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tamoxifen 10 mg tablet

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Uses

Breast Cancer

Adjuvant Therapy

Tamoxifen is used alone as an adjunct to surgery and radiation therapy for the treatment of breast cancer in women with negative axillary lymph nodes and in postmenopausal women with positive axillary lymph nodes. Adjuvant tamoxifen therapy reduces the occurrence of contralateral breast cancer in premenopausal or postmenopausal women with breast cancer.

A systematic overview of randomized clinical studies evaluating the effects of adjuvant tamoxifen for early breast cancer shows increases in 10-year survival and disease-free survival rates in patients receiving tamoxifen 20-40 mg daily for 1-5 years or longer (median 2 years). Among women with estrogen receptor-positive or estrogen receptor-unknown breast cancer and and positive nodes who received about 5 years of tamoxifen therapy, overall survival at 10 years was 61.4% compared with 50.5% for patients who did not receive tamoxifen. Among women with estrogen receptor-positive or estrogen receptor-unknown breast cancer and negative nodes who received about 5 years of tamoxifen therapy, overall survival at 10 years was 78.9% compared with 73.3% for patients who did not receive tamoxifen. Both the absolute risk of relapse and the absolute benefit of treatment with tamoxifen were greater in women with positive nodes than in women with negative nodes. Greater reductions in the annual odds of recurrence or death were observed in patients 50 years of age or older and in patients with estrogen receptor-positive tumors. The reduction in disease recurrence and mortality was greater in those studies that used tamoxifen for about 5 years rather than shorter periods.There was no indication that dosages exceeding 20 mg daily were more effective.

Tamoxifen is used alone as an adjunct to surgery and radiation therapy in the treatment of breast cancer in women with negative axillary lymph nodes. Several controlled studies have demonstrated an improvement in disease-free survival for women with node-negative breast cancer who received adjuvant therapy with tamoxifen or combination chemotherapy compared with no therapy until relapse; the relative efficacy and safety of adjuvant therapy with tamoxifen or combination chemotherapy have not been established to date. In several of these studies, tamoxifen therapy was beneficial regardless of patient age or estrogen- or progesterone-receptor status, but current experience and follow-up are insufficient to elucidate fully the influence of menopausal and steroid-receptor status on outcome of therapy in patients with node-negative breast cancer receiving adjuvant therapy. Adjuvant therapy with tamoxifen has been associated with reductions in tumor recurrence at both local and distant sites, including reductions in new primary tumors in the contralateral breast, with a relatively low incidence of clinically important adverse effects. Current data indicate that adjuvant therapy with tamoxifen or combination chemotherapy generally reduces the rate of recurrence by one-fourth to one-third, although the reduction in absolute risk of recurrence appears to be relatively modest (e.g., 4-15%). The optimal duration of adjuvant therapy with tamoxifen in women with node-negative breast cancer has not been established; however, studies in which the drug was administered for about 5 years appear to demonstrate the greatest reductions in recurrence rates.

Longer therapy (i.e., beyond 5 years) with tamoxifen is not recommended for routine use in women with node-negative breast cancer, since findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol B-14 and other studies indicate a lack of additional benefit associated with tamoxifen beyond 5 years of therapy. The NSABP protocol B-14 was designed to compare benefits of 5- versus 10-year adjuvant therapy with tamoxifen (20 mg daily) therapy in women with negative axillary lymph nodes who had estrogen receptor-positive breast cancer. Findings from this large, randomized, placebo-controlled study (in which patients who received tamoxifen for 5 years and had no recurrence of the disease at that time were randomized to receive the drug for another 5 years) indicate a disease-free survival after 4 years of follow-up in 92% of women who received tamoxifen for 5 years and then placebo versus 86% of women scheduled to receive the drug for 10 years. Because the possibility of a potential detrimental effect associated with tamoxifen therapy beyond 5 years could not be excluded and the unlikelihood that additional benefit would emerge after 10 years of treatment, the NSABP Protocol B-14 was discontinued.

Although current evidence clearly demonstrates a beneficial effect of adjuvant therapy with either tamoxifen or combination chemotherapy in node-negative breast cancer in women, controversy currently exists regarding which patients with node-negative disease should receive such adjuvant therapy following surgery. Some clinicians advocate the use of such adjuvant therapy in most or all women with node-negative breast cancer, while other clinicians suggest that the toxicities, costs, and/or other quality-of-life considerations of such adjuvant therapy outweigh the currently defined benefits in many patients with node-negative breast cancer. Although all patients with node-negative breast cancer are at some risk for recurrence, women with tumors smaller than 1 cm have an excellent prognosis, and the role of adjuvant therapy in providing substantial benefit in such women remains to be more fully elucidated. An expert panel convened by the National Institutes of Health has stated that most women with node-negative breast cancer are cured by total mastectomy and axillary dissection or segmental (partial mastectomy, lumpectomy, breast conservation) mastectomy and axillary dissection followed by radiation therapy and suggests that the use of adjuvant therapy with tamoxifen or combination chemotherapy in such patients be individualized based on consideration of the risk of recurrent disease without such adjuvant therapy, the expected reduction in risk and improvement in the quality of life with such adjuvant therapy, and the potential adverse effects of such therapy. The role of such adjuvant therapy in improving the quality of life in patients with node-negative breast cancer continues to be evaluated.

Tamoxifen also is used alone as an adjunct to surgery and radiation therapy in the treatment of breast cancer in postmenopausal women with positive axillary lymph nodes. Numerous studies have shown that adjuvant therapy with tamoxifen alone increases disease-free survival in postmenopausal women whose tumors contain hormone receptors and who have positive axillary lymph nodes, and most experts now regard adjuvant tamoxifen as standard therapy for these patients. The effect of the drug on overall survival continues to be evaluated. The therapeutic benefit of tamoxifen alone may correlate with increasing quantity of hormone receptors in the tumor and may be greatest in patients with 4 or more positive nodes, but further evaluation is needed. Tamoxifen also has been used in conjunction with combination chemotherapy as adjuvant therapy following surgery in postmenopausal women or women 50 years of age or older with positive nodes. The relative value of adjuvant tamoxifen alone or in conjunction with combination chemotherapy in postmenopausal women with receptor-containing tumors and positive nodes remains to be fully evaluated; several studies indicate that disease-free survival in these patients is greater following adjuvant therapy consisting of tamoxifen plus combination chemotherapy regimens than following adjuvant therapy consisting of combination chemotherapy regimens alone, but some data suggest that the benefit may be limited to the subgroup of patients with 4 or more positive nodes. Although the use of adjuvant tamoxifen in postmenopausal women with positive nodes whose tumors were estrogen-receptor-negative had been regarded as generally ineffective, current evidence indicates that the drug also can be of value in these patients, albeit producing less marked benefit than in patients with estrogen-receptor-positive disease; further, some data suggest that adjuvant therapy consisting of tamoxifen plus combination chemotherapy may be more effective than adjuvant combination chemotherapy alone in these patients.

Metastatic Breast Cancer

Tamoxifen citrate is used in the palliative treatment of advanced (i.e., disseminated) breast cancer in postmenopausal women. Tamoxifen appears to be at least as effective as estrogen or androgen therapy in postmenopausal women and appears to cause a lower incidence of severe adverse effects. Tamoxifen also appears to be as effective as and better tolerated than aminoglutethimide therapy in postmenopausal women but may produce a lower incidence of response in patients with bone metastases. Patients most likely to respond to tamoxifen therapy include those with tumors containing estrogen receptors, those who are several years postmenopausal, those with soft tissue metastases, and those who have responded to previous hormone therapy. Because of its degree of efficacy and good tolerance in geriatric patients, tamoxifen may be preferred in such patients with recurrent disease or in those with advanced primary tumors that are not suitable for surgical treatment.

Tamoxifen also is used in the palliative treatment of advanced (metastatic) breast cancer in premenopausal women as an alternative to ovarian ablative therapy (oophorectomy or radiation). Current evidence suggests that patients with tumors containing estrogen receptors are more likely to respond to tamoxifen therapy than those with estrogen receptor-negative tumors. While objective response rate, time to treatment failure (relapse or progression), and overall survival appear to be similar in premenopausal women receiving tamoxifen or ovarian ablative therapy, current data and experience are inadequate to establish therapeutic equivalence. Some premenopausal women with disease progression during tamoxifen therapy subsequently respond to ovarian ablation. While some evidence suggests that an initial response to tamoxifen may be associated with a greater likelihood of subsequent response to ablative therapy following disease progression, failure to respond initially to tamoxifen does not preclude the possibility of subsequent response to ovarian ablation (i.e., some premenopausal women not responding initially to tamoxifen subsequently have responded to ablation).

The possible role of tamoxifen in combination chemotherapy regimens is still being evaluated.

Reduction in the Incidence of Breast Cancer in Women at High Risk

Tamoxifen is used to reduce the incidence of breast cancer in women at high risk for developing the disease.

Clinical Trials

The current indication for use of tamoxifen in reduction of the incidence of breast cancer is based principally on the results of the Breast Cancer Prevention Trial (BCPT; also known as the NSABP P-1 trial), a double-blind, randomized, placebo-controlled clinical trial conducted in the US, which was stopped early because of the clear evidence of a reduction in the incidence of invasive breast cancer among women at high risk for the disease who received tamoxifen therapy.

Tamoxifen is the first drug therapy that has been shown to decrease the incidence of breast cancer among women at high risk for developing the disease and can now be considered an alternative to the only other established preventative treatment, prophylactic bilateral mastectomy (typically total mastectomy accompanied by breast reconstruction), a somewhat drastic intervention that generally is reserved for women with exceptionally high risk of developing breast cancer. The reduction in the incidence of a second primary cancer in the contralateral breast in women with early breast cancer who received adjuvant therapy with tamoxifen provided the rationale for the study of the drug in the primary prevention of breast cancer. However, tamoxifen therapy did not completely eliminate the risk of developing breast cancer, and the longer term effects of the drug are not known. No effect of tamoxifen on overall or breast cancer-related mortality was observed in this study. Because the study was terminated prematurely, it remains to be established whether such primary prevention simply delays breast cancer development and/or makes subsequent treatment more difficult or whether an actual long-term mortality benefit will be observed.

In the BCPT, 13,388 women aged 35 years and older who were at high risk for developing breast cancer were randomized to receive either tamoxifen 10 mg twice daily or placebo twice daily for 5 years. Data available as of January 31, 1998, for 13,114 women at a median follow-up of 4.2 years showed a 44% reduction in the incidence of invasive breast cancer in women receiving tamoxifen versus placebo (86 versus 156 cases, respectively); data available as of March 31, 1998, for 13,175 women at a median follow-up of 4.6 years showed a 49% reduction in the incidence of invasive breast cancer among women receiving tamoxifen (89 cases) compared with those receiving placebo (175 cases). Reductions in the incidence of breast cancer were observed in all age groups (35-49, 50-59, and 60 years of age and older), in women with or without lobular carcinoma in situ (LCIS; a marker lesion that indicates increased risk of developing invasive breast cancer), and in women at each risk level specified in the study. According to characteristics of the breast tumors that developed in women during the study, use of tamoxifen decreased the incidence of small, estrogen receptor-positive tumors but did not affect the incidence of estrogen receptor-negative or larger (exceeding 2 cm in diameter at the time of diagnosis) tumors. Currently, 9 participants in the study have died of breast cancer (3 in the tamoxifen group, 6 in the placebo group). A nonsignificant decrease in the incidence of ductal carcinoma in situ (DCIS), a noninvasive breast cancer, was observed among women receiving tamoxifen versus placebo (23 versus 35 cases; according to data available as of January 31, 1998).

Tamoxifen therapy is associated with an increased risk of serious adverse effects, including uterine malignancies (see Cautions: Mutagenicity and Carcinogenicity), pulmonary embolism, deep-vein thrombosis, and stroke (see Cautions: Cardiovascular Effects). In the BCPT, the risk of these adverse effects was increased particularly among tamoxifen-treated women who were 50 years of age or older.

Secondary objectives of the BCPT included study of the effects of tamoxifen on the incidence of ischemic heart disease (see Pharmacology: Effects on Lipoproteins) and bone fractures (see Pharmacology: Effects on Bone). No difference in the incidence of ischemic events or osteoporotic fractures was observed among women receiving tamoxifen or placebo.

About 39% of the participants in the BCPT were women aged 35-49 years, 31% were 50-59 years, and 30% were 60 years or older. Despite efforts to enroll members of minority groups in the trial, only about 4% of participants represented minority groups (e.g., African American, Asian American, Hispanic), and the generalizability of the study results, including the size of the treatment effect as well as the risk of adverse effects, to these populations is uncertain.

Additional clinical trials investigating the use of tamoxifen for the prevention of breast cancer are being conducted in other countries, including the UK and Italy. Following completion of a pilot study in the UK involving 2012 women, recruitment of 15,000 women at high risk of breast cancer has begun for a trial of tamoxifen for the prevention of breast cancer (International Breast Cancer Intervention Study [ IBIS]). In 1992, recruitment of women 35 years of age or older who had undergone a hysterectomy was begun for a tamoxifen chemoprevention trial in Milan, Italy; following enrollment and randomization of 5408 women, recruitment was terminated earlier than planned because of the large number of women dropping out of the study and concerns regarding the adverse effects of tamoxifen.

In contrast to the findings of the BCPT, interim analysis of data from these studies did not indicate a reduction in the incidence of breast cancer among women receiving tamoxifen compared with those receiving placebo. The interaction of several factors may have contributed to the differing outcomes of the European studies of tamoxifen for the prevention of breast cancer compared with the results of the BCPT, including smaller sample size, differing study populations (e.g., fewer older women in the UK and Italian studies than in the BCPT), and differences in the degree of risk of developing breast cancer among study populations (e.g., lower risk of developing breast cancer among participants in the Italian study compared with those in the BCPT). Concomitant use of hormone replacement therapy as allowed by study protocol in the European trials is a potential confounding factor, although no evidence of such an effect has been detected. Another possible explanation is that the reduction in the incidence of breast cancer observed with tamoxifen therapy represents a treatment effect on early occult breast cancers rather than prevention of breast cancer and that this effect does not persist with longer duration of follow-up (median follow-up of 70 months in the UK study versus 54.6 months in the BCPT). Consistent with findings from the BCPT, an increased incidence of deep vein thrombosis, pulmonary embolism, stroke, and endometrial cancer has been observed in patients receiving tamoxifen versus placebo in these trials.

Risk Assessment

Benefit of tamoxifen for the primary prevention of breast cancer currently has been demonstrated only for women at high risk of developing breast cancer. Women are advised to consult with a health-care professional to determine their risk of developing breast cancer, and formal risk assessment by an oncology expert should be considered before the initiation of tamoxifen therapy. NCI and NSABP have developed a computer-based tool that will help women consult with health-care providers regarding their personal risk and benefit for tamoxifen therapy. Materials for calculating a woman's risk of developing breast cancer will be provided by the manufacturer of the drug, and examples of profiles that define a woman as being at high risk for developing breast cancer are included in the prescribing information for tamoxifen.

In the BCPT, women aged 60 years and older were eligible for enrollment based on age alone because the risk of breast cancer increases with increasing age. Women aged 35 years or older who had been diagnosed with LCIS were eligible for the study based on that diagnosis alone. Other women aged 35-59 years were eligible to participate in the study if they had a 5-year predicted risk of breast cancer scored as 1.67% or greater according to calculations with a statistical model known as the Gail model, which considers a combination of risk factors including number of first-degree relatives (i.e., mother, sister, daughter) diagnosed with breast cancer, number of breast biopsies, presence or absence of atypical hyperplasia on breast biopsy, age at menarche (i.e., first menstrual period), and either nulliparity or age at first live birth.

The following profiles are examples predicting a 5-year risk of 1.67% or greater according to the Gail model; although these examples are arranged in ascending order by age, they do not necessarily represent ascending order of risk:Age 35 years or older, one first-degree relative with a history of breast cancer, a personal history of 2 or more benign breast biopsies, and a personal history of a breast biopsy showing atypical hyperplasiaAge 35 years or older, one first-degree relative with a history of breast cancer, a personal history of 2 or more benign breast biopsies, age at first live birth 25 years or older, and age at menarche (first menstrual period) 11 years or youngerAge 35 years or older, at least 2 first-degree relatives with a history of breast cancer, and a personal history of at least one breast biopsyAge 35 years or older and LCISAge 40 years or older, at least 2 first-degree relatives with a history of breast cancer, and age at first live birth either 19 years or younger or 29 years or olderAge 40 years or older, 2 first-degree relatives with a history of breast cancer, and nulliparous (no children)Age 40 years or older, one first-degree relative with a history of breast cancer, and a personal history of a breast biopsy showing atypical hyperplasiaAge 45 years or older and at least 2 first-degree relatives with a history of breast cancerAge 45 years or older, at least 2 first-degree relatives with a history of breast cancer, and age at first live birth 24 years or youngerAge 45 years or older, one first-degree relative with a history of breast cancer, and age at menarche 11 years or youngerAge 45 years or older, one first-degree relative with a history of breast cancer, and a personal history of at least one breast biopsyAge 45 years or older, one first-degree relative with a history of breast cancer, a personal history of a benign breast biopsy, age at menarche 11 years or younger, and age at first live birth 20 years or olderAge 50 years or older, one first-degree relative with a history of breast cancer, and age at first live birth 20 years or olderAge 50 years or older, history of breast biopsy showing atypical hyperplasia, and age at first live birth 20 years or olderAge 50 years or older, history of one breast biopsy showing atypical hyperplasia, age at first live birth 30 years or older, and age at menarche 11 years or youngerAge 50 years or older, history of breast biopsy showing atypical hyperplasia, and nulliparous (no children)Age 50 years or older, history of breast biopsy showing atypical hyperplasia, and age at menarche 11 years or youngerAge 50 years or older, history of at least 2 breast biopsies with a history of atypical hyperplasia, and age at first live birth 30 years or olderAge 55 years or older and one first-degree relative with a history of breast cancerAge 55 years or older, one first-degree relative with a history of breast cancer, a personal history of a benign breast biopsy, and age at menarche 11 years or youngerAge 55 years or older, age at menarche 11 years or younger, and age at first live birth 30 years or olderAge 55 years and history of breast biopsy showing atypical hyperplasiaAge 55 years or older, history of at least 2 breast biopsies with a history of atypical hyperplasia, and age at first live birth 20 years or olderAge 60 years or older (equivalent to 5-year predicted breast cancer risk of 1.67% according to the Gail model)

Although each of the above profiles represents a 5-year predicted breast cancer risk of at least 1.67%, the absolute risk for these profiles varies (including both low and high risk scores) and must be calculated using the Gail model. Because the degree of risk differs according to the specific values applied to each variable in the Gail model and the combination of these individual risk factors, calculation of the 5-year predicted absolute risk for breast cancer provides the best estimate of risk to be used in judging possible benefit of tamoxifen therapy. In the BCPT, 25% of the women had a 5-year predicted breast cancer risk of 2% or less, 57.6% had a risk of 2.01-5%, and 17.4% had a risk of 5% or greater. Health-care professionals can request a Gail Model Risk Assessment Tool by phone at 800-456-3669 (ext 3838).

For women aged 60 years or older, no additional risk factors were required for participation in the BCPT. However, a woman aged 50 years or older must consider other factors before choosing to take tamoxifen (e.g., whether she has had a hysterectomy). For women in the BCPT, particularly those aged 50 years or older, tamoxifen increased the risk of uterine malignancies (see Uterine Cancer in Cautions: Mutagenicity and Carcinogenicity), pulmonary embolism, deep vein thrombosis, and stroke (see Cautions: Cardiovascular Effects). Following assessment of the risk of developing breast cancer, the decision regarding use of tamoxifen for reduction in the incidence of breast cancer should be based on an individual assessment of the benefits versus risks of tamoxifen therapy.(See Benefit Versus Risk in Uses: Reduction in the Incidence of Breast Cancer in Women at High Risk.)

Although other criteria may identify women at high risk for the development of breast cancer, the benefit of tamoxifen therapy in these groups is unknown. Women with BRCA1 or BRCA2 genetic mutations are known to be at high risk for developing breast cancer, but the effect of tamoxifen on breast cancer incidence in women with inherited mutations has not been established. Some evidence suggests that plasma IGF-1 concentrations may be useful in identifying premenopausal women who are at high risk of breast cancer, but additional studies are needed to confirm this correlation and establish the benefit of tamoxifen therapy in such women.

Benefit Versus Risk

The benefit of tamoxifen as preventive therapy must be weighed against the risks associated with its use, and such treatment may not be appropriate in some women despite a high risk of breast cancer. The decision to initiate tamoxifen therapy for the prevention of breast cancer is complex and must be individualized.

Although women aged 50 years and older receiving tamoxifen may benefit from a reduced incidence of breast cancer, women in this age group also are at greater risk of serious, and sometimes fatal, adverse effects associated with tamoxifen therapy, such as pulmonary embolism and stroke. Some experts suggest that for women in their 60s who have not had a hysterectomy and whose only risk factor for breast cancer is age, the risks associated with tamoxifen therapy may outweigh its benefits.

Women with risk factors for thrombosis, including hypertension, diabetes, smoking, and/or obesity, must consider that tamoxifen increases the risk of serious thrombosis.

Women with BRCA1 or BRCA2 genetic mutations, which place them at high risk for developing breast cancer, have been proposed as candidates for tamoxifen preventive therapy, but the effect of tamoxifen on breast cancer incidence in women with inherited mutations has not been established. One small study showed that breast tumors arising in women with the BRCA1 mutation were less likely to be estrogen receptor-positive and thus may be less likely to respond to tamoxifen preventive therapy. In an independent study, retrospective analysis of anonymous blood samples taken from participants in the BCPT will be used to determine the percentage of the study population with genetic risk factors for breast cancer (i.e., BRCA1 or BRCA2 gene alterations) and to examine whether tamoxifen therapy decreased the risk of developing breast cancer in this subset; however, interpretation of the group data to determine the benefit of tamoxifen therapy in women with BRCA1 or BRCA2 mutations will be limited because this question was not included in the initial design of the study. Further evidence is needed to establish the effect of tamoxifen therapy on the prevention of breast cancer in this population.

Because of the small number (about 4%) of minority participants (e.g., African American, Asian American, Hispanic) in the BCPT, the generalizability of the study results, including the size of the treatment effect as well as the risk of adverse effects, to these populations is uncertain.

Although some experts believe that the benefits of preventive therapy with tamoxifen outweigh the risks, others have voiced concern about the numbers of healthy women that will be treated with the drug and subjected to possibly life-threatening adverse effects before the long-term preventive benefit and adverse effects of tamoxifen are known. Reduction in the incidence of breast cancer is now a labeled use of tamoxifen in the US, but some experts had urged that the use of tamoxifen as a primary preventive therapy outside of clinical trials be discouraged until further data are available.

Clarification of the risks and benefits of tamoxifen, including differential effects according to age and menopausal status, awaits further analysis of data from the BCPT and other ongoing trials. Because the BCPT was stopped early and study participants who were receiving placebo are now being offered the opportunity to begin taking tamoxifen or participate in another clinical trial, information on the long-term benefits and adverse effects of tamoxifen obtained from further follow-up of this study will be limited, and the mature results of ongoing trials, such as the IBIS and the European studies, will be important in establishing the risks and benefits of preventive therapy with tamoxifen.

Although tamoxifen therapy may reduce the incidence of breast cancer in women at high risk, it does not replace the need for clinical surveillance, and regular breast examination and screening with mammography are advised in such patients.

Duration of Therapy

The duration of therapy with tamoxifen for the prevention of breast cancer has not been established. Among women receiving tamoxifen for the treatment of node-negative, estrogen receptor-positive breast cancer, no additional benefit but an increased incidence of adverse effects was observed with more prolonged therapy (10 years versus 5 years). Although it remains unclear whether tamoxifen therapy beyond 5 years is safe, a 5-year duration of tamoxifen therapy currently is being recommended for the prevention of breast cancer in women at high risk of the disease principally because of negative findings and a lack of additional benefit associated with more prolonged therapy with the drug as an adjuvant in the treatment of breast cancer.(See Breast Cancer: Adjuvant Therapy, in Uses.)

Continuing Research

The NSABP has proposed another clinical trial known as STAR (Study of Tamoxifen and Raloxifene), scheduled to begin recruiting participants in 1999, in which tamoxifen will be compared with raloxifene (another estrogen agonist-antagonist, which is labeled for the prevention of osteoporosis in postmenopausal women but that also has shown chemopreventive activity in breast cancer) for the primary prevention of breast cancer in postmenopausal women at increased risk for developing breast cancer who are at least 35 years of age. Other agents being investigated for the chemoprevention of breast cancer include other antiestrogens or estrogen agonist-antagonists (e.g., toremifene, droloxifene), retinoids (e.g, fenretinide), and micronutrients (e.g., vitamin E, selenium). Although studies have shown some evidence of an association between breast cancer and lifestyle factors such as dietary fat intake, alcohol consumption, and exercise, further studies are needed to confirm whether changing such behaviors reduces a woman's risk of developing the disease.

Because of the substantial risk of developing breast cancer (1 in 8 women in the US will develop breast cancer during her lifetime) and the burden of mortality caused by this disease (about 43,500 women will die from breast cancer in the US in 1998), continuing research of prevention, particularly chemoprevention, is warranted.

Male Breast Cancer

Tamoxifen is used in the palliative treatment of advanced (metastatic) breast cancer in men. Breast cancer is a relatively rare disease in men and accounts only for about 0.5-1% of all breast cancers in the US. Cancer of the male breast appears to be biologically similar to the disease in women; however, centrally located lesions predominate in men, and tumors in males usually contain a higher frequency of hormone receptors than in females. Since the therapeutic benefit of tamoxifen may correlate with increasing quantity of hormone receptors in the tumor, the high frequency of hormone receptors in men may explain the high response rate of male breast carcinoma to endocrine therapy. Treatment to date has been similar to that for women with breast cancer; however, experience in men is very limited.

Combined results of several studies and published case reports showed an objective response (complete and partial) rate of about 50% in males with advanced (metastatic) breast cancer treated with tamoxifen. In addition to that in the breast, tumor regression is apparent in affected bone, soft tissue, liver, and lungs. Some experts consider tamoxifen the first-line hormonal therapy in males with with estrogen receptor-containing tumors and positive nodes. Since limited evidence suggests that objective response rates may be similar in males receiving tamoxifen or testicular ablative therapy and acceptance of drug therapy is better than of hormonal ablative therapy, tamoxifen is rapidly replacing orchiectomy in the palliative treatment of advanced breast cancer when estrogen receptors are present. Male breast cancer that progresses during tamoxifen therapy subsequently may respond to testicular ablation. Tamoxifen alone or in conjunction with combination chemotherapy also is used as an adjunct to surgery in the treatment of breast cancer in men with positive axillary lymph nodes. Limited data indicate that disease-free 5-year survival is greater in males receiving adjuvant tamoxifen therapy compared with those not receiving the drug. Although randomized, controlled trials would be needed to evaluate systematically the role of tamoxifen in systemic adjuvant therapy in men with breast cancer, it is unlikely that such studies can be performed because of the rarity of this condition.

Other Uses

Tamoxifen has been used to stimulate ovulation in appropriately selected anovulatory women desiring pregnancy, especially in those with oligomenorrhea or amenorrhea who were previously receiving oral contraceptives. Limited data suggest that tamoxifen therapy may be useful for the management of some types of mastalgia (e.g., cyclical), but additional studies are needed to evaluate the efficacy, safety, and dosage of the drug for this condition. Limited data also suggest that an occasional patient with malignant carcinoid tumor and carcinoid syndrome may have a beneficial response to tamoxifen.

Dosage and Administration

Administration

Tamoxifen citrate is administered orally.

Dosage

Dosage of tamoxifen citrate is expressed in terms of tamoxifen.

Breast Cancer

Adjuvant Therapy

When tamoxifen is used alone as an adjunct to surgery and radiation therapy in the treatment of breast cancer, the usual dosage of the drug is 20-40 mg daily. Dosages exceeding 20 mg daily should be given in divided doses (morning and evening). There is no evidence that higher dosages are necessary. The optimum duration of adjuvant tamoxifen therapy has not been established, but therapy for about 5 years is more effective than shorter courses of therapy. Longer therapy (i.e., beyond 5 years) with tamoxifen is not recommended for routine use in women with node-negative breast cancer, since findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol B-14 and other studies indicate a lack of additional benefit associated with tamoxifen beyond 5 years of therapy.

When tamoxifen is used in combination with chemotherapy as an adjunct to surgery in the treatment of breast cancer in postmenopausal women or in women 50 years of age or older who have positive axillary lymph nodes, the usual dosage of the drug is 10 mg twice daily. The optimum duration of adjuvant tamoxifen therapy has not been established.

Metastatic Breast Cancer

For the treatment of metastatic breast cancer in women, the usual dosage of tamoxifen is 20-40 mg daily. Dosages exceeding 20 mg daily should be given in divided doses (morning and evening). Because there does not appear to be any significant difference in response rates with the two dosages, most clinicians believe that 20 mg daily usually should be used initially. If an objective response to the drug occurs, it usually is evident within 4-10 weeks; however, several months of therapy may be required before an objective response occurs in patients with bone metastases.

Reduction in the Incidence of Breast Cancer in Women at High Risk

For reduction in the incidence of breast cancer in women at high risk, the recommended dosage of tamoxifen is 20 mg daily. Because of negative findings and a lack of additional benefit associated with more prolonged therapy with the drug as an adjuvant in the treatment of breast cancer, a 5-year duration of tamoxifen therapy currently is being recommended for the prevention of breast cancer in women at high risk of the disease.

Male Breast Cancer

For the treatment of advanced (metastatic) breast cancer in men, the usual dosage of tamoxifen is 20-40 mg daily. Dosages exceeding 20 mg daily should be given in divided doses (morning and evening). When tamoxifen alone or in combination with radiation therapy was used as an adjunct to surgery in the treatment of breast cancer in men, a tamoxifen dosage of 20 mg daily was used, usually for 1-2 years. The optimum duration of adjuvant tamoxifen therapy has not been established; however, since adjuvant therapy of about 5 years appears to be more effective than shorter courses of therapy in women with breast cancer, some clinicians suggest the same prolonged tamoxifen course for male patients.

Other Uses

To stimulate ovulation, 5-40 mg of tamoxifen has been administered twice daily for 4 days.

Cautions

The manufacturer states that the adverse effect profile of tamoxifen in breast cancer patients generally appears to be similar for men and women. Adverse effects of tamoxifen citrate usually are relatively mild and rarely severe enough to necessitate discontinuance of the drug in patients with breast cancer. Tamoxifen usually is well tolerated in male patients with breast cancer. In the Breast Cancer Prevention Trial (BCPT), 15% of women receiving tamoxifen withdrew from the trial for medical reasons (e.g., hot flushes, vaginal discharge) compared with 9.7% of women receiving placebo.

Tamoxifen therapy is associated with increased risk of serious adverse effects, including uterine cancer, pulmonary embolism, deep-vein thrombosis, and stroke in women receiving the drug for reduction in the incidence of breast cancer (i.e., women at high risk for breast cancer or women with ductal carcinoma in situ). In the BCPT, the risk of these adverse effects was increased particularly among tamoxifen-treated women who were 50 years of age or older.

Cardiovascular Effects

Adverse cardiovascular effects of tamoxifen include thrombotic and venous thromboembolic events such as stroke, pulmonary embolism, and deep-vein thrombosis.

Thromboembolic Events

In the BCPT, women without a history of pulmonary emboli receiving tamoxifen had an approximately threefold increase in the risk of developing a pulmonary embolism (18 versus 6 cases; incidence rate of 0.75 versus 0.25 per 1000 women-years) compared with those receiving placebo. Three women in the study, all of whom were receiving tamoxifen, died of pulmonary embolism. Of the cases of pulmonary embolism, 87% occurred in women at least 50 years of age at the time of randomization; among women receiving tamoxifen in the BCPT, episodes of pulmonary embolism occurred on average at 27 months (range: 2-60 months) following initiation of therapy with the drug.

Although the difference was not significant, the risk of deep-vein thrombosis was increased (relative risk of 1.6) among women receiving tamoxifen versus placebo in the BCPT (35 versus 22 cases according to data available as of March 31, 1998). A similar increase in relative risk of deep-vein thrombosis was observed in women aged 49 years and younger as in women aged 50 years or older, although fewer events occurred in younger women. Women who had thromboembolic events were at risk for a second related event (7 of 25 women receiving placebo and 5 of 48 women receiving tamoxifen according to data available as of January 31, 1998). Among women receiving tamoxifen in the BCPT, episodes of deep-vein thrombosis occurred on average at 19 months (range: 2-57 months) following initiation of therapy with the drug. Thrombotic events, including deep-vein thrombosis, pulmonary embolism, and superficial phlebitis, also have been reported in 1.7% of women receiving tamoxifen as adjuvant therapy for the treatment of breast cancer; at least 2 deaths have occurred in patients with breast cancer who had thrombotic events during tamoxifen therapy. Clotting factor abnormalities have been observed with prolonged tamoxifen therapy at usual dosages, and antithrombin III, fibrinogen, and platelet counts have been decreased minimally; the relationship, if any, of such changes to thromboembolic phenomena is unclear.

Although the difference was not significant, an increase in the incidence of stroke was observed in women receiving tamoxifen (38 events) versus placebo (24 events) in the BCPT (relative risk of 1.59 and 95% confidence interval of 0.93-2.77 according to data available as of March 31, 1998). Hemorrhagic strokes accounted for 10 of 38 (26%) or 6 of 24 (25%) strokes in women receiving tamoxifen or placebo, respectively. Occlusive strokes accounted for 21 of 38 (55%) or 14 of 24 (58%) strokes in women receiving tamoxifen or placebo, respectively. Among women receiving tamoxifen or placebo, 7 of 38 (18%) or 4 of 24 (17%) strokes, respectively, were of unknown etiology. Fatal stroke occurred in 4 women receiving tamoxifen and in 3 women receiving placebo. Among women experiencing stroke, 88% occurred in women aged 50 years or older at the time of randomization. Among women receiving tamoxifen in the BCPT, episodes of stroke occurred on average at 30 months (range: 1-63 months) following initiation of therapy with the drug.

Vasomotor Symptoms

In clinical studies, vasomotor symptoms (i.e., hot flushes [flashes]) occur more frequently in patients receiving tamoxifen than in those receiving placebo. Hot flushes are one of the most common adverse effects reported in women receiving tamoxifen for the treatment or prevention of breast cancer. In the BCPT, hot flushes occurred in 81% of women receiving tamoxifen compared with 69% of those receiving placebo. In addition, more women who were receiving tamoxifen versus placebo reported hot flushes that were quite a bit or extremely bothersome (46 versus 29%). Withdrawal from the trial because of hot flushes occurred more frequently among women receiving tamoxifen versus placebo (3.1 versus 1.5%). In some patients, clonidine may ameliorate tamoxifen-induced hot flushes.

Effects on Lipoproteins

Hyperlipidemias have been reported in patients receiving tamoxifen. Hypertriglyceridemia has been reported in patients with breast cancer receiving tamoxifen and may be severe, particularly in patients with a known history of elevated triglyceride levels, such as those associated with familial hypertriglyceridemia. Although tamoxifen-induced hypertriglyceridemia may respond to withdrawal of the drug or treatment with lipid-lowering agents, such as fibrates, at least one patient developed fulminant pancreatitis and subsequently died. Periodic monitoring of plasma triglyceride concentrations is advised in patients with preexisting hyperlipidemias during the entire duration of tamoxifen therapy since onset of hypertriglyceridemia may be delayed.

Potentially beneficial estrogenic effects, including decreased total and low-density lipoprotein concentrations and decreased cardiovascular morbidity and mortality (particularly in postmenopausal women), also have been observed in women receiving prolonged tamoxifen therapy.(See Pharmacology: Effects on Lipoproteins.)

Other Cardiovascular Effects

Fluid retention has been reported in women receiving tamoxifen as adjuvant therapy for breast cancer. Edema has also been reported in women with metastatic breast cancer receiving tamoxifen.

Genitourinary and Renal Effects

Vaginal discharge and menstrual irregularities occur more frequently in patients receiving tamoxifen than in those receiving placebo. Vaginal discharge, occurring in 55%, was one of the most common adverse effects reported among women receiving tamoxifen for the primary prevention of breast cancer in the BCPT. In addition, more women who were receiving tamoxifen versus placebo reported vaginal discharge that was moderately, quite a bit, or extremely bothersome (29 versus 13%). Withdrawal from the trial because of vaginal discharge occurred more frequently among women receiving tamoxifen versus placebo (0.5 versus 0.1%). Vaginal bleeding may occur with tamoxifen therapy. Vaginal dryness and pruritus vulvae have been reported infrequently in women receiving tamoxifen for metastatic breast cancer.

An increased incidence of endometrial changes, including hyperplasia and polyps, has been associated with tamoxifen therapy. The underlying mechanism of these changes appears to be related to the estrogenic properties of tamoxifen. Endometriosis and uterine fibroids, possibly resulting from tamoxifen's partial estrogenic activity, have been reported rarely in women receiving tamoxifen. In addition, ovarian cysts have been observed in a small number of premenopausal patients with advanced breast cancer who have been treated with tamoxifen. An increased incidence of uterine fibroids (in premenopausal and postmenopausal women) and benign ovarian cysts (in premenopausal women) also was noted in women receiving tamoxifen in a study for the prevention of breast cancer.

Loss of libido and impotence have been reported in some male patients and resulted in discontinuance of tamoxifen therapy. In oligospermic men who were receiving tamoxifen therapy, increased lutropin (luteinizing hormone, LH), follitropin (follicle-stimulating hormone, FSH), testosterone, and estrogen concentrations were reported. Priapism has been reported in at least one patient receiving tamoxifen.

Increased serum BUN and/or creatinine also has been reported in patients receiving tamoxifen as adjuvant therapy for breast cancer.

Musculoskeletal Effects

Musculoskeletal pain and bone pain have been reported in patients with breast cancer receiving tamoxifen. Increased bone and tumor pain or flare have occurred with tamoxifen therapy for metastatic breast cancer and are sometimes associated with a good tumor response. Patients with increased bone pain may require additional analgesics. Patients with soft tissue disease may demonstrate sudden increases in the size of preexisting lesions, sometimes associated with marked erythema within and surrounding the lesions, and/or development of new lesions. If bone pain and disease flare occur, they are usually apparent shortly after initiation of tamoxifen therapy and generally subside rapidly. Management of tamoxifen-related flare includes supportive care and possibly interruption of treatment with the drug, with subsequent reinstitution of therapy at a reduced dosage (i.e., 5-10 mg daily) and gradual increases to the usual dosage; in some cases, prednisone may be added concomitantly for 1-2 weeks.

Hypercalcemia, in some cases life-threatening, may occur during initial tamoxifen therapy in patients with metastatic breast cancer who have bone metastases. Periodic determination of serum calcium concentrations should be performed during initial therapy in these patients (e.g., once or twice weekly during the first 2-3 weeks of therapy) and appropriate treatment initiated if hypercalcemia occurs. If hypercalcemia is severe, the drug should be discontinued. Following appropriate management of hypercalcemia, tamoxifen therapy may be reinstituted with caution and careful monitoring, at a reduced dosage or concomitantly with a low dosage of prednisone.

A potentially beneficial estrogenic effect of prolonged tamoxifen therapy is preservation of bone mineral density of the lumbar spine in postmenopausal women.(See Pharmacology: Effects on Bone.)

Ocular Effects

Tamoxifen rarely has been associated with ocular toxicity. Retinopathy, corneal opacities, and decreased visual acuity have occurred in patients receiving extremely high dosages (e.g., 180-320 mg daily) of tamoxifen for longer than 1 year. Ocular effects such as visual disturbances, decrement in color vision perception, corneal changes, cataracts, need for cataract surgery, optic neuritis, retinal vein thrombosis, intraretinal crystals, posterior subcapsular opacities, and/or retinopathy have also been reported in patients receiving recommended dosages of the drug. A slightly increased rate of developing cataracts and a greater risk of developing cataracts and undergoing cataract surgery were observed in women receiving tamoxifen in the BCPT.

Hepatic Effects

Changes in hepatic enzyme concentrations (e.g., increased serum AST [SGOT] or ALT [SGPT] concentrations) and increased bilirubin and/or alkaline phosphatase concentrations have been reported in patients receiving tamoxifen therapy. Rarely, more severe hepatic abnormalities, including fatty changes in the liver, cholestasis, hepatitis, hepatic necrosis, and death, have occurred. A causal relationship of these adverse hepatic effects to tamoxifen has not been established; however, following rechallenge with tamoxifen, adverse hepatic effects occurred in some patients.

GI Effects

Adverse GI effects of tamoxifen, including nausea, anorexia, distaste for food, and abdominal cramps, have been reported in patients with breast cancer.

Nervous System Effects

Adverse nervous system effects reported in patients receiving tamoxifen for metastatic breast cancer include dizziness, lightheadedness, headache, fatigue, and mental depression.

Hematologic Effects

Thrombocytopenia (platelet counts of 50,000-100,000/mm and, infrequently, lower) occasionally has occurred in patients receiving tamoxifen for the treatment of breast cancer; however, platelet counts returned to normal even though tamoxifen therapy was continued. Hemorrhagic episodes have occurred rarely in patients with severe thrombocytopenia. Neutropenia, pancytopenia, and leukopenia (white blood cell count less than 3000/mm), sometimes associated with anemia and/or thrombocytopenia, also have been reported and may be severe. A causal relationship of the drug to some of these hematologic reactions has not been established.

Purpuric vasculitis, which was unresponsive to prednisone 25 mg daily but resolved completely following drug withdrawal, has been reported in at least one patient receiving tamoxifen.

Dermatologic Effects

Thinning and/or partial loss of hair occurs infrequently in patients receiving tamoxifen for metastatic breast cancer. Erythema multiforme, Stevens-Johnson syndrome, and bullous pemphigoid have been reported rarely in patients receiving tamoxifen. Skin changes have occurred in patients receiving tamoxifen as adjuvant therapy for breast cancer.

Other Adverse Effects

Other adverse effects reported in patients receiving tamoxifen as adjuvant therapy for breast cancer or for metastatic breast cancer include weight loss, fatigue, and cough.

Precautions and Contraindications

Serious, life-threatening or fatal events associated with tamoxifen used for reduction in the incidence of breast cancer (i.e., women at high risk for breast cancer and women with ductal carcinoma in situ) include endometrial cancer, uterine sarcoma, stroke, and pulmonary embolism. Healthcare providers should discuss the potential benefits versus risks of tamoxifen therapy with women considering use of the drug to potentially reduce their risk of developing breast cancer.

Because of the increased risk of thromboembolic events associated with tamoxifen therapy in the BCPT, tamoxifen for reduction in the incidence of breast cancer is contraindicated in women with a history of deep-vein thrombosis or pulmonary embolism. Use of tamoxifen to reduce the incidence of breast cancer also is contraindicated in women who require anticoagulant therapy with a coumarin derivative. Women receiving or who have received tamoxifen should promptly seek medical attention for symptoms of unexplained shortness of breath or leg swelling/tenderness.

Use of tamoxifen is associated with an increased incidence of uterine malignancies.(See Cautions: Mutagenicity and Carcinogenicity.) Women receiving tamoxifen or women with a history of having received tamoxifen who report abnormal vaginal bleeding should be evaluated promptly. Women receiving or who have received tamoxifen should receive routine gynecologic care and should be advised to report promptly any abnormal gynecologic symptoms, such as menstrual irregularities, abnormal vaginal bleeding, change in vaginal discharge, or pelvic pain/pressure, to their physician.

Women receiving or who have received tamoxifen also should seek prompt medical attention for new breast lumps. Women should inform all care providers, regardless of the reason for evaluation, that they are receiving tamoxifen therapy.

Women receiving tamoxifen to reduce the incidence of breast cancer should receive clinical evaluation including a breast examination, a mammogram, and a gynecologic examination prior to the initiation of therapy with the drug. Such clinical evaluation should be repeated at regular intervals during tamoxifen therapy. The same type of clinical evaluation should be followed for women receiving tamoxifen as adjuvant therapy for breast cancer. Women receiving tamoxifen for the treatment of metastatic breast cancer should review this clinical monitoring plan with their care provider and select the appropriate modalities and schedule of evaluation.

The manufacturer states that tamoxifen should be used with caution in patients with leukopenia and thrombocytopenia, and periodic complete blood counts, including platelet counts, should be performed in patients receiving the drug. The manufacturer also states that periodic liver function tests should be obtained.

Because of infrequent reports of lipoprotein abnormalities in patients receiving tamoxifen, including cases of hypertriglyceridemia, marked hyperlipoproteinemia, periodic monitoring of serum triglycerides and cholesterol is recommended during tamoxifen therapy in patients with a preexisting hyperlipoproteinemia. However, potentially beneficial estrogenic effects on lipoproteins (e.g., decreased total and low-density lipoproteins concentrations) also may occur.

Patients complaining of visual changes or abnormalities during tamoxifen therapy should be assessed carefully for possible ocular toxicity. Women receiving or who have received tamoxifen should seek prompt medical attention for changes in vision.

Women who are at high risk of developing breast cancer may consider tamoxifen therapy to reduce the incidence of breast cancer. Women who are considering use of tamoxifen for reduction in the incidence of breast cancer should consult a health-care professional to assess their risk of breast cancer and weigh the potential benefits and risks of therapy. Women should be informed and understand that while tamoxifen therapy may reduce the incidence of breast cancer, it may not eliminate risk of the disease. In the BCPT, tamoxifen decreased the incidence of small, estrogen receptor-positive tumors, but did not alter the incidence of larger (exceeding 2 cm in diameter) or estrogen receptor-negative breast tumors. In other clinical trials that were smaller than the BCPT and enrolled women at a lower risk for breast cancer, no difference in the number of cases of breast cancer was observed in women receiving tamoxifen or placebo. In women with breast cancer who are at high risk of developing a second breast cancer, treatment with about 5 years of tamoxifen reduced the annual incidence rate of a second breast cancer by approximately 50%.

Women who are pregnant or who plan to become pregnant should not use tamoxifen to reduce the risk of breast cancer.(See Cautions: Pregnancy, Fertility, and Lactation.)

Tamoxifen is contraindicated in patients with known hypersensitivity to the drug.

Pediatric Precautions

The manufacturer states that safety and efficacy of tamoxifen in pediatric patients have not been established.

Geriatric Precautions

In the BCPT, 16% of the study participants were 65 years of age or older and 6% were at least 70 years of age. Reductions in the incidence of breast cancer were observed in women receiving tamoxifen across all age groups. Across all other outcomes, the results in the subset of women 65 years of age or older reflect the results observed in the subset of women at least 50 years of age. In this trial, the risk of serious adverse effects (e.g., endometrial cancer, pulmonary embolism, deep-vein thrombosis, stroke) was greatest in women 50 years of age and older.

Mutagenicity and Carcinogenicity

Mutagenicity

No evidence of tamoxifen-induced mutagenicity was observed in various in vivo and in vitro tests with prokaryotic and eukaryotic test systems in the presence of drug metabolizing systems. However, increased levels of DNA adducts have been found in the livers of rats exposed to tamoxifen. Tamoxifen also has been found to increase levels of micronucleus formation in vitro in human lymphoblastoid cell lines (MCL-5). Thus, tamoxifen is potentially genotoxic in animals and in humans.

Carcinogenicity

Tamoxifen is carcinogenic in animals and humans.

Uterine Cancer

In athymic mice, tamoxifen has stimulated the growth of certain endometrial tumors. An increased incidence of uterine sarcoma, endometrial cancer, and endometrial changes including hyperplasia and polyps, has been reported in women receiving tamoxifen. The incidence and pattern of this increase is related to the estrogenic activity of tamoxifen. Some evidence suggests that prior exposure to hormone replacement therapy may contribute to the development of endometrial cancer and may be a confounding factor in determining the effect of tamoxifen therapy on the uterus.

An increased incidence of uterine cancer, sometimes fatal, has been reported in women receiving tamoxifen. Most uterine malignancies associated with tamoxifen therapy are classified as adenocarcinoma of the endometrium; however, rare uterine sarcomas, including malignant mixed mullerian tumors, also have been reported.

Uterine sarcoma has been reported more frequently among women receiving long-term therapy (i.e., exceeding 2 years) with tamoxifen than among women not receiving the drug. Among women enrolled in the BCPT, uterine sarcomas were reported in 4 women receiving tamoxifen versus none of the women receiving placebo (an incidence of 0.17 and 0 per 1000 women-years, respectively). Uterine sarcoma generally is associated with more advanced disease at the time of diagnosis, poorer prognosis, and shorter survival.

Current evidence indicates that long-term (i.e., exceeding 2 years) tamoxifen therapy is associated with an increased risk (3.1-7.5 times that in untreated women) of developing endometrial cancer. In a large controlled study of adjuvant tamoxifen therapy (40 mg daily for 2-5 years) in women with early breast carcinoma, the relative risk of developing endometrial cancers associated with tamoxifen therapy was 5.6 times that of the control group (23 of 1372 tamoxifen-treated women and 4 of 1357 women in the control group developed cancers of the uterus). After approximately 6.8 years of follow-up in the National Surgical Adjuvant Breast and Bowel Project (NSABP B-14) study, 15 of 1419 women randomized to receive tamoxifen 20 mg daily for 5 years developed uterine cancer; 2 of 1424 women who were receiving placebo initially, but who subsequently received tamoxifen for recurrent breast carcinoma, also developed uterine cancer. The relative risk of endometrial cancer in the tamoxifen-treated women was 7.5; most of the uterine cancers in tamoxifen-treated patients with breast cancer were diagnosed at an early stage, but deaths resulting from uterine cancer associated with tamoxifen therapy for the treatment of breast cancer have been reported.

Women receiving tamoxifen for the prevention of breast cancer in the BCPT had an approximately 3.1 times greater risk of developing an endometrial adenocarcinoma than women receiving placebo (53 versus 17 cases or an incidence of 2.2 versus 0.71 per 1000 women-years at a median follow-up of 6.9 years). The increased risk of developing endometrial cancer in women receiving tamoxifen for the prevention of breast cancer occurred predominantly in women aged 50 years or older at the time of randomization (relative risk of 4.5 according to data available as of January 31, 1998; relative risk of 4.01 according to data available as of March 31, 1998). According to age at the time of diagnosis of endometrial cancer, increase in risk of endometrial cancer was similar for women 49 years of age or younger (relative risk of 2.21) and women 50 years of age or older (relative risk of 2.5), although fewer cases of endometrial cancer occurred in younger women. Among women receiving tamoxifen in the BCPT, endometrial cancer was diagnosed on average at 32 months (range: 1-61 months) following initiation of therapy with the drug.

All but one of the women in the BCPT who developed endometrial cancer (a study participant receiving placebo who subsequently died of endometrial cancer) had early-stage disease that can be treated effectively with surgery (i.e., hysterectomy) with or without postoperative radiation therapy. The distribution according to stage of endometrial cancer (according to FIGO) was similar among women receiving tamoxifen or placebo.

Approximately 37% of the participants receiving tamoxifen or placebo in the BCPT had undergone a hysterectomy prior to enrollment in the study and therefore were not at risk for the development of endometrial cancer. For women in the BCPT who had an intact uterus, endometrial sampling (i.e., examination of cells from the lining of the uterus) did not alter the rate of detection of endometrial cancer; currently, no data suggest that routine endometrial sampling in asymptomatic women receiving tamoxifen to reduce the incidence of breast cancer would be beneficial. Endometrial cancer often is associated with clinical manifestations, such as abnormal vaginal bleeding or pelvic pain. About 88% of cases of endometrial cancer diagnosed in tamoxifen-treated women in the BCPT were associated with symptoms.

Endometrial hyperplasia can be a premalignant change. In one study of postmenopausal women receiving tamoxifen for the prevention of breast cancer, 16% developed atypical hyperplasia while no cases occurred in those receiving placebo; 8% of women receiving tamoxifen had an endometrial polyp compared with 2% of those receiving placebo. These findings were based on screening of a randomized cohort of women from the study who had not been screened before the initiation of therapy, and some of the women also were receiving hormone replacement therapy as permitted by the study protocol. Optimal management of women who develop endometrial changes during tamoxifen therapy remains to be elucidated; the value of progestins in reversing such hyperplasia is not established nor are their effects on breast cancer in tamoxifen-treated women adequately studied. Screening and management of women who develop endometrial hyperplasia during tamoxifen therapy should be individualized, weighing the risks and benefits of continued therapy with the drug.

Endometriosis also has been reported. In addition, variations in the karyopyknotic index on vaginal smears and varying degrees of estrogenic effects on the Papanicolaou test also have been reported in postmenopausal women receiving the drug. The manufacturer states that patients receiving or having previously received tamoxifen should undergo routine gynecologic examinations, and they should be advised to report promptly any menstrual irregularities, abnormal vaginal bleeding, change in vaginal discharge, or pelvic pain/pressure to their clinician; the cause of such effects should be evaluated promptly.

Liver Cancer

In rats given 5, 20, or 35 mg/kg of tamoxifen daily for up to 2 years, hepatocellular carcinoma occurred at all dosages. The incidence of this carcinoma in rats receiving 20 or 35 mg/kg daily (69%) was substantially greater than that in those given 5 mg/kg daily (14%), and the incidence in rats given 5 mg/kg daily was substantially greater than that in controls. In addition, limited data from other studies in rats revealed hepatic tumors that were malignant in one of the studies.

In a study of women with breast cancer receiving tamoxifen (40 mg daily) or no adjuvant endocrine therapy for 2-5 years, 3 cases of liver cancer were reported in women receiving tamoxifen versus 1 case in the control group. No cases of liver cancer currently have been reported (at a median follow-up of 4.6 years) among women receiving either tamoxifen or placebo in the BCPT.

Other Cancers

Granulosa cell ovarian tumors and interstitial cell testicular tumors were observed in mice receiving the drug; however, the relevance of these findings to humans is not known.

Data from the NSABP B-14 study did not reveal an increased incidence of carcinomas other than uterine carcinomas. However, several second primary tumors occurring at sites other than the endometrium have been reported in clinical studies; it currently is not known whether an increased risk of these carcinomas is associated with tamoxifen therapy, and additional studies are needed to evaluate the risk of this carcinogenicity. Tamoxifen therapy has been associated with a reduced incidence of second primary breast carcinomas.

Pregnancy, Fertility, and Lactation

Pregnancy

Tamoxifen may cause fetal harm when administered to pregnant women. Effects on reproductive function are expected from the antiestrogenic properties of the drug. In reproduction studies in rats using tamoxifen dosages equal to or less than the human dosage, nonteratogenic developmental skeletal changes were observed and were found to be reversible. In fertility studies in rats and teratology studies in rabbits using dosages at or below those used in humans, a lower incidence of egg implantation and a higher incidence of fetal death or retarded in utero growth were observed, reportedly with slower learning behavior in some rat offspring compared with historical controls, although this latter effect is not clearly established. No teratogenic effects were observed in monkeys receiving tamoxifen during the period of organogenesis or the last half of pregnancy; although the dosage employed was high enough to terminate pregnancy in some of the animals, those that maintained pregnancy delivered offspring without evidence of teratogenicity. In reproduction studies in rats using tamoxifen dosages 0.3-2.4 times the maximum recommended dosages in humans on a mg/m basis, changes in both male and female similar to those caused by estradiol, ethynylestradiol, and diethylstilbestrol (DES) (no longer commercially available in the US) were observed. Although the clinical importance of these changes is unknown, some of these changes, especially vaginal adenosis, are similar to those observed in young women who were exposed to DES in utero; such women have a greater risk (1 in 1000) of developing clear-cell adenocarcinoma of the vagina or cervix. To date, in utero exposure to tamoxifen has not been shown to cause vaginal adenosis or clear-cell adenocarcinoma of the vagina or cervix in young women. However, only a small number of young women have been exposed to tamoxifen in utero; of these, a smaller number have been followed long enough (15-20 years) to determine whether vaginal or cervical neoplasia could occur as a result of exposure to tamoxifen.

There are no adequate and well-controlled studies using tamoxifen in pregnant women. There have been reports of spontaneous abortions, birth defects, fetal deaths, and vaginal bleeding. Women should not become pregnant while receiving the drug, and those of childbearing potential should use an effective barrier or other nonhormonal method of contraception during tamoxifen therapy. When tamoxifen is administered during pregnancy or if the patient becomes pregnant while receiving the drug or within approximately 2 months after discontinuance of therapy with tamoxifen, the patient should be informed of the potential hazard to the fetus, including the possible long-term risk of a DES-like syndrome.

For sexually active women of childbearing potential who are receiving tamoxifen for reduction in the incidence of breast cancer, therapy with the drug should be initiated during menstruation. In women with menstrual irregularity, pregnancy testing with a negative β-HCG should be confirmed immediately prior to the initiation of tamoxifen therapy.

Fertility

A decreased number of implantations, as well as death of all fetuses, was observed in reproduction studies in male and female rats receiving tamoxifen.

Lactation

It is not known if tamoxifen is distributed into milk. Because of the potential for serious adverse reactions to tamoxifen in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Drug Interactions

Anticoagulants

Tamoxifen has been reported to potentiate the hypoprothrombinemic effect of warfarin. In patients stabilized on warfarin therapy, substantial prolongations in prothrombin time have occurred within several days to weeks after initiation of tamoxifen therapy; overt signs of bleeding (e.g., hematemesis, hematuria, subdural hematoma, intraocular hemorrhage) also have occurred during concomitant therapy with the drugs. While the mechanism for this interaction currently is not known, tamoxifen and coumarin-derivative anticoagulants should be used concomitantly with caution. If the drugs are used concomitantly, the patient and prothrombin time should be monitored closely and dosage of the anticoagulant adjusted accordingly.

Other Drugs

Tamoxifen, N-desmethyltamoxifen, and 4-hydroxytamoxifen have been found to be potent inhibitors of hepatic cytochrome P-450 mixed function oxidases; the effect of tamoxifen on the metabolism and excretion of other antineoplastic drugs, such as cyclophosphamide, and other drugs that require mixed function oxidases for activation, is unknown. In at least one patient receiving tamoxifen and phenobarbital concomitantly, serum tamoxifen concentrations were decreased by about 80%; however, the clinical importance of this interaction is not known. Serum tamoxifen and N-desmethyltamoxifen concentrations reportedly were increased in patients receiving bromocriptine and tamoxifen concomitantly. An increased risk of thromboembolic events has been observed in patients receiving tamoxifen concomitantly with cytotoxic drugs.

Pharmacokinetics

Limited information is available on the pharmacokinetics of tamoxifen citrate.

Absorption

Tamoxifen appears to be absorbed slowly following oral administration, with peak serum concentrations generally occurring about 3-6 hours after a single dose. The extent of absorption in humans has not been adequately determined, but limited data from animal studies suggest that the drug is well absorbed. Data from animal studies also suggest that tamoxifen and/or its metabolites undergo extensive enterohepatic circulation.

Following oral administration, peak serum tamoxifen concentrations average about 17 ng/mL after a single 10-mg dose, about 40 ng/mL after a single 20-mg dose, and 65-70 ng/mL after a single 40-mg dose; however, there is considerable interindividual variation in serum tamoxifen concentrations attained after single doses and at steady state with continuous dosing. Following a single oral dose of tamoxifen, peak serum concentrations of N-desmethyltamoxifen, the major metabolite of the drug, generally range from about 15-50% those of unchanged tamoxifen; however, with continuous dosing, steady-state serum concentrations of N-desmethyltamoxifen generally range from about 1-2 times those of unchanged tamoxifen. Following continuous administration in patients receiving oral tamoxifen 10 mg twice daily for 3 months, steady-state plasma concentrations of tamoxifen and N-desmethyltamoxifen average about 120 ng/mL (range: 67-183 ng/mL) and 336 ng/mL (range: 148-654 ng/mL), respectively.Steady-state serum concentrations of tamoxifen are generally attained after 3-4 weeks of continuous dosing, while those of N-desmethyltamoxifen are generally attained after 3-8 weeks of continuous dosing. Steady-state serum concentrations can be attained more rapidly with a loading-dose regimen, but there is no therapeutic advantage with such a regimen. In a 3-month crossover study, the steady-state oral bioavailability of 20-mg tamoxifen tablets (administered once daily) was similar to that of 10-mg tablets (administered twice daily).

Distribution

Distribution of tamoxifen and its metabolites into human body tissues and fluids has not been fully characterized. In a study in a limited number of women given radiolabeled tamoxifen prior to hysterectomy, concentrations of radioactivity in uterine tissues were greater than those in serum 4-96 hours after the drug was given; highest uterine concentrations of radioactivity were present in the endometrium. Tamoxifen metabolites are distributed into bile in animals. Distribution of tamoxifen and its principal metabolites in the cytosol of human breast tumor tissue generally appears to parallel the relative concentrations present in serum, although cytosol concentrations may exhibit even greater interindividual variation than serum concentrations.

It is not known if tamoxifen is distributed into milk.

Elimination

Limited data suggest that tamoxifen has a distribution half-life of 7-14 hours and an elimination half-life of about 5-7 days (range: 3-21 days). The elimination half-life of N-desmethyltamoxifen, the major metabolite, is estimated to be 9-14 days.

Tamoxifen is rapidly and extensively metabolized, principally by demethylation and to a small degree by subsequent deamination and also by hydroxylation. Initial studies suggested that 4-hydroxytamoxifen (metabolite B) was the major metabolite of the drug, but subsequent studies using improved assay methodologies have shown that 4-hydroxytamoxifen is a minor metabolite and that the major metabolite is N-desmethyltamoxifen (metabolite X). The biologic activity of N-desmethyltamoxifen appears to be similar to that of tamoxifen.N-Desmethyltamoxifen undergoes demethylation to form N,N-desdimethyltamoxifen (metabolite Z) which undergoes subsequent deamination to form the primary alcohol metabolite (metabolite Y). Both 4-hydroxytamoxifen and a side chain primary alcohol derivative of tamoxifen have been identified as minor metabolites in plasma. 3,4-Dihydroxytamoxifen and an unidentified metabolite (metabolite E) also have been detected in plasma in small amounts. With continuous administration of tamoxifen, serum concentrations of N-desmethyltamoxifen are generally about 1-2 times those of unchanged tamoxifen, while those of N,N-desdimethyltamoxifen are about 20-40% those of unchanged tamoxifen and those of the primary alcohol metabolite are about 5-25% those of unchanged tamoxifen; concentrations of the hydroxylated metabolites and metabolite E appear to be less than 5% of those of unchanged tamoxifen. The relative contribution of tamoxifen and its metabolites to the in vivo antiestrogenic and antitumor effects of the drug remain to be fully elucidated, but results of various in vitro and in vivo studies suggest that the in vivo effects of tamoxifen result from the combined actions of unchanged drug and several of the identified metabolites.

The excretory fate of tamoxifen and its metabolites has not been well characterized. Following oral administration of a 20-mg dose of radiolabeled tamoxifen in women, approximately 65% of the administered dose was excreted in feces over a 2-week period, mainly as polar conjugates; unchanged tamoxifen and unconjugated metabolites accounted for less than 30% of the fecal radioactivity. Unchanged tamoxifen and N-desmethyltamoxifen have been detected in urine in small amounts. In animals, tamoxifen and/or its metabolites appear to undergo extensive enterohepatic circulation and are excreted in feces and urine as glucuronides, other conjugates, and unidentified polar metabolites.

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