Tamoxifen Citrate

INDICATIONS AND USAGE Metastatic Breast Cancer: Tamoxifen citrate tablets are effective in the treatment of metastatic breast cancer in women and men. In premenopausal women with metastatic breast cancer, tamoxifen citrate tablets are an alternative to oophorectomy or ovarian irradiation. Available evidence indicates that patients whose tumors are estrogen receptor positive are more likely to benefit from tamoxifen citrate tablets therapy. Adjuvant Treatment of Breast Cancer: Tamoxifen citrate tablets are indicated for the treatment of node-positive breast cancer in women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation. In some tamoxifen citrate adjuvant studies, most of the benefit to date has been in the subgroup with four or more positive axillary nodes. Tamoxifen citrate tablets are 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 tamoxifen citrate tablets therapy are likely to be beneficial. Tamoxifen citrate tablets reduces the occurrence of contralateral breast cancer in patients receiving adjuvant tamoxifen citrate tablets therapy for breast cancer. Ductal Carcinoma in Situ (DCIS): In women with DCIS, following breast surgery and radiation, tamoxifen citrate tablets are indicated to reduce the risk of invasive breast cancer (see BOXED WARNING at the beginning of the label). The decision regarding therapy with tamoxifen citrate tablets for the reduction in breast cancer incidence should be based upon an individual assessment of the benefits and risks of tamoxifen citrate tablets therapy. Current data from clinical trials support five years of adjuvant tamoxifen citrate tablets therapy for patients with breast cancer. Reduction in Breast Cancer Incidence in High Risk Women: Tamoxifen citrate tablets are 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). Tamoxifen citrate tablets are 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 his …

DOSAGE AND ADMINISTRATION For patients with breast cancer, the recommended daily dose is 20 to 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 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 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 tamoxifen citrate therapy for patients with breast cancer. Ductal Carcinoma in Situ (DCIS): The recommended dose is tamoxifen citrate 20 mg daily for 5 years. Reduction in Breast Cancer Incidence in High Risk Women: The recommended dose is tamoxifen citrate 20 mg daily for 5 years. There are no data to support the use of tamoxifen citrate other than for 5 years (See CLINICAL PHARMACOLOGY-Clinical Studies - Reduction in Breast Cancer Incidence in High Risk Women ).

CONTRAINDICATIONS Tamoxifen citrate tablets are 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: Tamoxifen citrate tablets are contraindicated in women who require concomitant coumarin-type anticoagulant therapy or in women with a history of deep vein thrombosis or pulmonary embolus.

ADVERSE REACTIONS Adverse reactions to tamoxifen 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 tamoxifen 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 tamoxifen and generally subside rapidly. In patients treated with tamoxifen for metastatic breast cancer, the most frequent adverse reaction to tamoxifen is hot flashes. Other adverse reactions which are seen infrequently are hypercalcemia, peripheral edema, distaste for food, pruritus vulvae, depression, dizziness, lightheadedness, 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 tamoxifen therapy to ovarian ablation in premenopausal patients with metastatic breast cancer. TAMOXIFEN All Effects % of Women OVARIAN ABLATION All Effects % of Women Adverse Reactions Some women had more than one adverse reaction. n = 104 n = 100 Flush 33 46 Amenorrhea 16 69 Altered Menses 13 5 Oligomenorrhea 9 1 Bone Pain 6 6 Menstrual Disorder 6 4 Nausea 5 4 Cough/Coughing 4 1 Edema 4 1 Fatigue 4 1 Musculoskeletal Pain 3 0 Pain 3 4 Ovarian Cyst(s) 3 2 Depression 2 2 Abdominal Cramps 1 2 Anorexia 1 2 Male Breast Cancer Tamoxifen is well tolerated in males with breast cancer. Reports from the literature and case reports suggest that the safety profile of tamoxifen 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 tamoxifen 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 tamoxifen 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 tamoxifen 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 tamoxifen-treated patients (through 5 years, 1.7% vs. 0.4%). Two of the patients treated with tamoxifen who had thrombotic events died. NSABP B-14 Study % of Women Adverse Effect TAMOXIFEN (n = 1,422) PLACEBO (n = 1,437) Hot Flashes 64 48 Fluid Retention 32 30 Vaginal Discharge 30 15 Nausea 26 24 Irregular Menses 25 19 Weight Loss (> 5%) 23 18 Skin Changes 19 15 Increased SGOT 5 3 Increased Bilirubin 2 1 Increased Creatinine 2 1 Thrombocytopenia Defined as a platelet count of 1.00 favor tamoxifen. 1,100 (36) 911 (29) 1.32 1.19 to 1.47 Fatigue/Asthenia 575 (19) 544 (18) 1.07 0.94 to 1.22 Mood Disturbances 597 (19) 554 (18) 1.10 0.97 to 1.25 Nausea and Vomiting 393 (13) 384 (12) 1.03 0.88 to 1.19 All Fractures 315 (10) 209 (7) 1.57 1.30 to 1.88 Fractures of Spine, Hip, or Wrist 133 (4) 91 (3) 1.48 1.13 to 1.95 Wrist/Colles' fractures 67 (2) 50 (2) Spine fractures 43 (1) 22 (1) Hip fractures 28 (1) 26 (1) Catarac …

Drug Interactions: When 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 CONTRAINDICATIONS ). There is an increased risk of thromboembolic events occurring when cytotoxic agents are used in combination with 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 tamoxifen citrate with concomitant phenobarbital exhibited a steady state serum level of tamoxifen lower than that observed for other patients (i.e., 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, tamoxifen citrate should not be administered with anastrozole (see CLINICAL PHARMACOLOGY – Drug- Drug Interactions section).

DESCRIPTION Tamoxifen citrate tablets, USP a nonsteroidal antiestrogen, are for oral administration. Tamoxifen citrate tablets are available as: 10 mg Tablets: Each tablet contains 15.2 mg of tamoxifen citrate USP equivalent to 10 mg of tamoxifen. 20 mg Tablets: Each tablet contains 30.4 mg of tamoxifen citrate USP equivalent to 20 mg of tamoxifen. Inactive Ingredients: corn starch (maize), croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, povidone and titanium dioxide. Chemically, 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 molecular 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 0.3159 mg/mL and in 0.02 N HCl at 37°C, it is 0.4045 mg/mL. Chemical Structure

OVERDOSAGE Signs observed at the highest doses following studies to determine LD 50 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 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 to 5 days of beginning tamoxifen citrate and cleared within 2 to 5 days after stopping therapy. No permanent neurologic toxicity was noted. One patient experienced a seizure several days after tamoxifen citrate was discontinued and neurotoxic symptoms had resolved. The causal relationship of the seizure to tamoxifen citrate therapy is unknown. Doses given in these patients were all greater than 400 mg/m 2 loading dose, followed by maintenance doses of 150 mg/m 2 of 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 2 loading dose, followed by maintenance doses of 80 mg/m 2 of tamoxifen citrate given twice a day. For a woman with a body surface area of 1.5 m 2 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.

HOW SUPPLIED Tamoxifen Citrate Tablets, USP 10 mg contains 15.2 mg of tamoxifen citrate equivalent to 10 mg of tamoxifen. The tablets are white to off-white, round, biconvex, film-coated, unscored tablets debossed with T10 on one side and plain on the other side. Bottles of 60 NDC 59651-299-60 Tamoxifen Citrate Tablets, USP 20 mg contains 30.4 mg of tamoxifen citrate equivalent to 20 mg of tamoxifen. The tablets are white to off-white, round, biconvex, film-coated, unscored tablets debossed with T20 on one side and plain on the other side. Bottles of 30 NDC 59651-300-30 Bottles of 90 NDC 59651-300-90 Store at 20° to 25°C (68° to 77°F) [see USP controlled room temperature]. Dispense in a well-closed, light-resistant container. The brands listed are the trademarks of their respective owners and are not trademarks of the Aurobindo Pharma Limited. Dispense with Medication Guide available at: www.aurobindousa.com/product-medication-guides. Distributed by: Aurobindo Pharma USA, Inc. 279 Princeton-Hightstown Road East Windsor, NJ 08520 Manufactured by: Eugia Pharma Specialities Limited Medchal-Malkajgiri District- 500101 India Issued: August 2019