5 ML fulvestrant 50 MG/ML Prefilled Syringe

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.

CONTRAINDICATIONS Fulvestrant Injection 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 Fulvestrant Injection [see Adverse Reactions ( 6.2 )]. Hypersensitivity. ( 4 )

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Many breast cancers have estrogen receptors (ER) and the growth of these tumors can be stimulated by estrogen. Fulvestrant is an estrogen receptor antagonist that binds to the estrogen receptor in a competitive manner with affinity comparable to that of estradiol and downregulates the ER protein in human breast cancer cells. In vitro studies demonstrated that fulvestrant is a reversible inhibitor of the growth of tamoxifen-resistant, as well as estrogen-sensitive human breast cancer (MCF-7) cell lines. In in vivo tumor studies, fulvestrant delayed the establishment of tumors from xenografts of human breast cancer MCF-7 cells in nude mice. Fulvestrant inhibited the growth of established MCF-7 xenografts and of tamoxifen-resistant breast tumor xenografts. Fulvestrant showed no agonist-type effects in in vivo uterotrophic assays in immature or ovariectomized mice and rats. In in vivo studies in immature rats and ovariectomized monkeys, fulvestrant blocked the uterotrophic action of estradiol. In postmenopausal women, the absence of changes in plasma concentrations of FSH and LH in response to fulvestrant treatment (250 mg monthly) suggests no peripheral steroidal effects. 12.2 Pharmacodynamics In a clinical study in postmenopausal women with primary breast cancer treated with single doses of fulvestrant 15-22 days prior to surgery, there was evidence of increasing down-regulation of ER with increasing dose. This was associated with a dose-related decrease in the expression of the progesterone receptor, an estrogen-regulated protein. These effects on the ER pathway were also associated with a decrease in Ki67 labeling index, a marker of cell proliferation. 12.3 Pharmacokinetics Absorption: The single dose and multiple dose PK parameters for the 500 mg dosing regimen with an additional dose (AD) at Day 15 are reported in Table 11. The additional dose of fulvestrant given two weeks after the initial dose allows for steady state concentrations to be reached within the first month of dosing. Table 11: Summary of Fulvestrant Pharmacokinetic Parameters [gMean (CV%)] in Postmenopausal Advanced Breast Cancer Patients after Intramuscular Administration 500 mg + AD Dosing Regimen C max (ng/mL) C min (ng/mL) AUC (ng.hr/mL) 500 mg + AD 1 Single dose 25.1 (35.3) 16.3 (25.9) 11400 (33.4) Multiple dose steady state 2 28.0 (27.9) 12.2 (21.7) 13100 (23.4) 1 Additional 500 mg dose given on Day 15 2 Month 3 Distribution: The apparent volume of distribution at steady state is approximately 3 to 5 L/kg. This suggests that distribution is largely extravascular. Fulvestrant is highly (99%) bound to plasma proteins; VLDL, LDL, and HDL lipoprotein fractions appear to be the major binding components. The role of sex hormone-binding globulin, if any, could not be determined. Metabolism: Biotransformation and disposition of fulvestrant in humans have been determined following intramuscular and intravenous administration of 14 C-labeled fulvestrant. Metabolism of fulvestrant appears to involve combinations of a number of possible biotransformation pathways analogous to those of endogenous steroids, including oxidation, aromatic hydroxylation, conjugation with glucuronic acid and/or sulphate at the 2, 3, and 17 positions of the steroid nucleus, and oxidation of the side chain sulphoxide. Identified metabolites are either less active or exhibit similar activity to fulvestrant in antiestrogen models. Studies using human liver preparations and recombinant human enzymes indicate that cytochrome P-450 3A4 (CYP 3A4) is the only P-450 isoenzyme involved in the oxidation of fulvestrant; however, the relative contribution of P-450 and non-P-450 routes in vivo is unknown. Excretion: Fulvestrant was rapidly cleared by the hepatobiliary route with excretion primarily via the feces (approximately 90%). Renal elimination was negligible (less than 1%). After an intramuscular injection of 250 mg, the clearance (Mean ± SD) was 690 ± 226 mL/min with an apparent half-life about 40 days. Special Populations: Geriatric: In patients with breast cancer, there was no difference in fulvestrant pharmacokinetic profile related to age (range 33 to 89 years). Gender: Following administration of a single intravenous dose, there were no pharmacokinetic differences between men and women or between premenopausal and postmenopausal women. Similarly, there were no differences between men and postmenopausal women after intramuscular administration. Race: In the advanced breast cancer treatment trials, the potential for pharmacokinetic differences due to race have been evaluated in 294 women including 87.4% Caucasian, 7.8% Black, and 4.4% Hispanic. No differences in fulvestrant plasma pharmacokinetics were observed among these groups. In a separate trial, pharmacokinetic data from postmenopausal ethnic Japanese women were similar to those obtained in non-Japanese patients. Drug-Drug Interactions: There are no known drug-drug interactions. Fulvestrant does not significantly inhibit any of the major CYP isoenzymes, including CYP 1A2, 2C9, 2C19, 2D6, and 3A4 in vitro , and studies of co-administration of fulvestrant with midazolam indicate that therapeutic doses of fulvestrant have no inhibitory effects on CYP 3A4 or alter blood levels of drug metabolized by that enzyme. Although fulvestrant is partly metabolized by CYP 3A4, a clinical study with rifampin, an inducer of CYP 3A4, showed no effect on the pharmacokinetics of fulvestrant. Also, results from a healthy volunteer study with ketoconazole, a potent inhibitor of CYP 3A4, indicated that ketoconazole had no effect on the pharmacokinetics of fulvestrant and dosage adjustment is not necessary in patients co-prescribed CYP 3A4 inhibitors or inducers [see Drug Interactions (7) ] . Data from a clinical trial in patients with breast cancer showed that there was no clinically relevant drug interaction when fulvestrant is co-administered with palbociclib, abemaciclib, or ribociclib.