Nolvadex Information
Nolvadex (Tamoxifen citrate) Boxed Warning
Some of the strokes, pulmonary emboli, and uterine malignancies were fatal.
Health care providers should discuss the potential benefits versus the potential risks of these serious events with women at high risk of breast cancer and women with DCIS considering Nolvadex (Tamoxifen citrate) to reduce their risk of developing breast cancer.
The benefits of Nolvadex (Tamoxifen citrate) outweigh its risks in women already diagnosed with breast cancer.
*Updated long-term follow-up data (median length of follow-up is 6.9 years) from NSABP P-1 study. See .
**See under
Nolvadex (Tamoxifen citrate) Description
Nolvadex (Tamoxifen citrate) ® (tamoxifen citrate) Tablets, a nonsteroidal antiestrogen, are for oral administration. Nolvadex (Tamoxifen citrate) Tablets are available as:
Each tablet contains 30.4 mg of tamoxifen citrate which is equivalent to 20 mg of tamoxifen.
Inactive Ingredients: carboxymethylcellulose calcium, magnesium stearate, mannitol and starch.
Chemically, Nolvadex (Tamoxifen citrate) is the trans-isomer of a triphenylethylene derivative. The chemical name is (Z)2-[4-(1,2-diphenyl-1-butenyl) phenoxy]-N, N-dimethylethanamine 2 hydroxy-1,2,3- propanetricarboxylate (1:1). The structural and empirical formulas are:
Tamoxifen citrate has a molecular weight of 563.62, the pKa' is 8.85, the equilibrium solubility in water at 37°C is 0.5 mg/mL and in 0.02 N HCl at 37°C, it is 0.2 mg/mL.
Nolvadex (Tamoxifen citrate) Clinical Pharmacology
Nolvadex (Tamoxifen citrate) is a nonsteroidal agent that has demonstrated potent antiestrogenic properties in animal test systems. The antiestrogenic effects may be related to its ability to compete with estrogen for binding sites in target tissues such as breast. Tamoxifen inhibits the induction of rat mammary carcinoma induced by dimethylbenzanthracene (DMBA) and causes the regression of already established DMBA-induced tumors. In this rat model, tamoxifen appears to exert its antitumor effects by binding the estrogen receptors.
In cytosols derived from human breast adenocarcinomas, tamoxifen competes with estradiol for estrogen receptor protein.
Nolvadex (Tamoxifen citrate) Indications And Usage
Nolvadex (Tamoxifen citrate) is indicated for the treatment of node-positive breast cancer in postmenopausal women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation. In some Nolvadex (Tamoxifen citrate) adjuvant studies, most of the benefit to date has been in the subgroup with four or more positive axillary nodes.
Nolvadex (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 Nolvadex (Tamoxifen citrate) therapy is likely to be beneficial.
Nolvadex (Tamoxifen citrate) reduces the occurrence of contralateral breast cancer in patients receiving adjuvant Nolvadex (Tamoxifen citrate) therapy for breast cancer.
In women with DCIS, following breast surgery and radiation, Nolvadex (Tamoxifen citrate) is indicated to reduce the risk of invasive breast cancer (see at the beginning of the label). The decision regarding therapy with Nolvadex (Tamoxifen citrate) for the reduction in breast cancer incidence should be based upon an individual assessment of the benefits and risks of Nolvadex (Tamoxifen citrate) therapy.
Current data from clinical trials support five years of adjuvant Nolvadex (Tamoxifen citrate) therapy for patients with breast cancer.
Nolvadex (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 at the beginning of the label).
Nolvadex (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:
Nolvadex (Tamoxifen citrate) Contraindications
Nolvadex (Tamoxifen citrate) is contraindicated in patients with known hypersensitivity to the drug or any of its ingredients.
Nolvadex (Tamoxifen citrate) Warnings
An increased incidence of uterine malignancies has been reported in association with Nolvadex (Tamoxifen citrate) treatment. The underlying mechanism is unknown, but may be related to the estrogen-like effect of Nolvadex (Tamoxifen citrate) . Most uterine malignancies seen in association with Nolvadex (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 Nolvadex (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 Nolvadex (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 Nolvadex (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 Nolvadex (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 Nolvadex (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 Nolvadex (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 Nolvadex (Tamoxifen citrate) group) endometrial cancers were diagnosed in symptomatic women, although 5 of 33 cases in the Nolvadex (Tamoxifen citrate) group occurred in asymptomatic women. Among women receiving Nolvadex (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 Nolvadex (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 Nolvadex (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 Nolvadex (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 Nolvadex (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 Nolvadex (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 Nolvadex (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 Nolvadex (Tamoxifen citrate) in five other NSABP clinical trials.
Any patient receiving or who has previously received Nolvadex (Tamoxifen citrate) who reports abnormal vaginal bleeding should be promptly evaluated. Patients receiving or who have previously received Nolvadex (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 Nolvadex (Tamoxifen citrate) to reduce the incidence of breast cancer would be beneficial.
An increased incidence of endometrial changes including hyperplasia and polyps have been reported in association with Nolvadex (Tamoxifen citrate) treatment. The incidence and pattern of this increase suggest that the underlying mechanism is related to the estrogenic properties of Nolvadex (Tamoxifen citrate) .
There have been a few reports of endometriosis and uterine fibroids in women receiving Nolvadex (Tamoxifen citrate) . The underlying mechanism may be due to the partial estrogenic effect of Nolvadex (Tamoxifen citrate) . Ovarian cysts have also been observed in a small number of premenopausal patients with advanced breast cancer who have been treated with Nolvadex (Tamoxifen citrate) .
Nolvadex (Tamoxifen citrate) has been reported to cause menstrual irregularity or amenorrhea.
There is evidence of an increased incidence of thromboembolic events, including deep vein thrombosis and pulmonary embolism, during Nolvadex (Tamoxifen citrate) therapy. When Nolvadex (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 Nolvadex (Tamoxifen citrate) should be carefully considered in women with a history of thromboembolic events. In a subsmall study (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 Nolvadex (Tamoxifen citrate) therapy.
Data from the NSABP P-1 trial show that participants receiving Nolvadex (Tamoxifen citrate) without a history of pulmonary emboli (PE) had a statistically significant increase in pulmonary emboli (18-Nolvadex (Tamoxifen citrate) , 6-placebo, RR=3.01, 95% CI: 1.15- 9.27). Three of the pulmonary emboli, all in the Nolvadex (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 Nolvadex (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 Nolvadex (Tamoxifen citrate) group (30-Nolvadex (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 Nolvadex (Tamoxifen citrate) ) and were at risk for complications of the event and its treatment (0/25 on placebo, 4/48 on Nolvadex (Tamoxifen citrate) ). Among women receiving Nolvadex (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 Nolvadex (Tamoxifen citrate) (24-Placebo; 34-Nolvadex (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 Nolvadex (Tamoxifen citrate) group were categorized as hemorrhagic. Seventeen of the 34 strokes in the Nolvadex (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 Nolvadex (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 Nolvadex (Tamoxifen citrate) , the events occurred between 1 and 63 months (average=30 months) from the start of treatment.
In the Swedish trial using adjuvant Nolvadex (Tamoxifen citrate) 40 mg/day for 2-5 years, 3 cases of liver cancer have been reported in the Nolvadex (Tamoxifen citrate) -treated group vs. 1 case in the observation group (See ). In other clinical trials evaluating Nolvadex (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 Nolvadex (Tamoxifen citrate) .
Nolvadex (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 Nolvadex (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 Nolvadex (Tamoxifen citrate) ). Serum lipids were not systematically collected.
Ocular disturbances, including corneal changes, decrement in color vision perception, retinal vein thrombosis, and retinopathy have been reported in patients receiving Nolvadex (Tamoxifen citrate) . An increased incidence of cataracts and the need for cataract surgery have been reported in patients receiving Nolvadex (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-Nolvadex (Tamoxifen citrate) ; 483-placebo; RR=1.13, 95% CI: 1.00-1.28) was observed. Among these same women, Nolvadex (Tamoxifen citrate) was associated with an increased risk of having cataract surgery (101-Nolvadex (Tamoxifen citrate) ; 63-placebo; RR=1.62, 95% CI 1.18-2.22) (See in ). Among all women on the trial (with or without cataracts at baseline), Nolvadex (Tamoxifen citrate) was associated with an increased risk of having cataract surgery (201-Nolvadex (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.
Nolvadex (Tamoxifen citrate) may cause fetal harm when administered to a pregnant woman. Women should be advised not to become pregnant while taking Nolvadex (Tamoxifen citrate) 2 months of discontinuing Nolvadex (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/m 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/m 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.
Nolvadex (Tamoxifen citrate) Precautions
Decreases in platelet counts, usually to 50,000-100,000/mm, infrequently lower, have been occasionally reported in patients taking Nolvadex (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 Nolvadex (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 Nolvadex (Tamoxifen citrate) ; this can sometimes be severe.
In the NSABP P-1 trial, 6 women on Nolvadex (Tamoxifen citrate) and 2 on placebo experienced grade 3-4 drops in platelet counts (≤50,000/mm).
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 Nolvadex (Tamoxifen citrate) (9% versus 3.5%, respectively).
When Nolvadex (Tamoxifen citrate) is used in combination with coumarin-type anticoagulants, a significant increase in anticoagulant effect may occur. Where such coadministration exists, careful monitoring of the patient's prothrombin time is recommended.
In the NSABP P-1 trial, women who required coumarin-type anticoagulants for any reason were ineligible for participation in the trial (See ).
There is an increased risk of thromboembolic events occurring when cytotoxic agents are used in combination with Nolvadex (Tamoxifen citrate) .
Tamoxifen reduced letrozole plasma concentrations by 37%. The effect of tamoxifen on metabolism and excretion of other antineoplastic drugs, such as cyclophosphamide and other drugs that require mixed function oxidases for activation, is not known. Tamoxifen and N-desmethyl tamoxifen plasma concentrations have been shown to be reduced when coadministered with rifampin or aminoglutethimide. Induction of CYP3A4-mediated metabolism is considered to be the mechanism by which these reductions occur; other CYP3A4 inducing agents have not been studied to confirm this effect.
One patient receiving Nolvadex (Tamoxifen citrate) with concomitant phenobarbital exhibited a steady state serum level of tamoxifen lower than that observed for other patients (ie, 26 ng/mL vs. mean value of 122 ng/mL). However, the clinical significance of this finding is not known. Rifampin induced the metabolism of tamoxifen and significantly reduced the plasma concentrations of tamoxifen in 10 patients. Aminoglutethimide reduces tamoxifen and N-desmethyl tamoxifen plasma concentrations. Medroxyprogesterone reduces plasma concentrations of N-desmethyl, but not tamoxifen.
Concomitant bromocriptine therapy has been shown to elevate serum tamoxifen and N-desmethyl tamoxifen.
Based on clinical and pharmacokinetic results from the anastrozole adjuvant trial, Nolvadex (Tamoxifen citrate) should not be administered with anastrozole (see section).
During postmarketing surveillance, T4 elevations were reported for a few postmenopausal patients which may be explained by increases in thyroid-binding globulin. These elevations were not accompanied by clinical hyperthyroidism.
Variations in the karyopyknotic index on vaginal smears and various degrees of estrogen effect on Pap smears have been infrequently seen in postmenopausal patients given Nolvadex (Tamoxifen citrate) .
In the postmarketing experience with Nolvadex (Tamoxifen citrate) , infrequent cases of hyperlipidemias have been reported. Periodic monitoring of plasma triglycerides and cholesterol may be indicated in patients with pre-existing hyperlipidemias (See section).
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/mbasis) 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/m 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/m basis).
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 Nolvadex (Tamoxifen citrate) is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Nolvadex (Tamoxifen citrate) , women taking Nolvadex (Tamoxifen citrate) should not breast feed.
The safety and efficacy of Nolvadex (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 Nolvadex (Tamoxifen citrate) therapy for girls have not been established.
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 Nolvadex (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 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 Nolvadex (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.
Nolvadex (Tamoxifen citrate) Adverse Reactions
Adverse reactions to Nolvadex (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 Nolvadex (Tamoxifen citrate) as compared to placebo.
Nolvadex (Tamoxifen citrate) Overdosage
Signs observed at the highest doses following studies to determine LD 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 Nolvadex (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 Nolvadex (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 Nolvadex (Tamoxifen citrate) was discontinued and neurotoxic symptoms had resolved. The causal relationship of the seizure to Nolvadex (Tamoxifen citrate) therapy is unknown. Doses given in these patients were all greater than 400 mg/m loading dose, followed by maintenance doses of 150 mg/m of Nolvadex (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/m loading dose, followed by maintenance doses of 80 mg/m of Nolvadex (Tamoxifen citrate) given twice a day. For a woman with a body surface area of 1.5 m 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.
Nolvadex (Tamoxifen citrate) Dosage And Administration
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 Nolvadex (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 Nolvadex (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 ). 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 Nolvadex (Tamoxifen citrate) therapy for patients with breast cancer.
