Tamoxifeno-Refasa

'Tamoxifeno-Refasa' is indicated for:

1. The treatment of breast cancer.

2. The treatment of anovulatory infertility.

Metastatic Breast Cancer

Tamoxifeno-Refasa (tamoxifen citrate) is effective in the treatment of metastatic breast cancer in women and men. In premenopausal women with metastatic breast cancer, Tamoxifeno-Refasa (tamoxifen citrate) 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 Tamoxifeno-Refasa (tamoxifen citrate) therapy.

Adjuvant Treatment of Breast Cancer

Tamoxifeno-Refasa (tamoxifen citrate) is indicated for the treatment of node-positive breast cancer in women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation. In some Tamoxifeno-Refasa (tamoxifen citrate) adjuvant studies, most of the benefit to date has been in the subgroup with four or more positive axillary nodes.

Tamoxifeno-Refasa (tamoxifen citrate) 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 Tamoxifeno-Refasa (tamoxifen citrate) therapy is likely to be beneficial.

Tamoxifeno-Refasa (tamoxifen citrate) reduces the occurrence of contralateral breast cancer in patients receiving adjuvant Tamoxifeno-Refasa (tamoxifen citrate) therapy for breast cancer.

Ductal Carcinoma in Situ (DCIS)

In women with DCIS, following breast surgery and radiation, Tamoxifeno-Refasa (tamoxifen citrate) is indicated to reduce the risk of invasive breast cancer (see BOXED WARNING at the beginning of the label). The decision regarding therapy with Tamoxifeno-Refasa (tamoxifen citrate) for the reduction in breast cancer incidence should be based upon an individual assessment of the benefits and risks of Tamoxifeno-Refasa (tamoxifen citrate) therapy.

Current data from clinical trials support five years of adjuvant Tamoxifeno-Refasa (tamoxifen citrate) therapy for patients with breast cancer.

Reduction in Breast Cancer Incidence in High Risk Women

Tamoxifeno-Refasa (tamoxifen citrate) is indicated to reduce the incidence of breast cancer in women at high risk for breast cancer. This effect was shown in a study of 5 years planned duration with a median follow-up of 4.2 years. Twenty-five percent of the participants received drug for 5 years. The longer-term effects are not known. In this study, there was no impact of tamoxifen on overall or breast cancer-related mortality (see BOXED WARNING at the beginning of the label).

Tamoxifeno-Refasa (tamoxifen citrate) is indicated only for high-risk women. “High risk” is defined as women at least 35 years of age with a 5-year predicted risk of breast cancer ≥ 1.67%, as calculated by the Gail Model.

Examples of combinations of factors predicting a 5-year risk ≥ 1.67% are:

Age 35 or older and any of the following combination of factors:

• One first degree relative with a history of breast cancer, 2 or more benign biopsies, and a history of a breast biopsy showing atypical hyperplasia; or
• At least 2 first degree relatives with a history of breast cancer, and a personal history of at least one breast biopsy; or
• LCIS

Age 40 or older and any of the following combination of factors:

• One first degree relative with a history of breast cancer, 2 or more benign biopsies, age at first live birth 25 or older, and age at menarche 11 or younger; or
• At least 2 first degree relatives with a history of breast cancer, and age at first live birth 19 or younger; or
• One first degree relative with a history of breast cancer, and a personal history of a breast biopsy showing atypical hyperplasia.

Age 45 or older and any of the following combination of factors:

• At least 2 first degree relatives with a history of breast cancer and age at first live birth 24 or younger; or
• One first degree relative with a history of breast cancer with a personal history of a benign breast biopsy, age at menarche 11 or less and age at first live birth 20 or more.

Age 50 or older and any of the following combination of factors:

• At least 2 first degree relatives with a history of breast cancer; or
• History of one breast biopsy showing atypical hyperplasia, and age at first live birth 30 or older and age at menarche 11 or less; or
• History of at least two breast biopsies with a history of atypical hyperplasia, and age at first live birth 30 or more.

Age 55 or older and any of the following combination of factors:

• One first degree relative with a history of breast cancer with a personal history of a benign breast biopsy, and age at menarche 11 or less; or
• History of at least 2 breast biopsies with a history of atypical hyperplasia, and age at first live birth 20 or older.

Age 60 or older and:

• 5-year predicted risk of breast cancer ≥ 1.67%, as calculated by the Gail Model.

For women whose risk factors are not described in the above examples, the Gail Model is necessary to estimate absolute breast cancer risk. Health Care Professionals can obtain a Gail Model Risk Assessment Tool by dialing 1-800-544-2007.

There are insufficient data available regarding the effect of Tamoxifeno-Refasa (tamoxifen citrate) on breast cancer incidence in women with inherited mutations (BRCA1, BRCA2) to be able to make specific recommendations on the effectiveness of Tamoxifeno-Refasa (tamoxifen citrate) in these patients.

After an assessment of the risk of developing breast cancer, the decision regarding therapy with Tamoxifeno-Refasa (tamoxifen citrate) for the reduction in breast cancer incidence should be based upon an individual assessment of the benefits and risks of Tamoxifeno-Refasa (tamoxifen citrate) therapy. In the NSABP P-1 trial, Tamoxifeno-Refasa (tamoxifen citrate) treatment lowered the risk of developing breast cancer during the follow-up period of the trial, but did not eliminate breast cancer risk (See Table 3 in CLINICAL PHARMACOLOGY).

Posology

1. Breast cancer:

Adults: The recommended daily dose of Tamoxifeno-Refasa is normally 20mg. No additional benefit, in terms of delayed recurrence or improved survival in patients, has been demonstrated with higher doses. Substantive evidence supporting the use of treatment with 30-40mg per day is not available, although these doses have been used in some patients with advanced disease.

Older people: Similar dosing regimens of Tamoxifeno-Refasa have been used in older people with breast cancer and in some of these patients it has been used as sole therapy.

2. Anovulatory infertility:

Before commencing any course of treatment, whether initial or subsequent, the possibility of pregnancy must be excluded. In women who are menstruating regularly, but with anovular cycles, the initial course of treatment consists of 20 mg given daily on the second, third, fourth and fifth days of the menstrual cycle. If unsatisfactory basal temperature records or poor pre-ovulatory cervical mucus indicate that this initial course of treatment has been unsuccessful, further courses may be given during subsequent menstrual periods, increasing the dosage to 40mg and then 80mg daily.

In women who are not menstruating regularly, the initial course may begin on any day. If no signs of ovulation are demonstrable, then a subsequent course of treatment may start 45 days later, with dosage increased as above. If a patient responds with menstruation, then the next course of treatment is commenced on the second day of the cycle.

Paediatric population

The use of Tamoxifeno-Refasa is not recommended in children. The safety and efficacy of Tamoxifeno-Refasa in children has not yet been established.

Method of administration

For administration by the oral route.

For patients with breast cancer, the recommended daily dose is 20-40 mg. Dosages greater than 20 mg per day should be given in divided doses (morning and evening).

In three single agent adjuvant studies in women, one 10 mg Tamoxifeno-Refasa (tamoxifen citrate) tablet was administered two (ECOG and NATO) or three (Toronto) times a day for two years. In the NSABP B-14 adjuvant study in women with node-negative breast cancer, one 10 mg Tamoxifeno-Refasa (tamoxifen citrate) tablet was given twice a day for at least 5 years. Results of the B-14 study suggest that continuation of therapy beyond five years does not provide additional benefit (see CLINICAL PHARMACOLOGY). In the EBCTCG 1995 overview, the reduction in recurrence and mortality was greater in those studies that used tamoxifen for about 5 years than in those that used tamoxifen for a shorter period of therapy. There was no indication that doses greater than 20 mg per day were more effective. Current data from clinical trials support 5 years of adjuvant Tamoxifeno-Refasa (tamoxifen citrate) therapy for patients with breast cancer.

Ductal Carcinoma in Situ (DCIS)

The recommended dose is Tamoxifeno-Refasa (tamoxifen citrate) 20 mg daily for 5 years.

Reduction in Breast Cancer Incidence in High Risk Women

The recommended dose is Tamoxifeno-Refasa (tamoxifen citrate) 20 mg daily for 5 years. There are no data to support the use of Tamoxifeno-Refasa (tamoxifen citrate) other than for 5 years (See CLINICAL PHARMACOLOGY-Clinical Studies - Reduction in Breast Cancer Incidence in High Risk Women).

Tamoxifeno-Refasa should not be used in the following:

- pregnancy.).

-

- concurrent anastrozole therapy.

- treatment for infertility. Patients with a personal or family history of confirmed idiopathic venous thromboembolic events or a known genetic defect.

Tamoxifeno-Refasa (tamoxifen citrate) 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

Tamoxifeno-Refasa (tamoxifen citrate) is contraindicated in women who require concomitant coumarin-type anticoagulant therapy or in women with a history of deep vein thrombosis or pulmonary embolus.

Menstruation is suppressed in a proportion of premenopausal women receiving Tamoxifeno-Refasa for the treatment of breast cancer.

An increased incidence of endometrial changes including hyperplasia, polyps, cancer and uterine sarcoma (mostly malignant mixed Mullerian tumours), has been reported in association with Tamoxifeno-Refasa treatment.The underlying mechanism is unknown but may be related to the oestrogen-like effect of Tamoxifeno-Refasa. Any patient receiving or having previously received Tamoxifeno-Refasa who reports abnormal gynaecological symptoms, especially vaginal bleeding, or who presents with menstrual irregularities, vaginal discharge and symptoms such as pelvic pain or pressure should be promptly investigated.

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 Tamoxifeno-Refasa. No causal link has been established and the clinical significance of these observations remains unclear.

Venous thromboembolism (VTE)

- A two- to three-fold increase in the risk for VTE has been demonstrated in healthy Tamoxifeno-Refasa-treated women.

- In patients with breast cancer, prescribers should obtain careful histories with respect to the patient's personal and family history of VTE.).

- The risk of VTE is further increased by severe obesity, increasing age and all other risk factors for VTE. The risks and benefits should be carefully considered for all patients before treatment with Tamoxifeno-Refasa. In patients with breast cancer, this risk is also increased by concomitant chemotherapy. Long-term anticoagulant prophylaxis may be justified for some patients with breast cancer who have multiple risk factors for VTE.

- Surgery and immobility: For patients being treated for infertility, Tamoxifeno-Refasa should be stopped at least 6 weeks before surgery or long-term immobility (when possible) and re-started only when the patient is fully mobile. For patients with breast cancer, Tamoxifeno-Refasa treatment should only be stopped if the risk of Tamoxifeno-Refasa-induced thrombosis clearly outweighs the risks associated with interrupting treatment. All patients should receive appropriate thrombosis prophylactic measures and should include graduated compression stockings for the period of hospitalisation, early ambulation, if possible, and anticoagulant treatment.

- If any patient presents with VTE, Tamoxifeno-Refasa should be stopped immediately and appropriate anti-thrombosis measures initiated. In patients being treated for infertility, Tamoxifeno-Refasa should not be re-started unless there is a compelling alternative explanation for their thrombotic event. In patients receiving Tamoxifeno-Refasa for breast cancer, the decision to re-start Tamoxifeno-Refasa should be made with respect to the overall risk for the patient. In selected patients with breast cancer, the continued use of Tamoxifeno-Refasa with prophylactic anticoagulation may be justified.

- All patients should be advised to contact their doctors immediately if they become aware of any symptoms of VTE.

In delayed microsurgical breast reconstruction Tamoxifeno-Refasa may increase the risk of microvascular flap complications.

In an uncontrolled trial in 28 girls aged 2-10 years with McCune Albright Syndrome (MAS), who received 20 mg once a day for up to 12 months duration, mean uterine volume increased after 6 months of treatment and doubled at the end of the one-year study. While this finding is in line with the pharmacodynamic properties of Tamoxifeno-Refasa, a causal relationship has not been established.

In the literature it has been shown that CYP2D6 poor metabolisers have a lowered plasma level of endoxifen, one of the most important active metabolites of Tamoxifeno-Refasa.

Concomitant medications that inhibit CYP2D6 may lead to reduced concentrations of the active metabolite endoxifen. Therefore, potent inhibitors of CYP2D6 (e.g. paroxetine, fluoxetine, quinidine, cinacalcet or bupropion) should whenever possible be avoided during Tamoxifeno-Refasa treatment. Tamoxifeno-Refasa contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Radiation recall has been reported very rarely in patients on Tamoxifeno-Refasa who have received prior radiotherapy. The reaction is usually reversible upon temporary cessation of therapy and re-challenge may result in a milder reaction. Treatment with Tamoxifeno-Refasa was continued in most cases.

WARNINGS

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 Tamoxifeno-Refasa (tamoxifen citrate). If hypercalcemia does occur, appropriate measures should be taken and, if severe, Tamoxifeno-Refasa (tamoxifen citrate) should be discontinued.

Effects on the Uterus-Endometrial Cancer and Uterine Sarcoma

An increased incidence of uterine malignancies has been reported in association with Tamoxifeno-Refasa (tamoxifen citrate) treatment. The underlying mechanism is unknown, but may be related to the estrogen-like effect of Tamoxifeno-Refasa (tamoxifen citrate). Most uterine malignancies seen in association with Tamoxifeno-Refasa (tamoxifen citrate) are classified as adenocarcinoma of the endometrium. However, rare uterine sarcomas, including malignant mixed mullerian tumors (MMMT), 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 Tamoxifeno-Refasa (tamoxifen citrate) than non-users. Some of the uterine malignancies (endometrial carcinoma or uterine sarcoma) have been fatal.

In the NSABP P-1 trial, among participants randomized to Tamoxifeno-Refasa (tamoxifen citrate) there was a statistically significant increase in the incidence of endometrial cancer (33 cases of invasive endometrial cancer, compared to 14 cases among participants randomized to placebo (RR=2.48, 95% CI: 1.27-4.92). The 33 cases in participants receiving Tamoxifeno-Refasa (tamoxifen citrate) were FIGO Stage I, including 20 IA, 12 IB, and 1 IC endometrial adenocarcinomas. In participants randomized to placebo, 13 were FIGO Stage I (8 IA and 5 IB) and 1 was FIGO Stage IV. Five women on Tamoxifeno-Refasa (tamoxifen citrate) and 1 on placebo received postoperative radiation therapy in addition to surgery. This increase was primarily observed among women at least 50 years of age at the time of randomization (26 cases of invasive endometrial cancer, compared to 6 cases among participants randomized to placebo (RR=4.50, 95% CI: 1.78-13.16). Among women ≤ 49 years of age at the time of randomization there were 7 cases of invasive endometrial cancer, compared to 8 cases among participants randomized to placebo (RR=0.94, 95% CI: 0.28-2.89). If age at the time of diagnosis is considered, there were 4 cases of endometrial cancer among participants ≤ 49 randomized to Tamoxifeno-Refasa (tamoxifen citrate) compared to 2 among participants randomized to placebo (RR=2.21, 95% CI: 0.4-12.0). For women ≥ 50 at the time of diagnosis, there were 29 cases among participants randomized to Tamoxifeno-Refasa (tamoxifen citrate) compared to 12 among women on placebo (RR=2.5, 95% CI: 1.3-4.9). The risk ratios were similar in the two groups, although fewer events occurred in younger women. Most (29 of 33 cases in the Tamoxifeno-Refasa (tamoxifen citrate) group) endometrial cancers were diagnosed in symptomatic women, although 5 of 33 cases in the Tamoxifeno-Refasa (tamoxifen citrate) group occurred in asymptomatic women. Among women receiving Tamoxifeno-Refasa (tamoxifen citrate) the events appeared between 1 and 61 months (average=32 months) from the start of treatment.

In an updated review of long-term data (median length of total follow-up is 6.9 years, including blinded follow-up) on 8,306 women with an intact uterus at randomization in the NSABP P-1 risk reduction trial, the incidence of both adenocarcinomas and rare uterine sarcomas was increased in women taking Tamoxifeno-Refasa (tamoxifen citrate). During blinded follow-up, there were 36 cases of FIGO Stage I endometrial adenocarcinoma (22 were FIGO Stage IA, 13 IB, and 1 IC) in women receiving Tamoxifeno-Refasa (tamoxifen citrate) and 15 cases in women receiving placebo [14 were FIGO Stage I (9 IA and 5 IB), and 1 case was FIGO Stage IV]. Of the patients receiving Tamoxifeno-Refasa (tamoxifen citrate) who developed endometrial cancer, one with Stage IA and 4 with Stage IB cancers received radiation therapy. In the placebo group, one patient with FIGO Stage 1B cancer received radiation therapy and the patient with FIGO Stage IVB cancer received chemotherapy and hormonal therapy. During total follow-up, endometrial adenocarcinoma was reported in 53 women randomized to Tamoxifeno-Refasa (tamoxifen citrate) (30 cases of FIGO Stage IA, 20 were Stage IB, 1 was Stage IC, and 2 were Stage IIIC), and 17 women randomized to placebo (9 cases were FIGO Stage IA, 6 were Stage IB, 1 was Stage IIIC, and 1 was Stage IVB) (incidence per 1,000 women-years of 2.20 and 0.71, respectively). Some patients received post-operative radiation therapy in addition to surgery. Uterine sarcomas were reported in 4 women randomized to Tamoxifeno-Refasa (tamoxifen citrate) (1 was FIGO IA, 1 was FIGO IB, 1 was FIGO IIA, and 1 was FIGO IIIC) and one patient randomized to placebo (FIGO 1A); incidence per 1,000 women-years of 0.17 and 0.04, respectively. Of the patients randomized to Tamoxifeno-Refasa (tamoxifen citrate) , the FIGO IA and IB cases were a MMMT and sarcoma, respectively; the FIGO II was a MMMT; and the FIGO III was a sarcoma; and the one patient randomized to placebo had a MMMT. A similar increased incidence in endometrial adenocarcinoma and uterine sarcoma was observed among women receiving Tamoxifeno-Refasa (tamoxifen citrate) in five other NSABP clinical trials.

Any patient receiving or who has previously received Tamoxifeno-Refasa (tamoxifen citrate) who reports abnormal vaginal bleeding should be promptly evaluated. Patients receiving or who have previously received Tamoxifeno-Refasa (tamoxifen citrate) should have annual gynecological examinations and they should promptly inform their physicians if they experience any abnormal gynecological symptoms, eg, menstrual irregularities, abnormal vaginal bleeding, changes in vaginal discharge, or pelvic pain or pressure.

In the P-1 trial, endometrial sampling did not alter the endometrial cancer detection rate compared to women who did not undergo endometrial sampling (0.6% with sampling, 0.5% without sampling) for women with an intact uterus. There are no data to suggest that routine endometrial sampling in asymptomatic women taking Tamoxifeno-Refasa (tamoxifen citrate) to reduce the incidence of breast cancer would be beneficial.

Non-Malignant Effects on the Uterus

An increased incidence of endometrial changes including hyperplasia and polyps have been reported in association with Tamoxifeno-Refasa (tamoxifen citrate) treatment. The incidence and pattern of this increase suggest that the underlying mechanism is related to the estrogenic properties of Tamoxifeno-Refasa (tamoxifen citrate).

There have been a few reports of endometriosis and uterine fibroids in women receiving Tamoxifeno-Refasa (tamoxifen citrate). The underlying mechanism may be due to the partial estrogenic effect of Tamoxifeno-Refasa (tamoxifen citrate). Ovarian cysts have also been observed in a small number of premenopausal patients with advanced breast cancer who have been treated with Tamoxifeno-Refasa (tamoxifen citrate).

Tamoxifeno-Refasa (tamoxifen citrate) has been reported to cause menstrual irregularity or amenorrhea.

Thromboembolic Effects of Tamoxifeno-Refasa (tamoxifen citrate)

There is evidence of an increased incidence of thromboembolic events, including deep vein thrombosis and pulmonary embolism, during Tamoxifeno-Refasa (tamoxifen citrate) therapy. When Tamoxifeno-Refasa (tamoxifen citrate) is coadminstered with chemotherapy, there may be a further increase in the incidence of thromboembolic effects. For treatment of breast cancer, the risks and benefits of Tamoxifeno-Refasa (tamoxifen citrate) should be carefully considered in women with a history of thromboembolic events. In a small substudy (N=81) of the NSABP P-1 trial, there appeared to be no benefit to screening women for Factor V Leiden and Prothrombin mutations G20210A as a means to identify those who may not be appropriate candidates for Tamoxifeno-Refasa (tamoxifen citrate) therapy.

Data from the NSABP P-1 trial show that participants receiving Tamoxifeno-Refasa (tamoxifen citrate) without a history of pulmonary emboli (PE) had a statistically significant increase in pulmonary emboli (18-Tamoxifeno-Refasa (tamoxifen citrate) , 6-placebo, RR=3.01, 95% CI: 1.15- 9.27). Three of the pulmonary emboli, all in the Tamoxifeno-Refasa (tamoxifen citrate) arm, were fatal. Eighty-seven percent of the cases of pulmonary embolism occurred in women at least 50 years of age at randomization. Among women receiving Tamoxifeno-Refasa (tamoxifen citrate) , the events appeared between 2 and 60 months (average=27 months) from the start of treatment.

In this same population, a non-statistically significant increase in deep vein thrombosis (DVT) was seen in the Tamoxifeno-Refasa (tamoxifen citrate) group (30-Tamoxifeno-Refasa (tamoxifen citrate) , 19-placebo; RR=1.59, 95% CI: 0.86-2.98). The same increase in relative risk was seen in women ≤ 49 and in women ≥ 50, although fewer events occurred in younger women. Women with thromboembolic events were at risk for a second related event (7 out of 25 women on placebo, 5 out of 48 women on Tamoxifeno-Refasa (tamoxifen citrate) ) and were at risk for complications of the event and its treatment (0/25 on placebo, 4/48 on Tamoxifeno-Refasa (tamoxifen citrate) ). Among women receiving Tamoxifeno-Refasa (tamoxifen citrate) , deep vein thrombosis events occurred between 2 and 57 months (average=19 months) from the start of treatment.

There was a non-statistically significant increase in stroke among patients randomized to Tamoxifeno-Refasa (tamoxifen citrate) (24-Placebo; 34-Tamoxifeno-Refasa (tamoxifen citrate) ; RR=1.42; 95% CI 0.82-2.51). Six of the 24 strokes in the placebo group were considered hemorrhagic in origin and 10 of the 34 strokes in the Tamoxifeno-Refasa (tamoxifen citrate) group were categorized as hemorrhagic. Seventeen of the 34 strokes in the Tamoxifeno-Refasa (tamoxifen citrate) group were considered occlusive and 7 were considered to be of unknown etiology. Fourteen of the 24 strokes on the placebo arm were reported to be occlusive and 4 of unknown etiology. Among these strokes 3 strokes in the placebo group and 4 strokes in the Tamoxifeno-Refasa (tamoxifen citrate) group were fatal. Eighty-eight percent of the strokes occurred in women at least 50 years of age at the time of randomization. Among women receiving Tamoxifeno-Refasa (tamoxifen citrate) , the events occurred between 1 and 63 months (average=30 months) from the start of treatment.

Effects on the liver: Liver cancer

In the Swedish trial using adjuvant Tamoxifeno-Refasa (tamoxifen citrate) 40 mg/day for 2-5 years, 3 cases of liver cancer have been reported in the Tamoxifeno-Refasa (tamoxifen citrate) -treated group vs. 1 case in the observation group (See PRECAUTIONS- Carcinogenesis). In other clinical trials evaluating Tamoxifeno-Refasa (tamoxifen citrate) , no cases of liver cancer have been reported to date.

One case of liver cancer was reported in NSABP P-1 in a participant randomized to Tamoxifeno-Refasa (tamoxifen citrate).

Effects on the liver: Non-malignant effects

Tamoxifeno-Refasa (tamoxifen citrate) has been associated with changes in liver enzyme levels, and on rare occasions, a spectrum of more severe liver abnormalities including fatty liver, cholestasis, hepatitis and hepatic necrosis. A few of these serious cases included fatalities. In most reported cases the relationship to Tamoxifeno-Refasa (tamoxifen citrate) is uncertain. However, some positive rechallenges and dechallenges have been reported.

In the NSABP P-1 trial, few grade 3-4 changes in liver function (SGOT, SGPT, bilirubin, alkaline phosphatase) were observed (10 on placebo and 6 on Tamoxifeno-Refasa (tamoxifen citrate) ). Serum lipids were not systematically collected.

Other cancers

A number of second primary tumors, occurring at sites other than the endometrium, have been reported following the treatment of breast cancer with Tamoxifeno-Refasa (tamoxifen citrate) in clinical trials. Data from the NSABP B-14 and P-1 studies show no increase in other (non-uterine) cancers among patients receiving Tamoxifeno-Refasa (tamoxifen citrate). Whether an increased risk for other (non-uterine) cancers is associated with Tamoxifeno-Refasa (tamoxifen citrate) is still uncertain and continues to be evaluated.

Effects on the Eye

Ocular disturbances, including corneal changes, decrement in color vision perception, retinal vein thrombosis, and retinopathy have been reported in patients receiving Tamoxifeno-Refasa (tamoxifen citrate). An increased incidence of cataracts and the need for cataract surgery have been reported in patients receiving Tamoxifeno-Refasa (tamoxifen citrate).

In the NSABP P-1 trial, an increased risk of borderline significance of developing cataracts among those women without cataracts at baseline (540-Tamoxifeno-Refasa (tamoxifen citrate) ; 483-placebo; RR=1.13, 95% CI: 1.00-1.28) was observed. Among these same women, Tamoxifeno-Refasa (tamoxifen citrate) was associated with an increased risk of having cataract surgery (101-Tamoxifeno-Refasa (tamoxifen citrate) ; 63-placebo; RR=1.62, 95% CI 1.18-2.22) (See Table 3 in CLINICAL PHARMACOLOGY). Among all women on the trial (with or without cataracts at baseline), Tamoxifeno-Refasa (tamoxifen citrate) was associated with an increased risk of having cataract surgery (201-Tamoxifeno-Refasa (tamoxifen citrate) ; 129-placebo; RR=1.58, 95% CI 1.26-1.97). Eye examinations were not required during the study. No other conclusions regarding non-cataract ophthalmic events can be made.

Pregnancy Category D

Tamoxifeno-Refasa (tamoxifen citrate) may cause fetal harm when administered to a pregnant woman. Women should be advised not to become pregnant while taking Tamoxifeno-Refasa (tamoxifen citrate) or within 2 months of discontinuing Tamoxifeno-Refasa (tamoxifen citrate) and should 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. In reproductive studies in rats at dose levels equal to or below the human dose, nonteratogenic developmental skeletal changes were seen and were found reversible. In addition, in fertility studies in rats and in teratology studies in rabbits using doses at or below those used in humans, a lower incidence of embryo implantation and a higher incidence of fetal death or retarded in utero growth were observed, with slower learning behavior in some rat pups when compared to historical controls. Several pregnant marmosets were dosed with 10 mg/kg/day (about 2-fold the daily maximum recommended human dose on a mg/m² basis) during organogenesis or in the last half of pregnancy. No deformations were seen and, although the dose was high enough to terminate pregnancy in some animals, those that did maintain pregnancy showed no evidence of teratogenic malformations.

In rodent models of fetal reproductive tract development, tamoxifen (at doses 0.002 to 2.4-fold the daily maximum recommended human dose on a mg/m² basis) caused changes in both sexes that are similar to those caused by estradiol, ethynylestradiol and diethylstilbestrol. Although the clinical relevance of these changes is unknown, some of these changes, especially vaginal adenosis, are similar to those seen in young women who were exposed to diethylstilbestrol in utero and who have a 1 in 1000 risk of developing clear-cell adenocarcinoma of the vagina or cervix. To date, in utero exposure to tamoxifen has not been shown to cause vaginal adenosis, or clear-cell adenocarcinoma of the vagina or cervix, in young women. However, only a small number of young women have been exposed to tamoxifen in utero, and a smaller number have been followed long enough (to age 15-20) to determine whether vaginal or cervical neoplasia could occur as a result of this exposure.

There are no adequate and well-controlled trials of tamoxifen in pregnant women. There have been a small number of reports of vaginal bleeding, spontaneous abortions, birth defects, and fetal deaths in pregnant women. If this drug is used during pregnancy, or the patient becomes pregnant while taking this drug, or within approximately two months after discontinuing therapy, the patient should be apprised of the potential risks to the fetus including the potential long-term risk of a DES-like syndrome.

Reduction in Breast Cancer Incidence in High Risk Women - Pregnancy Category D

For sexually active women of child-bearing potential, Tamoxifeno-Refasa (tamoxifen citrate) therapy should be initiated during menstruation. In women with menstrual irregularity, a negative B-HCG immediately prior to the initiation of therapy is sufficient (See PRECAUTIONS-INFORMATION FOR PATIENTS - Reduction in Breast Cancer Incidence in High Risk Women).

PRECAUTIONS

General

Decreases in platelet counts, usually to 50,000-100,000/mm³, infrequently lower, have been occasionally reported in patients taking Tamoxifeno-Refasa (tamoxifen citrate) for breast cancer. In patients with significant thrombocytopenia, rare hemorrhagic episodes have occurred, but it is uncertain if these episodes are due to Tamoxifeno-Refasa (tamoxifen citrate) 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 Tamoxifeno-Refasa (tamoxifen citrate) ; this can sometimes be severe.

In the NSABP P-1 trial, 6 women on Tamoxifeno-Refasa (tamoxifen citrate) and 2 on placebo experienced grade 3-4 drops in platelet counts ( ≤ 50,000/mm³).

Information for Patients

Patients should be instructed to read the Medication Guide supplied as required by law when Tamoxifeno-Refasa is dispensed. The complete text of the Medication Guide is reprinted at the end of this document.

Reduction in Invasive Breast Cancer and DCIS in Women with DCIS

Women with DCIS treated with lumpectomy and radiation therapy who are considering Tamoxifeno-Refasa (tamoxifen citrate) to reduce the incidence of a second breast cancer event should assess the risks and benefits of therapy, since treatment with Tamoxifeno-Refasa (tamoxifen citrate) decreased the incidence of invasive breast cancer, but has not been shown to affect survival (See Table 1 in CLINICAL PHARMACOLOGY).

Reduction in Breast Cancer Incidence in High Risk Women

Women who are at high risk for breast cancer can consider taking Tamoxifeno-Refasa (tamoxifen citrate) therapy to reduce the incidence of breast cancer. Whether the benefits of treatment are considered to outweigh the risks depends on a woman's personal health history and on how she weighs the benefits and risks. Tamoxifeno-Refasa (tamoxifen citrate) therapy to reduce the incidence of breast cancer may therefore not be appropriate for all women at high risk for breast cancer. Women who are considering Tamoxifeno-Refasa (tamoxifen citrate) therapy should consult their health care professional for an assessment of the potential benefits and risks prior to starting therapy for reduction in breast cancer incidence (See Table 3 in CLINICAL PHARMACOLOGY). Women should understand that Tamoxifeno-Refasa (tamoxifen citrate) reduces the incidence of breast cancer, but may not eliminate risk. Tamoxifeno-Refasa (tamoxifen citrate) decreased the incidence of small estrogen receptor positive tumors, but did not alter the incidence of estrogen receptor negative tumors or larger tumors. In women with breast cancer who are at high risk of developing a second breast cancer, treatment with about 5 years of Tamoxifeno-Refasa (tamoxifen citrate) reduced the annual incidence rate of a second breast cancer by approximately 50%.

Women who are pregnant or who plan to become pregnant should not take Tamoxifeno-Refasa (tamoxifen citrate) to reduce her risk of breast cancer. Effective nonhormonal contraception must be used by all premenopausal women taking Tamoxifeno-Refasa (tamoxifen citrate) and for approximately two months 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 child-bearing potential, Tamoxifeno-Refasa (tamoxifen citrate) therapy should be initiated during menstruation. In women with menstrual irregularity, a negative B-HCG immediately prior to the initiation of therapy is sufficient (See WARNINGS-Pregnancy Category D).

Two European trials of tamoxifen to reduce the risk of breast cancer were conducted and showed no difference in the number of breast cancer cases between the tamoxifen and placebo arms. These studies had trial designs that differed from that of NSABP P-1, were smaller than NSABP P-1, and enrolled women at a lower risk for breast cancer than those in P-1.

Monitoring During Tamoxifeno-Refasa (tamoxifen citrate) Therapy

Women taking or having previously taken Tamoxifeno-Refasa (tamoxifen citrate) should be instructed to seek prompt medical attention for new breast lumps, vaginal bleeding, gynecologic symptoms (menstrual irregularities, changes in vaginal discharge, or pelvic pain or pressure), symptoms of leg swelling or tenderness, unexplained shortness of breath, or changes in vision. Women should inform all care providers, regardless of the reason for evaluation, that they take Tamoxifeno-Refasa (tamoxifen citrate).

Women taking Tamoxifeno-Refasa (tamoxifen citrate) to reduce the incidence of breast cancer should have a breast examination, a mammogram, and a gynecologic examination prior to the initiation of therapy. These studies should be repeated at regular intervals while on therapy, in keeping with good medical practice. Women taking Tamoxifeno-Refasa (tamoxifen citrate) as adjuvant breast cancer therapy should follow the same monitoring procedures as for women taking Tamoxifeno-Refasa (tamoxifen citrate) for the reduction in the incidence of breast cancer. Women taking Tamoxifeno-Refasa (tamoxifen citrate) as treatment for metastatic breast cancer should review this monitoring plan with their care provider and select the appropriate modalities and schedule of evaluation.

Laboratory Tests

Periodic complete blood counts, including platelet counts, and periodic liver function tests should be obtained.

During the ATAC trial, more patients receiving anastrozole were reported to have an elevated serum cholesterol compared to patients receiving Tamoxifeno-Refasa (tamoxifen citrate) (9% versus 3.5%, respectively).

Carcinogenesis

A conventional carcinogenesis study in rats at doses of 5, 20, and 35 mg/kg/day (about one, three and seven-fold the daily maximum recommended human dose on a mg/m²basis) administered by oral gavage for up to 2 years) revealed a significant increase in hepatocellular carcinoma at all doses. The incidence of these tumors was significantly greater among rats administered 20 or 35 mg/kg/day (69%) compared to those administered 5 mg/kg/day (14%). In a separate study, rats were administered tamoxifen at 45 mg/kg/day (about nine-fold the daily maximum recommended human dose on a mg/m² basis); hepatocellular neoplasia was exhibited at 3 to 6 months.

Granulosa cell ovarian tumors and interstitial cell testicular tumors were observed in two separate mouse studies. The mice were administered the trans and racemic forms of tamoxifen for 13 to 15 months at doses of 5, 20 and 50 mg/kg/day (about one-half, two and five-fold the daily recommended human dose on a mg/m² basis).

Mutagenesis

No genotoxic potential was found in a conventional battery of in vivo and in vitro tests with pro- and eukaryotic test systems with drug metabolizing systems. However, increased levels of DNA adducts were observed by ³²P post-labeling in DNA from rat liver and cultured human lymphocytes. Tamoxifen also has been found to increase levels of micronucleus formation in vitro in human lymphoblastoid cell line (MCL-5). Based on these findings, tamoxifen is genotoxic in rodent and human MCL-5 cells.

Impairment of Fertility

Tamoxifen produced impairment of fertility and conception in female rats at doses of 0.04 mg/kg/day (about 0.01-fold the daily maximum recommended human dose on a mg/m² basis) when dosed for two weeks prior to mating through day 7 of pregnancy. At this dose, fertility and reproductive indices were markedly reduced with total fetal mortality. Fetal mortality was also increased at doses of 0.16 mg/kg/day (about 0.03-fold the daily maximum recommended human dose on a mg/m² basis) when female rats were dosed from days 7-17 of pregnancy. Tamoxifen produced abortion, premature delivery and fetal death in rabbits administered doses equal to or greater than 0.125 mg/kg/day (about 0.05-fold the daily maximum recommended human dose on a mg/m² basis). There were no teratogenic changes in either rats or rabbits.

Pregnancy Category D

See WARNINGS.

Nursing Mothers

Tamoxifen has been reported to inhibit lactation. Two placebo-controlled studies in over 150 women have shown that tamoxifen significantly inhibits early postpartum milk production. In both studies tamoxifen was administered within 24 hours of delivery for between 5 and 18 days. The effect of tamoxifen on established milk production is not known.

There are no data that address whether tamoxifen is excreted into human milk. If excreted, there are no data regarding the effects of tamoxifen in breast milk on the breastfed infant or breastfed animals. However, direct neonatal exposure of tamoxifen to mice and rats (not via breast milk) produced 1) reproductive tract lesions in female rodents (similar to those seen in humans after intrauterine exposure to diethylstilbestrol) and 2) functional defects of the reproductive tract in male rodents such as testicular atrophy and arrest of spermatogenesis.

It is not known if Tamoxifeno-Refasa (tamoxifen citrate) is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Tamoxifeno-Refasa (tamoxifen citrate) , women taking Tamoxifeno-Refasa (tamoxifen citrate) should not breast feed.

Reduction in Breast Cancer Incidence in High Risk Women with DCIS

It is not known if Tamoxifeno-Refasa (tamoxifen citrate) is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Tamoxifeno-Refasa (tamoxifen citrate) , women taking Tamoxifeno-Refasa (tamoxifen citrate) should not breast feed.

Pediatric Use

The safety and efficacy of Tamoxifeno-Refasa (tamoxifen citrate) for girls aged two to 10 years with McCune-Albright Syndrome and precocious puberty have not been studied beyond one year of treatment. The long-term effects of Tamoxifeno-Refasa (tamoxifen citrate) therapy for girls have not been established. In adults treated with Tamoxifeno-Refasa (tamoxifen citrate) , an increase in incidence of uterine malignancies, stroke and pulmonary embolism has been noted (see BOXED WARNING, and CLINICAL PHARMACOLOGY-Clinical Studies-McCune-Albright Syndrome subsection).

Geriatric Use

In the NSABP P-1 trial, the percentage of women at least 65 years of age was 16%. Women at least 70 years of age accounted for 6% of the participants. A reduction in breast cancer incidence was seen among participants in each of the subsets: A total of 28 and 10 invasive breast cancers were seen among participants 65 and older in the placebo and Tamoxifeno-Refasa (tamoxifen citrate) groups, respectively. Across all other outcomes, the results in this subset reflect the results observed in the subset of women at least 50 years of age. No overall differences in tolerability were observed between older and younger patients (See CLINICAL PHARMACOLOGY - Clinical Studies - Reduction in Breast Cancer Incidence in High Risk Women section).

In the NSABP B-24 trial, the percentage of women at least 65 years of age was 23%. Women at least 70 years of age accounted for 10% of participants. A total of 14 and 12 invasive breast cancers were seen among participants 65 and older in the placebo and Tamoxifeno-Refasa (tamoxifen citrate) groups, respectively. This subset is too small to reach any conclusions on efficacy. Across all other endpoints, the results in this subset were comparable to those of younger women enrolled in this trial. No overall differences in tolerability were observed between older and younger patients.

Tabulated list of adverse reactions

Unless specified, the following frequency categories were calculated from the number of adverse events reported in a large phase III study conducted in 9366 postmenopausal women patients with operable breast cancer treated for 5 years and unless specified, no account was taken of the frequency within the comparative treatment group or whether the investigator considered it to be related to study medication.

Table 1 Adverse Drug Reactions (ADR) seen with Tamoxifeno-Refasa

^a This adverse drug reaction was not reported in the Tamoxifeno-Refasa arm (n= 3094) of the above study; however, it has been reported in other trials or from other sources. The frequency has been calculated using the upper limit of the 95% confidence interval for the point estimate (based on 3/X, where X represents the total sample size e.g. 3094). This is calculated as 3/3094 which equates to a frequency category of 'rare'.

^b The event was not observed in other major clinical studies. The frequency has been calculated using the upper limit of the 95% confidence interval for the point estimate (based on 3/X, where X represents the total sample size of 13,357 patients in the major clinical studies). This is calculated as 3/13,357 which equates to a frequency category of 'very rare'.

Side effects can be classified as either due to the pharmacological action of the drug, e.g. hot flushes, vaginal bleeding, vaginal discharge, pruritus vulvae and tumour flare, or as more general side effects, e.g. gastrointestinal intolerance, headache, light-headedness and occasionally, fluid retention and alopecia.

When side effects are severe, it may be possible to control them by a simple reduction of dosage (to not less than 20 mg/day) without loss of control of the disease. If side effects do not respond to this measure, it may be necessary to stop the treatment.

Skin rashes (including rare reports of erythema multiforme, Stevens- Johnson syndrome, cutaneous vasculitis and bullous pemphigoid) and commonly hypersensitivity reactions including angioedema have been reported.

Uncommonly, patients with bony metastases have developed hypercalcaemia on initiation of therapy.

Cases of visual disturbances, including rare reports of corneal changes, and common reports of retinopathy have been described in patients receiving Tamoxifeno-Refasa therapy. Cataracts have been reported commonly in association with the administration of Tamoxifeno-Refasa.

Cases of optic neuropathy and optic neuritis have been reported in patients receiving Tamoxifeno-Refasa and, in a small number of cases, blindness has occurred.

Sensory disturbances (including paraesthesia and dysgeusia) have been reported commonly in patients receiving Tamoxifeno-Refasa.

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

Falls in platelet count, usually to 80,000 to 90,000 per cu mm but occasionally lower, have been reported in patients taking Tamoxifeno-Refasa for breast cancer.

Leucopenia has been observed following the administration of Tamoxifeno-Refasa, sometimes in association with anaemia and/or thrombocytopenia. Neutropenia has been reported on rare occasions; this can sometimes be severe, and very rarely cases of agranulocytosis have been reported.

There is evidence of ischaemic cerebrovascular events and thromboembolic events, including deep vein thrombosis, microvascular thrombosis and pulmonary embolism, occurring commonly during Tamoxifeno-Refasa therapy. When Tamoxifeno-Refasa is used in combination with cytotoxic agents, there is an increased risk of thromboembolic events occurring.

Leg cramps and myalgia have been reported commonly in patients receiving Tamoxifeno-Refasa.

Uncommonly, cases of interstitial pneumonitis have been reported.

Tamoxifeno-Refasa has been associated with changes in liver enzyme levels and with a spectrum of more severe liver abnormalities which in some cases were fatal, including fatty liver, cholestasis and hepatitis, liver failure, cirrhosis, and, hepatocellular injury (including hepatic necrosis).

Commonly, elevation of serum triglyceride levels, in some cases with pancreatitis, may be associated with the use of Tamoxifeno-Refasa.

Cystic ovarian swellings have rarely been observed in women receiving Tamoxifeno-Refasa.

Vaginal polyps have rarely been observed in women receiving Tamoxifeno-Refasa.

Cutaneous lupus erythematosus has been observed very-rarely in patients receiving Tamoxifeno-Refasa.

Porphyria cutanea tarda has been observed very-rarely in patients receiving Tamoxifeno-Refasa.

Fatigue has been reported very commonly in patients taking Tamoxifeno-Refasa.

Radiation Recall has been observed very rarely in patients receiving Tamoxifeno-Refasa.

Uncommonly incidences of endometrial cancer and rare instances of uterine sarcoma (mostly malignant mixed Mullerian tumours) has been reported in association with Tamoxifeno-Refasa treatment.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

Adverse reactions to Tamoxifeno-Refasa (tamoxifen citrate) 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 Tamoxifeno-Refasa (tamoxifen citrate) 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 Tamoxifeno-Refasa (tamoxifen citrate) and generally subside rapidly.

In patients treated with Tamoxifeno-Refasa (tamoxifen citrate) for metastatic breast cancer, the most frequent adverse reaction to Tamoxifeno-Refasa (tamoxifen citrate) 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.

Premenopausal Women

The following table summarizes the incidence of adverse reactions reported at a frequency of 2% or greater from clinical trials (Ingle, Pritchard, Buchanan) which compared Tamoxifeno-Refasa (tamoxifen citrate) therapy to ovarian ablation in premenopausal patients with metastatic breast cancer.

Male Breast Cancer

Tamoxifeno-Refasa (tamoxifen citrate) is well tolerated in males with breast cancer. Reports from the literature and case reports suggest that the safety profile of Tamoxifeno-Refasa (tamoxifen citrate) in males is similar to that seen in women. Loss of libido and impotence have resulted in discontinuation of tamoxifen therapy in male patients. Also, in oligospermic males treated with tamoxifen, LH, FSH, testosterone and estrogen levels were elevated. No significant clinical changes were reported.

Adjuvant Breast Cancer

In the NSABP B-14 study, women with axillary node-negative breast cancer were randomized to 5 years of Tamoxifeno-Refasa (tamoxifen citrate) 20 mg/day or placebo following primary surgery. The reported adverse effects are tabulated below (mean follow-up of approximately 6.8 years) showing adverse events more common on Tamoxifeno-Refasa (tamoxifen citrate) than on placebo. The incidence of hot flashes (64% vs. 48%), vaginal discharge (30% vs. 15%), and irregular menses (25% vs. 19%) were higher with Tamoxifeno-Refasa (tamoxifen citrate) compared with placebo. All other adverse effects occurred with similar frequency in the 2 treatment groups, with the exception of thrombotic events; a higher incidence was seen in Tamoxifeno-Refasa (tamoxifen citrate) -treated patients (through 5 years, 1.7% vs. 0.4%). Two of the patients treated with Tamoxifeno-Refasa (tamoxifen citrate) who had thrombotic events died.

In the Eastern Cooperative Oncology Group (ECOG) adjuvant breast cancer trial, Tamoxifeno-Refasa (tamoxifen citrate) or placebo was administered for 2 years to women following mastectomy. When compared to placebo, Tamoxifeno-Refasa (tamoxifen citrate) showed a significantly higher incidence of hot flashes (19% vs. 8% for placebo). The incidence of all other adverse reactions was similar in the 2 treatment groups with the exception of thrombocytopenia where the incidence for Tamoxifeno-Refasa (tamoxifen citrate) was 10% vs. 3% for placebo, an observation of borderline statistical significance.

In other adjuvant studies, Toronto and Tamoxifeno-Refasa (tamoxifen citrate) Adjuvant Trial Organization (NATO), women received either Tamoxifeno-Refasa (tamoxifen citrate) or no therapy. In the Toronto study, hot flashes were observed in 29% of patients for Tamoxifeno-Refasa (tamoxifen citrate) vs. 1% in the untreated group. In the NATO trial, hot flashes and vaginal bleeding were reported in 2.8% and 2.0% of women, respectively, for Tamoxifeno-Refasa (tamoxifen citrate) vs. 0.2% for each in the untreated group.

Anastrozole Adjuvant Trial - Study of Anastrozole compared to Tamoxifeno-Refasa (tamoxifen citrate) for Adjuvant Treatment of Early Breast Cancer (see CLINICAL PHARMACOLOGY - Clinical Studies).

At a median follow-up of 33 months, the combination of anastrozole and Tamoxifeno-Refasa (tamoxifen citrate) did not demonstrate any efficacy benefit when compared to Tamoxifeno-Refasa (tamoxifen citrate) therapy given alone in all patients as well as in the hormone receptor positive subpopulation. This treatment arm was discontinued from the trial. The median duration of adjuvant treatment for safety evaluation was 59.8 months and 59.6 months for patients receiving anastrozole 1 mg and Tamoxifeno-Refasa (tamoxifen citrate) 20 mg, respectively.

Adverse events occurring with an incidence of at least 5% in either treatment group during treatment or within 14 days of the end of treatment are presented in the following table.

Adverse events occurring with an incidence of at least 5% in either treatment group during treatment, or within 14 days of the end of treatment

Certain adverse events and combinations of adverse events were prospectively specified for analysis, based on the known pharmacologic properties and side effect profiles of the two drugs (see the following table).

Number (%) of Patients with Pre-Specified Adverse Event in the Anastrozole Adjuvant Trial¹

Patients receiving anastrozole had an increase in joint disorders (including arthritis, arthrosis and arthralgia) compared with patients receiving Tamoxifeno-Refasa (tamoxifen citrate). Patients receiving anastrozole had an increase in the incidence of all fractures (specifically fractures of spine, hip and wrist) [315 (10%)] compared with patients receiving Tamoxifeno-Refasa (tamoxifen citrate) [209 (7%)]. Patients receiving anastrozole had a decrease in hot flashes, vaginal bleeding, vaginal discharge, endometrial cancer, venous thromboembolic events and ischemic cerebrovascular events compared with patients receiving Tamoxifeno-Refasa (tamoxifen citrate).

Patients receiving Tamoxifeno-Refasa (tamoxifen citrate) had a decrease in hypercholesterolemia (108 [3.5%]) compared to patients receiving anastrozole (278 [9%]). Angina pectoris was reported in 71 [2.3%] patients in the anastrozole arm and 51 [1.6%] patients in the Tamoxifeno-Refasa (tamoxifen citrate) arm; myocardial infarction was reported in 37 [1.2%] patients in the anastrozole arm and in 34 [1.1%] patients in the Tamoxifeno-Refasa (tamoxifen citrate) arm.

Results from the adjuvant trial bone substudy, at 12 and 24 months demonstrated that patients receiving anastrozole had a mean decrease in both lumbar spine and total hip bone mineral density (BMD) compared to baseline. Patients receiving Tamoxifeno-Refasa (tamoxifen citrate) had a mean increase in both lumbar spine and total hip BMD compared to baseline.

Ductal Carcinoma in Situ (DCIS)

The type and frequency of adverse events in the NSABP B-24 trial were consistent with those observed in the other adjuvant trials conducted with Tamoxifeno-Refasa (tamoxifen citrate).

Reduction in Breast Cancer Incidence in High Risk Women

In the NSABP P-1 Trial, there was an increase in five serious adverse effects in the Tamoxifeno-Refasa (tamoxifen citrate) group: endometrial cancer (33 cases in the Tamoxifeno-Refasa (tamoxifen citrate) group vs. 14 in the placebo group); pulmonary embolism (18 cases in the Tamoxifeno-Refasa (tamoxifen citrate) group vs. 6 in the placebo group); deep vein thrombosis (30 cases in the Tamoxifeno-Refasa (tamoxifen citrate) group vs. 19 in the placebo group); stroke (34 cases in the Tamoxifeno-Refasa (tamoxifen citrate) group vs. 24 in the placebo group); cataract formation (540 cases in the Tamoxifeno-Refasa (tamoxifen citrate) group vs. 483 in the placebo group) and cataract surgery (101 cases in the Tamoxifeno-Refasa (tamoxifen citrate) group vs. 63 in the placebo group) (See WARNINGS and Table 3 in CLINICAL PHARMACOLOGY).

The following table presents the adverse events observed in NSABP P-1 by treatment arm. Only adverse events more common on Tamoxifeno-Refasa (tamoxifen citrate) than placebo are shown.

In the NSABP P-1 trial, 15.0% and 9.7% of participants receiving Tamoxifeno-Refasa (tamoxifen citrate) and placebo therapy, respectively withdrew from the trial for medical reasons. The following are the medical reasons for withdrawing from Tamoxifeno-Refasa (tamoxifen citrate) and placebo therapy, respectively: Hot flashes (3.1% vs. 1.5%) and Vaginal Discharge (0.5% vs. 0.1%).

In the NSABP P-1 trial, 8.7% and 9.6% of participants receiving Tamoxifeno-Refasa (tamoxifen citrate) and placebo therapy, respectively withdrew for non-medical reasons.

On the NSABP P-1 trial, hot flashes of any severity occurred in 68% of women on placebo and in 80% of women on Tamoxifeno-Refasa (tamoxifen citrate). Severe hot flashes occurred in 28% of women on placebo and 45% of women on Tamoxifeno-Refasa (tamoxifen citrate). Vaginal discharge occurred in 35% and 55% of women on placebo and Tamoxifeno-Refasa (tamoxifen citrate) respectively; and was severe in 4.5% and 12.3% respectively. There was no difference in the incidence of vaginal bleeding between treatment arms.

Pediatric Patients - McCune-Albright Syndrome

Mean uterine volume increased after 6 months of treatment and doubled at the end of the one-year study. A causal relationship has not been established; however, as an increase in the incidence of endometrial adenocarcinoma and uterine sarcoma has been noted in adults treated with Tamoxifeno-Refasa (see BOXED WARNING), continued monitoring of McCune-Albright patients treated with Tamoxifeno-Refasa (tamoxifen citrate) for long-term effects is recommended. The safety and efficacy of Tamoxifeno-Refasa (tamoxifen citrate) for girls aged two to 10 years with McCune-Albright Syndrome and precocious puberty have not been studied beyond one year of treatment. The long-term effects of Tamoxifeno-Refasa (tamoxifen citrate) therapy in girls have not been established.

Postmarketing experience

Less frequently reported adverse reactions are vaginal bleeding, vaginal discharge, menstrual irregularities, skin rash and headaches. Usually these have not been of sufficient severity to require dosage reduction or discontinuation of treatment. Very rare reports of erythema multiforme, Stevens-Johnson syndrome, bullous pemphigoid, interstitial pneumonitis, and rare reports of hypersensitivity reactions including angioedema have been reported with Tamoxifeno-Refasa (tamoxifen citrate) therapy. In some of these cases, the time to onset was more than one year. Rarely, elevation of serum triglyceride levels, in some cases with pancreatitis, may be associated with the use of Tamoxifeno-Refasa (tamoxifen citrate) (see PRECAUTIONS- Drug/Laboratory Testing Interactions section).

On theoretical grounds an overdosage would be expected to cause enhancement of the pharmacological side-effects mentioned above. Observations in animals show that extreme overdosage (100 - 200 times recommended daily dose) may produce oestrogenic effects.

There have been reports in the literature that Tamoxifeno-Refasa given at several times the standard dose may be associated with prolongation of the QT interval of the ECG.

There is no specific antidote to overdosage, and treatment must be symptomatic.

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. In a study of advanced metastatic cancer patients which specifically determined the maximum tolerated dose of Tamoxifeno-Refasa (tamoxifen citrate) in evaluating the use of very high doses to reverse multidrug resistance, acute neurotoxicity manifested by tremor, hyperreflexia, unsteady gait and dizziness were noted. These symptoms occurred within 3-5 days of beginning Tamoxifeno-Refasa (tamoxifen citrate) and cleared within 2-5 days after stopping therapy. No permanent neurologic toxicity was noted. One patient experienced a seizure several days after Tamoxifeno-Refasa (tamoxifen citrate) was discontinued and neurotoxic symptoms had resolved. The causal relationship of the seizure to Tamoxifeno-Refasa (tamoxifen citrate) therapy is unknown. Doses given in these patients were all greater than 400 mg/m² loading dose, followed by maintenance doses of 150 mg/m² of Tamoxifeno-Refasa (tamoxifen citrate) given twice a day.

In the same study, prolongation of the QT interval on the electrocardiogram was noted when patients were given doses higher than 250 mg/m² loading dose, followed by maintenance doses of 80 mg/m² of Tamoxifeno-Refasa (tamoxifen citrate) given twice a day. For a woman with a body surface area of 1.5 m² the minimal loading dose and maintenance doses given at which neurological symptoms and QT changes occurred were at least 6 fold higher in respect to the maximum recommended dose.

No specific treatment for overdosage is known; treatment must be symptomatic.