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Tamoxifen

Author: Preeti Patel Editor: Tibb F. Jacobs Updated: 3/28/2025 11:55:32 PM

Indications

Tamoxifen is a selective estrogen receptor modulator (SERM) medication used to treat breast cancer in both men and women and as a prophylactic agent against breast cancer in women. The drug was first synthesized in 1962 and initially intended to be a birth control drug, but it failed in that indication. However, it has since become a highly effective anticancer medication.[1] Tamoxifen is specifically indicated for the treatment of breast cancer in various settings, with evidence suggesting that patients with estrogen receptor–positive tumors derive the most benefit.[2]

Tamoxifen has several off-label uses, although additional data may be required to support them. The American Society of Clinical Oncology (ASCO) guidelines recommend tamoxifen for treating hormone receptor-positive metastatic breast cancer in various settings. In premenopausal patients, tamoxifen serves as a first-line option in basic settings and may be combined with ovarian ablation or suppression in more advanced cases. For postmenopausal patients with disease progression, tamoxifen remains a viable treatment option. For patients with hormone receptor–positive metastatic breast cancer who experience progression despite prior therapy, tamoxifen may be offered, particularly in basic and resource-limited settings where ovarian suppression is unavailable. In more advanced cases, tamoxifen is considered a key treatment option for managing hormone receptor-positive disease in constrained healthcare environments.[3]

The ASCO recommends tamoxifen as adjuvant endocrine therapy for men with hormone receptor–positive breast cancer for an initial duration of 5 years. A gonadotropin-releasing hormone agonist or antagonist combined with an aromatase inhibitor may be considered as an alternative for men with contraindications to tamoxifen. Additionally, men who have completed 5 years of tamoxifen therapy, tolerated it well, and remain at high risk of recurrence may be offered an additional 5 years of treatment.[3]

FDA-Approved Indications

Tamoxifen is a medication approved by the US Food and Drug Administration (FDA) for several indications in the treatment and management of breast cancer, including:

  • Treatment of breast cancer in both females and males.[4]
  • Adjuvant treatment of breast cancer following primary treatment with surgery and radiation.[5]
  • Treatment of female patients with ductal carcinoma in situ (DCIS; noninvasive breast cancer) after surgery and radiation to reduce the risk of invasive breast cancer.[6]
  • Breast cancer risk reduction in certain high-risk patients, with a 5-year risk of 1.67%, as calculated by the Gail model.[7]

Off-Label Uses

Treatment with tamoxifen extends beyond its FDA-approved indications to several off-label uses in various medical conditions, including:

  • Progressive or recurrent desmoid tumors in combination with sulindac.[8]
  • Recurrent, metastatic, or high-risk endometrioid histologies.[9][10]
  • Primary or secondary gynecomastia and associated breast pain.[11]
  • Infertility through the induction of ovulation.[12]
  • Oligospermia in combination with testosterone.[13]
  • Coronary arteriosclerosis prophylaxis in men with a triple vessel disease.[14]
  • Advanced or recurrent ovarian cancer.[15][16]
  • Bladder cancer.[17]
  • Lung cancer, in addition to initial chemotherapy.[18][19]
  • Precocious puberty due to McCune-Albright syndrome in females.[20]
  • Metastatic malignant melanoma in combination with agents including carmustine, cisplatin, and dacarbazine.[21][22][23][24]
  • Benign mammary dysplasia.[25]
  • Bone metastasis.[26]
  • Carcinoid tumor.[27]
  • Cutaneous polyarteritis nodosa.[28]
  • Hypertrophy of the uterus.[29]
  • Meningioma.[30]
  • Primary breast pain, premenstrual mastodynia, or breast pain originating from liver cirrhosis.[31][32][33][34]
  • Postmenopausal osteoporosis prophylaxis.[35]
  • Improvement of length and quality of life in patients with retinoblastoma, in addition to treatment protocols.[36]
  • Riedel thyroiditis.[37]
  • Solid tumor secondary malignant neoplasms.[38]

Mechanism of Action

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Mechanism of Action

Tamoxifen exhibits both estrogenic agonist and antagonist effects in different parts of the body. This drug selectively binds to estrogen receptors, producing a combination of estrogenic and anti-estrogenic effects, making its action patient-specific as a SERM. In breast tissue, tamoxifen competes with estrogen for binding sites, exerting antiestrogenic and antitumor effects. Tamoxifen slows cell cycling through downstream intracellular processes, classifying it as cytostatic. In bone, it stimulates estrogen receptors rather than blocking them, exerting an estrogenic agonist effect, which may help prevent osteoporosis in postmenopausal women.[39] Additionally, tamoxifen acts as an estrogen agonist in the hypothalamus of premenopausal women, which increases gonadotropin levels and potentially induces ovulation.[40] 

The therapeutic efficacy of tamoxifen is primarily due to its role as an estrogen receptor antagonist. Resistance to therapy is often linked to the loss of its cellular target, the estrogen receptor, with the absence of estrogen receptor expression being the primary mechanism underlying tamoxifen resistance.[41] In addition, resistance to tamoxifen results from genetic alterations, epigenetic changes, and shifts in the tumor microenvironment. Long noncoding RNAs (lncRNAs), which regulate transcription and protein stability, also have a significant role in tamoxifen resistance. Dysregulated lncRNAs interact with other RNAs and proteins, further reducing the efficacy of tamoxifen.[42]

Pharmacokinetics

Absorption: Peak plasma concentrations of tamoxifen typically reach within about 5 hours after oral administration. The plasma concentration then declines in a biphasic manner.

Distribution: Tamoxifen is widely distributed throughout the body, with N-desmethyl tamoxifen being the primary metabolite found in plasma. The distribution of tamoxifen and its metabolites is influenced by the steady-state plasma concentrations achieved during chronic dosing.

Metabolism: Tamoxifen is primarily metabolized in the liver. The primary metabolites are N-desmethyl tamoxifen and endoxifen.[43] Tamoxifen is metabolized by cytochrome P450 enzymes, including CYP3A, CYP2C9, and CYP2D6. Additionally, tamoxifen inhibits P-glycoprotein.[44]

Elimination: Tamoxifen is primarily excreted in the feces as polar conjugates, with less than 30% of the drug excreted unchanged or as unconjugated metabolites. The half-life of tamoxifen is between 5 and 7 days, while its active metabolite, N-desmethyl-tamoxifen, has a half-life of 14 days.[45]

Administration

Available Dosage Forms and Strengths

Tamoxifen is available in tablet form (10 mg or 20 mg) or as an oral solution (10 mg/5 mL). When administered orally, the supplied dosing cup should be used to ensure accurate dosing.[46]

Adult Dosages

  • The ASCO guidelines for Adjuvant Endocrine Therapy of Hormone Receptor–Positive Breast Cancer recommend a daily dosage of 20 mg for breast cancer prevention after the completion of chemotherapy. The duration of therapy depends on the patient's menopausal status and typically lasts between 5 and 10 years.[47] 
  • For metastatic breast cancer, a daily dosage of 20 to 40 mg is recommended, although doses above 20 mg have not demonstrated additional clinical benefit.[48] In some off-label clinical trials, a dose of 10 mg was used. Tamoxifen can be taken with or without food.
  • For high-risk females, the recommended tamoxifen dosage for breast cancer prophylaxis is 20 mg daily for 5 years.
  • For DCIS, the recommended tamoxifen dosage is 20 mg daily for 5 years, taken orally following breast cancer surgery and radiation therapy, to reduce the risk of invasive breast cancer.[49]
  • Model-informed precision dosing of tamoxifen may optimize endoxifen levels, potentially improving patient outcomes, compared to standard dosing. However, therapeutic drug monitoring is essential for further dosage adjustments and personalized treatment. Additional research is needed to confirm these benefits.[50]

Off-Label Dosages

The off-label dosages of tamoxifen for various conditions are listed below.

  • Mastalgia: 10 mg orally once daily for 4 months.
  • Ovulation induction: 5 to 40 mg orally once daily for 4 days.
  • Precocious puberty (ages 2-10): 20 mg orally daily for female patients with McCune-Albright syndrome.[20][40]

Specific Patient Populations

Hepatic impairment: No dosage adjustments are recommended in the product labeling, as this has not been studied.

Renal impairment: A study found that tamoxifen is safe and effective for patients with gynecological cancer and chronic kidney disease without significant adverse reactions.[51]

Pregnancy considerations: Tamoxifen may cause fetal harm and should not be used during pregnancy. Women should avoid pregnancy while taking tamoxifen and for at least 2 months after discontinuation, using barrier or nonhormonal contraception. Although tamoxifen does not cause infertility, its antiestrogenic effects can impact reproductive function. Reports have indicated vaginal bleeding, spontaneous abortion, congenital disabilities, and fetal death in pregnant women. If a patient takes tamoxifen during pregnancy or becomes pregnant within 2 months of discontinuing it, they should be informed about the potential risks to the fetus, including the possibility of diethylstilbestrol-like syndrome.[52]

Breastfeeding considerations: Tamoxifen and its active metabolites are detectable in breast milk and can accumulate over time during treatment, potentially suppressing lactation. Therefore, breastfeeding should be avoided while undergoing tamoxifen therapy and for 3 months after discontinuing treatment due to the risk of harm to the infant.[46]

Pediatric patients: According to product labeling, the safety and efficacy of tamoxifen for girls aged between 2 and 10 with McCune-Albright syndrome and precocious puberty have not been studied beyond 1 year. However, a study of 8 female patients with McCune-Albright syndrome demonstrated that tamoxifen treatment for 3 to 8 years led to the cessation of vaginal bleeding, stabilization of bone age, and improved final height prediction, supporting its potential role in managing Mas-related growth disturbances.[53]

Older patients: In the National Surgical Adjuvant Breast and Bowel Project Prevention trial (NSABP P-1), both the tamoxifen and placebo groups showed a reduction in breast cancer incidence among women aged 65 and older. Similarly, in the NSABP B-24 trial, although the subset of women aged 65 and older was small, their outcomes were comparable to those of younger participants. No significant differences in tolerability were observed between older and younger patients.[54]

Adverse Effects

Similar to many cancer treatments, tamoxifen is associated with a range of adverse effects, although severe or fatal outcomes are rare. Common adverse effects observed in the treatment include hot flashes, irregular periods, and vaginal discharge. Other frequently reported adverse effects include peripheral edema, hypertension, mood changes, pain, depression, skin changes, skin rashes, nausea, vomiting, weakness, arthritis, arthralgia, lymphedema, and pharyngitis. Less common adverse effects include insomnia, dizziness, headache, weight gain, abdominal pain, diarrhea, indigestion, urinary tract infections, thrombocytopenia, back pain, alopecia, ostealgia, and cataracts. Given the wide range of potential adverse effects, patients should discuss any adverse effects they experience with their healthcare provider.[55]

Tamoxifen may cause a local disease flare, leading to increased bone and tumor pain. This reaction is often associated with a positive tumor response and typically resolves quickly. In patients with bone metastases, hypercalcemia may occur. Tamoxifen should be discontinued if hypercalcemia becomes severe and unmanageable.[56] Tamoxifen can also increase metalloproteinase activity and reduce tendon strength, potentially contributing to tendon rupture. A reported case suggests tamoxifen as a likely cause of Achilles tendon injury, highlighting the need for further investigation.[57] Adjuvant tamoxifen therapy in premenopausal women with breast cancer has been associated with significant bone loss, particularly in the lumbar spine, after 3 years of treatment. Further research is needed to fully assess its long-term effects on bone mineral density.[58]

Drug-Drug Interactions

Anastrozole: Coadministration of anastrozole and tamoxifen citrate in patients with breast cancer results in a reduced plasma concentration of anastrozole compared to its use alone. However, this combination does not affect the pharmacokinetics of tamoxifen or its metabolite, N-desmethyl tamoxifen. Tamoxifen citrate should not be administered concurrently with anastrozole.

Letrozole: Tamoxifen may decrease letrozole's plasma concentration by competing with the aromatase enzyme, potentially reducing its effectiveness.

Rifampin: Rifampin can significantly reduce tamoxifen plasma levels by inducing cytochrome P450 3A4 enzymes.[59]

Medroxyprogesterone: Medroxyprogesterone may reduce the plasma concentration of N-desmethyl tamoxifen; therefore, caution is recommended when administered together.

Anastrozole: Anastrozole's plasma concentration was found to be lowered when coadministered with tamoxifen citrate to breast cancer patients, compared to when the drug was administered alone. However, this combination did not affect the pharmacokinetics of tamoxifen or its metabolite, N-desmethyl tamoxifen. Therefore, tamoxifen citrate should not be used concurrently with anastrozole.

Cytotoxic agents: Combining cytotoxic drugs with tamoxifen increases the risk of thromboembolic events.

CYP2D6 inhibitors: Coadministration of selective serotonin reuptake inhibitors, such as paroxetine (a potent CYP2D6 inhibitor), significantly reduces plasma concentrations of endoxifen (a key active metabolite of tamoxifen). Venlafaxine, a weaker CYP2D6 inhibitor, causes only a mild reduction in endoxifen concentrations.[60]

Drug-Laboratory Interactions

Thyroid function: Elevated thyroxine (or T4) levels have been observed in some postmenopausal patients, likely due to an increase in thyroid-binding globulin. However, these changes do not result in clinical hyperthyroidism.

Contraindications

Tamoxifen should not be used in patients with a known allergy to the drug or any of its components, nor should it be coadministered with warfarin. For patients at high risk for breast cancer or DCIS who are taking tamoxifen for breast cancer risk reduction, it should be avoided if there is a history of deep vein thrombosis or pulmonary embolism. In patients who have been diagnosed with breast cancer, the benefits generally outweigh the risks; however, it should still be used with caution in those with a history of thromboembolic events.

Box Warnings

Tamoxifen carries a boxed warning for uterine malignancies, pulmonary embolism, and stroke in patients at high risk for cancer or those with DCIS.[61] In female patients, tamoxifen is associated with an increased incidence of uterine or endometrial cancers, some of which may be fatal. However, in patients diagnosed with breast cancer, the benefits of tamoxifen generally outweigh the risks.[62] Meta-analyses suggest that the Factor V Leiden mutation is a predictor of thromboembolic events.[63]

Warnings and Precautions

Pharmacogenetics: Patients who are poor CYP2C9 metabolizers should exercise caution.[64] A meta-analysis suggests that impaired cytochrome CYP2D6 metabolism is associated with a higher risk of recurrence or death in patients with breast cancer who are treated with tamoxifen. Pharmacogenetics-guided tamoxifen therapy may potentially improve outcomes, warranting further prospective studies.[65]

Ocular adverse effects: Tamoxifen has been associated with several eye-related issues, including corneal changes, impaired color vision, retinal vein thrombosis, and retinopathy. Patients on tamoxifen may also face an increased risk of cataracts and may require cataract surgery. A study examining tamoxifen retinopathy in breast cancer patients using fundus photography and optical coherence tomography found a higher prevalence than previously estimated with fundus exams alone. Risk factors for developing retinopathy included a high body mass index and hyperlipidemia. Long-term tamoxifen use in female breast cancer patients significantly raises the risk of cataract development and the need for surgery.

Agranulocytosis: Rare reports of tamoxifen-induced hematological toxicity have been documented, with prolonged use potentially causing global bone marrow suppression. Agranulocytosis is likely the result of a type II immune-mediated hypersensitivity reaction.[66]

Monitoring

All patients on tamoxifen should undergo routine laboratory work, including a complete blood count with platelets, serum calcium, and liver function tests. Female patients should be monitored for abnormal vaginal bleeding and receive baseline and routine breast and gynecologic exams. Additionally, patients should be vigilant for signs and symptoms of deep vein thrombosis or pulmonary embolism.

Other monitoring parameters may vary depending on patient-specific factors. In patients with preexisting hyperlipidemia, triglycerides and cholesterol levels should be monitored.[67] Patients taking vitamin K antagonists should have their international normalized ratio (INR) and prothrombin time (PT) regularly monitored.[68] Reproductive-age female patients should undergo a pregnancy test before starting treatment and use reliable birth control methods during treatment.[69] Premenopausal women should have a bone mineral density test to monitor for potential bone loss. Additionally, all patients should undergo an ophthalmic examination if they experience vision problems or develop cataracts.[70] 

A case report describes a patient with major depressive disorder and generalized anxiety disorder who attempted suicide after starting tamoxifen for breast cancer. Discontinuing tamoxifen resolved her symptoms, suggesting its potential psychiatric adverse effects due to estrogen receptor modulation and neurotransmitter dysregulation. This underscores the importance of vigilant monitoring in patients with preexisting psychiatric disorders.[71]

Toxicity

Signs and Symptoms of Overdose

No cases of drug overdose have been reported during the review of the literature. However, according to product labeling and clinical studies, neurotoxicity has been observed in patients with advanced metastatic cancer who received high doses of tamoxifen. Clinical features included tremor, dizziness, hyperreflexia, and unsteady gait, which developed within 3 to 5 days of initiating therapy and resolved within 2 to 5 days after discontinuing tamoxifen.

A patient also experienced a seizure several days after discontinuing the medication, although the causal relationship to tamoxifen remains unclear. No permanent neurological toxicity was observed in any of the patients. Additionally, prolongation of the QT interval was noted in patients receiving doses higher than the standard level. While tamoxifen may contribute to QT prolongation, particularly when combined with other QT-prolonging drugs, the risk remains low with typical 20 mg daily doses. However, caution is still advised when coadministering tamoxifen with medications that impact the QT interval.[72]

Management of Overdose

Currently, no antidote is available for tamoxifen overdose. In the event of drug overdose, supportive care should be provided, and consultation with an oncologist is recommended. Additionally, the poison control center should be contacted for the latest recommendations.

Enhancing Healthcare Team Outcomes

Interprofessional collaboration and effective communication are essential for improving outcomes, particularly for patients undergoing cancer treatments. Oncologists should conduct a thorough evaluation of each patient and choose a treatment regimen tailored to both clinical guidelines and patient-specific factors. For example, tamoxifen may be unsuitable for patients with estrogen receptor–negative breast cancer. In such cases, the expertise of an oncology-specialized pharmacist can be crucial. Additionally, clinicians, including advanced practice providers, should remain vigilant about the potential adverse effects of tamoxifen and monitor patients closely, adjusting treatment plans as necessary to ensure optimal outcomes.

Oncology nurses should be vigilant in identifying the more severe adverse effects of tamoxifen and monitor their patients for these issues, promptly reporting any concerns to the interprofessional clinical team. Pharmacists should support the clinical team by reviewing the patient’s complete medication regimen and ensuring no potential interactions with other medications exist. All members of the interprofessional healthcare team should provide patient counseling and address any questions, as an informed patient is more likely to adhere to treatment and self-report potential issues. While roles may overlap across various healthcare professions, each team member plays a crucial part in optimizing therapeutic outcomes and minimizing adverse events. Effective collaboration and communication among clinicians, oncologists, pharmacists, and nurses are essential for reducing the risk of adverse effects and improving patient outcomes in tamoxifen therapy.

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