Nolvadex (Tamoxifen)

NOLVADEX® NOLVADEX®-D

Zeneca

Tamoxifen Citrate

Antineoplastic

Action And Clinical Pharmacology: Tamoxifen, the active ingredient, is a nonsteroidal agent which has demonstrated potent antiestrogenic properties in animal test systems. The antiestrogenic effects are related to its ability to compete with estrogen for binding sites in target tissues such as breast and uterus. 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 to estrogen receptors.

In cytosols derived from human endometrium and human breast and uterine adenocarcinomas, tamoxifen competes with estradiol for estrogen receptor protein.

Reports of advanced breast cancer trials conducted worldwide, however, indicate that, using established criteria, there is an objective response rate (complete and partial remission) to tamoxifen of approximately 10% in patients with estrogen receptor negative tumors which may indicate other mechanisms of action. A further small percentage of patients show positive benefit in that they are reported to fall into the disease stabilization category. This may be explained by the shortcomings of the assay procedure or by actions of tamoxifen at loci other than the estrogen receptor.

Ranges as large as 0 to 300 fmol/mg protein have been reported in histologically comparable portions of the same tumor. In addition, the collection, transport and storage of tumor specimens can affect the validity of current estrogen receptor assays.

The apparent discrepancy in correlation between estrogen receptor status and clinical response may also be explained by recent in vitro evidence indicating that not all of the growth inhibiting effects of tamoxifen are mediated through the estrogen receptor. Tamoxifen has been shown to have a low affinity for the androgen receptor and on a binding site distinct from the estrogen receptor. The possibility also exists that tamoxifen interferes with the action of hormonal steroids on cell growth, that it could modulate the action of peptide hormones at their receptors by effects on cell membranes, and that it inhibits prostaglandin synthetase thereby having the potential to limit tumor growth. It is recognized that tamoxifen also displays estrogenic-like effects on several body systems including the endometrium, bone and blood lipids.

Therefore, although evidence suggests that patients with estrogen receptor positive tumors are more likely to respond, tamoxifen therapy may be considered in patients whose estrogen receptor status is unknown, in doubt or negative.

Pharmacokinetics: Preliminary pharmacokinetics in women using radiolabeled tamoxifen have shown that most of the radioactivity is slowly excreted in the feces, with only small amounts appearing in urine. The drug is excreted mainly as conjugates, with unchanged drug and hydroxylated metabolites accounting for 30% of the total. Blood levels of total radioactivity following single oral doses of approximately 0.3 mg/kg reached peak values of 0.06 to 0.14 µg/mL at 3 to 7 hours after dosing, with only 20 to 30% of the drug present as tamoxifen. There was an initial half-life of 7 to 14 hours with secondary peaks 4 or more days later. The prolongation of blood levels and fecal excretion is believed to be due to enterohepatic circulation.

Indications And Clinical Uses: In the treatment of breast cancer in estrogen receptor positive tumors.

Contra-Indications: In persons hypersensitive to this product.

Pregnancy: Tamoxifen must not be given during pregnancy. There have been a small number of reports of spontaneous abortions, birth defects and fetal deaths after women have taken tamoxifen, although no causal relationship has been established.

Reproductive toxicology studies in rats, rabbits and monkeys have shown no teratogenic potential.

In rodent models of fetal reproductive tract development, tamoxifen was associated with changes similar to those caused by estradiol, ethynylestradiol, clomiphene and diethylstilbestrol (DES). Although the clinical relevance of these changes is unknown, some of them, especially vaginal adenosis, are similar to those seen in young women who were exposed to DES in utero and who have a 1 in 1 000 risk of developing clear-cell carcinoma of the vagina or cervix. Only a small number of pregnant women have been exposed to tamoxifen. Such exposure has not been reported to cause subsequent vaginal adenosis or clear-cell carcinoma of the vagina or cervix in young women exposed in utero to tamoxifen.

Women should be advised not to become pregnant while taking tamoxifen and should use barrier or other nonhormonal contraceptive methods if sexually active. Premenopausal patients must be carefully examined before treatment to exclude the possibility of pregnancy. Women should be informed of the potential risks to the fetus, should they become pregnant while taking tamoxifen or within 2 months of cessation of therapy.

Manufacturers’ Warnings In Clinical States: Tamoxifen should be used only for the conditions listed under the Indications section.

Disturbances of menstrual function, including oligomenorrhea and amenorrhea, have been reported in a proportion of premenopausal women receiving tamoxifen for the treatment of breast cancer. Available information indicates that in those women receiving tamoxifen for up to 2 years for the treatment of early breast cancer who develop disturbances of menstrual function on treatment, a proportion return to normal cyclical bleeding on cessation of therapy.

Hepatocellular carcinomas as well as cataracts have been reported in the 2-year oncogenicity study in rats receiving tamoxifen. Gonadal tumors have been reported in mice receiving tamoxifen in long-term studies. The clinical relevance of these findings has not been established.

A number of second primary tumors, occurring at sites other than the endometrium and the opposite breast, have been reported in clinical trials, following the treatment of breast cancer patients with tamoxifen. No causal link has been established and the clinical significance of these observations remains unclear.

Precautions: Tamoxifen should be used cautiously in patients with existing thrombocytopenia or leukopenia. Decreases in platelet counts, usually to 50 000 to 100 000/mm infrequently lower, have been observed occasionally during treatment with tamoxifen. However, no hemorrhagic tendency has been reported, and the platelet counts returned to normal levels even though treatment with tamoxifen was continued.

Transient decreases in leukocytes also have been observed occasionally during treatment. Although it was uncertain if these occasional incidences of leukopenia and thrombocytopenia were due to tamoxifen therapy, complete blood counts, including platelet counts, should be obtained periodically.

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 tamoxifen. Any symptoms suggestive of hypercalcemia should be evaluated promptly. Patients who have metastatic bone disease should have periodic serum calcium determinations during the first few weeks of tamoxifen therapy. If hypercalcemia is present, appropriate measures should be taken and, if severe, tamoxifen should be discontinued.

The first patient follow-up should be done within 1 month following initiation of treatment. Thereafter, examinations may be performed at 1- to 2-month intervals. If adverse reactions such as hot flashes, nausea or vomiting occur, and are severe, they may be controlled in some patients by a reduction of dosage (within the recommended dose range) without loss of effect on the disease.

Bone pain, if it should occur, may require the use of analgesics.

An increased incidence of endometrial cancer has been reported in association with tamoxifen treatment. The incidence and pattern of this increase suggest that the underlying mechanism may be related to estrogenic properties of tamoxifen. Any patients receiving tamoxifen or having previously received tamoxifen who report abnormal gynecological symptoms, especially vaginal bleeding, should be promptly investigated. Ovarian cysts have been observed in a small number of premenopausal patients with advanced breast cancer who have been treated with tamoxifen.

In clinical studies, the median duration of treatment before the onset of a definite objective response has been 2 months. However, approximately 25% of patients who eventually responded were treated for 4 or more months before a definite objective response was recorded.

The duration of treatment with tamoxifen will depend on the patient’s response. The drug should be continued as long as there is a favorable response.

With obvious disease progression, the drug should be discontinued. However, because an occasional patient will have a local disease flare (see Adverse Effects) or an increase in bone pain shortly after starting tamoxifen, it is sometimes difficult during the first few weeks of treatment to determine whether the patient’s disease is progressing or whether it will stabilize or respond to continued treatment. There are data to suggest that, if possible, treatment should not be discontinued before a minimum of 3 to 4 weeks.

Drug Interactions: When tamoxifen 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.

When tamoxifen is used in combination with cytotoxic agents, there is increased risk of thromboembolic events occurring.

Lactation: It is not known if tamoxifen is excreted in human milk and, therefore, the drug is not recommended during lactation. The decision either to discontinue nursing or discontinue tamoxifen should take into account the importance of the drug to the mother.

Adverse Reactions: The most frequent adverse reactions to tamoxifen are hot flashes, nausea and vomiting. These may occur in up to 25% of all patients and are rarely severe enough to require discontinuation of treatment.

Less frequently reported adverse reactions are vaginal bleeding, vaginal discharge and skin rash. Usually these have not been of sufficient severity to require dosage reduction or discontinuation of treatment.

Increased bone and tumor pain and also local disease flare have occurred. These are sometimes associated with a good tumor response. Patients with soft tissue disease may have sudden increases in the size of pre-existing 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 tamoxifen and generally subside rapidly.

Other adverse reactions which are seen infrequently are hypercalcemia, peripheral edema, distaste for food, pruritus vulvae, depression, dizziness, light-headedness, headache and alopecia. Isolated cases of erythema multiforme, Stevens-Johnson syndrome and bullous pemphigoid, have also been reported.

Elevation of ALT, AST and GGT levels has been reported infrequently during tamoxifen therapy. Overt cholestasis has occurred less frequently and, in addition, there have been rare reports of benign, symptomatic hepatic cyst, peliosis hepatitis and fatty liver.

Ocular changes have been reported in a few breast cancer patients who, as part of a clinical trial, were treated for periods longer than 1 year with doses of tamoxifen that were at least 4 times the highest recommended daily dose of 40 mg. In each instance, the total amount of drug exceeded 100 g. These changes were a retinopathy and, in a few patients, corneal changes and decreased visual acuity. There were multiple light refractile opacities in the paramacular area, and macular edema. The corneal lesions consist of whorl-like superficial opacities. Ophthalmologic examinations of selected patients who received long-term therapy with tamoxifen at recommended doses did not detect any ocular pathology attributable to the drug.

In addition, a number of cases of ocular changes including visual disturbance, cataracts, and/or corneal changes and/or retinopathy have been reported in patients treated with tamoxifen at recommended doses. It is uncertain if these effects are due to tamoxifen, however, cataracts have been seen in the 2-year oncogenicity study in rats.

Uterine fibroids and endometrial changes including hyperplasia and polyps have been reported.

Leukopenia has been observed following the administration of tamoxifen, sometimes in association with anemia and/or thrombocytopenia. Neutropenia has been reported on rare occasions; this can sometimes be severe.

There have been infrequent reports of thromboembolic events occurring during tamoxifen therapy. There is some evidence of an increased incidence of these events during tamoxifen therapy, although a causal relationship with tamoxifen has not been established.

Symptoms And Treatment Of Overdose: Symptoms: Acute overdosage in humans has not been reported. Possible overdosage effects might include hot flashes, nausea, vomiting and vaginal bleeding.

Treatment: No specific treatment for overdosage is known and treatment must be symptomatic. In the case of accidental ingestion by a child, gastric emptying is suggested.

Dosage And Administration: The recommended daily dose is 20 to 40 mg in a single or 2 divided doses. The lowest effective dose should be used.

Availability And Storage: Nolvadex: Each off-white to white, round, film-coated, biconvex tablet, intagliated with NOLVADEX 10 on one face and plain on the reverse, contains: tamoxifen citrate 15.2 mg, equivalent to 10 mg of tamoxifen. Nonmedicinal ingredients: cornstarch, croscarmellose sodium, gelatin, lactose, macrogol, magnesium stearate, methylhydroxypropylcellulose, and titanium dioxide. Energy: 1.68 kJ (0.4 kcal)/tablet. Alcohol-, sodium- and tartrazine-free. Containers of 250. Plain and unit dose packs of 60.

Nolvadex-D: Each off-white to white, octagonal, film-coated, biconvex tablet, intagliated with NOLVADEX D on one face and plain on the reverse, contains: tamoxifen citrate 30.4 mg equivalent to 20 mg tamoxifen. Nonmedicinal ingredients: cornstarch, croscarmellose sodium, gelatin, lactose, macrogol, magnesium stearate, methylhydroxypropylcellulose, and titanium dioxide. Energy: 3.36 kJ (0.8 kcal)/tablet. Alcohol-, sodium- and tartrazine-free. Plain and unit dose packs of 30 and 60.

Store at room temperature protected from light.

NOLVADEX® NOLVADEX®-D Zeneca Tamoxifen Citrate Antineoplastic

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