SOLTAMOX

SOLTAMOX (tamoxifen citrate) oral solution is for oral administration. Tamoxifen citrate is an estrogen agonist/antagonist. 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, empirical formula, and molecular weight are as follows: C 32 H 37 NO 8 M.W. 563.62 Tamoxifen citrate has a pKa′ of 8.85. The equilibrium solubility in water at 37°C is 0.5 mg/mL, and is 0.2 mg/mL in 0.02 N HCl at 37°C. Each 10 mL of SOLTAMOX oral solution contains 20 mg tamoxifen, equivalent to 30.4 mg tamoxifen citrate. The oral solution is a sugar-free, clear colorless liquid, with licorice and aniseed odor and taste supplied in a 150 mL bottle with a dosing cup. SOLTAMOX oral solution contains the following inactive ingredients: ethanol, glycerol, propylene glycol, sorbitol solution, licorice flavor, aniseed flavor, purified water. Chemical Structure

SOLTAMOX is an estrogen agonist/antagonist indicated: For treatment of adult patients with estrogen receptor-positive metastatic breast cancer ( 1.1 ) For adjuvant treatment of adult patients with early stage estrogen receptor- positive breast cancer ( 1.2 ) To reduce risk of invasive breast cancer following breast surgery and radiation in adult women with ductal carcinoma in situ (DCIS) ( 1.3 ) To reduce the incidence of breast cancer in adult women at high risk ( 1.4 ) 1.1 Metastatic Breast Cancer SOLTAMOX is indicated for the treatment of adult patients with estrogen receptor-positive metastatic breast cancer. 1.2 Adjuvant Treatment of Breast Cancer SOLTAMOX is indicated: for the adjuvant treatment of adult patients with early stage estrogen receptor-positive breast cancer to reduce the occurrence of contralateral breast cancer in adult patients when used as adjuvant therapy for the treatment of breast cancer. 1.3 Ductal Carcinoma in Situ In adult women with DCIS, following breast surgery and radiation, SOLTAMOX is indicated to reduce the risk of invasive breast cancer [see Boxed Warning and Clinical Studies (14.3) ] . 1.4 Reduction in Breast Cancer Incidence in Women at High Risk SOLTAMOX is indicated to reduce the incidence of breast cancer in adult women at high risk for breast cancer. [see Boxed Warning and Clinical Studies (14.4) ] .

Metastatic breast cancer: 20-40 mg per day. For doses greater than 20 mg per day, administer in divided doses (morning and evening). ( 2 ) Adjuvant treatment of breast cancer, DCIS, reduction of breast cancer incidence in women at high risk: 20 mg per day ( 2 ) Metastatic Breast Cancer For patients with breast cancer, the recommended daily dose of SOLTAMOX is 20 to 40 mg. Doses greater than 20 mg per day should be given in divided doses (morning and evening). Adjuvant Treatment of Breast Cancer For use in the adjuvant setting, the recommended dose of SOLTAMOX is 20 mg daily for 5-10 years [see Clinical Studies (14.2) ] . Doses greater than 20 mg daily yield no additional clinical benefit. Ductal Carcinoma in Situ For patients with DCIS, the recommended dose of SOLTAMOX is 20 mg daily for 5 years. Reduction in Breast Cancer Incidence in Women at High Risk In the risk reduction setting, the recommended dose of SOLTAMOX is 20 mg daily for 5 years .

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 )

The following serious adverse reactions are discussed below and elsewhere in the labeling: Uterine malignancies [see Boxed Warning , Warnings and Precautions (5.1) , and Clinical Studies (14.4) ] Thromboembolic events [see Boxed Warning , Warnings and Precautions (5.2) , and Clinical Studies (14.4) ] Embryo-Fetal Toxicity [see Warnings and Precautions (5.3) , and Use in Specific Populations (8.1 , 8.3) ] Liver cancer [see Warnings and Precautions (5.4) ] Most common adverse reactions: hot flashes, mood disturbances, vaginal discharge, vaginal bleeding, nausea, and fluid retention ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Mayne Pharma at 1-844-825-8500 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Patients with Metastatic Breast Cancer In patients treated with tamoxifen for metastatic breast cancer, the most frequent adverse reaction was hot flashes. Other adverse reactions which were seen less commonly are hypercalcemia, peripheral edema, distaste for food, pruritus vulvae, depression, dizziness, lightheadedness, headache, hair thinning and/or partial hair loss, and vaginal dryness. Increased bone, tumor pain and local disease flare have occurred. 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 occurred, the bone pain or disease flares were seen shortly after starting tamoxifen and generally subsided rapidly. Premenopausal Women with Metastatic Breast Cancer Table 1 summarizes the incidence of adverse reactions reported at a frequency of 2% or greater from clinical trials that compared tamoxifen therapy to ovarian ablation in premenopausal patients with metastatic breast cancer. Table 1: Adverse Reactions (frequency ≥2% in either arm) from Trials Comparing Tamoxifen to Ovarian Ablation in Premenopausal Women with Metastatic Breast Cancer % of Women Tamoxifen N=104 Ovarian Ablation N=100 Adverse Reactions Some women had more than one adverse reaction. 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 Adverse Reactions in 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 per day or placebo following primary surgery [see Clinical Studies (14.2) ]. Table 2 presents the most common adverse reactions (mean follow-up of approximately 6.9 years) that were more common on tamoxifen than placebo. Table 2: Most Common Adverse Reactions in Women with Axillary Node-Negative Breast Cancer (Study NSABP B-14) % of Women 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 < 100,000/mm 3 2 1 Thrombotic events Two of the tamoxifen-treated patients who had thrombotic events died. Deep vein thrombosis 0.8 0.2 Pulmonary embolism 0.5 0.2 Superficial phlebitis 0.4 0 In the Eastern Cooperative Oncology Group (ECOG) adjuvant breast cancer trial [see Clinical Studies (14.2) ] , tamoxifen or placebo was administered for 2 years to women following mastectomy. When compared to placebo, tamoxifen showed a higher incidence of hot flashes (19% vs. 8% for placebo). The incidence of all other adverse reactions was similar in the two treatment groups with the exception of thrombocytopenia, where the incidence for tamoxifen was 10% vs. 3% for placebo. In other adjuvant studies [the Toronto study and Tamoxifen Adjuvant Trial Organization (NATO)], women received either tamoxifen or no therapy [see Clinical Studies (14.2) ] . In the Toronto study, hot flashes were observed in 29% of patients for tamoxifen 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 vs. 0.2% for each in the untreated group. Anastrozole Adjuvant Trial (ATAC: Arimidex, Tamoxifen, Alone or in Combination) – Study of Anastrozole Compared to Tamoxifen for Adjuvant Treatment of Early Breast Cancer At a median follow-up of 33 months, the combination of anastrozole and tamoxifen did not demonstrate an efficacy benefit when compared to tamoxifen monotherapy in all patients as well as in the hormone receptor- positive subpopulation. The combination 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 20 mg monotherapy, respectively. Adverse reactions occurring with an incidence of at least 5% in either single-drug treatment group during treatment or within 14 days of the end of treatment are presented in Table 3. Table 3: Adverse Reactions Occurring with an Incidence of at Least 5% in Either Single-Drug Treatment Group During Treatment or Within 14 Days of the End of Treatment in the ATAC Trial % of Women Body system and adverse reactions by COSTART-preferred term COSTART: Coding Symbols for Thesaurus of Adverse Reaction Terms. A patient may have had more than 1 adverse reaction, including more than 1 adverse reaction in the same body system. Tamoxifen N=3,094 Anastrozole N=3,092 Body as a whole Asthenia 18 19 Pain 16 17 Back pain 10 10 Accidental injury 10 10 Abdominal pain 9 9 Infection 9 9 Headache 8 10 Flu syndrome 6 6 Cyst 5 5 Chest pain 5 7 Neoplasm 5 5 Cardiovascular Vasodilatation 41 36 Hypertension 11 13 Digestive Nausea 11 11 Constipation 8 8 Diarrhea 7 9 Dyspepsia 6 7 Gastrointestinal disorder 5 7 Hemic and lymphatic Lymphedema 11 10 Anemia 5 4 Metabolic and nutritional Peripheral edema 11 10 Weight gain 9 9 Hypercholesterolemia 3 9 Musculoskeletal Arthritis 14 17 Arthralgia 11 15 Osteoporosis 7 11 Fracture 7 10 Bone pain 6 7 Joint disorder 5 6 Myalgia 5 6 Arthrosis 5 7 Nervous system Depression 12 13 Insomnia 9 10 Dizziness 8 8 Anxiety 6 6 Paresthesia 5 7 Respiratory Pharyngitis 14 14 Cough increased 9 8 Dyspnea 8 8 Sinusitis 5 6 Bronchitis 5 5 Skin and appendages Rash 13 11 Sweating 6 5 Special senses Cataract specified 7 6 Urogenital Urinary tract infection 10 8 Leukorrhea 9 3 Vaginal hemorrhage Vaginal hemorrhage without further diagnosis 6 4 Breast pain 6 8 Vaginitis 5 4 Vulvovaginitis 5 6 Breast neoplasm 5 5 Certain adverse reactions and combinations of adverse reactions were prospectively specified for analysis in the ATAC trial, based on the known pharmacologic properties and safety profiles of the two drugs (Table 4). Table 4: Percentage of Patients with Pre-Specified Adverse Reactions in the ATAC Trial Patients with multiple events in the same category are counted only once in that category. % of Women Odds Ratio The odds ratios <1 favor anastrozole and those >1 favor tamoxifen. 95% CI Tamoxifen N=3,094 Anastrozole N=3,092 Hot flashes 41 36 0.80 0.73 to 0.89 Musculoskeletal events Refers to joint symptoms, including joint disorder, arthritis, arthrosis and arthralgia. 29 36 1.32 1.19 to 1.47 Mood disturbances 18 19 1.10 0.97 to 1.25 Fatigue/asthenia 18 19 1.07 0.94 to 1.22 Vaginal discharge 13 4 0.24 0.19 to 0.30 Nausea and vomiting 12 13 1.03 0.88 to 1.19 Vaginal bleeding 10 5 0.50 0.41 to 0.61 Cataracts 7 6 0.85 0.69 to 1.04 All fractures 7 10 1.57 1.30 to 1.88 Fractures of spine, hip, or wrist 3 4 1.48 1.13 to 1.95 Wrist/Colles' fractures 2 2 Hip fractures 1 1 Spine fractures 1 1 Venous thromboembolic events 5 3 0.61 0.47 to 0.80 Deep venous thromboembolic events 2 2 0.64 0.45 to 0.93 Ischemic cerebrovascular events 3 2 0.70 0.50 to 0.97 Ischemic cardiovascular disease 3 4 1.23 0.95 to 1.60 Endometrial cancer Percentages calculated based upon the numbers of women who had not undergone hysterectomy at baseline. 0.6 0.2 0.31 0.10 to 0.94 Adverse Reactions in Ductal Carcinoma in Situ The types and frequency of adverse reactions in the NSABP B-24 trial in women with DCIS were consistent with those observed in the other adjuvant trials conducted with tamoxifen [see Clinical Studies (14.3) ] . Adverse Reactions in Women at High Risk for Breast Cancer In the NSABP P-1 trial, there was an increase in five serious adverse reactions in the tamoxifen group [see Warnings and Precautions (5.1 , 5.2 , and 5.8) and Clinical Studies (14.4) ] : endometrial cancer (33 cases in the tamoxifen group vs. 14 in the placebo group); pulmonary embolism (18 cases in the tamoxifen group vs. 6 in the placebo group); deep vein thrombosis (30 cases in the tamoxifen group vs. 19 in the placebo group); stroke (34 cases in the tamoxifen group vs. 24 in the placebo group); cataract formation (540 cases in the tamoxifen group vs. 483 in the placebo group), and cataract surgery (101 cases in the tamoxifen group vs. 63 in the placebo group). Table 5 presents the adverse reactions observed in NSABP P-1 by treatment arm. Only adverse reactions more common on tamoxifen than placebo are shown. Table 5: Most Common Adverse Reactions in Women at High Risk for Breast Cancer (Study NSABP P-1) % of Women Tamoxifen N=6,681 Placebo N=6,707 Self-Reported Symptoms N=6,441 Number with quality of life questionnaires N=6,469 Hot flashes 80 68 Vaginal discharge 55 35 Vaginal bleeding 23 22 Laboratory Abnormalities N=6,520 Number with treatment follow-up forms N=6,535 Platelets decreased 0.7 0.3 Adverse Reactions N=6,492 Number with adverse reaction forms N=6,484 Mood changes 11.6 10.8 Infection/sepsis 6.0 5.1 Constipation 4.4 3.2 Skin changes 5.6 4.7 Alopecia 5.2 4.4 Allergy 2.5 2.1 In the NSABP P-1 trial, 15.0% and 9.7% of participants receiving tamoxifen and placebo therapy, respectively, withdrew from the trial for medical reasons including the following: hot flashes (3.1% vs. 1.5%, respectively) and vaginal discharge (0.5% vs. 0.1% respectively). Severe hot flashes occurred in 28% of women on placebo and 45% of women on tamoxifen. Vaginal discharge was severe in 4.5% on placebo and 12.3% on tamoxifen. SOLTAMOX-related Adverse Reactions In a single-dose pharmacokinetic study in healthy perimenopausal and postmenopausal women, throat irritation was reported by 3 of 60 evaluable subjects (5%) in the SOLTAMOX treatment group while none of the subjects in the tamoxifen citrate tablet group reported this event. All cases were mild, occurred within an hour after dosing, and resolved within 24 hours. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of tamoxifen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and Subcutaneous Disorders: Erythema multiforme, Stevens-Johnson syndrome, bullous pemphigoid Respiratory, Thoracic, Mediastinal Disorders: Interstitial pneumonitis Immune System Disorders: Hypersensitivity reactions including angioedema; in some of these cases, the time to onset was more than one year. Gastrointestinal Disorder s: Elevation of serum triglyceride levels, in some cases with pancreatitis Men with Metastatic Breast Cancer Loss of libido and impotence have resulted in discontinuation of tamoxifen therapy in male patients. In oligospermic males treated with tamoxifen, LH, FSH, testosterone, and estrogen levels were elevated, with no reported associated clinical changes.

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 [see Clinical Studies (14.2) ] . 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 [see Clinical Pharmacology (12.3) ]. 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 [see Clinical Pharmacology (12.3) ] . 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 [see Clinical Pharmacology (12.3) ] . 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.

Store at room temperatures 20° to 25°C (68° - 77°F); excursions permitted between 15° to 30°C (59° - 86°F) [see USP Controlled Room Temperature]. DO NOT freeze or refrigerate. Store in original packaging in order to protect from light. Discard any unused portion after 3 months of first opening of the bottle.