Tamoxifen Drug Information

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 ).

Pulmonary Embolism 0.5 0.2 Superficial Phlebitis 0.4 0.0

In the Eastern Cooperative Oncology Group (ECOG) adjuvant breast cancer trial, tamoxifen citrate or placebo was administered for 2 years to women following mastectomy. When compared to placebo, 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 tamoxifen citrate was 10% vs. 3% for placebo, an observation of borderline statistical significance. In other adjuvant studies, Toronto and Tamoxifen Citrate Adjuvant Trial Organization (NATO), women received either tamoxifen citrate or no therapy.

In the Toronto study, hot flashes were observed in 29% of patients for 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 tamoxifen citrate vs. 0.2% for each in the untreated group. Anastrozole Adjuvant Trial - Study of Anastrozole compared to 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 tamoxifen citrate did not demonstrate any efficacy benefit when compared to 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 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 COSTART Coding Symbols for Thesaurus of Adverse Reaction Terms. N = Number of patients receiving the treatment. * A patient may have had more than 1 adverse event, including more than 1 adverse event in the same body system. † Vaginal Hemorrhage without further diagnosis. ** The combination arm was discontinued due to lack of efficacy benefit at 33 months of follow-up. Body system and adverse event by COSTART-preferred term* Anastrozole 1 mg (N = 3092) Tamoxifen Citrate 20 mg (N = 3094) Body as a whole Asthenia 575 544 Pain 533 485 Back pain 321 309 Headache 314 249 Abdominal pain 271 276 Infection 285 276 Accidental injury 311 303 Flu syndrome 175 195 Chest pain 200 150 Neoplasm 162 144 Cyst 138 162 Cardiovascular Vasodilatation 1104 1264 Hypertension 402 349 Digestive Nausea 343 335 Constipation 249 252 Diarrhea 265 216 Dyspepsia 206 169 Gastrointestinal disorder 210 158 Hemic and lymphatic Lymphoedema 304 341 Anemia 113 159 Metabolic and nutritional Peripheral edema 311 343 Weight gain 285 274 Hypercholesterolemia 278 108 Musculoskeletal Arthritis 512 445 Arthralgia 467 344 Osteoporosis 325 226 Fracture 315 209 Bone pain 201 185 Arthrosis 207 156 Joint Disorder 184 160 Myalgia 179 160 Nervous system Depression 413 382 Insomnia 309 281 Dizziness 236 234 Anxiety 195 180 Paraesthesia 215 145 Respiratory Pharyngitis 443 422 Cough increased 261 287 Dyspnea 234 237 Sinusitis 184 159 Bronchitis 167 153 Skin and appendages Rash 333 387 Sweating 145 177 Special Senses Cataract Specified 182 213 Urogenital Leukorrhea 86 286 Urinary tract infection 244 313 Breast pain 251 169 Breast Neoplasm 164 139 Vulvovaginitis 194 150 Vaginal Hemorrhage † 122 180 Vaginitis 125 158 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 Trial 1 1 Patients with multiple events in the same category are counted only once in that category. 2 Refers to joint symptoms, including joint disorder, arthritis, arthrosis and arthralgia. 3 Percentages calculated based upon the numbers of patients with an intact uterus at baseline. 4 The odds ratios < 1.00 favor Anastrozole and those > 1.00 favor Tamoxifen Citrate Anastrozole N=3092 (%) Tamoxifen Citrate N=3094 (%) Odds- ratio 4 95% CI 4 Hot Flashes 1104 1264 0.80 0.73 to 0.89 Musculoskeletal Events 2 1100 911 1.32 1.19 to 1.47 Fatigue/Asthenia 575 544 1.07 0.94 to 1.22 Mood Disturbances 597 554 1.10 0.97 to 1.25 Nausea and Vomiting 393 384 1.03 0.88 to 1.19 All Fractures 315 209 1.57 1.30 to 1.88 Fractures of Spine, Hip, or Wrist 133 91 1.48 1.13 to 1.95 Wrist/Colles’ fractures 67 50 Spine fractures 43 22 Hip fractures 28 26 Cataracts 182 213 0.85 0.69 to 1.04 Vaginal Bleeding 167 317 0.50 0.41 to 0.61 Ischemic Cardiovascular Disease 127 104 1.23 0.95 to 1.60 Vaginal Discharge 109 408 0.24 0.19 to 0.30 Venous Thromboembolic events 87 140 0.61 0.47 to 0.80 Deep Venous Thromboembolic Events 48 74 0.64 0.45 to 0.93 Ischemic Cerebrovascular Event 62 88 0.70 0.50 to 0.97 Endometrial Cancer 3 4 13 0.31 0.10 to 0.94 Patients receiving anastrozole had an increase in joint disorders (including arthritis, arthrosis and arthralgia) compared with patients receiving tamoxifen citrate.

Patients receiving anastrozole had an increase in the incidence of all fractures (specifically fractures of spine, hip and wrist) compared with patients receiving tamoxifen citrate. 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 tamoxifen citrate. Patients receiving tamoxifen citrate had a decrease in hypercholesterolemia compared to patients receiving anastrozole.

Angina pectoris was reported in 71 patients in the anastrozole arm and 51 patients in the tamoxifen citrate arm; myocardial infarction was reported in 37 patients in the anastrozole arm and in 34 patients in the 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 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 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 tamoxifen citrate group: endometrial cancer (33 cases in the tamoxifen citrate group vs. 14 in the placebo group); pulmonary embolism (18 cases in the tamoxifen citrate group vs. 6 in the placebo group); deep vein thrombosis (30 cases in the tamoxifen citrate group vs. 19 in the placebo group); stroke (34 cases in the tamoxifen citrate group vs. 24 in the placebo group); cataract formation (540 cases in the tamoxifen citrate group vs. 483 in the placebo group) and cataract surgery (101 cases in the 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 tamoxifen citrate than placebo are shown. 1 Number with Quality of Life Questionnaires 2 Number with Treatment Follow-up Forms 3 Number with Adverse Drug Reaction Forms NSABP P-1 Trial: All Adverse Events % of Women TAMOXIFEN CITRATE N=6681 PLACEBO N=6707 Self Reported Symptoms N=6441 1 N=6469 1 Hot Flashes 80 68 Vaginal Discharges 55 35 Vaginal Bleeding 23 22 Laboratory Abnormalities N=6520 2 N=6535 2 Platelets decreased 0.7

Adverse Effects N=6492 3 N=6484 3 Other Toxicities Mood 11.6 10.8 Infection/Sepsis

6.0

Constipation 4.4 3.2 Alopecia 5.2 4.4 Skin 5.6 4.7 Allergy 2.5 2.1

In the NSABP P-1 trial, 15.0% and 9.7% of participants receiving tamoxifen citrate and placebo therapy, respectively withdrew from the trial for medical reasons. The following are the medical reasons for withdrawing from 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 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 tamoxifen citrate.

Severe hot flashes occurred in 28% of women on placebo and 45% of women on tamoxifen citrate. Vaginal discharge occurred in 35% and 55% of women on placebo and 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 tamoxifen citrate (see BOXED WARNING ), continued monitoring of McCune-Albright patients treated with tamoxifen citrate for long-term effects is recommended. The safety and efficacy of 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 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 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 tamoxifen citrate (see PRECAUTIONS- Drug/Laboratory Testing Interactions section). To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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).

Pediatric Use: The safety and efficacy of 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 tamoxifen citrate therapy for girls have not been established. In adults treated with 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).

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.

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.