Fulvestrant for Breast Cancer

INDICATIONS AND USAGE Monotherapy Fulvestrant injection is indicated for the treatment of: • Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer in postmenopausal women not previously treated with endocrine therapy, or • HR-positive advanced breast cancer in postmenopausal women with disease progression following endocrine therapy. Combination Therapy • Fulvestrant injection is indicated for the treatment of: • HR-positive, HER2-negative advanced or metastatic breast cancer in postmenopausal women in combination with ribociclib as initial endocrine based therapy or following disease progression on endocrine therapy. • HR-positive, HER2-negative advanced or metastatic breast cancer in combination with palbociclib or abemaciclib in women with disease progression after endocrine therapy. Fulvestrant injection is an estrogen receptor antagonist indicated for the treatment of: • Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer in postmenopausal women not previously treated with endocrine therapy. ( 1 ) • HR-positive advanced breast cancer in postmenopausal women with disease progression following endocrine therapy. ( 1 ) • HR-positive, HER2-negative advanced or metastatic breast cancer in postmenopausal women in combination with ribociclib, as initial endocrine based therapy or following disease progression on endocrine therapy. (1) • HR-positive, HER2-negative advanced or metastatic breast cancer in combination with palbociclib or abemaciclib in women with disease progression after endocrine therapy. ( 1 )

DOSAGE AND ADMINISTRATION Fulvestrant injection 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 fulvestrant injection 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 fulvestrant injection is used in combination with palbociclib, abemaciclib, or ribociclib, the recommended dose of fulvestrant injection 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 fulvestrant injection 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 fulvestrant injection 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 fulvestrant injection 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 fulvestrant injection X 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 . Fulvestrant injection 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 fulvestrant injection is used in combination with palbociclib, abemaciclib, or ribociclib, refer to monotherapy dose modification instructions for fulvestrant injection. 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 fulvestrant injection at the dorsogluteal injection site [see Warnings and Precautions (5.3) and Adverse Reactions (6.1) ] . The proper method of administration of fulvestrant injection for intramuscular use is described in the following instructions. For each single-dose prefilled syringe: Remove glass syringe barrel from tray and check that it is not damaged. Remove perforated patient record label from syringe. Inspect drug product in glass syringe for any visible particulate matter or discoloration prior to use. Discard if particulate matter or discoloration is present. Peel open the safety needle (SafetyGlide™) outer packaging. Hold the syringe upright on the ribbed part (C). With the other hand, take hold of the cap (A) and carefully TWIST THE CAP COUNTER-CLOCKWISE 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). 7. 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: 8. Pull shield straight off needle to avoid damaging needle point. 9. Remove needle sheath. 10. Expel excess gas from the syringe (a small gas bubble may remain). 11. 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. 12. 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. 13. Discard the empty syringe into an approved sharps collector in accordance with applicable regulations and institutional policy. 14. Repeat steps 1 through 13 for second syringe. How To Use Fulvestrant injection 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. fulvestrant-inj-fig-1.jpg fulvestrant-inj-fig-2.jpg fulvestrant-inj-fig-3.jpg fulvestrant-inj-fig-4.jpg fulvestrant-inj-fig-5.jpg 2.1 Recommended Dose Monotherapy The recommended dose of fulvestrant injection 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 fulvestrant injection is used in combination with palbociclib, abemaciclib, or ribociclib, the recommended dose of fulvestrant injection 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 fulvestrant injection 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 fulvestrant injection 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 fulvestrant injection is used in combination with

WARNINGS AND PRECAUTIONS Risk of Bleeding: Use with caution in patients with bleeding diatheses, thrombocytopenia, or anticoagulant use. ( 5.1 ) Increased Exposure in Patients with He patic Impairment: Use a 250 mg dose for patients with moderate hepatic impairment. ( 2.2 , 5.2 , 8.6 ) Injection Site Reaction: Use caution while administering fulvestrant injection at the dorsogluteal injection site due to the proximity of the underlying sciatic nerve. ( 5.3 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.4 , 8.1 , 8.3 ) Immunoassay Measurement of Serum Estradiol: Fulvestrant injection can interfere with estradiol measurement by immunoassay, resulting in falsely elevated estradiol levels. ( 5.5 ) 5.1 Risk of Bleeding Because fulvestrant injection is administered intramuscularly, it should be used with caution in patients with bleeding diatheses, thrombocytopenia, or anticoagulant use. 5.2 Increased Exposure in Patients with Hepatic Impairment The safety and pharmacokinetics of fulvestrant injection were evaluated in a study in seven subjects with moderate hepatic impairment (Child-Pugh class B) and seven subjects with normal hepatic function. Exposure was increased in patients with moderate hepatic impairment, therefore, a dose of 250 mg is recommended [see Dosage and Administration (2.2) ]. Fulvestrant injection has not been studied in patients with severe hepatic impairment (Child-Pugh class C) [see Use in Specific Populations (8.6) ]. 5.3 Injection Site Reaction Injection site related events including sciatica, neuralgia, neuropathic pain, and peripheral neuropathy have been reported with fulvestrant injection. Caution should be taken while administering fulvestrant injection at the dorsogluteal injection site due to the proximity of the underlying sciatic nerve [see Dosage and Administration (2.3) and Adverse Reactions (6.1) ] . 5.4 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, Fulvestrant injection can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of fulvestrant to pregnant rats and rabbits during organogenesis resulted in embryo-fetal toxicity at daily doses that are significantly less than the maximum recommended human dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with fulvestrant injection and for one year after the last dose [see Use in Specific Populations (8.1) , ( 8.3 ) and Clinical Pharmacology (12.1) ]. 5.5 Immunoassay Measurement of Serum Estradiol Due to structural similarity of fulvestrant and estradiol, fulvestrant injection can interfere with estradiol measurement by immunoassay, resulting in falsely elevated estradiol levels. 5.1 Risk of Bleeding Because fulvestrant injection is administered intramuscularly, it should be used with caution in patients with bleeding diatheses, thrombocytopenia, or anticoagulant use. 5.2 Increased Exposure in Patients with Hepatic Impairment The safety and pharmacokinetics of fulvestrant injection were evaluated in a study in seven subjects with moderate hepatic impairment (Child-Pugh class B) and seven subjects with normal hepatic function. Exposure was increased in patients with moderate hepatic impairment, therefore, a dose of 250 mg is recommended [see Dosage and Administration (2.2) ]. Fulvestrant injection has not been studied in patients with severe hepatic impairment (Child-Pugh class C) [see Use in Specific Populations (8.6) ]. 5.3 Injection Site Reaction Injection site related events including sciatica, neuralgia, neuropathic pain, and peripheral neuropathy have been reported with fulvestrant injection. Caution should be taken while administering fulvestrant injection at the dorsogluteal injection site due to the proximity of the underlying sciatic nerve [see Dosage and Administration (2.3) and Adverse Reactions (6.1) ] . 5.4 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, Fulvestrant injection can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of fulvestrant to pregnant rats and rabbits during organogenesis resulted in embryo-fetal toxicity at daily doses that are significantly less than the maximum recommended human dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with fulvestrant injection and for one year after the last dose [see Use in Specific Populations (8.1) , ( 8.3 ) and Clinical Pharmacology (12.1) ]. 5.5 Immunoassay Measurement of Serum Estradiol Due to structural similarity of fulvestrant and estradiol, fulvestrant injection can interfere with estradiol measurement by immunoassay, resulting in falsely elevated estradiol levels.

DRUG INTERACTIONS 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 )

ADVERSE REACTIONS 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 Fulvestrant Injection 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 Fulvestrant Injection patients and were not dose-dependent. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Meitheal Pharmaceuticals, Inc. at 1-844-824-8426 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 Fulvestrant Injection 500 mg and Fulvestrant Injection 250 mg (CONFIRM) The following adverse reactions (ARs) were calculated based on the safety analysis of CONFIRM comparing the administration of Fulvestrant Injection 500 mg intramuscularly once a month with Fulvestrant Injection 250 mg intramuscularly once a month. The most frequently reported adverse reactions in the Fulvestrant Injection 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 Fulvestrant Injection 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) 1 Including more severe injection site related sciatica, neuralgia, neuropathic pain, and peripheral neuropathy. Adverse Reactions Fulvestrant Injection 500 mg N=361 % Fulvestrant Injection 250 mg N=374 % Body as a Whole Injection Site Pain 1 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 Fulvestrant Injection 500 mg to Fulvestrant Injection 250 mg, post-baseline increases of ≥1 CTC grade in either AST, ALT, or alkaline phosphatase were observed in >15% of patients receiving Fulvestrant Injection. 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 Fulvestrant Injection arms. Comparison of Fulvestrant Injection 500 mg and Anastrozole 1 mg (FALCON) The safety of Fulvestrant Injection 500 mg versus anastrozole 1 mg was evaluated in FALCON. The data described below reflect exposure to Fulvestrant Injection 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 Fulvestrant Injection, and in 3 of 232 (1.3%) patients receiving anastrozole. Adverse reactions leading to discontinuation for those patients receiving Fulvestrant Injection 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 Fulvestrant Injection arm were arthralgia, hot flash, fatigue and nausea. Adverse reactions reported in patients who received Fulvestrant Injection 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 Fulvestrant Injection 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 1 1 In FALCON, post-baseline increases of ≥1 CTC grade in either AST, ALT, or alkaline phosphatase were observed in >10% of patients receiving Fulvestrant Injection. Grade 3-4 increases were observed in 1%-3% of patients. Laboratory Parameters Fulvestrant Injection 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 Fulvestrant Injection 250 mg and Anastrozole 1 mg in Combined Trials (Studies 0020 and 0021) The most commonly reported adverse reactions in the Fulvestrant Injection 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 Fulvestrant Injection 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 Fulvestrant Injection 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 Fulvestrant Injection 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) 1 Including more severe injection site related sciatica, neuralgia, neuropathic pain, and peripheral neuropathy. All patients on Fulvestrant Injection received injections, but only those anastrozole patients who were in Study 0021 received placebo injections. Adverse Reactions Fulvestrant Injection 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 1 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 Fulvestrant Injection 500 mg plus palbociclib 125 mg/day versus Fulvestrant Injection plus placebo was evaluated in PALOMA-3. The data described below reflect exposure to Fulvestrant Injection plus palbociclib in 345 out of 517 patients with HR-positive, HER2-negative advanced or metastatic breast cancer who received at least 1 dose o