NOLVADEX (tamoxifen citrate) Tablets, a nonsteroidal antiestrogen, are for oral administration. NOLVADEX Tablets are available as:
10 mg Tablets:
Each tablet contains 15.2 mg of tamoxifen citrate which is equivalent to 10 mg of tamoxifen.
20 mg Tablets:
Each tablet contains 30.4 mg of tamoxifen citrate which is equivalent to 20 mg of tamoxifen.
Inactive Ingredients: carboxymethylcellulose calcium, magnesium stearate, mannitol and starch.
Chemically, NOLVADEX is the trans-isomer of a triphenylethylene derivative. The chemical name is (Z)2-[4-(1,2-diphenyl-1-butenyl) phenoxy]-N, N-dimethylethanamine 2 hydroxy-1,2,3- propanetricarboxylate (1:1).
Tamoxifen citrate has a molecular weight of 563.62, the pKa' is 8.85, the equilibrium solubility in water at 37آ°C is 0.5 mg/mL and in 0.02 N HCl at 37آ°C, it is 0.2 mg/mL.
NOLVADEX is a nonsteroidal agent that has demonstrated potent antiestrogenic properties in animal test systems. The antiestrogenic effects may be related to its ability to compete with estrogen for binding sites in target tissues such as breast. Tamoxifen inhibits the induction of rat mammary carcinoma induced by dimethylbenzanthracene (DMBA) and causes the regression of already established DMBA-induced tumors. In this rat model, tamoxifen appears to exert its antitumor effects by binding the estrogen receptors.
In cytosols derived from human breast adenocarcinomas, tamoxifen competes with estradiol for estrogen receptor protein.
Indications and usage:
Metastatic Breast Cancer:
NOLVADEX is effective in the treatment of metastatic breast cancer in women and men. In premenopausal women with metastatic breast cancer, NOLVADEX is an alternative to oophorectomy or ovarian irradiation. Available evidence indicates that patients whose tumors are estrogen receptor positive are more likely to benefit from NOLVADEX therapy.
Adjuvant Treatment of Breast Cancer:
NOLVADEX is indicated for the treatment of node-positive breast cancer in postmenopausal women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation. In some NOLVADEX adjuvant studies, most of the benefit to date has been in the subgroup with four or more positive axillary nodes.
NOLVADEX is indicated for the treatment of axillary node-negative breast cancer in women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation.
The estrogen and progesterone receptor values may help to predict whether adjuvant NOLVADEX therapy is likely to be beneficial.
NOLVADEX reduces the occurrence of contralateral breast cancer in patients receiving adjuvant NOLVADEX therapy for breast cancer.
Ductal Carcinoma in Situ (DCIS):
In women with DCIS, following breast surgery and radiation, NOLVADEX is indicated to reduce the risk of invasive breast cancer (see BOXED WARNING at the beginning of the label). The decision regarding therapy with NOLVADEX for the reduction in breast cancer incidence should be based upon an individual assessment of the benefits and risks of NOLVADEX therapy.
Current data from clinical trials support five years of adjuvant NOLVADEX therapy for patients with breast cancer.
Reduction in Breast Cancer Incidence in High Risk Women:
NOLVADEX is indicated to reduce the incidence of breast cancer in women at high risk for breast cancer.
NOLVADEX is contraindicated in patients with known hypersensitivity to the drug or any of its ingredients.
Reduction in Breast Cancer Incidence in High Risk Women and Women with DCIS:
NOLVADEX is contraindicated in women who require concomitant coumarin-type anticoagulant therapy or in women with a history of deep vein thrombosis or pulmonary embolus.
Warnings and precautions:
Effects in Metastatic Breast Cancer Patients:
As with other additive hormonal therapy (estrogens and androgens), hypercalcemia has been reported in some breast cancer patients with bone metastases within a few weeks of starting treatment with NOLVADEX. If hypercalcemia does occur, appropriate measures should be taken and, if severe, NOLVADEX should be discontinued.
Decreases in platelet counts, usually to 50,000-100,000/mm3, infrequently lower, have been occasionally reported in patients taking NOLVADEX for breast cancer. In patients with significant thrombocytopenia, rare hemorrhagic episodes have occurred, but it is uncertain if these episodes are due to NOLVADEX therapy. Leukopenia has been observed, sometimes in association with anemia and/or thrombocytopenia. There have been rare reports of neutropenia and pancytopenia in patients receiving NOLVADEX; this can sometimes be severe.
In the NSABP P-1 trial, 6 women on NOLVADEX and 2 on placebo experienced grade 3-4 drops in platelet counts (≤50,000/mm3).
When NOLVADEX is used in combination with coumarin-type anticoagulants, a significant increase in anticoagulant effect may occur. Where such coadministration exists, careful monitoring of the patient's prothrombin time is recommended.
In the NSABP P-1 trial, women who required coumarin-type anticoagulants for any reason were ineligible for participation in the trial (See CONTRAINDICATIONS).
There is an increased risk of thromboembolic events occurring when cytotoxic agents are used in combination with NOLVADEX.
Tamoxifen reduced letrozole plasma concentrations by 37%. The effect of tamoxifen on metabolism and excretion of other antineoplastic drugs, such as cyclophosphamide and other drugs that require mixed function oxidases for activation, is not known. Tamoxifen and N-desmethyl tamoxifen plasma concentrations have been shown to be reduced when coadministered with rifampin or aminoglutethimide. Induction of CYP3A4-mediated metabolism is considered to be the mechanism by which these reductions occur; other CYP3A4 inducing agents have not been studied to confirm this effect.
One patient receiving NOLVADEX with concomitant phenobarbital exhibited a steady state serum level of tamoxifen lower than that observed for other patients (ie, 26 ng/mL vs. mean value of 122 ng/mL). However, the clinical significance of this finding is not known. Rifampin induced the metabolism of tamoxifen and significantly reduced the plasma concentrations of tamoxifen in 10 patients. Aminoglutethimide reduces tamoxifen and N-desmethyl tamoxifen plasma concentrations. Medroxyprogesterone reduces plasma concentrations of N-desmethyl, but not tamoxifen.
Concomitant bromocriptine therapy has been shown to elevate serum tamoxifen and N-desmethyl tamoxifen.
Based on clinical and pharmacokinetic results from the anastrozole adjuvant trial, NOLVADEX should not be administered with anastrozole.
Pregnancy and lactation:
Pregnancy Category D:
Tamoxifen has been reported to inhibit lactation.
It is not known if NOLVADEX is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from NOLVADEX, women taking NOLVADEX should not breast feed.
Adverse reactions to NOLVADEX are relatively mild and rarely severe enough to require discontinuation of treatment in breast cancer patients.
Continued clinical studies have resulted in further information which better indicates the incidence of adverse reactions with NOLVADEX as compared to placebo.
Metastatic Breast Cancer:
Increased bone and tumor pain and, also, local disease flare have occurred, which are sometimes associated with a good tumor response. Patients with increased bone pain may require additional analgesics. Patients with soft tissue disease may have sudden increases in the size of preexisting lesions, sometimes associated with marked erythema within and surrounding the lesions and/or the development of new lesions. When they occur, the bone pain or disease flare are seen shortly after starting NOLVADEX and generally subside rapidly.
In patients treated with NOLVADEX for metastatic breast cancer, the most frequent adverse reaction to NOLVADEX is hot flashes.
Other adverse reactions which are seen infrequently are hypercalcemia, peripheral edema, distaste for food, pruritus vulvae, depression, dizziness, light-headedness, headache, hair thinning and/or partial hair loss, and vaginal dryness.
Signs observed at the highest doses following studies to determine LD50 in animals were respiratory difficulties and convulsions.
Acute overdosage in humans has not been reported.
Store at controlled room temperature, 20-25°C (68-77°F) . Dispense in a well-closed, light-resistant container.