romidepsin due to an increased risk of QT prolongation; increased romidepsin exposure may also occur. If coadministration is necessary, monitor ECG and electrolytes at baseline and periodically during 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. Romidepsin has also been reported to prolong the QT interval. Tamoxifen may increase exposure to romidepsin via inhibition of P-glycoprotein (P-gp). Additionally, there is an increased risk of thromboembolic events occurring when cytotoxic agents are used in combination with tamoxifen.
    Rufinamide: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as tamoxifen, may occur during concurrent use with rufinamide.
    Ruxolitinib: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as tamoxifen, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    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 and P-glycoprotein (P-gp) inhibitor; saquinavir boosted with ritonavir is a strong CYP3A4 inhibitor and a substrate of P-gp. The concentrations of saquinavir and/or tamoxifen may be increased, thus increasing the risk of drug toxicity and proarrhythmic effects.
    Saxagliptin: (Minor) Monitor patients for hypoglycemia if saxagliptin and tamoxifen are used together. The metabolism of saxagliptin is primarily mediated by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP 3A4/5 inhibitors such as tamoxifen.
    Sertraline: (Moderate) Caution is advised with the concomitant use of tamoxifen and sertraline 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. There have been postmarketing reports of QT prolongation and 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.
    Silodosin: (Moderate) Silodosin is extensively metabolized by hepatic cytochrome P450 3A4 and is a P-glycoprotein (P-gp) substrate. In theory, drugs that inhibit CYP3A4 and P-gp such as tamoxifen may cause significant increases in silodosin plasma concentrations.
    Simeprevir: (Major) Concomitant use of simeprevir and tamoxifen may result in increased simeprevir exposure and decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. If it is not possible to avoid concomitant use, monitor patients for increased side effects of simeprevir and changes in the therapeutic efficacy of tamoxifen. Simeprevir is a weak CYP3A4 inhibitor; tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent, CYP2C9 and CYP2C19, to other potent active metabolites including endoxifen, which are then inactivated by sulfotransferase 1A1 (SULT1A1). Simeprevir may inhibit the metabolism of tamoxifen to these metabolites, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. Additionally, simeprevir is a substrate of P-glycoprotein (P-gp); tamoxifen inhibits P-gp.
    Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with tamoxifen. Taking these drugs together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the drug transporter P-glycoprotein (P-gp); tamoxifen is an inhibitor of P-gp. Tamoxifen is also an inhibitor of the hepatic enzyme CYP3A4. Velpatasvir is a CYP3A4 substrate.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Use caution when administering velpatasvir with tamoxifen. Taking these drugs together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the drug transporter P-glycoprotein (P-gp); tamoxifen is an inhibitor of P-gp. Tamoxifen is also an inhibitor of the hepatic enzyme CYP3A4. Velpatasvir is a CYP3A4 substrate.
    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) Caution is advised with the concomitant use of tamoxifen and sorafenib due to an increased risk of QT prolongation. If coadministration is necessary, ECG monitoring is recommended; closely monitor the patient for 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. Sorafenib has been associated with QT prolongation.
    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) St. John's Wort, Hypericum perforatum is a potent CYP3A4 inducer, as well as a moderate inducer of CYP2C9 and CYP2C19. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent, CYP2C9 and CYP2C19, to other potent active metabolites including endoxifen, which are then inactivated by sulfotransferase 1A1 (SULT1A1). St. John's Wort may induce the CYP3A4 metabolism of tamoxifen to these metabolites, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. Plasma concentrations of these active metabolites have been significantly reduced when coadministered with other strong CYP3A4 inducers. If it is not possible to avoid concomitant use, monitor patients for changes in the therapeutic efficacy of tamoxifen.
    Streptogramins: (Major) Quinupristin is a strong CYP3A4 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent, CYP2C9 and CYP2C19, to other potent active metabolites including endoxifen, which are then inactivated by sulfotransferase 1A1 (SULT1A1). Quinupristin may inhibit the CYP3A4 metabolism of tamoxifen to these metabolites, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. Concomitant use of dalfopristin; quinupristin and tamoxifen may result in decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. If it is not possible to avoid concomitant use, monitor patients for changes in the therapeutic efficacy of tamoxifen.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Moderate) Caution is advised with the concomitant use of tamoxifen and sulfamethoxazole; trimethoprim 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 resulting in ventricular tachycardia and TdP has been reported during postmarketing use of sulfamethoxazole; trimethoprim. (Moderate) Caution is advised with the concomitant use of tamoxifen and trimethoprim 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 resulting in ventricular tachycardia and TdP has been reported during postmarketing use of sulfamethoxazole; trimethoprim.
    Sulfinpyrazone: (Major) Sulfinpyrazone is a moderate CYP2C9 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a smaller extent by CYP2C9, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Theoretically, concomitant use of sulfinpyrazone and tamoxifen may result in decreased concentrations of the active metabolites of tamoxifen; the clinical significance of this interaction is not known.
    Sunitinib: (Major) Caution is advised with the concomitant use of tamoxifen and sunitinib 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. Sunitinib can also prolong the QT interval.
    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.
    Telaprevir: (Major) Concomitant use of telaprevir and tamoxifen may result in increased telaprevir exposure and decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. If it is not possible to avoid concomitant use, monitor patients for increased side effects of telaprevir and changes in the therapeutic efficacy of tamoxifen. Telaprevir is a strong CYP3A4 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Telaprevir may inhibit the CYP3A4 metabolism of tamoxifen to these metabolites. Additionally, telaprevir is a substrate of P-glycoprotein (P-gp); tamoxifen inhibits P-gp.
    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) Concomitant use of tamoxifen and telithromycin may cause an increased risk of QT prolongation and torsade de pointes (TdP); reduced tamoxifen efficacy and/or increased tamoxifen toxicity is also possible. If coadministration is unavoidable, monitor for altered tamoxifen efficacy, increased tamoxifen-related adverse effects, and evidence 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. Telithromycin is associated with QT prolongation and TdP. Telithromycin may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP3A4.
    Telmisartan: (Moderate) Telmisartan is a weak CYP2C19 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a smaller extent by CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Theoretically, concomitant use of telmisartan and tamoxifen may result in decreased concentrations of the active metabolites of tamoxifen; the clinical significance of this interaction is not known.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and tamoxifen is necessary, as the systemic exposure of both tamoxifen and its main metabolite, N-desmethyl tamoxifen have been shown to be reduced when coadministered with CYP3A4 inducers, resulting in reduced efficacy; exposure to telotristat ethyl may also be increased. If these drugs are used together, monitor patients for suboptimal efficacy of tamoxifen as well as an increase in adverse reactions related to telotristat ethyl. N-desmethyl tamoxifen is the main metabolite of tamoxifen, with similar biological activity to tamoxifen, and is formed predominantly via CYP3A4/5; other potent, active metabolites, which have up to 100 times greater affinity for the estrogen receptor and 30- to 100-fold greater potency in suppressing estrogen-dependent cell proliferation, are catalyzed primarily by CYP2D6 from either tamoxifen or N-desmethyl tamoxifen. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate. Additionally, the active metabolite of telotristat ethyl, telotristat, is a substrate of P-glycoprotein (P-gp) and tamoxifen is a P-gp inhibitor. Exposure to telotristat ethyl may increase.
    Temsirolimus: (Moderate) Use caution if coadministration of temsirolimus with tamoxifen is necessary, and monitor for an increase in temsirolimus-related adverse reactions. Temsirolimus is a P-glycoprotein (P-gp) substrate. Tamoxifen is a P-gp inhibitor; coadministration may increase plasma concentrations of temsirolimus (and active metabolite, sirolimus).
    Tenofovir Alafenamide: (Minor) Close clinical monitoring is advised when administering tamoxifen with tenofovir alafenamide due to an increased potential for adverse events. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of these drugs. Tamoxifen is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a substrate for P-gp. Coadministration may result in increased tenofovir plasma concentrations. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Tenofovir, PMPA: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as tamoxifen. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Terbinafine: (Major) Concomitant use may result in decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. Monitor patients for changes in the therapeutic efficacy of tamoxifen. Terbinafine is a moderate CYP2D6 inhibitor. Tamoxifen is metabolized by CYP2D6 to the potent active metabolite 4-hydroxytamoxifen. 4-hydroxytamoxifen is further metabolized to endoxifen by CYP3A4/5. Active metabolite, N-desmethyl-tamoxifen, is also metabolized to endoxifen by CYP2D6. Terbinafine may inhibit the metabolism of tamoxifen to these metabolites, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors. A trial of 1,298 patients with breast cancer compared the rate of breast cancer recurrence in patients treated with tamoxifen with or without a CYP2D6 inhibitor. Patients who received tamoxifen in combination with a CYP2D6 inhibitor had a significantly higher rate of breast cancer recurrence at 2 years (13.9% v. 7.5%, p < 0.001). A separate observational study of 1,990 patients assessed event free time with adjuvant tamoxifen treatment for breast cancer. Only 215 of these patients were administered a CYP2D6 inhibitor, however no clinically significant differences were observed with the addition of a CYP2D6 inhibitor.
    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.
    Teriflunomide: (Moderate) Use caution when administering teriflunomide and tamoxifen concurrently. In vivo data suggest that teriflunomide is a weak inducer of CYP1A2. Coadministration of teriflunomide with CYP1A2 substrates, such as tamoxifen, may decrease tamoxifen exposure and lead to a reduction in efficacy.
    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.
    Ticagrelor: (Major) Concomitant use of ticagrelor and tamoxifen may result in decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. If it is not possible to avoid concomitant use, monitor patients for changes in the therapeutic efficacy of tamoxifen. Ticagrelor is a weak CYP3A4 inhibitor. Tamoxifen by CYP3A4, CYP2D6, and to a lesser extent, CYP2C9 and CYP2C19, to other potent active metabolites including endoxifen, which are then inactivated by sulfotransferase 1A1 (SULT1A1). Ticagrelor may inhibit the metabolism of tamoxifen to these metabolites, which have up to 33 times more affinity for the estrogen receptor than tamoxifen.
    Ticlopidine: (Moderate) Ticlopidine is a CYP2C19 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a smaller extent by CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Theoretically, concomitant use of ticlopidine and tamoxifen may result in decreased concentrations of the active metabolites of tamoxifen; the clinical significance of this interaction is not known.
    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: (Major) Tipranavir is a strong inhibitor of CYP3A4 and CYP2D6, as well as a moderate CYP2C19 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Tipranavir may inhibit the metabolism of tamoxifen to these metabolites. Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors. A trial of 1,298 patients with breast cancer compared the rate of breast cancer recurrence in patients treated with tamoxifen with or without a CYP2D6 inhibitor. Patients who received tamoxifen in combination with a CYP2D6 inhibitor had a significantly higher rate of breast cancer recurrence at 2 years (13.9% v. 7.5%, p < 0.001). A separate observational study of 1,990 patients assessed event free time with adjuvant tamoxifen treatment for breast cancer. Only 215 of these patients were administered a CYP2D6 inhibitor, however no clinically significant differences were observed with the addition of a CYP2D6 inhibitor. Tipranavir is also a CYP3A4 and P-glycoprotein (P-gp) substrate; tamoxifen inhibits both CYP3A4 and P-gp. Concomitant use may result in increased side effects of tipranavir and decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. Consider avoiding concomitant use of tipranavir and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for tipranavir side effects and changes in the therapeutic efficacy of tamoxifen.
    Tizanidine: (Moderate) Caution is advised with the concomitant use of tamoxifen and tizanidine 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. Tizanidine administration may also result in QT prolongation.
    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.
    Tolvaptan: (Major) Coadministration of tolvaptan and tamoxifen may result in increased exposure to tolvaptan; reduce the tolvaptan dose if necessary. Tolvaptan is a substrate for P-gp. Tamoxifen is a P-gp inhibitor.
    Topiramate: (Major) Topiramate is a CYP3A4 inducer and a weak CYP2C19 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Topiramate may affect the metabolism of tamoxifen to these metabolites; plasma concentrations of tamoxifen its active metabolites have been reduced when coadministered other CYP3A4 inducers. The clinical significance of this interaction is not known. If coadministration is necessary, monitor for tamoxifen efficacy.
    Topotecan: (Major) Avoid the concomitant use of tamoxifen, a P-glycoprotein (P-gp) inhibitor, with oral topotecan, a P-gp substrate; P-gp inhibitors have less of an effect on intravenous topotecan and these may be coadministered with caution. If coadministration of tamoxifen and oral topotecan is necessary, carefully monitor for increased toxicity of topotecan, including severe myelosuppression and diarrhea. In a pharmacokinetic cohort study, coadministration of oral topotecan with a potent P-gp inhibitor (n = 8) increased the Cmax and AUC of topotecan by 2 to 3-fold (p = 0.008); coadministration with intravenous topotecan (n = 8) increased total topotecan exposure by 1.2-fold (p = 0.02) and topotecan lactone by 1.1-fold (not significant).
    Toremifene: (Major) Caution is advised with the concomitant use of tamoxifen and toremifene 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. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Trabectedin: (Moderate) Use caution if coadministration of trabectedin and tamoxifen is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate; tamoxifen and some if its active metabolites are inhibitors of CYP3A. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Trandolapril; Verapamil: (Major) Concomitant use of verapamil and tamoxifen may result in increased verapamil exposure and decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. If it is not possible to avoid concomitant use, monitor patients for increased verapamil side effects and changes in the therapeutic efficacy of tamoxifen. Verapamil is a CYP3A4 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent, CYP2C9 and CYP2C19, to other potent active metabolites including endoxifen, which are then inactivated by sulfotransferase 1A1 (SULT1A1). Verapamil may inhibit the metabolism of tamoxifen to these metabolites, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. Additionally, verapamil is a substrate of P-glycoprotein (P-gp); tamoxifen inhibits P-gp.
    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: (Minor) 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.
    Trimethoprim: (Moderate) Caution is advised with the concomitant use of tamoxifen and trimethoprim 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 resulting in ventricular tachycardia and TdP has been reported during postmarketing use of sulfamethoxazole; trimethoprim.
    Trimipramine: (Minor) 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.
    Valproic Acid, Divalproex Sodium: (Moderate) Valproic acid, divalproex sodium is a moderate inhibitor of CYP2C9 and a weak CYP2C19 and CYP3A4 inhibitor; valproic acid also induces CYP3A4. Tamoxifen is metabolized by CYP3A4 and CYP2D6, and to a smaller extent by CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). By inhibiting CYP3A4, CYP2C9, and CYP2C19, valproic acid may decrease the formation of the active metabolites of tamoxifen; plasma concentrations of tamoxifen and its active metabolites have also been reduced when coadministered with other CYP3A4 inducers. Concomitant use may result in decreased concentrations of the active metabolites of tamoxifen, which may compromise efficacy. If it is not possible to avoid concomitant use, monitor patients for changes in the therapeutic efficacy of tamoxifen.
    Vandetanib: (Major) Avoid coadministration of tamoxifen with vandetanib due to an increased risk of QT prolongation and torsade de pointes (TdP). If coadministration is necessary, an ECG is needed, as well as more frequent monitoring of the QT interval. If QTcF is greater than 500 msec, interrupt vandetanib dosing until the QTcF is less than 450 msec; then, vandetanib may be resumed at a reduced dose. 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 also been described when tamoxifen is used at lower doses. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction).
    Vemurafenib: (Major) Caution is advised with the concomitant use of tamoxifen and vemurafenib due to an increased risk of QT prolongation; increased vemurafenib and tamoxifen exposure and reduced tamoxifen efficacy are also possible. If coadministration is necessary, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation and decreased efficacy of tamoxifen. 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. Vemurafenib has been associated with QT prolongation. Vemurafenib may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP2D6. Tamoxifen may also increase exposure to vemurafenib via inhibition of P-glycoprotein (P-gp).
    Venetoclax: (Major) Avoid the concomitant use of venetoclax and tamoxifen; venetoclax is a substrate of CYP3A4 and P-glycoprotein (P-gp) and tamoxifen is a CYP3A4 and P-gp inhibitor. Consider alternative agents. If concomitant use of these drugs is required, reduce the venetoclax dosage by at least 50% (maximum dose of 200 mg/day). If tamoxifen is discontinued, wait 2 to 3 days and then resume the recommended venetoclax dosage (or prior dosage if less). Monitor patients for signs and symptoms of venetoclax toxicity such as hematologic toxicity, GI toxicity, and tumor lysis syndrome. In a drug interaction study (n = 11), the venetoclax Cmax and AUC values were increased by 106% and 78%, respectively, when a P-gp inhibitor was co-administered in healthy subjects.
    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 also been described when tamoxifen is used at lower doses. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has been reported with postmarketing use.
    Verapamil: (Major) Concomitant use of verapamil and tamoxifen may result in increased verapamil exposure and decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. If it is not possible to avoid concomitant use, monitor patients for increased verapamil side effects and changes in the therapeutic efficacy of tamoxifen. Verapamil is a CYP3A4 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent, CYP2C9 and CYP2C19, to other potent active metabolites including endoxifen, which are then inactivated by sulfotransferase 1A1 (SULT1A1). Verapamil may inhibit the metabolism of tamoxifen to these metabolites, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. Additionally, verapamil is a substrate of P-glycoprotein (P-gp); tamoxifen inhibits P-gp.
    Vigabatrin: (Major) Vigabatrin should not be used with other drugs associated with serious ophthalmic effects (e.g., retinopathy or glaucoma) unless the benefit of treatment clearly outweighs the risks. Tamoxifen use has been associated with corneal changes, decrement in color vision perception (visual impairment), retinal thrombosis, and retinopathy. Additionally, vigabatrin is a CYP2C9 inducer. Tamoxifen is metabolized by CYP3A4 and CYP2D6, and to a lesser extent by CYP2C9, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Theoretically, by inducing CYP2C9, vigabatrin may increase the concentrations of the active metabolites of tamoxifen, which may increase toxicity
    Vinblastine: (Major) Use caution and monitor patients for an earlier onset and/or an increased severity of vinca alkaloid-related adverse effects, including neurotoxicity and myelosuppression, if tamoxifen and vinca alkaloids are used concomitantly. Tamoxifen is a P-glycoprotein (P-gp) inhibitor, and vinca alkaloids are P-gp substrates; coadministration may cause the metabolism of vinca alkaloids to be decreased.
    Vinca alkaloids: (Major) Use caution and monitor patients for an earlier onset and/or an increased severity of vinca alkaloid-related adverse effects, including neurotoxicity and myelosuppression, if tamoxifen and vinca alkaloids are used concomitantly. Tamoxifen is a P-glycoprotein (P-gp) inhibitor, and vinca alkaloids are P-gp substrates; coadministration may cause the metabolism of vinca alkaloids to be decreased.
    Vincristine Liposomal: (Major) Use caution and monitor patients for an earlier onset and/or an increased severity of vinca alkaloid-related adverse effects, including neurotoxicity and myelosuppression, if tamoxifen and vinca alkaloids are used concomitantly. Tamoxifen is a P-glycoprotein (P-gp) inhibitor, and vinca alkaloids are P-gp substrates; coadministration may cause the metabolism of vinca alkaloids to be decreased.
    Vincristine: (Major) Use caution and monitor patients for an earlier onset and/or an increased severity of vinca alkaloid-related adverse effects, including neurotoxicity and myelosuppression, if tamoxifen and vinca alkaloids are used concomitantly. Tamoxifen is a P-glycoprotein (P-gp) inhibitor, and vinca alkaloids are P-gp substrates; coadministration may cause the metabolism of vinca alkaloids to be decreased.
    Vinorelbine: (Major) Use caution and monitor patients for an earlier onset and/or an increased severity of vinca alkaloid-related adverse effects, including neurotoxicity and myelosuppression, if tamoxifen and vinca alkaloids are used concomitantly. Tamoxifen is a P-glycoprotein (P-gp) inhibitor, and vinca alkaloids are P-gp substrates; coadministration may cause the metabolism of vinca alkaloids to be decreased.
    Vorapaxar: (Moderate) Use caution during concurrent use of vorapaxar and tamoxifen. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with tamoxifen, a CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Voriconazole: (Major) Concomitant use of tamoxifen and voriconazole may cause an increased risk of QT prolongation and torsade de pointes (TdP); reduced tamoxifen efficacy and/or increased tamoxifen toxicity is also possible. If coadministration is unavoidable, monitor for altered tamoxifen efficacy, increased tamoxifen-related adverse effects, and evidence 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. Voriconazole has been associated with QT prolongation and rare cases of TdP. Voriconazole may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP3A4.
    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 also been described when tamoxifen is used at lower doses. Vorinostat therapy is also associated with a risk of QT prolongation.
    Warfarin: (Major) Tamoxifen can significantly increase the INR in patients receiving coumarin anticoagulants such as warfarin. Signs of abnormal bleeding, including hematemesis, hematuria, subdural hematoma, and intraocular hemorrhage, also have been reported during concomitant administration of these agents. The effect of tamoxifen on stable warfarin therapy may not be realized for several weeks after the initiation of tamoxifen therapy. Tamoxifen is contraindicated in women who require concomitant coumarin-type anticoagulant therapy when it is used for the reduction in breast cancer incidence in high risk women with ductal carcinoma in situ (DCIS). In the P-1 trial, women who required coumarin-type anticoagulants for any reason were ineligible for participation in the trial. If tamoxifen and warfarin are coadministered, carefully monitor the patient's prothrombin time and INR.
    Zafirlukast: (Major) Zafirlukast is a CYP2C9 inhibitor and, in vitro, an inhibitor of CYP3A4. Tamoxifen by CYP3A4, CYP2D6, and to a lesser extent, CYP2C9 and CYP2C19, to other potent active metabolites including endoxifen, which are then inactivated by sulfotransferase 1A1 (SULT1A1). Zafirlukast may inhibit the metabolism of tamoxifen to these metabolites, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. Concomitant use may result in decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. If it is not possible to avoid concomitant use, monitor patients for changes in the therapeutic efficacy of tamoxifen.
    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 also been described when tamoxifen is used at lower doses. Ziprasidone has been associated with a possible risk for QT prolongation and/or TdP. In one study, ziprasidone increased the QT interval 10 msec more than placebo at the maximum recommended dosage. 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

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

    MECHANISM OF ACTION

    Mechanism of Action: Tamoxifen has mixed estrogenic antagonist and agonist properties. Tamoxifen binds to estrogen receptors (ER) and induces conformational changes in the receptor. For example, tamoxifen stimulates ER in bone and may actually prevent postmenopausal osteoporosis and has antiestrogenic effects on breast tissue. The ability of tamoxifen and other drugs to produce both estrogenic and antiestrogenic affects is most likely due to interaction with other coactivators or corepressors in the tissue and binding with different estrogen receptors, ER-alpha or ER-beta. The tissue distribution of ER-alpha and ER-beta suggest different functions for these receptors.Subsequent to tamoxifen ER binding, the expression of estrogen dependent genes (RNA transcription) is blocked or altered. The binding of tamoxifen to the nuclear chromatin of these tissues is prolonged, resulting in reduced DNA polymerase activity, impaired thymidine utilization, blockade of estradiol uptake, and decreased estrogen response. Most of tamoxifen's activity occurs in the G2-phase. Cell cycling is slowed by the drug's activity in the nucleus. Therefore, tamoxifen is cytostatic. Tamoxifen also affects other growth factors. Tamoxifen decreases insulin-like growth factor type 1, a factor that stimulates cancer cell growth and development and induces the secretion of transforming growth factor beta (TGF-beta) which is associated with inhibiting the activity of breast cancer cells. In addition, tamoxifen induces the re-expression of the tumor suppressor gene maspin in breast cancer tissue. In breast cancer, maspin gene expression is diminished or lost, whereas the maspin protein is abundant in normal breast cells. The presence of maspin has been shown to prevent tumor invasion and metastasis; the use of tamoxifen reintroduces maspin into breast cancer cells and may cause the carcinoma to be less invasive.Tamoxifen also can be used to induce ovulation in anovulatory women. Tamoxifen stimulates the hypothalamus to release gonadotropin-releasing hormone, thereby prompting the release of hormones from the pituitary. The subsequent effect on the ovaries results in ovulation.

    PHARMACOKINETICS

    Tamoxifen is administered orally as tablets or a solution.
     
    Affected cytochrome P450 isoenzymes and drug transporters:  CYP3A4, CYP2C9, CYP2D6, P-gp
    Tamoxifen is extensively metabolized in the liver by the cytochrome P450 (CYP) system, specifically CYP 3A, 2C9, and 2D6. It also inhibits P-glycoprotein (P-gp). The main metabolite found in plasma is N-desmethyl tamoxifen, which has similar biological activity to tamoxifen and is formed predominantly via CYP3A4/5. Other active metabolites include 4-hydroxytamoxifen, which is predominantly catalyzed by CYP2D6 from tamoxifen, and endoxifen, which is catalyzed predominantly by CYP2D6 from N-desmethyl tamoxifen and to a lesser extent by CYP3A4/5 from 4-hydroxytamoxifen. Endoxifen and 4-hydroxytamoxifen have a 100-fold greater affinity for the estrogen receptor and 30- to 100-fold greater potency in suppressing estrogen-dependent cell proliferation than tamoxifen. Endoxifen concentrations may reach up to 20-fold higher than 4-hydroxytamoxifen. Genetic polymorphisms in CYP2D6 have been shown to result in lower concentrations of endoxifen. Similarly, medications that inhibit CYP2D6 may result in clinically significant reductions in endoxifen formation. Studies have shown poorer clinical outcomes in patients who have genetic polymorphisms that result in a decrease or loss of CYP2D6 function. Tamoxifen and some of its active metabolites are inhibitors of CYP3A4.
     
    Tamoxifen has a biphasic elimination with an initial half-life of 7—14 hours and a terminal elimination half-life of 5—7 days. Steady-state plasma concentrations of N-desmethyl tamoxifen are achieved in 8 weeks, suggesting a half-life for this metabolite of approximately 14 days. Tamoxifen undergoes some enterohepatic circulation. Both the unchanged drug and its metabolites are excreted primarily in the feces, largely as polar conjugates. Unchanged parent compound and unconjugated metabolites account for less than 30% of excretion.

    Oral Route

    Tamoxifen is rapidly absorbed from the GI tract. Bioavailability is comparable between the 10 mg PO twice a day and 20 mg PO once a day dosage regimens and between the tablets and oral solution. Food does not affect the bioavailability of the oral solution. Following a single oral dose of tamoxifen 20 mg, an average peak plasma concentration of 40 ng/ml (range 35—45 ng/ml) occurs in approximately 5 hours. Chronic administration of tamoxifen 10 mg twice daily for 3 months results in average steady-state tamoxifen plasma concentrations of 120 ng/ml (67—183 ng/ml); following 20 mg tamoxifen once daily for 3 months the average steady-state tamoxifen level is 122 ng/ml (range 71—183 ng/ml).
     
    Following chronic administration of tamoxifen 10 mg twice daily or 20 mg once daily for 3 months, the average steady-state levels of N-desmethyl tamoxifen are 336 ng/ml (range 148—654 ng/ml) and 353 ng/ml (range 152—706 ng/ml), respectively. Tamoxifen accumulates after repeated administration and reaches steady-state plasma concentrations in 4 weeks.