Tamoxifen (Systemic)


VA CLASSIFICATION
Primary: AN500

Commonly used brand name(s): Apo-Tamox; Gen-Tamoxifen; Nolvadex; Nolvadex-D; Novo-Tamoxifen; Tamofen; Tamone.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antineoplastic—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Carcinoma, breast (treatment)—Node-negative: Tamoxifen is indicated for adjuvant treatment of axillary node-negative breast cancer in women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation {01}. Data are insufficient to predict which women are most likely to benefit and to determine if tamoxifen provides any benefit in women with tumors of less than 1 cm {01}.
—Node-positive: Tamoxifen is indicated for adjuvant treatment of axillary node-positive breast cancer in postmenopausal women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation {01}. In some tamoxifen adjuvant studies, most of the benefit to date has been in the subgroup with four or more positive axillary nodes {01}.

Note: The estrogen and progesterone receptor values may help to predict whether adjuvant tamoxifen therapy is likely to be beneficial in node-negative or node-positive breast cancer. {01} {02}

—Advanced disease: Tamoxifen is indicated in the treatment of metastatic breast cancer in men and women {01}.
—The labeling states that tamoxifen is effective in premenopausal women as an alternative to oophorectomy or ovarian irradiation {01}. Available evidence indicates that women whose tumors are estrogen receptor–positive are more likely to benefit from tamoxifen therapy {01}.

Carcinoma, breast (prophylaxis)—Tamoxifen is indicated to reduce the risk of developing breast cancer in women who have been determined to be at high risk for developing this cancer. A woman is considered to be at high risk if she is at least 35 years of age and has a 5-year predicted risk of developing breast cancer greater than or equal to 1.67% (based on the Gail Model Risk Assessment Tool) {01}.
—Risk factors that predict a 5-year risk of ³ 1.67%:
—   • Age ³ 35 years and any of the following combinations of factors:   —One first-degree relative with a history of breast cancer, two or more benign biopsies, and a history of a breast biopsy that has shown atypical hyperplasia; or {01}
   —At least two first-degree relatives with a history of breast cancer, and a personal history of at least one benign breast biopsy; or {01}
   —Lobular carcinoma in situ (LCIS) {01}

   • Age ³ 40 years and any of the following combinations of factors:   —One first-degree relative with a history of breast cancer, two or more benign biopsies, age at first live birth was ³ 25 years of age, and age at menarche was £ 11 years of age; or {01}
   —At least two first-degree relatives with a history of breast cancer and age at first live birth was £ 19 years of age; or {01}
   —One first-degree relative with a history of breast cancer and a personal history of benign breast biopsy that has shown atypical hyperplasia {01}

   • Age ³ 45 years and any of the following combinations of factors:   —At least two first-degree relatives with a history of breast cancer and age at first live birth was £ 24 years of age; or {01}
   —One first-degree relative with a history of breast cancer, a personal history of benign breast biopsy, age at first live birth was ³ 20 years of age, and age at menarche was £ 11 years of age {01}

   • Age ³ 50 years and any of the following combinations of factors:   —At least two first-degree relatives with a history of breast cancer; or {01}
   —History of one benign breast biopsy showing atypical hyperplasia, age at first live birth was ³ 30 years of age, and age at menarche was £ 11 years of age; or {01}
   —History of at least two breast biopsies with a history of atypical hyperplasia and age at first live birth was ³ 30 years of age {01}

   • Age ³ 55 years and any of the following combinations of factors:   —One first-degree relative with a history of breast cancer, a personal history of benign breast biopsy, and age at menarche was £ 11 years of age; or {01}
   —History of at least two breast biopsies with a history of atypical hyperplasia and age at first live birth was ³ 20 years of age {01}

   • Age ³ 60 years:   —5 year predicted risk of breast cancer ³ 1.67 %, as calculated by the Gail Model



Note: Women whose risk factors are not described in the above examples should have their absolute breast cancer risk estimated using the Gail Model. The Gail Model Risk Assessment Tool is available for health care professionals by calling 1-800-456-3669 (extension 3838) {01}.


Carcinoma, breast, ductal, in situ (prophylaxis) 1—Tamoxifen is indicated to reduce the risk of invasive breast cancer in women with ductal carcinoma in situ (DCIS) who have undergone breast surgery and radiation treatment.{59}

[Melanoma, malignant (treatment)]1—Tamoxifen is indicated, in combination with other agents, in the treatment of malignant melanoma {42} {43}.

[Carcinoma, endometrial (treatment) ]1—Tamoxifen, in combination with other agents, is considered reasonable medical therapy at some point in the management of endometrial carcinoma {44} {45} {46} {47} {48} {49} {50} {51} {52} {53} {54} {55} {56} {57} {58} (Evidence rating: IA).

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Note: Pharmacokinetic studies have been done in women only.


Physicochemical characteristics:
Molecular weight—
    563.65 {04}

pKa—
    8.85 {01}

Mechanism of action/Effect:

Tamoxifen is a nonsteroidal antiestrogen {01} agent that also has weak estrogenic effects. The exact mechanism of antineoplastic action is unknown, but may be related to its antiestrogen effects; tamoxifen blocks uptake of estradiol.


Other actions/effects:

Tamoxifen may induce ovulation in anovulatory women, stimulating release of gonadotropin-releasing hormone from the hypothalamus, which in turn stimulates release of pituitary gonadotropins. In oligospermic males, tamoxifen increases serum concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and estrogen {01}. Tamoxifen and some of its metabolites ( N-desmethyltamoxifen, 4-hydroxytamoxifen) are potent inhibitors of hepatic cytochrome P450 mixed function oxidases {01}; however, the clinical significance of these effects has not been determined {01}.

Biotransformation:

Hepatic. Enterohepatic circulation is believed to account for prolongation of blood concentrations and fecal excretion of tamoxifen {01}.

Half-life:

Distribution—7 to 14 hours; secondary peaks at 4 or more days may be due to enterohepatic circulation.

Elimination—May exceed 7 days.

Onset of action:

An objective response usually occurs within 4 to 10 weeks of therapy, but may take several months in patients with bone metastases.

Duration of action:

Estrogen antagonism may persist for several weeks following a single dose.

Elimination:
    Primary route—Biliary/fecal, mostly as metabolites.
    Secondary route—Renal (only small amounts).


Precautions to Consider

Note: Unless otherwise noted, information in this section is based on reports on women treated with tamoxifen.


Carcinogenicity

An increased incidence of endometrial cancer has been associated with tamoxifen treatment in humans {01} {05} {06} {07} {08} {09} {10} {11} {12} {13} {14} {15} {16} {17} {18}. A large randomized study in Sweden found a significantly increased incidence of uterine cancer in women who took tamoxifen as compared with those who received placebo {01}. In the ongoing NSABP B-14 study, an increased incidence of uterine cancer has also been noted {01}; deaths have been reported {01}.

Hepatic carcinogenicity of tamoxifen in rats is well established {01} {33} {34} {35}. Studies in rats at doses of 5, 20, and 35 mg per kg of body weight (mg/kg) per day for up to 2 years found an increased incidence of hepatocellular carcinoma at all doses; the incidence was highest at doses of 20 or 35 mg/kg per day {01}. In a 13-month study of endocrine changes in immature and mature mice, granulosa cell ovarian tumors and interstitial cell testicular tumors were found in tamoxifen-treated mice but not in controls {01}.

Mutagenicity

No genotoxic potential was found in a conventional battery of in vivo and in vitro tests with prokaryotic and eukaryotic test systems with drug-metabolizing systems present {01}. However, increased levels of DNA adducts have been found in the livers of rats exposed to tamoxifen {01}. Tamoxifen also has been found to increase levels of micronucleus formation in vitro in human lymphoblastoid cell line (MCL-5). {01}

Pregnancy/Reproduction
Fertility—
Tamoxifen may induce ovulation in women {01}.

Tamoxifen affects reproductive function in rats at doses somewhat higher than the human dose.

Pregnancy—
Although adequate and well-controlled studies have not been done in humans, spontaneous abortions, birth defects, fetal deaths, and vaginal bleeding have been reported {01}. Because of tamoxifen's estrogenic effect, the possibility of a diethylstilbestrol (DES)-like syndrome in females whose mothers took tamoxifen during pregnancy should be kept in mind {01}. In rodent models of fetal reproductive tract development, at doses of 0.3 to 2.4 times the maximum recommended human dose (MRHD), tamoxifen caused changes in both sexes that are similar to those caused by estradiol, ethynyl estradiol, and DES {01}; some of these changes, especially vaginal adenosis, are similar to those found in young women who were exposed in utero to DES and who have a 1 in 1000 risk of developing clear-cell adenocarcinoma of the vagina or cervix {01}. Duration of follow-up of the few women exposed to tamoxifen in utero to date has not been long enough to confirm or disprove this risk with its use in humans {01}.

In general, use of a barrier or nonhormonal contraceptive is recommended during (and for about 2 months after) tamoxifen therapy in sexually active women {01}.

At dose levels at or below the human dose, reversible nonteratogenic developmental skeletal changes occurred in rats, and a lower incidence of embryo implantation and higher incidence of fetal death or retarded in utero growth occurred in rats and rabbits, as well as impaired learning behavior in some rat pups {01}.


For reducing the risk of breast cancer in high-risk women

Tamoxifen should not be used to reduce the risk of breast cancer in women who are pregnant or who plan on becoming pregnant. For women of child-bearing age, it is recommended that tamoxifen therapy be initiated during menstruation or if there are menstrual irregularities, it is recommended that a negative beta-human chorionic gonadotropin ( B-HCG) test be obtained immediately prior to initiation of treatment with tamoxifen {01}.


FDA Pregnancy Category D.

Breast-feeding

It is not known whether tamoxifen is distributed into breast milk {01}. Although very little information is available regarding distribution of antineoplastic agents into breast milk, breast-feeding is not recommended during chemotherapy because of the risks to the infant (adverse effects, mutagenicity, carcinogenicity).

Geriatrics


Appropriate studies on the relationship of age to the effects of tamoxifen have not been performed in the geriatric population. However, this medication is commonly used in elderly patients {01} and geriatrics-specific problems that would limit the usefulness of this medication in the elderly have not been reported and are not expected.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Because tamoxifen and its metabolites are potent inhibitors of cytochrome P450 mixed function oxidases, there is a potential for interaction with medications that require mixed function oxidases for activation {01}.
Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Estrogens    (may interfere with tamoxifen's therapeutic effect)


Bromocriptine    (concomitant use may increase serum levels of tamoxifen {01})


When using for reducing the risk of breast cancer in high-risk women
» Anticoagulants, coumarin-derivative    (Tamoxifen may cause blood clots; concomitant use is not recommended)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Calcium concentrations, serum    (may be increased infrequently, usually in patients with bone metastases; the effect appears to be transient)


Cholesterol and
Triglycerides    (increases in serum concentrations have been seen infrequently {01})


Hepatic enzymes    (serum values may be increased {01} {32}; rarely, more severe abnormalities, including fatty liver, cholestasis, and hepatitis, have occurred {01} {32}; fatalities have been reported {01})


Karyopyknotic index on vaginal smears    (variations have been seen infrequently in postmenopausal women treated with tamoxifen {01})


Papanicolaou (Pap) test    (various degrees of estrogen effect have been seen infrequently in postmenopausal women treated with tamoxifen {01})


Thyroxine (T 4)    (increases in serum concentrations have been reported in a few patients {01}, possibly as a result of increases in thyroid-binding globulin {01}; however, clinical hyperthyroidism has not been reported {01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:

When used for reducing the risk of breast cancer in high-risk women:
» Thromboembolic events, history of    (Thromboembolic events, including pulmonary emboli and deep venous thrombosis, have occurred in women treated with tamoxifen {01})


Risk-benefit should be considered when the following medical problems exist
Cataracts or vision disturbances    (visual disturbances, including corneal changes, cataracts, and retinopathy, have been reported in patients receiving tamoxifen {01})


Hyperlipidemia    (increased serum lipid concentrations have been reported infrequently {01})


Leukopenia    (leukopenia has been reported occasionally in patients receiving tamoxifen {01})


» Sensitivity to tamoxifen{01}
Thrombocytopenia    (thrombocytopenia has been reported occasionally in patients receiving tamoxifen, although platelet counts recovered even with continued therapy {01})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Calcium concentrations, serum    (recommended at periodic intervals in patients with bone metastases during initial period of therapy)


Cholesterol concentrations, serum and
Triglyceride concentrations, serum    (may be recommended at periodic intervals in patients with pre-existing hyperlipidemias {01})


Complete blood count    (may be appropriate at periodic intervals, although leukopenia and thrombocytopenia have not been definitely attributed to tamoxifen)


» Gynecologic examinations    (recommended at regular intervals in women taking tamoxifen to detect possible endometrial cancers {01})


Hepatic function tests    (recommended at periodic intervals during therapy {01})


Ophthalmologic examinations    (recommended prior to initiation of therapy and at periodic intervals during therapy {23} {25})


When used for reducing the risk of breast cancer in high-risk women:
» Breast examinations and
» Mammograms    (recommended prior to initiation of therapy and at periodic intervals during therapy {01})




Side/Adverse Effects

Note: Side/adverse effects usually are relatively mild {01}.
Although information is limited, the side effect profile in men seems to be similar to that in women {01}.
A transient, sometimes severe, increase in bone or tumor pain may occur shortly after initiation of therapy but usually subsides with continued tamoxifen treatment. Analgesics may be required during this time {01}.
Tamoxifen induces ovulation, which puts women at risk for becoming pregnant.
Ovarian cysts have been reported in a small number of premenopausal women treated with tamoxifen for advanced breast carcinoma {01}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent or rare
In both females and males
    
Confusion
    
erythema multiforme, bullous pemphigoid, or Stevens-Johnson syndrome{01} (blistering, peeling, or loosening of skin and mucous membranes)
    
hepatotoxicity{01} (yellow eyes or skin)—usually asymptomatic
    
ocular toxicity, including retinopathy, keratopathy, cataracts, and optic neuritis{01}{19}{20}{21}{22}{23}{24}{25}{26}{27}{28}{29} (blurred vision)—may be asymptomatic initially
    
pulmonary embolism (shortness of breath)
    
thrombosis (pain or swelling in legs)
    
weakness or sleepiness

Note: Erythema multiforme, bullous pemphigoid, and Stevens-Johnson syndrome have been reported rarely {01}.
Hepatotoxicity usually consists of elevated hepatic enzyme values {19}. However, more serious liver abnormalities, including fatty liver, cholestasis, and hepatitis, have occurred {19}; fatalities have been reported {19}.
Ocular toxicity previously was thought to occur only after high (240 to 320 mg per day), prolonged (17 months or more) tamoxifen dosage. However, there are reports of retinopathy or keratopathy occurring at lower doses (10 to 40 mg per day) {19} {20} {21} {22} {23} {24} {25} {26} {27} and after only a few weeks of tamoxifen therapy {22} {24}, although they are still most commonly associated with several months' therapy. Ocular toxicity may {20} {21} {24} {25} {26} or may not {20} {23} be reversible following withdrawal of tamoxifen. A number of reports included recommendations for baseline and periodic ocular examinations during tamoxifen therapy to detect subclinical toxicity and permit withdrawal of tamoxifen at early stages of toxicity {23} {25}.


In females only
    
Endometrial hyperplasia{01} , endometrial polyps{01} , or endometrial carcinoma{01}{05}{06}{07}{08}{09}{10}{11}{12}{13}{14}{15}{16}{17}{18} (change in vaginal discharge; pain or feeling of pressure in pelvis; vaginal bleeding)




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent (³ 10%)
In females only
    
Hot flashes
    
weight gain

Note: Weight gain is an effect of estrogen.



Incidence less frequent
In both females and males
    
Headache
    
nausea and/or vomiting, mild{36}
    
skin rash or dryness
    
transient local disease flare{38} (bone pain)

Note: Incidence of nausea and/or vomiting is higher with higher doses {37}.
Transient local disease flare may also consist of hypercalcemia and/or spinal cord compression {39}, as well as a sudden increase in the size of pre-existing lesions in patients with soft tissue disease, sometimes associated with marked erythema within and surrounding the lesions and/or the development of new lesions {01}. Bone pain or other disease flare usually occurs shortly after initiation of therapy {01} and subsides within 1 to 2 weeks {40}.


In females only
    
Changes in menstrual period
    
itching in genital area
    
vaginal discharge{01}

In males only
    
Impotence or decrease in sexual interest{01}




Those not indicating need for medical attention
Incidence less frequent or rare
    
Hair thinning or partial hair loss{01}





Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
Acute tamoxifen overdose has not been reported. However, acute neurotoxicity, including tremors, hyperflexia, unsteady gait, and dizziness, has been reported following administration of very high doses of tamoxifen (> 400 mg per square meter of body surface area [mg/m 2], followed by maintenance doses of 150 mg/m 2 twice a day) {01}. Prolonged QT intervals have been reported in patients who were given doses of tamoxifen greater than 250 mg/m 2 (loading dose), followed by maintenance doses of 80 mg/m 2 twice a day {01}.

Treatment of overdose
Neurotoxic symptoms begin 3 to 5 days after the initiation of high-dose tamoxifen therapy and resolve within 2 to 5 days after withdrawal of tamoxifen {01}.

There is no specific treatment for overdose of tamoxifen. Patients should be treated symptomatically {01}.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Tamoxifen (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to tamoxifen

Pregnancy—Use not recommended because of risk of miscarriage, death of the fetus, birth defects, and vaginal bleeding; advisability of using nonhormonal contraception during (and for about 2 months following) therapy; telling physician immediately if pregnancy is suspected





Breast-feeding—Not recommended because of risk of serious side effects
Other medications, especially courmarin-derivative anticoagulants
Other medical problems, especially history of thromboembolic events

Proper use of this medication
» Importance of not taking more or less medication than the amount prescribed

» Frequency of nausea and vomiting; importance of continuing medication despite stomach upset

Checking with physician if vomiting occurs shortly after dose is taken

» Proper dosing
Not taking at all; not doubling doses

» Proper storage

Precautions while using this medication
» Importance of close monitoring by the physician

For women: May increase fertility; advisability of using nonhormonal contraception during therapy; telling physician immediately if pregnancy is suspected


Side/adverse effects
For women: Increased risk of endometrial carcinoma

Signs of potential side effects, especially confusion, erythema multiforme, bullous pemphigoid, Stevens-Johnson syndrome, hepatotoxicity, retinopathy, keratopathy, cataracts, optic neuritis, pulmonary embolus, thrombosis, weakness or sleepiness, endometrial hyperplasia, endometrial polyps, and endometrial carcinoma

Physician or nurse can help in dealing with side effects


General Dosing Information
Patients receiving tamoxifen should be under the supervision of a physician experienced in cancer chemotherapy.

If side effects are severe, dosage may sometimes be reduced without loss of control of the disease.

If severe hypercalcemia occurs, tamoxifen should be discontinued {01}.

Ophthalmologic examination is recommended if visual disturbances occur, and withdrawal of tamoxifen should be considered if retinopathy or keratopathy is detected {41}.


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.


TAMOXIFEN CITRATE TABLETS USP

Note: The dosing and strengths available are expressed in terms of tamoxifen base.


Usual adult dose
Breast carcinoma
Node-negative or node-positive: In women—Oral, 10 mg (base) two times a day (in the morning and evening) {01}.

Metastatic: In men and women—Oral, 10 to 20 mg (base) two times a day (in the morning and evening) {01}.

Breast carcinoma (prophylaxis)
Oral, 20 mg (base) daily for five years.

[Melanoma, malignant]1 or
[Carcinoma, endometrial]1
Consult medical literature and manufacturer's literature for specific dosages.

Ductal carcinoma in situ (prophylaxis)1
Oral, 20 mg (base) daily for 5 years.{59}


Strength(s) usually available
U.S.—


10 mg (base) (Rx) [Nolvadex (carboxymethylcellulose calcium ) (magnesium stearate) ( mannitol) (starch)][Generic]


20 mg (base) (Rx) [Nolvadex (carboxymethylcellulose calcium ) (magnesium stearate) ( mannitol) (starch)][Generic]

Canada—


10 mg (base) (Rx) [Apo-Tamox] [Gen-Tamoxifen] [Nolvadex] [Novo-Tamoxifen] [Tamofen] [Tamone]


20 mg (base) (Rx) [Apo-Tamox] [Gen-Tamoxifen] [Nolvadex-D] [Novo-Tamoxifen] [Tamofen] [Tamone]

Packaging and storage:
Store between 20 and 25 °C (68 and 77 °F), unless otherwise specified by manufacturer. Store in a well-closed, light-resistant container.



Revised: 11/20/2000



References
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  1. Product Information: Nolvadex©, tamoxifen. AstraZeneca, Wilmington, DE, (PI revised 06/2000) reviewed 11/2000.
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