Tamone (Tamoxifen Citrate)

TAMONE®

Pharmacia & Upjohn

Tamoxifen Citrate

Antineoplastic

Action And Clinical Pharmacology: Tamoxifen 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. 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.

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.

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

Tamoxifen, alone or in combination with cytotoxic agents, is effective in significantly lowering recurrences of breast cancer in estrogen receptor positive tumors.

Contra-Indications: Hypersensitivity to tamoxifen.

Pregnancy: Tamoxifen must not be given during pregnancy. Premenopausal patients must be carefully examined before treatment to exclude the possibility of pregnancy.

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

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 returns 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.

Precautions: Tamoxifen should be used cautiously in patients with existing thrombocytopenia or leukopenia. Transient 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 without loss of effect on the disease.

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

If abnormal vaginal bleeding occurs during therapy, appropriate examinations should be performed to rule out a genital tract malignancy.

In clinical studies, the median duration of treatment before the onset of a definite objective response has been 2 months. However, approximately one-quarter 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, tamoxifen 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.

Adverse Reactions: The most frequent adverse reactions to tamoxifen are hot flashes, nausea and vomiting. These may occur in up to one-quarter 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 noted infrequently are hypercalcemia, peripheral edema, distaste for food, pruritus vulvae, depression, dizziness, lightheadedness and headache.

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

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 few 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 an ongoing 2-year oncogenicity study in rats.

There have been infrequent reports of thromboembolic events occurring during tamoxifen therapy. As an increased incidence of these events is known to occur in patients with malignant disease, a causal relationship with tamoxifen has not been established.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Acute overdosage in humans has not been reported. Possible overdosage effects might include hot flashes, nausea, vomiting and vaginal bleeding. No specific treatment for overdosage is known and treatment must be symptomatic.

In case of accidental ingestion by a child, gastric emptying is suggested.

Dosage And Administration: The recommended daily dose of tamoxifen is 20 to 40 mg. The lowest effective dose should be used.

10 mg: 1 or 2 tablets twice a day, morning and evening. The lowest effective dose should be used.

20 mg: 1 or 2 tablets once a day. The lowest effective dose should be used.

Availability And Storage: 10 mg: Each white, round, biconvex tablet, impressed with F on one face and 10 on the reverse, contains: tamoxifen citrate 15.2 mg (equivalent to tamoxifen 10 mg). Nonmedicinal ingredients: maize starch, magnesium stearate, lactose, povidone and sodium starch glycolate. Containers of 60 and 250. Blister packs of 10 strips of 10 tablets.

20 mg: Each white, round, biconvex tablet, impressed with F on one face and 20 on the reverse, contains: tamoxifen citrate 30.4 mg (equivalent to tamoxifen 20 mg). Nonmedicinal ingredients: maize starch, magnesium stearate, lactose, povidone and sodium starch glycolate. Containers of 30 and 100. Blister packs of 10 strips of 10 tablets.

Store at room temperature (15 to 30°C), protected from light.

TAMONE® Pharmacia & Upjohn Tamoxifen Citrate Antineoplastic

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