Tamoxifen Citrate

Pronunciation

Pronunciation: ta-MOX-i-fen SI-trate
Class: Antiestrogen

Trade Names

Tamoxifen Citrate
- Tablets, oral 10 mg
- Tablets, oral 20 mg

Apo-Tamox (Canada)
Gen-Tamoxifen (Canada)
Nolvadex-D (Canada)
Tamofen (Canada)

Pharmacology

A nonsteroidal agent with antiestrogenic properties.

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Pharmacokinetics

Absorption

Tamoxifen C max is 40 ng/mL (range, 35 to 45 ng/mL), T max is approximately 5 h after dosing, and steady state is achieved in approximately 4 wk. N-desmethyl tamoxifen C max is 15 ng/mL (range, 10 to 20 ng/mL). Steady state is achieved in approximately 8 wk.

Metabolism

Tamoxifen is extensively metabolized. The major metabolite is N-desmethyl tamoxifen with biological activity similar to tamoxifen. It is a substrate of CYP-450 3A, 2C9, 2D6, and an inhibitor of P-glycoprotein.

Elimination

Tamoxifen half-life is 5 to 7 days; 65% of a dose is excreted over a 2-wk period, with fecal excretion as the primary route of elimination. N-desmethyl tamoxifen half-life is approximately 14 days.

Special Populations

Hepatic Function Impairment

The effects of reduced liver function have not been determined.

Elderly

The effects of age on the pharmacokinetics of tamoxifen have not been determined.

Children

In pediatric patients, an average steady-state C max and AUC were 187 ng/mL and 4,110 ng•h/mL, respectively, and steady-state C max occurred approximately 8 h after dosing. Cl/F as body weight adjusted in female pediatric patients was approximately 2.3-fold higher than in female breast cancer patients. In the youngest cohort of female pediatric patients (2 to 6 y of age), Cl/F was 2.6-fold higher; in the oldest cohort (7 to 10.9 y of age), Cl/F was approximately 1.9-fold higher.

Gender

The effects of gender on the pharmacokinetics of tamoxifen have not been determined.

Race

The effects of race on the pharmacokinetics of tamoxifen have not been determined.

Indications and Usage

For the treatment of node-positive breast cancer in postmenopausal women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation; for the treatment of axillary node-negative breast cancer in women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation; in women with ductal carcinoma in situ (DCIS) following breast surgery and radiation to reduce the risk of invasive breast cancer; treatment of metastatic breast cancer in women and men; to reduce the incidence of breast cancer in women at high risk of breast cancer.

Unlabeled Uses

Ovulation stimulation in specially selected anovulatory women desiring pregnancy; management and treatment of some types of mastalgia (eg, cyclical); malignant carcinoid tumor and carcinoid syndrome; migraine associated with menstruation; oligozoospermia; McCune-Albright syndrome in female pediatric patients (in combination with other agents); metastatic melanoma; desmoid tumors; gynecomastia.

Contraindications

Hypersensitivity to drug; women who require concomitant coumarin-type anticoagulant therapy or women with a history of deep vein thrombosis (DVT) or pulmonary embolus (PE) (reduction of breast cancer incidence in high-risk women/DCIS only).

Dosage and Administration

Breast Cancer
Adults

PO 20 to 40 mg daily for 5 y.

Ductal Carcinoma In Situ, Reduction in Breast Cancer Incidence in High-Risk Women
Adults

PO 20 mg daily for 5 y.

General Advice

  • Divide dosages greater than 20 mg/day (morning and evening).

Storage/Stability

Store between 68° and 77°F. Protect from light.

Drug Interactions

Aminoglutethimide

Tamoxifen concentrations may be reduced. Coadministration is not recommended.

Anastrozole

Plasma concentrations of anastrozole may be decreased. Do not coadminister.

Bromocriptine

Tamoxifen concentrations may be increased. An addition, bromocriptine GI adverse reactions (eg, abdominal pain) may be increased. Avoid coadministration if serious bromocriptine adverse reactions occur.

Cation exchange resins (eg, sodium polystyrene sulfonate)

Coadministration of cation exchange resins and tamoxifen may cause serious GI adverse events such as colonic necrosis. Coadministration is not recommended.

CYP2D6 inhibitors (eg, bupropion, paroxetine)

Pharmacologic effects of tamoxifen may be decreased, increasing the risk of breast cancer recurrence. Inhibition of CYP2D6 may decrease the formation of endoxifen, an active metabolite of tamoxifen. Avoid coadministration.

Cytotoxic agents

Increased risk of thromboembolic events.

Letrozole

Plasma concentrations may be decreased by tamoxifen, reducing the therapeutic effect. Close clinical and laboratory monitoring for signs of reduced antitumor effects of letrozole is warranted.

Medroxyprogesterone

Medroxyprogesterone reduces plasma concentrations of N-desmethyl tamoxifen (metabolite) but not tamoxifen.

Mitomycin C

Toxic effects of mitomycin C and tamoxifen may be increased. Anemia, thrombocytopenia, and hemolytic uremic syndrome may develop. If coadministration cannot be avoided, closely monitor the clinical and hematologic status of the patient.

Phenobarbital

One patient receiving tamoxifen with concomitant phenobarbital exhibited steady-state serum concentrations of tamoxifen lower than that observed for other patients. The clinical relevance of this is unknown.

Rifamycins (eg, rifampin)

Tamoxifen plasma levels may be reduced, decreasing the antiestrogenic effect. It may be necessary to increase the tamoxifen dose during coadministration. In addition, concentrations of the active metabolite of tamoxifen, endoxifen, may be elevated, increasing the risk of adverse reactions. Monitor for adverse reactions.

Warfarin

Increased hypoprothrombinemic effect. Carefully monitor anticoagulant activity.

Laboratory Test Interactions

Thyroxine elevations. Variations in the karyopyknotic index on vaginal smears and various degrees of estrogen effect on Papanicolaou tests.

Adverse Reactions

Cardiovascular

Vasodilation (41%); hypertension (11%); venous thromboembolic events (5%); ischemic cerebrovascular events (3%); angina pectoris, DVT events (2%); MI, PE (1%).

CNS

Asthenia/fatigue, mood disturbances (18%); depression (12%); insomnia (9%); dizziness, headache (8%); anxiety (6%); paresthesia (5%); fatigue (4%).

Dermatologic

Flushing (33%); skin changes (19%); rash (13%); sweating (6%); alopecia (5%); bullous pemphigoid, erythema multiforme, Stevens-Johnson syndrome (postmarketing).

EENT

Pharyngitis (14%); cataract (7%).

GI

Nausea (26%); vomiting (12%); constipation (8%); diarrhea (7%); dyspepsia (6%); GI disorder (5%); anorexia (1%).

Genitourinary

Vaginal discharge (55%); irregular menses (25%); vaginal bleeding (23%); amenorrhea (16%); UTI (10%); leukorrhea, oligomenorrhea (9%); breast pain, menstrual disorder, vaginal hemorrhage (6%); breast neoplasm, vaginitis, vulvovaginitis (5%); ovarian cysts (3%), endometrial cancer (1%); loss of libido/impotence in men.

Hematologic-Lymphatic

Lymphedema (11%); thrombocytopenia (10%); anemia (5%).

Lab Tests

Increased AST (5%); increased bilirubin, increased creatinine (2%); elevated luteinizing hormone, follicle-stimulating hormone, estrogen, and testosterone in men; elevated triglycerides in some cases with pancreatitis (postmarketing).

Metabolic-Nutritional

Fluid retention (32%); weight loss (23%); peripheral edema (11%); weight gain (9%); hypercholesterolemia (4%).

Musculoskeletal

Musculoskeletal events (29%); arthritis (14%); arthralgia (11%); back pain (10%); fracture, osteoporosis (7%); bone pain (6%); arthrosis, joint disorder, myalgia (5%); musculoskeletal pain (3%).

Respiratory

Cough (9%); dyspnea (8%); bronchitis, sinusitis (5%); interstitial pneumonitis (postmarketing).

Miscellaneous

Hot flashes (80%); pain (16%); accidental injury (10%); abdominal pain, infection (9%); flu syndrome, infection/sepsis (6%); chest pain, cyst, neoplasm (5%); edema (4%); abdominal cramps (1%); hypersensitivity, including angioedema (postmarketing).

Precautions

Warnings

Serious and life-threatening events associated with tamoxifen in the risk-reduction setting (women at high risk of cancer and women with DCIS) include uterine malignancies, stroke, and PE. Uterine malignancies consist of both endometrial adenocarcinoma and uterine sarcoma. Some of the strokes, PE, and uterine malignancies were fatal. Discuss the potential benefits versus the potential risks of these serious events with women at high risk of breast cancer and with women with DCIS considering tamoxifen to reduce their risks of developing breast cancer. The benefits of tamoxifen outweigh its risks in women already diagnosed with breast cancer.


Monitor

Perform gynecological examinations annually. Obtain periodic CBC, including platelet counts, and periodic LFTs. Periodic monitoring of plasma triglycerides and cholesterol may be indicated in patients with preexisting hyperlipidemias.


Pregnancy

Category D . Tamoxifen may cause fetal harm when administered to a pregnant woman. Advise women not to become pregnant while taking or within 2 mo of discontinuing tamoxifen and to use barrier or nonhormonal contraceptive measures if sexually active. Tamoxifen does not cause infertility, even in the presence of menstrual irregularity. Effects on reproductive functions are expected from the antiestrogenic properties of the drug.

Lactation

Undetermined. Women taking tamoxifen should not breast-feed.

Children

Safety and efficacy have not been established.

Hematologic effects

Thrombocytopenia, leukopenia, and neutropenia and/or pancytopenia have occurred.

Hepatic effects

Liver cancer, changes in liver enzyme levels, fatty liver, cholestasis, hepatitis, and hepatic necrosis have occurred. A few of these serious cases included fatalities.

Hypercalcemia

Hypercalcemia has been reported in some breast cancer patients with bone metastases within a few weeks of starting treatment.

Nonmalignant uterine effects

An increased incidence of endometrial changes, including hyperplasia and polyps, have been reported. Endometriosis, uterine fibroids, ovarian cysts, menstrual irregularity, and amenorrhea have been reported.

Ophthalmic effects

Ocular disturbances, including corneal changes, decrement in color perception, retinal vein thrombosis, and retinopathy, have been reported. An increased incidence of cataracts and the need for cataract surgery have been reported.

Overdosage

Symptoms

Convulsions, neurotoxicity, QT interval changes.

Patient Information

  • Advise patients to review the Medication Guide before using the first time and with each refill.
  • Advise patients that tamoxifen reduces the incidence of breast cancer but may not eliminate risk. Instruct patients on the benefits of tamoxifen versus the risk.
  • Women with DCIS treated with lumpectomy and radiation therapy who are considering tamoxifen to reduce the incidence of a second breast cancer event should assess the risks and benefits of therapy because treatment with tamoxifen decreased the incidence of invasive breast cancer but has not been shown to affect survival.
  • Advise women who are receiving or who have previously received tamoxifen to have regular gynecologic examinations and promptly inform their health care provider of menstrual irregularities, abnormal vaginal bleeding, change in vaginal discharge, or pelvic pain or pressure.
  • Women who are pregnant or who plan to become pregnant should not take tamoxifen to reduce the risk of breast cancer. Effective nonhormonal contraception must be used by all premenopausal women taking tamoxifen and for approximately 2 mo after discontinuing therapy if they are sexually active. Tamoxifen does not cause infertility, even in the presence of menstrual irregularity. For sexually active women of childbearing potential, initiate therapy during menstruation. In women with menstrual irregularity, a negative beta chorionic gonadotropin immediately prior to the initiation of therapy is sufficient.
  • Advise patients to notify their health care provider of pain/swelling/tenderness of legs, unexplained shortness of breath, changes in vision, new breast lumps, vaginal bleeding, or gynecologic symptoms (eg, menstrual irregularities, changes in vaginal discharge, pelvic pain or pressure).

Copyright © 2009 Wolters Kluwer Health.

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