Faslodex Drug Information

• FASLODEX 500 mg should be administered intramuscularly into the buttocks (gluteal area) slowly (1 - 2 minutes per injection) as two 5 mL injections, one in each buttock, on Days 1, 15, 29, and once monthly thereafter. ( 2.1 , 14 )
• A dose of 250 mg is recommended in patients with moderate hepatic impairment to be administered intramuscularly into the buttock (gluteal area) slowly (1 - 2 minutes) as one 5 mL injection on Days 1, 15, 29, and once monthly thereafter. ( 2.2 , 5.2 , 8.6 ) 2.1 Recommended Dose Monotherapy The recommended dose of FASLODEX is 500 mg to be administered intramuscularly into the buttocks (gluteal area) slowly (1 - 2 minutes per injection) as two 5 mL injections, one in each buttock, on Days 1, 15, 29, and once monthly thereafter [see Clinical Studies (14) ] . Combination Therapy When FASLODEX is used in combination with palbociclib, abemaciclib, or ribociclib, the recommended dose of FASLODEX is 500 mg to be administered intramuscularly into the buttocks (gluteal area) slowly (1 - 2 minutes per injection) as two 5 mL injections, one in each buttock, on Days 1, 15, 29, and once monthly thereafter. When FASLODEX is used in combination with palbociclib, the recommended dose of palbociclib is a 125 mg capsule taken orally once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete cycle of 28 days. Palbociclib should be taken with food. Refer to the Full Prescribing Information for palbociclib. When FASLODEX is used in combination with abemaciclib, the recommended dose of abemaciclib is 150 mg orally, twice daily. Abemaciclib may be taken with or without food. Refer to the Full Prescribing Information for abemaciclib. When FASLODEX is used in combination with ribociclib, the recommended dose of ribociclib is 600 mg taken orally, once daily for 21 consecutive days followed by 7 days off treatment resulting in a complete cycle of 28 days. Ribociclib can be taken with or without food. Refer to the Full Prescribing Information for ribociclib. Pre/perimenopausal women treated with the combination of FASLODEX plus palbociclib, abemaciclib, or ribociclib, should be treated with luteinizing hormone-releasing hormone (LHRH) agonists according to current clinical practice standards [see Clinical Studies (14) ] . 2.2 Dose Modification Monotherapy Hepatic Impairment: A dose of 250 mg is recommended for patients with moderate hepatic impairment (Child-Pugh class B) to be administered intramuscularly into the buttock (gluteal area) slowly (1 - 2 minutes) as one 5 mL injection on Days 1, 15, 29, and once monthly thereafter. FASLODEX has not been evaluated in patients with severe hepatic impairment (Child-Pugh class C) [see Warnings and Precautions (5.2) and Use in Specific Populations (8.6) ] . Combination Therapy When FASLODEX is used in combination with palbociclib, abemaciclib, or ribociclib, refer to monotherapy dose modification instructions for FASLODEX. Refer to the Full Prescribing Information of co-administered palbociclib, abemaciclib, or ribociclib for dose modification guidelines in the event of toxicities, for use with concomitant medications, and other relevant safety information. 2.3 Administration Technique Administer the injection according to the local guidelines for performing large volume intramuscular injections. NOTE: Due to the proximity of the underlying sciatic nerve, caution should be taken if administering FASLODEX at the dorsogluteal injection site [see Warnings and Precautions (5.3) and Adverse Reactions (6.1) ]. The proper method of administration of FASLODEX for intramuscular use is described in the following instructions. For each single-dose prefilled syringe: 1. Remove glass syringe barrel from tray and check that it is not damaged. 2. Remove perforated patient record label from syringe. 3. Inspect drug product in glass syringe for any visible particulate matter or discoloration prior to use. Discard if particulate matter or discoloration is present. 4. Peel open the safety needle (SafetyGlide™) outer packaging. 5. Hold the syringe upright on the ribbed part (C). With the other hand, take hold of the cap (A) and carefully tilt cap back and forth (DO NOT TWIST CAP) until the cap disconnects for removal (see Figure 1). 6. Pull the cap (A) off in a straight upward direction. DO NOT TOUCH THE STERILE SYRINGE TIP (Luer-Lok) (B) (see Figure 2). 1. Attach the safety needle to the syringe tip (Luer-Lok). Twist needle until firmly seated (see Figure 3). Confirm that the needle is locked to the Luer connector before moving or tilting the syringe out of the vertical plane to avoid spillage of syringe contents. For Administration: 1. Pull shield straight off needle to avoid damaging needle point. 2. Remove needle sheath. 3. Expel excess gas from the syringe (a small gas bubble may remain). 4. Administer intramuscularly slowly (1-2 minutes/injection) into the buttock (gluteal area). For user convenience, the needle ‘bevel up’ position is orientated to the lever arm, as shown in Figure 4. 1. After injection, immediately activate the lever arm to deploy the needle shielding by applying a single-finger stroke to the activation assisted lever arm to push the lever arm completely forward. Listen for a click. Confirm that the needle shielding has completely covered the needle (see Figure 5). NOTE: Activate away from self and others. 1. Discard the empty syringe into an approved sharps collector in accordance with applicable regulations and institutional policy. 2. Repeat steps 1 through 13 for second syringe. How To Use FASLODEX For the 2 x 5 mL syringe package, the contents of both syringes must be injected to receive the 500 mg recommended dose. SAFETYGLIDE™ INSTRUCTIONS FROM BECTON DICKINSON SafetyGlide ™ is a trademark of Becton Dickinson and Company. Important Administration Information To help avoid HIV (AIDS), HBV (Hepatitis), and other infectious diseases due to accidental needlesticks, contaminated needles should not be recapped or removed, unless there is no alternative or that such action is required by a specific medical procedure. Hands must remain behind the needle at all times during use and disposal. Do not autoclave SafetyGlide™ Needle before use. Becton Dickinson guarantees the contents of their unopened or undamaged packages to be sterile, non-toxic, and non-pyrogenic. Figure 1 Figure 2 Figure 3 Figure 4 Figure 5

• The following adverse reactions are discussed in more detail in other sections of the labeling:
• Risk of Bleeding [see Warnings and Precautions (5.1) ]
• Increased Exposure in Patients with Hepatic Impairment [see Warnings and Precautions (5.2) ]
• Injection Site Reaction [see Warnings and Precautions (5.3) ]
• Embryo-Fetal Toxicity [see Warnings and Precautions (5.4) ]
• The most common adverse reactions occurring in ≥5% of patients receiving FASLODEX 500 mg were: injection site pain, nausea, bone pain, arthralgia, headache, back pain, fatigue, pain in extremity, hot flash, vomiting, anorexia, asthenia, musculoskeletal pain, cough, dyspnea, and constipation. (6.1)
• Increased hepatic enzymes (ALT, AST, ALP) occurred in >15% of FASLODEX patients and were not dose-dependent. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 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, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice. Monotherapy Comparison of FASLODEX 500 mg and FASLODEX 250 mg (CONFIRM) The following adverse reactions (ARs) were calculated based on the safety analysis of CONFIRM comparing the administration of FASLODEX 500 mg intramuscularly once a month with FASLODEX 250 mg intramuscularly once a month. The most frequently reported adverse reactions in the FASLODEX 500 mg group were injection site pain (11.6% of patients), nausea (9.7% of patients), and bone pain (9.4% of patients); the most frequently reported adverse reactions in the FASLODEX 250 mg group were nausea (13.6% of patients), back pain (10.7% of patients), and injection site pain (9.1% of patients). Table 1 lists adverse reactions reported with an incidence of 5% or greater, regardless of assessed causality, from CONFIRM. Table 1: Adverse Reactions in CONFIRM (≥5% in Either Treatment Group) Adverse Reactions FASLODEX 500 mg N=361 % FASLODEX 250 mg N=374 % Body as a Whole Injection Site Pain Including more severe injection site related sciatica, neuralgia, neuropathic pain, and peripheral neuropathy. 12 9 Headache 8 7 Back Pain 8 11 Fatigue 8 6 Pain in Extremity 7 7 Asthenia 6 6 Vascular System Hot Flash 7 6 Digestive System Nausea 10 14 Vomiting 6 6 Anorexia 6 4 Constipation 5 4 Musculoskeletal System Bone Pain 9 8 Arthralgia 8 8 Musculoskeletal Pain 6 3 Respiratory System Cough 5 5 Dyspnea 4 5 In the pooled safety population (N=1127) from clinical trials comparing FASLODEX 500 mg to FASLODEX 250 mg, post-baseline increases of ≥1 CTC grade in either AST, ALT, or alkaline phosphatase were observed in >15% of patients receiving FASLODEX. Grade 3-4 increases were observed in 1-2% of patients. The incidence and severity of increased hepatic enzymes (ALT, AST, ALP) did not differ between the 250 mg and the 500 mg FASLODEX arms. Comparison of FASLODEX 500 mg and Anastrozole 1 mg (FALCON) The safety of FASLODEX 500 mg versus anastrozole 1 mg was evaluated in FALCON. The data described below reflect exposure to FASLODEX in 228 out of 460 patients with HR-positive advanced breast cancer in postmenopausal women not previously treated with endocrine therapy who received at least one (1) dose of treatment in FALCON. Permanent discontinuation associated with an adverse reaction occurred in 4 of 228 (1.8%) patients receiving FASLODEX and in 3 of 232 (1.3%) patients receiving anastrozole. Adverse reactions leading to discontinuation for those patients receiving FASLODEX included drug hypersensitivity (0.9%), injection site hypersensitivity (0.4%), and elevated liver enzymes (0.4%). The most common adverse reactions (≥10%) of any grade reported in patients in the FASLODEX arm were arthralgia, hot flash, fatigue, and nausea. Adverse reactions reported in patients who received FASLODEX in FALCON at an incidence of ≥5% in either treatment arm are listed in Table 2, and laboratory abnormalities are listed in Table 3. Table 2: Adverse Reactions in FALCON Adverse Reactions FASLODEX 500 mg N=228 Anastrozole 1 mg N=232 All Grades % Grade 3 or 4 % All Grades % Grade 3 or 4 % Vascular Disorders Hot flash 11 0 10 0 Gastrointestinal Disorders Nausea 11 0 10 <1 Diarrhea 6 0 6 <1 Musculoskeletal and Connective Tissue Disorders Arthralgia 17 0 10 0 Myalgia 7 0 3 0 Pain in extremity 6 0 4 0 Back pain 9 <1 6 0 General Disorders and Administration Site Conditions Fatigue 11 <1 7 <1 Table 3: Laboratory Abnormalities in FALCON In FALCON, post-baseline increases of ≥1 CTC grade in either AST, ALT, or alkaline phosphatase were observed in >10% of patients receiving FASLODEX. Grade 3-4 increases were observed in 1%-3% of patients. Laboratory Parameters FASLODEX 500 mg N=228 Anastrozole 1 mg N=232 All Grades % Grade 3 or 4 % All Grades % Grade 3 or 4 % Alanine aminotransferase increased (ALT) 7 1 3 0 Aspartate aminotransferase increased (AST) 5 1 3 <1 Comparison of FASLODEX 250 mg and Anastrozole 1 mg in Combined Trials (Studies 0020 and 0021) The most commonly reported adverse reactions in the FASLODEX and anastrozole treatment groups were gastrointestinal symptoms (including nausea, vomiting, constipation, diarrhea, and abdominal pain), headache, back pain, vasodilatation (hot flashes), and pharyngitis. Injection site reactions with mild transient pain and inflammation were seen with FASLODEX and occurred in 7% of patients given the single 5 mL injection (Study 0020) and in 27% of patients given the 2 x 2.5 mL injections (Study 0021) in the two clinical trials that compared FASLODEX 250 mg and anastrozole 1 mg. Table 4 lists adverse reactions reported with an incidence of 5% or greater, regardless of assessed causality, from the two controlled clinical trials comparing the administration of FASLODEX 250 mg intramuscularly once a month with anastrozole 1 mg orally once a day. Table 4: Adverse Reactions in Studies 0020 and 0021 (≥5% from Combined Data) Adverse Reactions FASLODEX 250 mg N=423 % Anastrozole 1 mg N=423 % Body as a Whole 68 68 Asthenia 23 27 Pain 19 20 Headache 15 17 Back Pain 14 13 Abdominal Pain 12 12 Injection Site Pain Including more severe injection site related sciatica, neuralgia, neuropathic pain, and peripheral neuropathy. All patients on FASLODEX received injections, but only those anastrozole patients who were in Study 0021 received placebo injections. 11 7 Pelvic Pain 10 9 Chest Pain 7 5 Flu Syndrome 7 6 Fever 6 6 Accidental Injury 5 6 Cardiovascular System 30 28 Vasodilatation 18 17 Digestive System 52 48 Nausea 26 25 Vomiting 13 12 Constipation 13 11 Diarrhea 12 13 Anorexia 9 11 Hemic and Lymphatic Systems 14 14 Anemia 5 5 Metabolic and Nutritional Disorders 18 18 Peripheral Edema 9 10 Musculoskeletal System 26 28 Bone Pain 16 14 Arthritis 3 6 Nervous System 34 34 Dizziness 7 7 Insomnia 7 9 Paresthesia 6 8 Depression 6 7 Anxiety 5 4 Respiratory System 39 34 Pharyngitis 16 12 Dyspnea 15 12 Cough Increased 10 10 Skin and Appendages 22 23 Rash 7 8 Sweating 5 5 Urogenital System 18 15 Urinary Tract Infection 6 4 Combination Therapy Combination Therapy with Palbociclib (PALOMA-3) The safety of FASLODEX 500 mg plus palbociclib 125 mg/day versus FASLODEX plus placebo was evaluated in PALOMA-3. The data described below reflect exposure to FASLODEX plus palbociclib in 345 out of 517 patients with HR-positive, HER2-negative advanced or metastatic breast cancer who received at least 1 dose of treatment in PALOMA-3. The median duration of treatment for FASLODEX plus palbociclib was 10.8 months while the median duration of treatment for FASLODEX plus placebo arm was 4.8 months. No dose reduction was allowed for FASLODEX in PALOMA-3. Dose reductions of palbociclib due to an adverse reaction of any grade occurred in 36% of patients receiving FASLODEX plus palbociclib. Permanent discontinuation associated with an adverse reaction occurred in 19 of 345 (6%) patients receiving FASLODEX plus palbociclib, and in 6 of 172 (3%) patients receiving FASLODEX plus placebo. Adverse reactions leading to discontinuation for those patients receiving FASLODEX plus palbociclib included fatigue (0.6%), infections (0.6%), and thrombocytopenia (0.6%). The most common adverse reactions (≥10%) of any grade reported in patients in the FASLODEX plus palbociclib arm by descending frequency were neutropenia, leukopenia, infections, fatigue, nausea, anemia, stomatitis, diarrhea, thrombocytopenia, vomiting, alopecia, rash, decreased appetite, and pyrexia. The most frequently reported Grade ≥3 adverse reactions (≥5%) in patients receiving FASLODEX plus palbociclib in descending frequency were neutropenia and leukopenia. Adverse reactions (≥10%) reported in patients who received FASLODEX plus palbociclib or FASLODEX plus placebo in PALOMA-3 are listed in Table 5, and laboratory abnormalities are listed in Table 6. Table 5: Adverse Reactions (≥10%) in PALOMA-3 Adverse Reactions FASLODEX plus Palbociclib N=345 FASLODEX plus Placebo N=172 All Grades % Grade 3 % Grade 4 % All Grades % Grade 3 % Grade 4 % Infections and Infestations Infections Infections includes all reported preferred terms (PTs) that are part of the System Organ Class Infections and infestations. 47 Most common infections (≥1%) include: nasopharyngitis, upper respiratory infection, urinary tract infection, influenza, bronchitis, rhinitis, conjunctivitis, pneumonia, sinusitis, cystitis, oral herpes, respiratory tract infection, gastroenteritis, tooth infection, pharyngitis, eye infection, herpes simplex, paronychia. 3 1 31 3 0 Blood and Lymphatic System Disorders Neutropenia 83 55 11 4 1 0 Leukopenia 53 30 1 5 1 1 Anemia 30 4 0 13 2 0 Thrombocytopenia 23 2 1 0 0 0 Metabolism and Nutrition Disorders Decreased appetite 16 1 0 8 1 0 Gastrointestinal Disorders Nausea 34 0 0 28 1 0 Stomatitis Stomatitis includes: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral pain, oropharyngeal discomfort, oropharyngeal pain, stomatitis. 28 1 0 13 0 0 Diarrhea 24 0 0 19 1 0 Vomiting 19 1 0 15 1 0 Skin and Subcutaneous Tissue Disorders Alopecia 18 Grade 1 events – 17%; Grade 2 events – 1%. N/A N/A 6 Grade 1 events – 6%. N/A N/A Rash Rash includes: rash, rash maculo-papular, rash pruritic, rash erythematous, rash papular, dermatitis, dermatitis acneiform, toxic skin eruption. 17 1 0 6 0 0 General Disorders and Administration Site Conditions Fatigue 41 2 0 29 1 0 Pyrexia 13 <1 0 5 0 0 Grading according to CTCAE v.4.0. CTCAE=Common Terminology Criteria for Adverse Events; N=number of patients; N/A=not applicable. Additional adverse reactions occurring at an overall incidence of <10.0% of patients receiving FASLODEX plus palbociclib in PALOMA-3 included asthenia (7.5%), aspartate aminotransferase increased (7.5%), dysgeusia (6.7%), epistaxis (6.7%), lacrimation increased (6.4%), dry skin (6.1%), alanine aminotransferase increased (5.8%), vision blurred (5.8%), dry eye (3.8%), and febrile neutropenia (0.9%). Table 6: Laboratory Abnormalities in PALOMA-3 Laboratory Parameters FASLODEX plus Palbociclib N=345 FASLODEX plus Placebo N=172 All Grades % Grade 3 % Grade 4 % All Grades % Grade 3 % Grade 4 % WBC decreased 99 45 1 26 0 1 Neutrophils decreased 96 56 11 14 0 1 Anemia 78 3 0 40 2 0 Platelets decreased 62 2 1 10 0 0 Aspartate aminotransferase increased 43 4 0 48 4 0 Alanine aminotransferase increased 36 2 0 34 0 0 N=number of patients; WBC=white blood cells. Combination Therapy with Abemaciclib (MONARCH 2) The safety of FASLODEX (500 mg) plus abemaciclib (150 mg twice daily) versus FASLODEX plus placebo was evaluated in MONARCH 2. The data described below reflect exposure to FASLODEX in 664 patients with HR-positive, HER2-negative advanced breast cancer who received at least one dose of FASLODEX plus abemaciclib or placebo in MONARCH 2. Median duration of treatment was 12 months for patients receiving FASLODEX plus abemaciclib and 8 months for patients receiving FASLODEX plus placebo. Dose reductions due to an adverse reaction occurred in 43% of patients receiving FASLODEX plus abemaciclib. Adverse reactions leading to dose reductions ≥5% of patients were diarrhea and neutropenia. Abemaciclib dose reduction due to diarrhea of any grade occurred in 19% of patients receiving FASLODEX plus abemaciclib compared to 0.4% of patients receiving FASLODEX plus placebo. Abemaciclib dose reductions due to neutropenia of any grade occurred in 10% of patients receiving FASLODEX plus abemaciclib compared to no patients receiving FASLODEX plus placebo. Permanent study treatment discontinuation due to an adverse event was reported in 9% of patients receiving FASLODEX plus abemaciclib and in 3% of patients receiving FASLODEX plus placebo. Adverse reactions leading to permanent discontinuation for patients receiving FASLODEX plus abemaciclib were infection (2%), diarrhea (1%), hepatotoxicity (1%), fatigue (0.7%), nausea (0.2%), abdominal pain (0.2%), acute kidney injury (0.2%), and cerebral infarction (0.2%). Deaths during treatment or during the 30-day follow up, regardless of causality, were reported in 18 cases (4%) of FASLODEX plus abemaciclib treated patients versus 10 cases (5%) of FASLODEX plus placebo treated patients. Causes of death for patients receiving FASLODEX plus abemaciclib included: 7 (2%) patient deaths due to underlying disease, 4 (0.9%) due to sepsis, 2 (0.5%) due to pneumonitis, 2 (0.5%) due to hepatotoxicity, and one (0.2%) due to cerebral infarction. The most common adverse reactions reported (≥20%) in the FASLODEX plus abemaciclib arm were diarrhea, fatigue, neutropenia, nausea, infections, abdominal pain, anemia, leukopenia, decreased appetite, vomiting, and headache (Table 7). The most frequently reported (≥5%) Grade 3 or 4 adverse reactions were neutropenia, diarrhea, leukopenia, anemia, and infections. Table 7: Adverse Reactions ≥10% of Patients Receiving FASLODEX Plus Abemaciclib and ≥2% Higher Than FASLODEX Plus Placebo in MONARCH 2 Adverse Reactions FASLODEX plus Abemaciclib N=441 FASLODEX plus Placebo N=223 All Grades % Grade 3 % Grade 4 % All Grades % Grade 3 % Grade 4 % Gastrointestinal Disorders Diarrhea 86 13 0 25 <1 0 Nausea 45 3 0 23 1 0 Abdominal pain Includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort, abdominal tenderness. 35 2 0 16 1 0 Vomiting 26 <1 0 10 2 0 Stomatitis 15 <1 0 10 0 0 Infections and Infestations Infections Includes upper respiratory tract infection, urinary tract infection, lung infection, pharyngitis, conjunctivitis, sinusitis, vaginal infection, sepsis. 43 5 <1 25 3 <1 Blood and Lymphatic System Disorders Neutropenia Includes neutropenia, neutrophil count decreased. 46 24 3 4 1 <1 Anemia Includes anemia, hematocrit decreased, hemoglobin decreased, red blood cell count decreased. 29 7 <1 4 1 0 Leukopenia Includes leukopenia, white blood cell count decreased. 28 9 <1 2 0 0 Thrombocytopenia Includes platelet count decreased, thrombocytopenia. 16 2 1 3 0 <1 General Disorders and Administration Site Conditions Fatigue Includes asthenia, fatigue. 46 3 0 32 <1 0 Edema peripheral 12 0 0 7 0 0 Pyrexia 11 <1 <1 6 <1 0 Metabolism and Nutrition Disorders Decreased appetite 27 1 0 12 <1 0 Respiratory, Thoracic, and Mediastinal Disorders Cough 13 0 0 11 0 0 Skin and Subcutaneous Tissue Disorders Alopecia 16 0 0 2 0 0 Pruritus 13 0 0 6 0 0 Rash 11 1 0 4 0 0 Nervous System Disorders Headache 20 1 0 15 <1 0 Dysgeusia 18 0 0 3 0 0 Dizziness 12 1 0 6 0 0 Investigations Alanine aminotransferase increased 13 4 <1 5 2 0 Aspartate aminotransferase increased 12 2 0 7 3 0 Creatinine increased 12 <1 0 <1 0 0 Weight decreased 10 <1 0 2 <1 0 Additional adverse reactions in MONARCH 2 include venous thromboembolic events (deep vein thrombosis, pulmonary embolism, cerebral venous sinus thrombosis, subclavian vein thrombosis, axillary vein thrombosis, and DVT inferior vena cava), which were reported in 5% of patients treated with FASLODEX plus abemaciclib as compared to 0.9% of patients treated with FASLODEX plus placebo. Table 8: Laboratory Abnormalities ≥10% in Patients Receiving FASLODEX Plus Abemaciclib and ≥2% Higher Than FASLODEX Plus Placebo in MONARCH 2 Laboratory Parameters Fulvestrant plus Abemaciclib N=441 Fulvestrant plus Placebo N=223 All Grades % Grade 3 % Grade 4 % All Grades % Grade 3 % Grade 4 % Creatinine increased 98 1 0 74 0 0 White blood cell decreased 90 23 <1 33 <1 0 Neutrophil count decreased 87 29 4 30 4 <1 Anemia 84 3 0 33 <1 0 Lymphocyte count decreased 63 12 <1 32 2 0 Platelet count decreased 53 <1 1 15 0 0 Alanine aminotransferase increased 41 4 <1 32 1 0 Aspartate aminotransferase increased 37 4 0 25 4 <1 Combination Therapy with Ribociclib (MONALEESA-3) The safety of FASLODEX 500 mg plus ribociclib 600 mg versus FASLODEX plus placebo was evaluated in MONALEESA-3. The data described below reflect exposure to FASLODEX plus ribociclib in 483 out of 724 postmenopausal patients with HR-positive, HER2-negative advanced or metastatic breast cancer for initial endocrine based therapy or after disease progression on endocrine therapy who received at least one dose of FASLODEX plus ribociclib or placebo in MONALEESA-3. Median duration of treatment was 15.8 months for FASLODEX plus ribociclib and 12 months for FASLODEX plus placebo. Dose reductions due to adverse reactions occurred in 32% of patients receiving FASLODEX plus ribociclib and in 3% of patients receiving FASLODEX plus placebo. Among patients receiving FASLODEX plus ribociclib, 8% were reported to have permanently discontinued both FASLODEX plus ribociclib, and 9% were reported to have discontinued ribociclib alone due to ARs. Among patients receiving FASLODEX plus placebo, 4% were reported to have permanently discontinued both FASLODEX and placebo and 2% were reported to have discontinued placebo alone due to ARs. Adverse reactions leading to treatment discontinuation of FASLODEX plus ribociclib (as compared to FASLODEX plus placebo) were ALT increased (5% vs. 0%), AST increased (3% vs. 0.6%), and vomiting (1% vs. 0%). The most common adverse reactions (reported at a frequency ≥20% on the FASLODEX plus ribociclib arm and ≥2% higher than FASLODEX plus placebo) were neutropenia, infections, leukopenia, cough, nausea, diarrhea, vomiting, constipation, pruritus, and rash. The most frequently reported Grade 3/4 adverse reactions (reported at a frequency ≥5%) in patients receiving FASLODEX plus ribociclib in descending frequency were neutropenia, leukopenia, infections, and abnormal liver function tests. Adverse reactions and laboratory abnormalities occurring in patients in MONALEESA-3 are listed in Table 9 and Table 10, respectively. Table 9: Adverse Reactions Occurring in ≥10% and ≥2% higher than FASLODEX plus Placebo Arm in MONALEESA-3 (All Grades) Adverse Reactions FASLODEX plus Ribociclib N=483 FASLODEX plus Placebo N=241 All Grades % Grade 3 % Grade 4 % All Grades % Grade 3 % Grade 4 % Infections and Infestations Infections Infections; urinary tract infections; respiratory tract infections; gastroenteritis; sepsis (<1%). 42 5 0 30 2 0 Blood and Lymphatic System Disorders Neutropenia 69 46 7 2 0 0 Leukopenia 27 12 <1 <1 0 0 Anemia 17 3 0 5 2 0 Metabolism and Nutrition Disorders Decreased appetite 16 <1 0 13 0 0 Nervous System Disorders Dizziness 13 <1 0 8 0 0 Respiratory, Thoracic, and Mediastinal Disorders Cough 22 0 0 15 0 0 Dyspnea 15 1 <1 12 2 0 Gastrointestinal Disorders Nausea 45 1 0 28 <1 0 Diarrhea 29 <1 0 20 <1 0 Vomiting 27 1 0 13 0 0 Constipation 25 <1 0 12 0 0 Abdominal pain 17 1 0 13 <1 0 Skin and Subcutaneous Tissue Disorders Alopecia 19 0 0 5 0 0 Pruritus 20 <1 0 7 0 0 Rash 23 <1 0 7 0 0 General Disorders and Administration Site Conditions Edema peripheral 15 0 0 7 0 0 Pyrexia 11 <1 0 7 0 0 Investigations Alanine aminotransferase increased 15 7 2 5 <1 0 Aspartate aminotransferase increased 13 5 1 5 <1 0 Grading according to CTCAE 4.03. CTCAE=Common Terminology Criteria for Adverse Events; N=number of patients Additional adverse reactions in MONALEESA-3 for patients receiving FASLODEX plus ribociclib included asthenia (14%), dyspepsia (10%), thrombocytopenia (9%), dry skin (8%), dysgeusia (7%), electrocardiogram QT prolonged (6%), dry mouth (5%), vertigo (5%), dry eye (5%), lacrimation increased (4%), erythema (4%), hypocalcemia (4%), blood bilirubin increased (1%), and syncope (1%). Table 10: Laboratory Abnormalities Occurring in ≥10% of Patients in MONALEESA-3 Laboratory parameters FASLODEX plus Ribociclib N=483 FASLODEX plus Placebo N=241 All Grades % Grade 3 % Grade 4 % All Grades % Grade 3 % Grade 4 % Hematology Leukocyte count decreased 95 25 <1 26 <1 0 Neutrophil count decreased 92 46 7 21 <1 0 Hemoglobin decreased 60 4 0 35 3 0 Lymphocyte count decreased 69 14 1 35 4 <1 Platelet count decreased 33 <1 1 11 0 0 Chemistry Creatinine increased 65 <1 <1 33 <1 0 Gamma-glutamyl transferase increased 52 6 1 49 8 2 Aspartate aminotransferase increased 49 5 2 43 3 0 Alanine aminotransferase increased 44 8 3 37 2 0 Glucose serum decreased 23 0 0 18 0 0 Phosphorous decreased 18 5 0 8 <1 0 Albumin decreased 12 0 0 8 0 0 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of FASLODEX. 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. For FASLODEX 250 mg, other adverse reactions reported as drug-related and seen infrequently (<1%) include thromboembolic phenomena, myalgia, vertigo, leukopenia, and hypersensitivity reactions, including angioedema and urticaria. Vaginal bleeding has been reported infrequently (<1%), mainly in patients during the first 6 weeks after changing from existing hormonal therapy to treatment with FASLODEX. If bleeding persists, further evaluation should be considered. Elevation of bilirubin, elevation of gamma GT, hepatitis, and liver failure have been reported infrequently (<1%).

• There are no known drug-drug interactions. Although, fulvestrant is metabolized by CYP 3A4 in vitro , drug interactions studies with ketoconazole or rifampin did not alter fulvestrant pharmacokinetics. Dose adjustment is not needed in patients co-prescribed CYP 3A4 inhibitors or inducers [see Clinical Pharmacology (12.3) ] .
• There are no known drug-drug interactions. (7)

Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, FASLODEX can cause fetal harm when administered to a pregnant woman . There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of fulvestrant to pregnant rats and rabbits during organogenesis caused embryo-fetal toxicity, including skeletal malformations and fetal loss, at daily doses that were 6% and 30% of the maximum recommended human dose based on mg/m 2, respectively . Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Administration of fulvestrant to rats prior to and up to implantation caused embryonic loss at daily doses that were 0.6% of the daily maximum recommended human dose based on mg/m 2. When fulvestrant was administered to pregnant rats during the period of organogenesis, intramuscular doses ≥0.1 mg/kg/day (6% of the human recommended dose based on mg/m 2 ) caused effects on embryo-fetal development consistent with its antiestrogenic activity. Fulvestrant caused an increased incidence of fetal abnormalities in rats (tarsal flexure of the hind paw at 2 mg/kg/day; equivalent to the human dose based on mg/m 2 ) and non-ossification of the odontoid and ventral tubercle of the first cervical vertebra at doses ≥0.1 mg/kg/day.

Fulvestrant administered at 2 mg/kg/day caused fetal loss. When administered to pregnant rabbits during the period of organogenesis, fulvestrant caused pregnancy loss at an intramuscular dose of 1 mg/kg/day (equivalent to the human dose based on mg/m 2 ). Further, at 0.25 mg/kg/day (30% the human dose based on mg/m 2 ), fulvestrant caused increases in placental weight and post-implantation loss in rabbits. Fulvestrant was associated with an increased incidence of fetal variations in rabbits (backwards displacement of the pelvic girdle, and 27 pre-sacral vertebrae at 0.25 mg/kg/day; 30% the human dose based on mg/m 2 ) when administered during the period of organogenesis.

Pediatric Use Safety and effectiveness in pediatric patients have not been established. A multi-center, single-arm, open-label, study of fulvestrant was conducted in 30 girls with McCune-Albright Syndrome (MAS) associated with Progressive Precocious Puberty (PPP). The median age at informed consent was 6 years old (range: 1 to 8). The first 10 patients initially received fulvestrant 2 mg/kg. Based on PK data from the first 6 patients, all 10 patients receiving 2 mg/kg were escalated to a dose of 4 mg/kg and all other patients received 4 mg/kg from study entry.

Baseline measurements for vaginal bleeding days, bone age, growth velocity, and Tanner staging for at least 6 months prior to study entry were provided retrospectively by the parent, guardian, or local consultant. All measurements during the study period were collected prospectively. Patients’ baseline characteristics included the following: a mean ± SD chronological age of 5.9 ± 1.8 years; a mean rate of bone age advancement (change in bone age in years divided by change in chronological age in years) of 2.0 ± 1.03; and a mean growth velocity z-score of 2.4 ± 3.26. Twenty-nine of 30 patients completed the 12-month study period.

The following results were observed: 35% (95% CI: 16%, 57%) of the 23 patients with baseline vaginal bleeding experienced a complete cessation of vaginal bleeding on-treatment (month 0 to 12); a reduction in the rate of bone age advancement during the 12-month study period compared to baseline (mean change=-0.9 ); and a reduction in mean growth velocity Z-score on-treatment compared to baseline (mean change=-1.1 ). There were no clinically meaningful changes in median Tanner stage (breast or pubic), mean uterine volume, or mean ovarian volume, or predicted adult height (PAH) on-treatment compared to baseline. The effect of FASLODEX on bone mineral density in children has not been studied and is not known. Eight patients (27%) experienced adverse reactions that were considered possibly related to FASLODEX. These included injection site reactions (inflammation, pain, hematoma, pruritus, rash), abdominal pain, contusion, tachycardia, hot flash, extremity pain, and vomiting.

Nine (30%) patients reported an SAE, none of which were considered related to FASLODEX. No patients discontinued study treatment due to an AE and no patients died. Pharmacokinetics The pharmacokinetics of fulvestrant was characterized using a population pharmacokinetic analysis with sparse samples per patient obtained from 30 female pediatric patients aged 1 to 8 years with PPP associated with MAS. Pharmacokinetic data from 294 postmenopausal women with breast cancer who received 125 or 250 mg monthly dosing regimen were also included in the analysis. In these pediatric patients receiving 4 mg/kg monthly intramuscular dose of fulvestrant, the geometric mean (SD) CL/F was 444 mL/min which was 32% lower than adults.

The geometric mean (SD) steady state trough concentration (C min,ss ) and AUC ss was 4.19 ng/mL and 3680 ng*hr/mL, respectively.

• is contraindicated in patients with a known hypersensitivity to the drug or to any of its components. Hypersensitivity reactions, including urticaria and angioedema, have been reported in association with FASLODEX [see Adverse Reactions (6.2) ].
• Hypersensitivity. (4)

Human experience of overdose with FASLODEX is limited. There are isolated reports of overdose with FASLODEX in humans. No adverse reactions were seen in healthy male and female volunteers who received intravenous fulvestrant, which resulted in peak plasma concentrations at the end of the infusion, that were approximately 10 to 15 times those seen after intramuscular injection.

The potential toxicity of fulvestrant at these or higher concentrations in cancer patients who may have additional comorbidities is unknown. There is no specific treatment in the event of fulvestrant overdose, and symptoms of overdose are not established. In the event of an overdose, healthcare practitioners should follow general supportive measures and should treat symptomatically.