TAMOXIFEN: 9,105 Adverse Event Reports & Safety Profile

DESCRIPTION Tamoxifen citrate tablets, USP, a nonsteroidal antiestrogen, are for oral administration. Chemically, tamoxifen 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 formula is as follows: C 26 H 29 NO•C 6 H 8 O 7 Molecular Weight:

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. 10 mg Tablets : Each tablet contains 15.2 mg of tamoxifen citrate, USP which is equivalent to 10 mg of tamoxifen. 20 mg Tablets : Each tablet contains 30.4 mg of tamoxifen citrate, USP which is equivalent to 20 mg of tamoxifen. Each tablet contains the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch. The structural formula for Tamoxifen citrate tablets, USP, a nonsteroidal antiestrogen, are for oral administration. Chemically, tamoxifen 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).

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 tablet therapy.

Adjuvant

Treatment of Breast Cancer Tamoxifen citrate tablets are 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 tamoxifen 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 tablet therapy is likely to be beneficial. Tamoxifen citrate tablets reduce the occurrence of contralateral breast cancer in patients receiving adjuvant tamoxifen citrate tablet 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 ). 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 tablet therapy. Current data from clinical trials support 5 years of adjuvant tamoxifen citrate tablet 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 citrate tablets on overall or breast cancer-related mortality (see BOXED WARNING ). 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, two or more benign biopsies, and a history of a breast biopsy showing atypical hyperplasia; or
• At least two 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, two or more benign biopsies, age at first live birth 25 or older, and age at menarche 11 or younger; or
• At least two 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 two 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 two 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 two 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.

Healthcare

Professionals can obtain a Gail Model Risk Assessment Tool by dialing Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX). There are insufficient data available regarding the effect of tamoxifen citrate tablets on breast cancer incidence in women with inherited mutations (BRCA1, BRCA2) to be able to make specific recommendations on the effectiveness of tamoxifen in these patients. After an assessment of the risk of developing breast cancer, 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 tablet therapy. In the NSABP P-1 trial, tamoxifen citrate tablet treatment lowered the risk of developing breast cancer during the follow-up period of the trial, but did not eliminate breast cancer risk (see CLINICAL PHARMACOLOGY: Table 3 ).

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 therapy for patients with breast cancer.

Ductal

Carcinoma in Situ (DCIS): The recommended dose is tamoxifen citrate tablets 20 mg daily for 5 years. Reduction in Breast Cancer Incidence in High Risk Women: The recommended dose is tamoxifen citrate tablets 20 mg daily for 5 years. There are no data to support the use of tamoxifen other than for 5 years (see CLINICAL PHARMACOLOGY, Clinical Studies , Reduction in Breast Cancer Incidence in High Risk Women ).

SOLTAMOX is contraindicated in patients with known hypersensitivity (e.g., angioedema, serious skin reactions) to tamoxifen or any other SOLTAMOX ingredient [see Adverse Reactions (6.2) ] . SOLTAMOX is contraindicated in patients who require concomitant warfarin therapy or have a history of deep vein thrombosis or pulmonary embolus if the indication for treatment is either reduction of breast cancer incidence in high-risk patients or risk reduction of invasive breast cancer after treatment of DCIS [see Warnings and Precautions (5.2) and Drug Interactions (7.2) ]. Known hypersensitivity to tamoxifen or any other SOLTAMOX ingredient ( 4 ) In patients who require concomitant warfarin therapy or have a history of deep vein thrombosis or pulmonary embolus, if the indication for treatment is either reduction of breast cancer incidence in high-risk patients or risk reduction of invasive breast cancer after treatment of DCIS ( 4 )

ADVERSE REACTIONS Adverse reactions to 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 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 pre-existing lesions, sometimes associated with marked erythema within and surrounding the lesions and/or the development of new lesions. When they occur, the bone pain or disease flare are seen shortly after starting tamoxifen citrate and generally subside rapidly. In patients treated with tamoxifen citrate for metastatic breast cancer, the most frequent adverse reaction to 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 tamoxifen citrate therapy to ovarian ablation in premenopausal patients with metastatic breast cancer. *Some women had more than one adverse reaction.

Tamoxifen Citrate

All Effects % of Women OVARIAN ABLATION All Effects % of Women Adverse Reactions* 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 citrate is well tolerated in males with breast cancer. Reports from the literature and case reports suggest that the safety profile of 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 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 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 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 tamoxifen citrate-treated patients (through 5 years, 1.7% vs. 0.4%). Two of the patients treated with tamoxifen citrate who had thrombotic events died. * Defined as a platelet count of <100,000/mm 3 NSABP B-14 Study Adverse Effect % of Women Tamoxifen Citrate (n=1422) Placebo (n=1437)

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* 2 1 Thrombotic Events Deep Vein Thrombosis 0.8

0.2 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 (19) 544 (18)

Pain

533 (17) 485 (16) Back pain 321 (10) 309 (10)

Headache

314 (10) 249 (8) Abdominal pain 271 (9) 276 (9)

Infection

285 (9) 276 (9) Accidental injury 311 (10) 303 (10) Flu syndrome 175 (6) 195 (6) Chest pain 200 (7) 150 (5)

Neoplasm

162 (5) 144 (5)

Cyst

138 (5) 162 (5)

Cardiovascular Vasodilatation

1104 (36) 1264 (41)

Hypertension

402 (13) 349 (11)

Digestive Nausea

343 (11) 335 (11)

Constipation

249 (8) 252 (8)

Diarrhea

265 (9) 216 (7)

Dyspepsia

206 (7) 169 (6) Gastrointestinal disorder 210 (7) 158 (5) Hemic and lymphatic Lymphoedema 304 (10) 341 (11)

Anemia

113 (4) 159 (5) Metabolic and nutritional Peripheral edema 311 (10) 343 (11) Weight gain 285 (9) 274 (9)

Hypercholesterolemia

278 (9) 108 (3.5)

Musculoskeletal Arthritis

512 (17) 445 (14)

Arthralgia

467 (15) 344 (11)

Osteoporosis

325 (11) 226 (7)

Fracture

315 (10) 209 (7) Bone pain 201 (7) 185 (6)

Arthrosis

207 (7) 156 (5)

Joint Disorder

184 (6) 160 (5)

Myalgia

179 (6) 160 (5) Nervous system Depression 413 (13) 382 (12)

Insomnia

309 (10) 281 (9)

Dizziness

236 (8) 234 (8)

Anxiety

195 (6) 180 (6)

Paraesthesia

215 (7) 145 (5)

Respiratory Pharyngitis

443 (14) 422 (14) Cough increased 261 (8) 287 (9)

Dyspnea

234 (8) 237 (8)

Sinusitis

184 (6) 159 (5)

Bronchitis

167 (5) 153 (5) Skin and appendages Rash 333 (11) 387 (13)

Sweating

145 (5) 177 (6)

Special Senses Cataract Specified

182 (6) 213 (7)

Urogenital Leukorrhea

86 (3) 286 (9) Urinary tract infection 244 (8) 313 (10) Breast pain 251 (8) 169 (6)

Breast Neoplasm

164 (5) 139 (5)

Vulvovaginitis

194 (6) 150 (5)

Vaginal

Hemorrhage † 122 (4) 180 (6)

Vaginitis

125 (4) 158 (5) 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 (36) 1264 (41) 0.80 0.73 to

0.89 Musculoskeletal Events 2 1100 (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)

Cataracts

182 (6) 213 (7) 0.85 0.69 to

1.04 Vaginal Bleeding 167 (5) 317 (10) 0.50 0.41 to

0.61 Ischemic Cardiovascular Disease 127 (4) 104 (3) 1.23 0.95 to

1.60 Vaginal Discharge 109 (4) 408 (13) 0.24 0.19 to

0.30 Venous Thromboembolic events 87 (3) 140 (5) 0.61 0.47 to

0.80 Deep Venous Thromboembolic Events 48 (2) 74 (2) 0.64 0.45 to

0.93 Ischemic Cerebrovascular Event 62 (2) 88 (3) 0.70 0.50 to

0.97 Endometrial Cancer 3 4 (0.2) 13 (0.6) 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) [315 (10%)] compared with patients receiving 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 tamoxifen citrate. Patients receiving 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 tamoxifen citrate arm; myocardial infarction was reported in 37 [1.2%] patients in the anastrozole arm and in 34 [1.1%] 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

0.3 Adverse Effects N=6492 3 N=6484 3 Other Toxicities Mood 11.6

10.8 Infection/Sepsis 6.0

5.1 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.

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 tamoxifen citrate. If hypercalcemia does occur, appropriate measures should be taken and, if severe, 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 tamoxifen citrate treatment. The underlying mechanism is unknown, but may be related to the estrogen-like effect of tamoxifen citrate. Most uterine malignancies seen in association with 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 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 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 to 4.92).

The

33 cases in participants receiving 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 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 to 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 to 2.89). If age at the time of diagnosis is considered, there were 4 cases of endometrial cancer among participants ≤ 49 randomized to tamoxifen citrate compared to 2 among participants randomized to placebo (RR=2.21, 95% CI: 0.4 to 12.0). For women ≥ 50 at the time of diagnosis, there were 29 cases among participants randomized to tamoxifen citrate compared to 12 among women on placebo (RR=2.5, 95% CI: 1.3 to 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 tamoxifen citrate group) endometrial cancers were diagnosed in symptomatic women, although 5 of 33 cases in the tamoxifen citrate group occurred in asymptomatic women. Among women receiving 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 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 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 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 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 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 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 tamoxifen citrate in five other NSABP clinical trials. Any patient receiving or who has previously received tamoxifen citrate who reports abnormal vaginal bleeding should be promptly evaluated. Patients receiving or who have previously received tamoxifen citrate should have annual gynecological examinations and they should promptly inform their physicians if they experience any abnormal gynecological symptoms, e.g., 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 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 tamoxifen citrate treatment. The incidence and pattern of this increase suggest that the underlying mechanism is related to the estrogenic properties of tamoxifen citrate. There have been a few reports of endometriosis and uterine fibroids in women receiving tamoxifen citrate. The underlying mechanism may be due to the partial estrogenic effect of tamoxifen citrate. Ovarian cysts have also been observed in a small number of premenopausal patients with advanced breast cancer who have been treated with tamoxifen citrate. Tamoxifen citrate has been reported to cause menstrual irregularity or amenorrhea.

Thromboembolic

Effects of Tamoxifen Citrate: There is evidence of an increased incidence of thromboembolic events, including deep vein thrombosis and pulmonary embolism, during tamoxifen citrate therapy. When 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 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 tamoxifen citrate therapy. Data from the NSABP P-1 trial show that participants receiving tamoxifen citrate without a history of pulmonary emboli (PE) had a statistically significant increase in pulmonary emboli (18-tamoxifen citrate, 6-placebo, RR=3.01, 95% CI: 1.15 to 9.27). Three of the pulmonary emboli, all in the 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 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 tamoxifen citrate group (30-tamoxifen citrate, 19-placebo; RR=1.59, 95% CI: 0.86 to 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 tamoxifen citrate) and were at risk for complications of the event and its treatment (0/25 on placebo, 4/48 on tamoxifen citrate). Among women receiving 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 tamoxifen citrate (24-Placebo; 34-tamoxifen citrate; RR=1.42; 95% CI 0.82 to 2.51). Six of the 24 strokes in the placebo group were considered hemorrhagic in origin and 10 of the 34 strokes in the tamoxifen citrate group were categorized as hemorrhagic. Seventeen of the 34 strokes in the 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 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 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 tamoxifen citrate 40 mg/day for 2 to 5 years, 3 cases of liver cancer have been reported in the tamoxifen citrate-treated group vs. 1 case in the observation group (See PRECAUTIONS- Carcinogenesis ). In other clinical trials evaluating 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 tamoxifen citrate. Effects on the liver: Non-malignant effects: 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 tamoxifen citrate is uncertain. However, some positive rechallenges and dechallenges have been reported. In the NSABP P-1 trial, few grade 3 to 4 changes in liver function (SGOT, SGPT, bilirubin, alkaline phosphatase) were observed (10 on placebo and 6 on 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 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 tamoxifen citrate. Whether an increased risk for other (non-uterine) cancers is associated with 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 tamoxifen citrate. An increased incidence of cataracts and the need for cataract surgery have been reported in patients receiving 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-tamoxifen citrate; 483-placebo; RR=1.13, 95% CI: 1.00 to 1.28) was observed. Among these same women, tamoxifen citrate was associated with an increased risk of having cataract surgery (101-tamoxifen citrate; 63-placebo; RR=1.62, 95% CI: 1.18 to 2.22) (See Table 3 in CLINICAL PHARMACOLOGY ). Among all women on the trial (with or without cataracts at baseline), tamoxifen citrate was associated with an increased risk of having cataract surgery (201-tamoxifen citrate; 129-placebo; RR=1.58, 95% CI: 1.26 to 1.97). Eye examinations were not required during the study. No other conclusions regarding non-cataract ophthalmic events can be made. Pregnancy: Tamoxifen citrate may cause fetal harm when administered to a pregnant woman. Women should be advised not to become pregnant while taking tamoxifen citrate or within 2 months of discontinuing 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 2 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 2 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 to 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: For sexually active women of child-bearing potential, 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 to 100,000/mm 3 , infrequently lower, have been occasionally reported in patients taking 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 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 tamoxifen citrate; this can sometimes be severe. In the NSABP P-1 trial, 6 women on tamoxifen citrate and 2 on placebo experienced grade 3 to 4 drops in platelet counts (≤50,000/mm 3 ). Information for Patients: Patients should be instructed to read the Medication Guide supplied as required by law when tamoxifen citrate 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 tamoxifen citrate to reduce the incidence of a second breast cancer event should assess the risks and benefits of therapy, since treatment with 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 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. 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 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 tamoxifen citrate reduces the incidence of breast cancer, but may not eliminate risk. 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 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 tamoxifen citrate to reduce her risk of breast cancer. Effective nonhormonal contraception must be used by all premenopausal women taking 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, 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 ).

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 NSABPP-1, and enrolled women at a lower risk for breast cancer than those in P-1.

Monitoring During Tamoxifen Citrate

Therapy: Women taking or having previously taken 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 tamoxifen citrate. Women taking 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 tamoxifen citrate as adjuvant breast cancer therapy should follow the same monitoring procedures as for women taking tamoxifen citrate for the reduction in the incidence of breast cancer. Women taking 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 tamoxifen citrate (9% versus 3.5%, respectively).

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).

Drug/Laboratory

Testing Interactions: 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 tamoxifen citrate. In the postmarketing experience with 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 ADVERSE REACTIONS-Postmarketing experience section). 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/m 2 basis) 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 2 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 2 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 32 P 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/m 2 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/m 2 basis) when female rats were dosed from days 7 to 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/m 2 basis). There were no teratogenic changes in either rats or rabbits. 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 tamoxifen citrate is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from tamoxifen citrate, women taking tamoxifen citrate should not breast feed. Reduction in Breast Cancer Incidence in High Risk Women with DCIS: It is not known if tamoxifen citrate is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from tamoxifen citrate, women taking tamoxifen citrate should not breast feed.

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).

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 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 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.

INTERACTIONS Anastrozole and letrozole: Should not be used in combination with tamoxifen. ( 7.1 ) Warfarin: Do not use in patients taking tamoxifen for DCIS and for reduction in breast cancer incidence in women at high risk. ( 4 ) Closely monitor coagulation indices for increased anticoagulant effect when used with tamoxifen for metastatic breast cancer or as adjuvant therapy. ( 7.2 )

7.1 Aromatase Inhibitors Anastrozole The combination of anastrozole and tamoxifen did not demonstrate any benefit when compared to tamoxifen alone and should be avoided in all patients <span class="opacity-50 text-xs">[see Clinical Studies (14.2) ]</span> . In the ATAC trial, coadministration of anastrozole and tamoxifen in breast cancer patients reduced the anastrozole plasma concentration by 27% compared to that achieved with anastrozole alone. The tamoxifen concentration was not altered <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>.

Letrozole

The concomitant use of letrozole with tamoxifen is not recommended because the efficacy of the combination in the adjuvant treatment of breast cancer has not been established. Tamoxifen reduced the plasma concentration of letrozole by 38% when these drugs were co-administered [see Clinical Pharmacology (12.3) ]. 7.2. Warfarin A marked increase in anticoagulant effect may occur when tamoxifen is used in combination with warfarin. Closely monitor coagulation indices in patients who are taking tamoxifen for either the treatment of metastatic breast cancer or as adjuvant therapy who require concomitant use of warfarin [see Contraindications (4) ] .

7.3 Inducers of CYP3A4 Strong CYP3A4 inducers should not be used with tamoxifen. Strong CYP3A4 inducers (e.g., rifampin) reduce tamoxifen AUC and C max <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

7.4 Strong Inhibitors of CYP2D6 The impact on the efficacy of tamoxifen with co-administration of strong CYP2D6 inhibitors (e.g., paroxetine) is not well established. Some studies have shown that the efficacy of tamoxifen may be reduced when the drugs are co-administered as a result of reduced levels of potent active metabolites of tamoxifen . However, other studies have failed to demonstrate such an effect <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

7.5 Drug-Laboratory Test Interactions There are postmarketing reports of T 4 elevations in postmenopausal patients taking tamoxifen that 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 seen in postmenopausal patients taking tamoxifen.