Pertuzumab

1 INDICATIONS AND USAGE PERJETA is a HER2/neu receptor antagonist indicated for: Use in combination with trastuzumab and docetaxel for treatment of adults with HER2-positive metastatic breast cancer (MBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. ( 1.1 ) Use in combination with trastuzumab and chemotherapy as neoadjuvant treatment of adults 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. ( 1.2 , 2.2 , 14.2 ) adjuvant treatment of adults with HER2-positive early breast cancer at high risk of recurrence ( 1.2 , 2.2 , 14.3 ) 1.1 Metastatic Breast Cancer (MBC) PERJETA is indicated for use in combination with trastuzumab and docetaxel for the treatment of adults 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) ] . 1.2 Early Breast Cancer (EBC) PERJETA is indicated for use in combination with trastuzumab and chemotherapy for the neoadjuvant treatment of adults 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 adults with HER2-positive early breast cancer at high risk of recurrence [see Dosage and Administration (2.2) and Clinical Studies (14.3) ] .

2 DOSAGE AND ADMINISTRATION For intravenous infusion only. Do not administer as an intravenous push or bolus. ( 2.5 ) HER2 testing: Perform using FDA-approved tests by laboratories with demonstrated proficiency. ( 2.1 ) The initial PERJETA dose is 840 mg administered as a 60-minute intravenous infusion, followed every 3 weeks thereafter by 420 mg administered as a 30 to 60 minute intravenous infusion. ( 2.3 ) MBC: Administer PERJETA, trastuzumab or trastuzumab hyaluronidase-oysk, and docetaxel every 3 weeks. ( 2.3 ) Neoadjuvant: Administer PERJETA, trastuzumab or trastuzumab hyaluronidase-oysk, and chemotherapy preoperatively every 3 weeks for 3 to 6 cycles. ( 2.3 ) Adjuvant: Administer PERJETA, trastuzumab or trastuzumab hyaluronidase-oysk, and chemotherapy postoperatively every 3 weeks for a total of 1 year (up to 18 cycles). ( 2.3 ) 2.1 Evaluation and Testing Before Initiating Perjeta Assess left ventricular ejection fraction (LVEF) prior to initiation of PERJETA and at regular intervals during treatment [see Boxed Warning , Dosage and Administration (2.4) , Warnings and Precautions (5.1) ]. Verify the pregnancy status of females of reproductive potential prior to the initiation of PERJETA [see Warnings and Precautions (5.2) , Use in Specific Populations (8.1 , 8.3) ]. 2.2 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. 2.3 Recommended Dosage and Administration The initial dose of PERJETA is 840 mg administered as a 60-minute intravenous infusion, followed every 3 weeks by a dose of 420 mg administered as an intravenous infusion over 30 to 60 minutes. When administered with PERJETA, the recommended initial dose of trastuzumab is 8 mg/kg administered as a 90-minute intravenous infusion, followed every 3 weeks by a dose of 6 mg/kg administered as an intravenous infusion over 30 to 90 minutes. When administered with PERJETA, the recommended initial dose of trastuzumab hyaluronidase-oysk is 600 mg/10,000 units (600 mg trastuzumab and 10,000 units hyaluronidase) administered subcutaneously over approximately 2 to 5 minutes once every three weeks irrespective of the patient's body weight. Administer PERJETA, trastuzumab or trastuzumab hyaluronidase-oysk, and taxane sequentially. PERJETA and trastuzumab or trastuzumab hyaluronidase-oysk can be given in any order. Administer taxane after PERJETA and trastuzumab or trastuzumab hyaluronidase-oysk. An observation period of 30 to 60 minutes is recommended after each PERJETA infusion and before commencement of any subsequent administration of trastuzumab or trastuzumab hyaluronidase-oysk, or taxane [see Warnings and Precautions (5.3) ]. In patients receiving an anthracycline-based regimen, administer PERJETA and trastuzumab or trastuzumab hyaluronidase-oysk after completion of the anthracycline. Metastatic Breast Cancer (MBC) When administered with PERJETA, 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. Neoadjuvant Treatment of Breast Cancer Administer PERJETA every 3 weeks for 3 to 6 cycles as part of one of the following treatment regimens [see Clinical Studies (14.2 , 14.3) ] : Four preoperative cycles of PERJETA in combination with trastuzumab or trastuzumab hyaluronidase-oysk and docetaxel followed by 3 postoperative cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC) Three or four preoperative cycles of FEC alone followed by 3 or 4 preoperative cycles of PERJETA in combination with docetaxel and trastuzumab or trastuzumab hyaluronidase-oysk Six preoperative cycles of PERJETA in combination with docetaxel, carboplatin, and trastuzumab (TCH) or trastuzumab hyaluronidase-oysk (escalation of docetaxel above 75 mg/m 2 is not recommended) Four preoperative cycles of dose-dense doxorubicin and cyclophosphamide (ddAC) alone followed by 4 preoperative cycles of PERJETA in combination with paclitaxel and trastuzumab or trastuzumab hyaluronidase-oysk Following surgery, administer PERJETA and trastuzumab or trastuzumab hyaluronidase-oysk to complete 1 year of treatment (up to 18 cycles) or until disease recurrence or unmanageable toxicity, whichever occurs first. Adjuvant Treatment of Breast Cancer As part of a regimen including standard anthracycline- and/or taxane-based chemotherapy, administer PERJETA in combination with trastuzumab or trastuzumab hyaluronidase-oysk every 3 weeks for a total of 1 year (up to 18 cycles) or until disease recurrence or unmanageable toxicity, whichever occurs first. Administer PERJETA on Day 1 of the first taxane-containing cycle [see Clinical Studies (14.3) ] . 2.4 Important Dosing Considerations Missed Dose The recommended dosage modifications for delayed or missed doses are listed in Table 1 . Table 1: Recommendations for Delayed or Missed Doses Time between two sequential doses PERJETA Trastuzumab (intravenous) Trastuzumab hyaluronidase-oysk < 6 weeks Administer PERJETA 420 mg intravenously as soon as possible. Do not wait until the next planned dose. Administer trastuzumab 6 mg/kg intravenously as soon as possible. Do not wait until the next planned dose. Administer trastuzumab hyaluronidase-oysk 600 mg/10,000 units subcutaneously as soon as possible. Do not wait until the next planned dose. ≥ 6 weeks Readminister PERJETA loading dose of 840 mg intravenously as a 60 minute infusion, followed by a maintenance dose of 420 mg administered intravenously over a period of 30 to 60 minutes every 3 weeks thereafter. Readminister trastuzumab loading dose of 8 mg/kg intravenously over approximately 90 minutes, followed by a maintenance dose of 6 mg/kg administered intravenously over a period of 30 or 90 minutes every 3 weeks thereafter. Permanently discontinue PERJETA if trastuzumab or trastuzumab hyaluronidase-oysk treatment is discontinued. Dose reductions are not recommended for PERJETA. For chemotherapy dose modifications, see relevant prescribing information. 2.5 Dosage Modification for Adverse Reactions Left Ventricular Dysfunction Assess left ventricular ejection fraction (LVEF) prior to initiation of PERJETA and at regular intervals during treatment. The recommended dosage modifications for LVEF decrease are listed in Table 2 [see Warnings and Precautions (5.1) ]. Table 2: Dose Modifications for Left Ventricular Dysfunction Pre-treatment LVEF: Monitor LVEF every: Withhold PERJETA and trastuzumab or trastuzumab hyaluronidase-oysk for at least 3 weeks for an LVEF decrease to: Resume PERJETA and trastuzumab or trastuzumab hyaluronidase-oysk after 3 weeks if LVEF has recovered to: 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 Early Breast Cancer ≥ 55% For patients receiving anthracycline-based chemotherapy, a LVEF of ≥ 50% is required after completion of anthracyclines, before starting PERJETA and trastuzumab or trastuzumab hyaluronidase-oysk. ~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 Infusion-Related Reactions The infusion rate of PERJETA may be slowed or interrupted if the patient develops an infusion-related reaction [see Warnings and Precautions (5.3) ] . Hypersensitivity Reactions/Anaphylaxis The infusion should be discontinued immediately if the patient experiences a serious hypersensitivity reaction [see Warnings and Precautions (5.4) ] . 2.6 Preparation for Administration Administer as an intravenous infusion only. Do not administer as an intravenous push or bolus. Do not mix PERJETA with other drugs. Preparation Prepare the solution for infusion, using aseptic technique, as follows: Parenteral drug products should be inspected visually for particulates and discoloration prior to administration, whenever solution and container permit. Withdraw the appropriate volume of PERJETA solution from the vial(s) using a sterile needle and syringe. Dilute into a 250 mL 0.45% Sodium Chloride Injection or 0.9% Sodium Chloride Injection infusion bag. Mix diluted solution by gentle inversion. Do not shake. Administer immediately once prepared. If the diluted infusion solution is not used immediately, it can be stored refrigerated at 2°C to 8°C (36 °F to 46 °F) for up to 24 hours. Dilute with 0.45% Sodium Chloride Injection or 0.9% Sodium Chloride Injection only. Do not use 5% Dextrose Injection.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: Left Ventricular Dysfunction [see Warnings and Precautions (5.1) ] Embryo-Fetal Toxicity [see Warnings and Precautions (5.2) ] Infusion-Related Reactions [see Warnings and Precautions (5.3) ] Hypersensitivity Reactions/Anaphylaxis [see Warnings and Precautions (5.4) ] Metastatic Breast Cancer The most common adverse reactions (> 30%) with PERJETA in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. ( 6.1 ) Neoadjuvant Treatment of Breast Cancer The most common adverse reactions (> 30%) with PERJETA in combination with trastuzumab and docetaxel were alopecia, diarrhea, nausea, and neutropenia. ( 6.1 ) The most common adverse reactions (>30%) with PERJETA in combination with trastuzumab and docetaxel when given for 3 cycles following 3 cycles of FEC were fatigue, alopecia, diarrhea, nausea, vomiting, and neutropenia. ( 6.1 ) The most common adverse reactions (>30%) with PERJETA in combination with docetaxel, carboplatin, and trastuzumab (TCH) were fatigue, alopecia, diarrhea, nausea, vomiting, neutropenia, thrombocytopenia, and anemia. ( 6.1 ) The most common adverse reactions (>30%) with PERJETA in combination with trastuzumab and paclitaxel when given for 4 cycles following 4 cycles of ddAC were nausea, diarrhea, alopecia, fatigue, constipation, peripheral neuropathy, and headache. ( 6.1 ) The most common adverse reactions (>30%) with PERJETA in combination with trastuzumab and docetaxel when given for 4 cycles following 4 cycles of FEC were diarrhea, nausea, alopecia, asthenia, constipation, fatigue, mucosal inflammation, vomiting, myalgia, and anemia. ( 6.1 ) Adjuvant Treatment of Breast Cancer The most common adverse reactions (>30%) with PERJETA in combination with trastuzumab and chemotherapy were diarrhea, nausea, alopecia, fatigue, peripheral neuropathy and vomiting. ( 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 clinical practice. Metastatic Breast Cancer (MBC) CLEOPATRA The safety of PERJETA in combination with trastuzumab and docetaxel was evaluated in a randomized trial (CLEOPATRA) in patients with HER2-positive metastatic breast cancer [see Clinical Studies (14.1) ] . Patients received either PERJETA administered at an initial dose of 840 mg followed by 420 mg every 3 weeks thereafter or placebo in combination with trastuzumab (initial dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks thereafter) and docetaxel (75 mg/m2 by intravenous infusion every 3 weeks for 6 cycles). The median duration of study treatment was 18.1 months for patients in the PERJETA-treated group. Permanent discontinuation of PERJETA, trastuzumab, and docetaxel due to adverse reactions occurred in 6% of patients. Adverse reactions that led to permanent discontinuation of PERJETA, trastuzumab, and docetaxel in >1% of patients were left ventricular dysfunction. The safety profile of PERJETA remained unchanged with an additional 2.75 years of follow-up (median total follow-up of 50 months) in CLEOPATRA. The most common adverse reactions (> 30%) with PERJETA in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue. An increased incidence of febrile neutropenia was observed for Asian patients in both treatment arms compared with patients of other races and from other geographic regions. Among Asian patients, the incidence of febrile neutropenia was higher in the pertuzumab-treated group (26%) compared with the placebo-treated group (12%). Table 3 summarizes the adverse reactions in CLEOPATRA that occurred ≥ 10% of patients in the PERJETA-treated group. Table 3: Adverse Reactions (≥ 10%) in Patients Who Received PERJETA in Combination with Trastuzumab and Docetaxel in CLEOPATRA Adverse Reactions PERJETA + trastuzumab + docetaxel n=407 % Placebo + trastuzumab + docetaxel n=397 % All Grades % Grades 3 – 4 % All Grades % Grades 3 – 4 % Gastrointestinal disorders Diarrhea 67 8 46 5 Nausea 42 1 42 0.5 Vomiting 24 1 24 2 Stomatitis 19 0.5 15 0.3 Constipation 15 0 25 1 Skin and subcutaneous tissue disorders Alopecia 61 0 60 0.3 Rash 34 0.7 24 0.8 Nail disorder 23 1 23 0.3 Pruritus 14 0 10 0 Dry skin 11 0 4 0 Blood and lymphatic system disorders Neutropenia 53 49 50 46 Anemia 23 2 19 4 Leukopenia 18 12 20 15 Febrile neutropenia In this table this denotes an adverse reaction that has been reported in association with a fatal outcome 14 13 8 7 General disorders and administration site conditions Fatigue 37 2 37 3 Mucosal inflammation 28 1 20 1 Asthenia 26 2 30 2 Peripheral edema 23 0.5 30 0.8 Pyrexia 19 1 18 0.5 Nervous system disorders Neuropathy peripheral 32 3 34 2 Headache 21 1 17 0.5 Dysgeusia 18 0 16 0 Dizziness 13 0.5 12 0 Metabolism and nutrition disorders Decreased appetite 29 2 26 2 Musculoskeletal and connective tissue disorders Myalgia 23 1 24 0.8 Arthralgia 15 0.2 16 0.8 Infections and infestations Upper respiratory tract infection 17 0.7 13 0 Nasopharyngitis 12 0 13 0.3 Respiratory, thoracic, and mediastinal disorders Dyspnea 14 1 16 2 Eye disorders Lacrimation increased 14 0 14 0 Psychiatric disorders Insomnia 13 0 13 0 Clinically relevant adverse reactions in < 10% of patients in the PERJETA-treated group in CLEOPATRA included paronychia (7%). Adverse Reactions Reported in Patients Receiving PERJETA and Trastuzumab After Discontinuation of Docetaxel In CLEOPATRA, adverse reactions that occurred after discontinuation of docetaxel included diarrhea (19%), upper respiratory tract infection (13%), rash (12%), headache (11%), and fatigue (11%). Neoadjuvant Treatment of Breast Cancer NeoSphere The safety of PERJETA was evaluated in a randomized trial (NeoSphere) in patients with operable, locally advanced, or inflammatory HER2-positive breast cancer (T2-4d) who were scheduled for neoadjuvant therapy [see Clinical Studies (14.2) ] . In combination with trastuzumab and docetaxel, PERJETA was given intravenously at an initial dose of 840 mg, followed by 420 mg every 3 weeks for 4 cycles. After surgery, patients in the PERJETA plus trastuzumab arm received docetaxel every 3 weeks for 4 cycles prior to FEC. Permanent discontinuation of neoadjuvant PERJETA due to an adverse reaction occurred in 0.9% of patients. The most common adverse reactions (> 30%) were alopecia, neutropenia, diarrhea, and nausea. The most common Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, and diarrhea. Table 4 summarizes the adverse reactions in NeoSphere that occurred ≥ 10% of patients who received neoadjuvant PERJETA with trastuzumab and docetaxel followed by FEC. Table 4: Adverse Reactions (≥ 10%) in Patients who Received Neoadjuvant PERJETA in NeoSphere Adverse Reactions Trastuzumab + docetaxel n=107 % PERJETA + trastuzumab + docetaxel n=107 % All Grades % Grades 3 – 4 % All Grades % Grades 3 – 4 % Skin and subcutaneous tissue disorders Alopecia 66 0 65 0 Rash 21 2 26 0.9 Blood and lymphatic system disorders Neutropenia 64 59 50 45 Leukopenia 21 11 9 5 Gastrointestinal disorders Nausea 36 0 39 0 Diarrhea 34 4 46 6 Vomiting 12 0 13 0 Stomatitis 7 0 18 0 General disorders and administration site conditions Fatigue 27 0 26 0.9 Mucosal inflammation 21 0 26 2 Asthenia 18 0 21 2 Pyrexia 10 0 17 0 Peripheral edema 10 0 3 0 Musculoskeletal and connective tissue disorders Myalgia 22 0 22 0 Arthralgia 8 0 10 0 Nervous system disorders Peripheral Sensory Neuropathy 12 0.9 8 0.9 Headache 11 0 11 0 Dysgeusia 10 0 15 0 Psychiatric disorders Insomnia 11 0 8 0 Metabolism and nutrition disorders Decreased appetite 7 0 14 0 Clinically relevant adverse reactions in < 10% of patients receiving neoadjuvant PERJETA with trastuzumab and docetaxel followed by FEC included anemia, febrile neutropenia, dizziness, upper respiratory tract infection, and increased lacrimation. Neoadjuvant Treatment of Breast Cancer TRYPHAENA The safety of PERJETA was evaluated in patients with HER2-positive locally advanced, operable, or inflammatory (T2-4d) breast cancer in TRYPHAENA [see Clinical Studies (14.2) ]. Adverse reactions resulting in permanent discontinuation of any component of neoadjuvant treatment occurred in 7% of patients receiving PERJETA in combination with trastuzumab and docetaxel following FEC and 8% for patients receiving PERJETA in combination with TCH. The most common adverse reactions (>2%) resulting in permanent discontinuation of PERJETA were left ventricular dysfunction, drug hypersensitivity, and neutropenia. For PERJETA administered in combination with trastuzumab and docetaxel for 3 cycles following 3 cycles of FEC, the most common adverse reactions (> 30%) were diarrhea, nausea, alopecia, neutropenia, vomiting, and fatigue. The most common Grade 3 – 4 adverse reactions (> 2%) were neutropenia, leukopenia, febrile neutropenia, diarrhea, left ventricular dysfunction, anemia, dyspnea, nausea, and vomiting. For PERJETA administered in combination with docetaxel, carboplatin, and trastuzumab (TCH) for 6 cycles, the most common adverse reactions (> 30%) were diarrhea, alopecia, neutropenia, nausea, fatigue, vomiting, anemia, and thrombocytopenia. The most common Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, anemia, leukopenia, diarrhea, thrombocytopenia, vomiting, fatigue, ALT increased, hypokalemia, and hypersensitivity. Table 5 summarizes the adverse reactions in TRYPHAENA that occurred in > 10% of patients who received neoadjuvant PERJETA with trastuzumab and docetaxel following FEC or who received neoadjuvant PERJETA in combination with TCH. Table 5: Adverse Reactions (≥ 10%) in Patients Receiving Neoadjuvant Treatment with PERJETA in TRYPHAENA Adverse Reactions PERJETA + trastuzumab + docetaxel following FEC PERJETA + TCH n=75 % n=76 % All Grades % Grades 3 – 4 % All Grades % Grades 3 – 4 % Gastrointestinal disorders Diarrhea 61 5 72 12 Nausea 53 3 45 0 Vomiting 36 3 39 5 Dyspepsia 8 0 22 0 Constipation 23 0 16 0 Stomatitis 17 0 12 0 Skin and subcutaneous tissue disorders Alopecia 52 0 55 0 Rash 11 0 21 1 Palmar-Plantar Erythrodysaesthesia Syndrome 11 0 8 0 Dry skin 9 0 11 0 Blood and lymphatic system disorders Neutropenia 47 43 49 46 Leukopenia 16 12 17 12 Anemia 9 4 38 17 Febrile neutropenia 9 9 17 17 Thrombocytopenia 1 0 30 12 General disorders and administration site conditions Fatigue 36 0 42 4 Mucosal inflammation 20 0 17 1 Pyrexia 9 0 16 0 Asthenia 15 1 13 1 Edema peripheral 4 0 9 0 Psychiatric disorders Insomnia 13 0 21 0 Nervous system disorders Headache 15 0 17 0 Dysgeusia 13 0 21 0 Dizziness 8 1 16 0 Neuropathy peripheral 1 0 11 0 Metabolism and nutrition disorders Decreased appetite 11 0 21 0 Respiratory, thoracic, and mediastinal disorders Epistaxis 11 0 16 1 Dyspnea 8 3 11 1 Oropharyngeal pain 7 0 12 0 Cough 5 0 12 0 Musculoskeletal and connective tissue disorders Myalgia 11 1 11 0 Arthralgia 12 0 7 0 Eye disorders Lacrimation increased 5 0 8 0 Investigations ALT increased 3 0 11 4 Immune system disorders Hypersensitivity 1 0 12 3 Clinically relevant adverse reactions in < 10% of patients who received neoadjuvant PERJETA with trastuzumab and docetaxel following FEC or who received neoadjuvant PERJETA in combination with TCH included nail disorder, paronychia, pruritus, upper respiratory tract infection, and nasopharyngitis. Neoadjuvant Treatment of Breast Cancer BERENICE The safety of PERJETA was evaluated in a two-arm non-randomized study (BERENICE) in patient with HER2-positive locally advanced, inflammatory, or early-stage HER2-positive breast cancer [see Clinical Studies (14.2) ]. Adverse reactions resulting in permanent discontinuation of any component of neoadjuvant treatment were 14% for patients receiving PERJETA in combination with trastuzumab and paclitaxel following ddAC and 8% for patients receiving PERJETA in combination with trastuzumab and docetaxel following FEC. The most common adverse reactions (>1%) resulting in permanent discontinuation of any component of neoadjuvant treatment were peripheral neuropathy, decreased ejection fraction, diarrhea, neutropenia and infusion-related reaction. For PERJETA administered in combination with trastuzumab and paclitaxel for 4 cycles following 4 cycles of ddAC, the most common adverse reactions (> 30%) were nausea, diarrhea, alopecia, fatigue, constipation, peripheral neuropathy and headache. The most common Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, decreased neutrophil count, decreased white blood cell count, anemia, diarrhea, peripheral neuropathy, increased ALT, and nausea. For PERJETA administered in combination with trastuzumab and docetaxel for 4 cycles following 4 cycles of FEC, the most common adverse reactions (> 30%) were diarrhea, nausea, alopecia, asthenia, constipation, fatigue, mucosal inflammation, vomiting, myalgia, and anemia. The most common Grade 3 – 4 adverse reactions (> 2%) were febrile neutropenia, diarrhea, neutropenia, decreased neutrophil count stomatitis, fatigue, vomiting, mucosal inflammation, neutropenic sepsis and anemia. Table 6 summarizes the adverse reactions in BERENICE that occurred in ≥ 10% of patients who received neoadjuvant PERJETA with trastuzumab and paclitaxel following ddAC or who received neoadjuvant PERJETA with trastuzumab and docetaxel following FEC. Table 6: Adverse Reactions (≥ 10%) of Patients Receiving Neoadjuvant PERJETA in Combination with Trastuzumab and Taxane Chemotherapy Following ddAC or FEC in BERENICE Adverse Reactions PERJETA + trastuzumab + paclitaxel following ddAC n=199 % PERJETA + trastuzumab + docetaxel following FEC n=198 % All Grades % Grades 3 – 4 % All Grades % Grades 3 – 4 % Gastrointestinal disorders Nausea 71 3 69 2 Diarrhea 67 3 69 10 Constipation 35 0.5 38 0.5 Vomiting 23 1 35 4 Stomatitis 25 0 27 5 Dyspepsia 19 0 16 0 Upper abdominal pain 6 0 13 0 Abdominal pain 5 0 10 0 Gastroesophageal reflux disease 12 0 2 0 Skin and subcutaneous tissue disorders Alopecia 62 0 59 0 Rash 14 0 11 0 Dry skin 14 0 10 0 Nail discoloration 15 0 2 0 Palmar-Plantar Erythrodysaesthesia Syndrome 6 0 10 0.5 General disorders and administration site conditions Fatigue 58 1 38 5 Asthenia 19 2 41 0 Mucosal inflammation 22 1 37 4 Pyrexia 15 0 18 0 Peripheral edema 9 0 12 1 Nervous system disorders Peripheral neuropathy 42 3 26 0.5 Headache 30 0.5 14 0.5 Dysgeusia 20 0 19 0.5 Paresthesia 15 0 9 0 Dizziness 12 0 8 0 Blood and lymphatic system disorders Anemia 27 3 30 3 Neutropenia 22 12 16 9 Febrile neutropenia 7 7 17 17 Musculoskeletal and connective tissue disorders Myalgia 20 0 33 1 Arthralgia 20 0 21 1 Back pain 10 0 9 0 Pain in extremity 10 0 8 0 Bone pain 12 0.5 5 0 Respiratory, thoracic, and mediastinal disorders Epistaxis 25 0 19 0 Dyspnea 15 0.5 15 0.5 Cough 20 0.5 9 0 Oropharyngeal pain 10 0 8 0.5 Metabolism and nutrition disorders Decreased appetite 20 0 23 0 Psychiatric disorders Insomnia 19 0 13 0 Vascular disorders Hot flush 19 0 13 0 Injury, poisoning and procedural complications Infusion-related reaction 16 1 13 1 Eye disorders Increased lacrimation 9 0 18 0 Investigations Decreased white blood cell count 11 4 3 2 Infections and infestations Urinary tract infection 11 1 2 0 Clinically relevant adverse reactions in < 10% of patients who received PERJETA in combination with trastuzumab and paclitaxel following ddAC or patients receiving PERJETA in combination with trastuzumab and docetaxel following FEC included pruritus, nail disorder, paronychia, upper respiratory tract infection, and nasopharyngitis. Adjuvant Treatment of Breast Cancer APHINITY The safety of PERJETA was evaluated in a multicenter, randomized, double-blind, placebo-controlled study (APHINITY) conducted in patients with HER2-positive early breast cancer who had their primary tumor excised prior to randomization [see Clinical Studies (14.3) ]. Patients were randomized to receive either PERJETA in combination with trastuzumab and chemotherapy or placebo in combination with trastuzumab and chemotherapy. Investigators selected one of three anthracycline-based or non-anthracycline-based chemotherapy regimens for patients. PERJETA and trastuzumab were administered intravenously every 3 weeks starting on Day 1 of the first taxane-containing cycle, for a total of 52 weeks (up to 18 cycles) or until recurrence, withdrawal of consent, or unmanageable toxicity. Serious adverse reactions (hospitalization) due to diarrhea in the PERJETA-treated group was 2.4%. The incidence of diarrhea was higher when chemotherapy was administered with PERJETA (61%) and was higher when administered with non-anthracycline based therapy (85%) than with anthracycline based therapy (67%). The median duration of diarrhea was 8 days. The median duration of Grade ≥3 diarrhea was 20 days. The incidence of diarrhea during the period PERJETA and trastuzumab were administered without chemotherapy was 18% in the PERJETA-treated group. Adverse reactions resulting in permanent discontinuation of any study therapy were 13% for patients in the PERJETA-treated group. Adverse reactions resulting in permanent discontinuation of PERJETA was 7%. The most common adverse reactions (>0.5%) resulting in permanent discontinuation of any study treatment were ejection fraction decreased, neuropathy peripheral, diarrhea, and cardiac failure. When PERJETA was administered in combination with trastuzumab and chemotherapy, the most common adverse reactions (> 30%) were diarrhea, nausea, alopecia, fatigue, peripheral neuropathy, and vomiting. The most common Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, diarrhea, neutrophil count decreased, anemia, white blood cell count decreased, leukopenia, fatigue, nausea, and stomatitis. Table 7 summarizes the adverse reactions that occurred in ≥ 10% of patients who received adjuvant PERJETA in combination with trastuzumab and chemotherapy followed by PERJETA and trastuzumab for a total of 52 weeks (up to 18 cycles) or until recurrence, withdrawal of consent, or unmanageable toxicity. Table 7: Adverse Reactions (≥ 10%) of Patients Receiving Adjuvant PERJETA in Combination with Trastuzumab and Chemotherapy Followed by PERJETA and Trastuzumab in APHINITY Adverse Reactions PERJETA + trastuzumab + chemotherapy n=2364 % Placebo + trastuzumab + chemotherapy n=2405 % All Grades % Grades 3 – 4 % All Grades % Grades 3 – 4 % Gastrointestinal disorders Diarrhea 71 10 45 4 Nausea 69 2 65 2 Vomiting 32 2 30 2 Constipation 29 0.5 32 0.3 Stomatitis 28 2 24 1 Dyspepsia 14 0 14 0 Abdominal pain 12 0.5 11 0.6 Abdominal pain upper 10 0.3 9 0.2 Skin and subcutaneous tissue disorders Alopecia 67 <0.1 67 <0.1 Rash 26 0.4 20 0.2 Pruritus 14 0.1 9 <0.1 Dry skin 13 0.1 11 <0.1 Nail disorder 12 0.2 12 0.1 General disorders and administration site conditions Fatigue 49 4 44 3 Mucosal inflammation 23 2 19 0.7 Asthenia 21 1 21 2 Pyrexia 20 0.6 20 0.7 Edema peripheral 17 0 20 0.2 Musculoskeletal and connective tissue disorders Arthralgia 29 0.9 33 1 Myalgia 26 0.9 30 1 Pain in extremity 10 0.2 10 0.2 Blood and lymphatic system disorders Anemia 28 7 23 5 Neutropenia 25 16 23 16 Febrile neutropenia In this table this denotes an adverse reaction that has been reported in association with a fatal outcome 12 12 11 11 Nervous system disorders Dysgeusia 26 0.1 22 <0.1 Neuropathy peripheral 33 1 32 1 Headache 22 0.3 23 0.4 Paresthesia 12 0.5 10 0.2 Dizziness 11 0 11 0.2 Metabolism and nutrition disorders Decreased appetite 24 0.8 20 0.4 Vascular disorders Hot flush 20 0.2 21 0.4 Respiratory, thoracic, and mediastinal disorders Epistaxis 18 <0.1 14 0 Cough 16 <0.1 15 <0.1 Dyspnea 12 0.4 12 0.5 Psychiatric disorders Insomnia 17 0.3 17 <0.1 Investigations Neutrophil count decreased 14 10 14 10 Eye disorders Lacrimation increased 13 0 13 <0.1 Infections and infestations Nasopharyngitis 13 <0.1 12 0.1 Injury, poisoning and procedural complications Radiation skin injury 13 0.3 11 0.3 Clinically relevant adverse reactions in < 10% of patients who received PERJETA in combination with trastuzumab and anthracycline-based or non-anthracycline-based chemotherapy regimens included l eukopenia, upper respiratory tract infection, and paronychia Adverse Reactions in Patients Receiving PERJETA and Trastuzumab After Discontinuation of Chemotherapy In APHINITY, adverse reactions that occurred after discontinuation of chemotherapy in >10% included diarrhea (18%), arthralgia (15%), radiation skin injury (12%), and hot flush (12%).

12.3 Pharmacokinetics Based on a population PK analysis that included 481 patients, pertuzumab demonstrated linear pharmacokinetics at a dose range of 2 – 25 mg/kg. With an initial dose of 840 mg followed by a maintenance dose of 420 mg every three weeks thereafter, the steady-state concentration of pertuzumab was reached after the first maintenance dose. Elimination The median clearance (CL) of pertuzumab was 0.24 L/day and the median half-life was 18 days. Specific Populations No clinically significant differences in the pharmacokinetics of pertuzumab were observed based on age, sex, ethnicity (Japanese vs. non-Japanese), or disease status (neoadjuvant or adjuvant vs. metastatic setting). No dose adjustments based on body weight or baseline albumin level are needed, as the exposure changes are not considered clinically relevant. Pertuzumab exposure in patients with mild (CLcr 60 to 90 mL/min, n=200) and moderate renal impairment (CLcr 30 to 60 mL/min, n=71) were similar to those in patients with normal renal function (CLcr greater than 90 mL/min, n=200). The pharmacokinetics of pertuzumab in patients with moderate to severe hepatic impairment or severe renal impairment is unknown.