Information for the Patient
Nolvadex-D
Pharmacology
Tamoxifen, the active ingredient, is a non-steroidal 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 tumours. In this rat model, tamoxifen appears to exert its antitumour 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.
In women with estrogen receptor-positive/unknown breast tumours, adjuvant tamoxifen has been shown to significantly reduce recurrence of the disease and improve 10-year survival, achieving a significantly greater effect with five years treatment than with 1 or 2 years treatment. These benefits appear to be largely irrespective of age, menopausal status, tamoxifen dose and additional chemotherapy.
Ranges as large as 0 to 300 fmol/mg protein have been reported in histologically comparable portions of the same tumour. In addition, the collection, transport and storage of tumour 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 tumour growth. It is recognized that tamoxifen also displays estrogenic-like effects on several body systems including the endometrium, bone and blood lipids.
Indications
Tamoxifen is indicated for the adjuvant treatment of early breast cancer in women with estrogen receptor positive tumors.
Tamoxifen is indicated for the treatment of women with hormone responsive locally advanced/metastatic breast cancer.
Precautions
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.
The use of tamoxifen in combination with an aromatase inhibitor as adjuvant therapy has not shown improved efficacy compared with tamoxifen alone.
The known principal pathway for tamoxifen metabolism in humans is demethylation, catalyzed by CYP3A4 enzymes. A pharmacokinetic interaction with the CYP3A4 inducing agent rifampicin, involving a reduction in tamoxifen plasma levels, has been reported in the literature. The relevance of this to clinical practice is not known.
Pharmacokinetic interaction with CYP2D6 inhibitors, showing a reduction in plasma level of an active tamoxifen metabolite, 4-hydroxy-N-desmethyltamoxifen (endoxifen), has been reported in the literature. Chronic use of CYP2D6 inhibitors, including certain SSRIs, can lead to reduced plasma concentrations of an active metabolite. The clinical significance in terms of the efficacy of tamoxifen is unclear (see Warnings).
Effect on Ability to Drive and Use Machinery: There is no evidence that tamoxifen results in impairment of these activities.
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.
The use of tamoxifen is not recommended in children, as safety and efficacy have not been established.
Supplied
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 of tamoxifen. Nonmedicinal ingredients: cornstarch, croscarmellose sodium, gelatin, lactose, macrogol 300, magnesium stearate, methylhydroxypropylcellulose and titanium dioxide. Blister packs of 30. Store at room temperature (15 to 30°C) protected from light.
Contraindications
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 diethylstilboestrol (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 1000 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.
When used in the prevention setting (an indication not approved in Canada), tamoxifen is contraindicated in patients with a history of stroke, deep venous thrombosis or pulmonary embolism, and in patients who are at an increased risk of developing endometrial cancer.
Warnings
Tamoxifen should be used only for the conditions listed under the Indications section.
An increased incidence of uterine malignancies has been reported in association with tamoxifen treatment. The underlying mechanism is unknown, but may be related to the estrogen-like effect of tamoxifen. Most uterine malignancies seen in association with tamoxifen are classified as adenocarcinoma of the endometrium. However, rare uterine sarcomas, including malignant mixed Mullerian tumors, have also been reported. Uterine sarcoma is generally associated with a higher FIGO stage (III/IV) at diagnosis, poorer prognosis, and shorter survival. Uterine sarcoma has been reported to occur more frequently among long-term users (≥2 years) of tamoxifen than non-users.
There is evidence of an increased incidence of thromboembolic events, including deep vein thrombosis and pulmonary embolism, during tamoxifen therapy. When tamoxifen is co-administered with chemotherapy, there may be a further increase in the incidence of thromboembolic effects. For treatment of breast cancer, the risks and benefits of tamoxifen should be carefully considered in women with a history of thromboembolic events.
An increased risk of stroke has been found to be associated with tamoxifen therapy in high-risk patients being treated for the prevention of breast cancer. The use of tamoxifen for the prevention of breast cancer is not an approved indication in Canada.
Incidence rates for the above events were estimated from a long-term clinical study called the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention (NSABP P-1) Trial. In this trial, high-risk patients were randomized to either tamoxifen therapy or placebo, for the prevention of breast cancer. Uterine malignancies were separated into cases of endometrial adenocarcinomas and uterine sarcomas. The relative risk of tamoxifen compared to placebo was 3.1 for endometrial cancer, 4.0 for uterine sarcomas, 1.6 for stroke, 3.0 for pulmonary embolism, and 1.6 for deep vein thrombosis.
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 have been reported in the 2-year oncogenicity study in rats receiving tamoxifen. In addition, gonadal tumors have been reported in mice receiving tamoxifen in long-term studies. The clinical relevance of these findings has not been established.
Cataracts were also reported in the 2 year oncogenicity study in rats, and since then it has been established that treatment with tamoxifen has been associated with an increased incidence of cataracts.
A number of second primary tumours, 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.
Adverse Effects
Side effects can be classified as either due to the pharmacological action of the drug, e.g., hot flushes, vaginal discharge, pruritus vulvae, or those requiring further investigations, such as vaginal bleeding (to exclude the possibility of endometrial malignancy) and tumor flare (to exclude the possibility of progressive disease). Side effects can also be classified as more general in nature such as gastrointestinal intolerance (including such events as nausea, vomiting, constipation and diarrhea), headache, light-headedness and occasionally fluid retention and alopecia. When such side effects are severe, it may be possible to control them by a simple reduction of dosage (within the recommended dose range) without loss of control of the disease (see Table 1).
Skin rashes (including isolated reports of erythema multiforme, Stevens-Johnson syndrome and bullous pemphigoid) and rare hypersensitivity reactions, including angioedema have been reported.
Increased bone and tumour pain and also local disease flare have occurred. These are sometimes associated with a good tumour 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. A small number of patients with bony metastases have developed hypercalcaemia on initiation of therapy.
Ocular changes have been reported in a few breast cancer patients who, as part of a clinical trial, were treated for periods longer than one year with doses of tamoxifen that were at least four 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. A number of cases of visual disturbances, including infrequent reports of corneal changes, and retinopathy have been described in patients receiving tamoxifen therapy. An increased incidence of cataracts has been reported in association with the administration of tamoxifen.
Cases of optic neuropathy and optic neuritis have been reported in patients receiving tamoxifen and, in a small number of cases, blindness has occurred.
Uterine fibroids, endometriosis and other endometrial changes including hyperplasia and polyps have been reported.
Falls in platelet count, usually only to 80 000 to 90 000 per cu mm but occasionally lower, have been reported in patients taking tamoxifen.
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 is evidence of an increased incidence of ischemic cerebrovascular events, thromboembolic events, including deep vein thrombosis and pulmonary embolism, during tamoxifen therapy (see Warnings). In the prevention setting, treatment with tamoxifen has been associated with an increased risk of stroke (see Warnings). When tamoxifen is used in combination with cytotoxic agents, there is an increased risk of thromboembolic events occurring.
Leg cramps have been reported commonly in patients receiving tamoxifen.
Very rarely, cases of interstitial pneumonitis have been reported.
Elevation of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transpeptidase (GGT) levels has been reported infrequently during tamoxifen citrate therapy, and on rare occasions with a spectrum of more severe liver abnormalities, including fatty liver, cholestasis and hepatitis. Very rarely, cases of hepatic cyst and peliosis hepatitis have also been reported.
Rarely, elevation of serum triglyceride levels, in some cases with pancreatitis, may be associated with the use of tamoxifen.
Cystic ovarian swellings have occasionally been observed in premenopausal women receiving tamoxifen.
An increased incidence of endometrial cancer and uterine sarcoma (mostly malignant mixed Mullerian tumors) has been reported in association with tamoxifen treatment.
Other adverse reactions which are seen infrequently are depression and distaste for food.
Overdose
Acute overdosage in humans has not been reported. Possible overdosage effects might include hot flashes, nausea, vomiting and vaginal bleeding.
There have been reports in the literature that tamoxifen given at several times the standard dose may be associated with prolongation of the QT interval of the ECG.
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
The use of tamoxifen is not recommended in children, as safety and efficacy have not been established.
