Pertuzumab, Trastuzumab, And Hyaluronidase-Zzxf

1 INDICATIONS AND USAGE PHESGO is a combination of pertuzumab and trastuzumab, HER2/neu receptor antagonists, and hyaluronidase, an endoglycosidase, indicated for: Use in combination with chemotherapy as: neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer. ( 1.1 ) adjuvant treatment of patients with HER2-positive early breast cancer at high risk of recurrence ( 1.1 ) Use in combination with docetaxel for treatment of patients with HER2-positive metastatic breast cancer (MBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. ( 1.2 ) 1.1 Early Breast Cancer (EBC) PHESGO is indicated for use in combination with chemotherapy for the neoadjuvant treatment of adult patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer [see Dosage and Administration (2.2) and Clinical Studies (14.2) ] . the adjuvant treatment of adult patients with HER2-positive early breast cancer at high risk of recurrence [see Dosage and Administration (2.2) and Clinical Studies (14.2) ] . Select patients for therapy based on an FDA-approved companion diagnostic test [see Dosage and Administration (2.1) ]. 1.2 Metastatic Breast Cancer (MBC) PHESGO is indicated for use in combination with docetaxel for the treatment of adult patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease [see Dosage and Administration (2.2) and Clinical Studies (14.1) ] . Select patients for therapy based on an FDA-approved companion diagnostic test [see Dosage and Administration (2.1) ].

2 DOSAGE AND ADMINISTRATION For subcutaneous use in the thigh only. ( 2.2 ) PHESGO has different dosage and administration instructions than intravenous pertuzumab and trastuzumab products. ( 2.2 ) Do not administer intravenously. ( 2.2 ) Perform HER2 testing using FDA-approved tests by laboratories with demonstrated proficiency. ( 1 , 2.1 ) The initial dose of PHESGO is 1,200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase administered subcutaneously over approximately 8 minutes, followed every 3 weeks by a dose of 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase administered subcutaneously over approximately 5 minutes. ( 2.2 ) Neoadjuvant: administer PHESGO by subcutaneous injection every 3 weeks and chemotherapy by intravenous infusion preoperatively for 3 to 6 cycles. ( 2.2 ) Adjuvant: administer PHESGO by subcutaneous injection every 3 weeks and chemotherapy by intravenous infusion postoperatively for a total of 1 year (up to 18 cycles). ( 2.2 ) MBC: administer PHESGO by subcutaneous injection and docetaxel by intravenous infusion every 3 weeks. ( 2.2 ) 2.1 Patient Selection Select patients based on HER2 protein overexpression or HER2 gene amplification in tumor specimens [see Indications and Usage (1) and Clinical Studies (14) ] . Assessment of HER2 protein overexpression and HER2 gene amplification should be performed using FDA-approved tests specific for breast cancer by laboratories with demonstrated proficiency. Information on the FDA-approved tests for the detection of HER2 protein overexpression and HER2 gene amplification is available at: http://www.fda.gov/CompanionDiagnostics. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. 2.2 Important Dosage and Administration Information PHESGO is for subcutaneous use only in the thigh. Do not administer intravenously. PHESGO has different dosage and administration instructions than intravenous pertuzumab, intravenous trastuzumab, and subcutaneous trastuzumab when administered alone. Do not substitute PHESGO for or with pertuzumab, trastuzumab, ado-trastuzumab emtansine, or fam-trastuzumab deruxtecan. PHESGO must always be administered by a healthcare professional. In patients receiving an anthracycline-based regimen for early breast cancer, administer PHESGO following completion of the anthracycline. In patients receiving PHESGO for early breast cancer with docetaxel or paclitaxel, administer docetaxel or paclitaxel after PHESGO. In patients receiving PHESGO for metastatic breast cancer with docetaxel, administer docetaxel after PHESGO. Observe patients for a minimum of 30 minutes after initial dose of PHESGO and 15 minutes after each maintenance dose of PHESGO for signs or hypersensitivity symptoms or administration-related reactions. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use [see Warnings and Precautions (5.5) ]. 2.3 Recommended Doses and Schedules The recommended dosage and administration schedule for PHESGO are shown in Table 1 . Table 1: Recommended Dosage and Administration Schedule Dose Strength Administration Instructions Initial dose 1,200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase in 15 mL Administer subcutaneously over approximately 8 minutes (1,200 mg, 600 mg, and 30,000 units/15 mL) Maintenance dose (administer every 3 weeks) 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase in 10 mL (600 mg, 600 mg, and 20,000 units/10 mL) Administer subcutaneously over approximately 5 minutes every 3 weeks No dose adjustments for PHESGO are required for patient body weight or for concomitant chemotherapy regimen. Patients currently receiving intravenous pertuzumab and trastuzumab can transition to PHESGO. In patients receiving intravenous pertuzumab and trastuzumab with < 6 weeks since their last dose, administer PHESGO as a maintenance dose of 600 mg pertuzumab/600 mg trastuzumab and every 3 weeks for subsequent administrations. In patients receiving intravenous pertuzumab and trastuzumab with ≥ 6 weeks since their last dose, administer PHESGO as an initial dose of 1,200 mg pertuzumab/600 mg trastuzumab, followed by a maintenance dose of 600 mg pertuzumab/600 mg trastuzumab every 3 weeks for subsequent administrations . Neoadjuvant Treatment of Breast Cancer Administer PHESGO every 3 weeks for 3 to 6 cycles as part of a treatment regimen for early breast cancer [see Clinical Studies (14.2) ] . Refer to the prescribing information for pertuzumab, administered in combination with trastuzumab and chemotherapy, for recommended dose and dosage modifications. Following surgery, patients should continue to receive PHESGO to complete 1 year of treatment (up to 18 cycles) or until disease recurrence or unmanageable toxicity, whichever occurs first, as a part of a complete regimen for early breast cancer. Adjuvant Treatment of Breast Cancer Administer PHESGO every 3 weeks for a total of 1 year (up to 18 cycles) or until disease recurrence or unmanageable toxicity, whichever occurs first, as part of a complete regimen for early breast cancer, including standard anthracycline- and/or taxane-based chemotherapy. Start PHESGO on Day 1 of the first taxane-containing cycle [see Clinical Studies (14.2) ] . Metastatic Breast Cancer (MBC) When administered with PHESGO, the recommended initial dose of docetaxel is 75 mg/m 2 administered as an intravenous infusion. The dose may be escalated to 100 mg/m 2 administered every 3 weeks if the initial dose is well tolerated. Administer PHESGO until disease progression or unmanageable toxicity, whichever occurs first. 2.4 Dose Modification Dose Modification for Delayed or Missed Doses For delayed or missed doses of PHESGO, if the time between two sequential injections is less than 6 weeks, administer the maintenance dose of 600 mg, 600 mg, and 20,000 units/10 mL. Do not wait until the next planned dose. If the time between two sequential injections is 6 weeks or more, re-administer the initial dose of 1,200 mg, 600 mg, and 30,000 units/15 mL, followed every 3 weeks thereafter by a maintenance dose of 600 mg, 600 mg, and 20,000 units/10 mL. For chemotherapy dose modifications, see relevant prescribing information. Cardiomyopathy [see Boxed Warning , Warnings and Precautions (5.1) ] Assess left ventricular ejection fraction (LVEF) prior to initiation of PHESGO and at regular intervals during treatment as indicated in Table 2 . The recommendations on dose modifications in the event of LVEF dysfunction are indicated in Table 2 [see Warnings and Precautions (5.1) ]. Table 2: Dose Modifications for Left Ventricular Dysfunction Pre-treatment LVEF: Monitor LVEF every: Withhold PHESGO for at least 3 weeks for an LVEF decrease to: Resume PHESGO after 3 weeks if LVEF has recovered to: Early Breast Cancer ≥ 55% For patients receiving anthracycline-based chemotherapy, a LVEF of ≥ 50% is required after completion of anthracyclines, before starting PHESGO ~12 weeks (once during neoadjuvant therapy) <50% with a fall of ≥10%-points below pre-treatment value Either ≥50% <10% points below pre-treatment value Metastatic Breast Cancer ≥ 50% ~12 weeks Either Either <40% 40%-45% with a fall of ≥10%-points below pre-treatment value >45% 40%-45% with a fall of <10%-points below pre-treatment value If after a repeat assessment within approximately 3 weeks, the LVEF has not improved, has declined further, and/or the patient is symptomatic, permanently discontinue PHESGO [see Warnings and Precautions (5.1) ] . Hypersensitivity and Administration-Related Reactions Discontinue the injection immediately if the patient experiences a serious hypersensitivity reaction (e.g. anaphylaxis) [see Warnings and Precautions (5.5) ] . 2.5 Preparation for Administration To prevent medication errors, it is important to check the vial labels to ensure that the drug being prepared and administered is PHESGO and not intravenous pertuzumab, or intravenous trastuzumab, or subcutaneous trastuzumab. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use vial if particulates or discoloration is present. Do not shake. Discard any unused portion remaining in the vial. For both the initial and maintenance dose, each corresponding PHESGO vial is ready-to-use for one subcutaneous injection and should not be diluted. A syringe, a transfer needle, and an injection needle are needed to withdraw PHESGO solution from the vial and inject it subcutaneously. PHESGO may be injected using 25G-27G (3/8"-5/8") hypodermic injection needles. To avoid needle clogging, attach the hypodermic injection needle to the syringe immediately prior to administration followed by volume adjustment to 15 mL (initial dose) and 10 mL (maintenance dose). If the dose is not to be administered immediately, and the solution of PHESGO has been withdrawn from the vial into the syringe, replace the transfer needle with a syringe closing cap. Label the syringe with the peel-off sticker and store the syringe in the refrigerator [2°C to 8°C (36°F to 46°F)] for up to 24 hours and at room temperature [20°C to 25°C (68°F to 77°F)] for up to 4 hours and avoid unnecessary storage. PHESGO is compatible with stainless steel, polypropylene, polycarbonate, polyethylene, polyurethane, polyvinyl chloride and fluorinated ethylene polypropylene. Administration Administer PHESGO 1,200 mg, 600 mg, 30,000 units/15 mL subcutaneously over approximately 8 minutes Administer PHESGO 600 mg, 600 mg, 20,000 units/10 mL subcutaneously over approximately 5 minutes The subcutaneous injection site should be alternated between the left and right thigh only. New injections should be given at least 1 inch (2.5 cm) from the previous site on healthy skin and never into areas where the skin is red, bruised, tender, or hard. Do not split the dose between two syringes or between two sites of administration. During the treatment course with PHESGO, other medications for subcutaneous administration should preferably be injected at different sites.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: Cardiomyopathy [see Warnings and Precautions (5.1) ] Embryo-Fetal Toxicity [see Warnings and Precautions (5.2) ] Pulmonary Toxicity [see Warnings and Precautions (5.3) ] Exacerbation of Chemotherapy-Induced Neutropenia [see Warnings and Precautions (5.4) ] Hypersensitivity and Administration-Related Reactions [see Warnings and Precautions (5.5) ] Neoadjuvant and Adjuvant Treatment of Breast Cancer The most common adverse reactions (>30%) with PHESGO were alopecia, nausea, diarrhea, anemia, and asthenia. ( 6.1 ) Metastatic Breast Cancer (based on intravenous pertuzumab ) The most common adverse reactions (> 30%) with pertuzumab in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 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. Neoadjuvant and Adjuvant Treatment of Breast Cancer The safety of PHESGO was evaluated in an open-label, multicenter, randomized trial (FeDeriCa) conducted in 500 patients with HER2 overexpressing early breast cancer [see Clinical Studies (14.2) ] . Patients were randomized to receive either PHESGO (1,200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase/15 mL) followed every 3 weeks by a maintenance dose of 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase/10 mL or the recommended dosages for intravenous pertuzumab and intravenous trastuzumab. Patients were randomized to receive 8 cycles of neoadjuvant chemotherapy with concurrent administration of 4 cycles of either PHESGO or intravenous pertuzumab and trastuzumab during cycles 5-8, followed by surgery. Following surgery, patients continued therapy with PHESGO alone or intravenous pertuzumab and trastuzumab (intravenous or subcutaneously administered) as treated prior to surgery, for an additional 14 cycles, to complete 18 cycles. The median duration of treatment for PHESGO was 24 weeks (range: 0-42 weeks). Serious adverse reactions occurred in 16% of patients who received PHESGO. Serious adverse reactions in > 1% of patients included febrile neutropenia (4%), neutropenic sepsis (1%), and neutrophil count decreased (1%). One fatal adverse reaction occurred in 1/248 (0.4%) of patients, which was due to acute myocardial infarction, and occurred prior to the start of HER2 targeted treatment with PHESGO. Adverse reactions resulting in permanent discontinuation of any study drug occurred in 8% of patients on the PHESGO arm. Adverse reactions which resulted in permanent discontinuation of PHESGO were ejection fraction decreased (1.2%), cardiac failure (0.8%), and pneumonitis/pulmonary fibrosis (0.8%). Dosage interruptions due to an adverse reaction occurred in 40% of patients who received PHESGO. Adverse reactions which required dosage interruption in > 1% of patients who received PHESGO included neutropenia (8%), neutrophil count decreased (4%), and diarrhea (7%). Table 3 summarizes the adverse reactions in FeDeriCa. Table 3: Adverse Reactions (≥5%) in Patients Who Received PHESGO in FeDeriCa Adverse Reactions PHESGO (n=248) Intravenous pertuzumab plus intravenous or subcutaneous trastuzumab (n=252) All Grades % Grades 3 – 4 % All Grades % Grades 3 – 4 % Skin and subcutaneous tissue disorders Alopecia 77 0 71 0.4 Dry skin 15 0.4 13 0 Rash 16 0.4 21 0 Nail discoloration 9 0 6 0 Erythema 9 0 5 0 Dermatitis 7 0 6 0 Nail disorder 7 0 7 0.4 Palmar-plantar erythrodysaesthesia syndrome 6 0.8 5 0.4 Gastrointestinal disorders Nausea 60 2 61 1.6 Diarrhea 60 7 57 4.8 Stomatitis 25 0.8 24 0.8 Constipation 22 0 21 0 Vomiting 20 0.8 19 1.2 Dyspepsia 14 0 12 0 Hemorrhoids 9 0 4.0 0 Abdominal pain upper 8 0 6 0 Abdominal pain 9 0.4 6 0 Blood and lymphatic system disorders Anemia 36 1.6 43 4.4 Neutropenia 22 14 27 14 Leukopenia 9 2.4 14 2 Febrile neutropenia 7 7 6 6 General disorders and administration site conditions Asthenia 31 0.4 32 2.4 Fatigue 29 2 24 2 Mucosal inflammation 15 0.8 20 1.2 Injection site reaction 15 0 0.8 0 Pyrexia 13 0 16 0.4 Edema peripheral 8 0 10 0 Malaise 7 0 6 0.4 Influenza-like illness 5 0 3.6 0 Nervous system disorders Dysgeusia 17 0 14 0 Peripheral sensory neuropathy 16 0.8 14 0.4 Headache 17 0 25 0.8 Neuropathy peripheral 12 0.4 15 2 Paresthesia 10 0.8 8 0 Dizziness 13 0 11 0 Investigations Weight decreased 11 0.8 6 0.8 Musculoskeletal and connective tissue disorders Myalgia 25 0.4 19 0.4 Arthralgia 24 0 28 0.4 Back pain 10 0 4.8 0 Bone pain 7 0 5 0 Pain in extremity 6 0 8 0 Muscle spasms 6 0 7 0 Musculoskeletal pain 6 0.4 8 0 Respiratory, thoracic and mediastinal disorder Cough 15 0.4 13 0 Epistaxis 12 0 14 0.4 Dyspnea 10 1.2 5 0 Rhinorrhea 7 0 4.4 0 Infections and infestations Upper respiratory tract infection 11 0 8 0.8 Nasopharyngitis 9 0 10 0 Paronychia 7 0.4 3.6 0 Urinary tract infection 7 0.4 5 0 Injury, poisoning and procedural complications Procedural pain 13 0 10 0 Radiation skin injury 19 0.4 19 0.4 Infusion related reaction 3.6 0 15 0.8 Metabolism and nutrition disorders Decreased appetite 17 0.8 19 0.4 Hypokalemia 7 1.6 8 0 Psychiatric disorders Insomnia 17 0 13 0.4 Eye disorders Lacrimation increased 5 0.4 6 0 Dry eye 5 0.4 3.2 0 Vascular disorders Hot flush 12 0 13 0 Clinically relevant adverse reactions in <5% of patients who received PHESGO include ejection fraction decreased (3.6%) and pruritus (3.2%). In the FeDeriCa trial, when PHESGO was administered alone, adverse reactions occurred in <10% of patients with the exception of radiation skin injury (20%), arthralgia (19%), diarrhea (17%), injection site reaction (13%), dyspepsia (12%), asthenia (11%), hot flush (11%), and pruritus (10%). Table 4 summarizes the laboratory abnormalities in FeDeriCa. Table 4: Select Laboratory Abnormalities (≥5%) that Worsened from Baseline in Patients Who Received PHESGO in FeDeriCa The denominator used to calculate the rate varied from 163 to 252 based on the number of patients with a baseline value and at least one post-treatment value. Laboratory Abnormality PHESGO (n=248) Intravenous pertuzumab plus intravenous or subcutaneous trastuzumab (n=252) All Grades % Grades 3 – 4 % All Grades % Grades 3 – 4 % Hematology Hemoglobin (low) 90 2.8 92 4.4 Lymphocytes, Absolute (low) 89 37 88 36 Total Leukocyte Count (low) 82 25 78 25 Neutrophils, Total Absolute (low) 68 30 67 33 Platelet (low) 27 0 28 0.4 Chemistry Creatinine (high) 84 0 87 0.4 Alanine aminotransferase (high) 58 1.6 68 2.4 Aspartate aminotransferase (high) 50 0.8 58 0.8 Potassium (low) 17 5.2 17 2.8 Albumin (low) 16 0 20 0.4 Potassium (high) 13 1.2 9 0 Sodium (low) 13 0.4 10 1.6 Bilirubin (high) 9 0 9 0.4 Glucose (low) 9 0 9 0.4 Sodium (high) 7 0.8 10 0.8 Other Clinical Trials Experience The safety of the addition of intravenous pertuzumab to trastuzumab in combination with chemotherapy has been established in studies conducted in patients with HER2 overexpressing early breast cancer. The following adverse reactions have been reported following administration of intravenous pertuzumab and trastuzumab: diarrhea, alopecia, nausea, fatigue, neutropenia, vomiting, peripheral neuropathy, constipation, anemia, asthenia, mucosal inflammation, myalgia, and thrombocytopenia. Refer to the Prescribing Information for pertuzumab for more information. The safety of intravenous pertuzumab, trastuzumab and docetaxel has been established in patients with HER2 overexpressing metastatic breast cancer. The following adverse reactions have been reported following administration of intravenous pertuzumab and trastuzumab: diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. Refer to the Prescribing Information for pertuzumab for more information. 6.2 Postmarketing Experience The following adverse reactions have been identified with the use of intravenous pertuzumab and trastuzumab. 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. Glomerulopathy Immune thrombocytopenia Tumor lysis syndrome (TLS): Patients with significant tumor burden (e.g. bulky metastases) may be at a higher risk. Patients could present with hyperuricemia, hyperphosphatemia, and acute renal failure which may represent possible TLS. Providers should consider additional monitoring and/or treatment as clinically indicated.

12.3 Pharmacokinetics The pharmacokinetics (PK) of pertuzumab and trastuzumab were characterized in the FeDeriCa trial following subcutaneous administration of PHESGO (1200 mg pertuzumab/600 mg trastuzumab initial dose followed by 600 mg pertuzumab/600 mg trastuzumab every 3 weeks) and intravenous administration of pertuzumab and trastuzumab (840 mg pertuzumab/8 mg/kg trastuzumab initial dose followed by 420 mg pertuzumab/6 mg/kg trastuzumab every 3 weeks). Trastuzumab is estimated to reach concentrations that are <1 mcg/mL by 7 months in at least 95% patients. Pertuzumab Cycle 7 C trough was 88.7 mcg/mL for PHESGO and 72.4 mcg/mL for intravenous pertuzumab with a geometric mean ratio (GMR) of 1.22 (90% CI: 1.14–1.31). Trastuzumab Cycle 7 C trough was 57.5 mcg/mL for PHESGO and 43.2 mcg/mL for intravenous trastuzumab with a GMR of 1.33 (90% CI: 1.24–1.43) [see Clinical Studies (14.2) ] . Following subcutaneous administration of PHESGO , the pertuzumab median Cycle 7 C max was 34% lower and AUC 0-21days was 5% higher than that following intravenous administration of pertuzumab. The median trastuzumab Cycle 7 C max was 31% lower and AUC 0-21days was 10% higher, than that following intravenous administration of trastuzumab. Absorption The mean absolute bioavailability (CV%) was 0.71 (18%) for pertuzumab and 0.77 (13%) for trastuzumab after subcutaneous administration of the approved recommended dosage of PHESGO. The median time to reach Cmax was 3.8 days for both pertuzumab and trastuzumab. Distribution The volume of distribution of pertuzumab and trastuzumab at steady state was 2.8 L and 2.9 L, respectively. Elimination For pertuzumab, the clearance (CV%) was 0.2 L/day (24%). For trastuzumab, the linear clearance was 0.1 L/day (30%); the non-linear elimination Vmax (CV%) was 12 mg/day (20%) and Km (CV%) was 34 mg/L (39%). The terminal half-life of pertuzumab and trastuzumab was 24 days and 22 days, respectively. Steady state concentration was achieved at Cycle 7 for pertuzumab and at Cycle 11 for trastuzumab. Specific Populations No dose adjustments based on body weight or baseline albumin level are needed, as the exposure changes are not considered clinically relevant. In patients with a body weight <58 kg, mean Cycle 7 AUC 0-21 days of trastuzumab was about 33% higher after PHESGO than after intravenous trastuzumab treatment, whereas in the highest BW group (>77 kg) Cycle 7 AUC 0-21 days was 24% lower after PHESGO than after intravenous trastuzumab treatment. However, no body weight-based dose adjustments are needed, as the exposure changes are not considered clinically relevant. No clinically significant differences in the pharmacokinetics of pertuzumab and trastuzumab were observed based on age (25 to 80 years), race (Asian and non-Asian), and renal impairment (creatinine clearance 30 mL/min or greater determined by Cockcroft-Gault). The effects of hepatic impairment on the pharmacokinetics of pertuzumab and trastuzumab are unknown. Drug Interaction Studies There have been no formal clinical drug interaction studies performed with PHESGO.