Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 28 August 2018

Indication(s)

1 INDICATIONS AND USAGE PERJETA is a HER2/neu receptor antagonist indicated for: Use in combination with trastuzumab and 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. (1.1) Use in combination with trastuzumab and 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. (1.2, 2.2, 14.2) adjuvant treatment of patients 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 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)]. 1.2 Early Breast Cancer (EBC) PERJETA is indicated for use in combination with trastuzumab and chemotherapy for the 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 [see Dosage and Administration (2.2) and Clinical Studies (14.2)]. the adjuvant treatment of patients with HER2-positive early breast cancer at high risk of recurrence [see Dosage and Administration (2.2) and Clinical Studies (14.3)].

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Advisory information

contraindications
4 CONTRAINDICATIONS PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients. PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients. (4)
Adverse reactions
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 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) The adverse reactions described in Table 2 were identified in 804 patients with HER2-positive metastatic breast cancer treated in CLEOPATRA. Patients were randomized to receive either PERJETA in combination with trastuzumab and docetaxel or placebo in combination with trastuzumab and docetaxel. The median duration of study treatment was 18.1 months for patients in the PERJETA-treated group and 11.8 months for patients in the placebo-treated group. No dose adjustment was permitted for PERJETA or trastuzumab. Adverse reactions resulting in permanent discontinuation of all study therapy were 6% in the PERJETA-treated group and 5% for patients in the placebo-treated group. The most common adverse reactions (>1%) that led to discontinuation of all study therapy was left ventricular dysfunction (1% for patients in the PERJETA-treated group and 2% for patients in the placebo-treated group). The most common adverse reactions that led to discontinuation of docetaxel alone were edema, fatigue, edema peripheral, neuropathy peripheral, neutropenia, nail disorder and pleural effusion. Table 2 reports the adverse reactions that occurred in at least 10% of patients in the PERJETA-treated group. 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%) seen with PERJETA in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common NCI - CTCAE v3.0 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 2 Summary of Adverse Reactions Occurring in ≥ 10% of Patients on the PERJETA Treatment Arm in CLEOPATRA Body System/ Adverse Reactions PERJETA + trastuzumab + docetaxel n=407 Frequency rate % Placebo + trastuzumab + docetaxel n=397 Frequency rate % All Grades % Grades 3 – 4 % All Grades % Grades 3 – 4 % General disorders and administration site conditions Fatigue 37 2 37 3 Mucosal inflammation 28 1 20 1 Asthenia 26 2 30 2 Edema peripheral 23 0.5 30 0.8 Pyrexia 19 1 18 0.5 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 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 Blood and lymphatic system disorders Neutropenia 53 49 50 46 Anemia 23 2 19 4 Leukopenia 18 12 20 15 Febrile neutropeniaIn this table this denotes an adverse reaction that has been reported in association with a fatal outcome 14 13 8 7 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 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 Metabolism and nutrition disorders Decreased appetite 29 2 26 2 Eye disorders Lacrimation increased 14 0 14 0 Psychiatric disorders Insomnia 13 0 13 0 The following clinically relevant adverse reactions were reported in < 10% of patients in the PERJETA-treated group in CLEOPATRA: Infections and infestations: Paronychia (7% in the PERJETA-treated group vs. 4% in the placebo-treated group) Adverse Reactions Reported in Patients Receiving PERJETA and Trastuzumab After Discontinuation of Docetaxel In CLEOPATRA, adverse reactions were reported less frequently after discontinuation of docetaxel treatment. All adverse reactions in the PERJETA and trastuzumab treatment group occurred in < 10% of patients with the exception of diarrhea (19%), upper respiratory tract infection (13%), rash (12%), headache (11%), and fatigue (11%). Neoadjuvant Treatment of Breast Cancer (NeoSphere) In NeoSphere, the most common adverse reactions seen with PERJETA in combination with trastuzumab and docetaxel administered for 4 cycles were similar to those seen in the PERJETA-treated group in CLEOPATRA. The most common adverse reactions (> 30%) were alopecia, neutropenia, diarrhea, and nausea. The most common NCI – CTCAE v3.0 Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, and diarrhea. In this group, one patient permanently discontinued neoadjuvant treatment due to an adverse event. Table 3 reports the adverse reactions that occurred in patients who received neoadjuvant treatment with PERJETA for breast cancer in NeoSphere. Table 3 Summary of Adverse Reactions Occurring in ≥ 10% in the Neoadjuvant Setting for Patients Receiving PERJETA in NeoSphere Body System/ Adverse Reactions Trastuzumab + docetaxel n=107 Frequency rate % PERJETA + trastuzumab + docetaxel n=107 Frequency rate % PERJETA + trastuzumab n=108 Frequency rate % PERJETA + docetaxel n=108 Frequency rate % All Grades % Grades 3 – 4 % All Grades % Grades 3 – 4 % All Grades % Grades 3 – 4 % All Grades % Grades 3 – 4 % General disorders and administration site conditions Fatigue 27 0 26 0.9 12 0 26 1 Mucosal inflammation 21 0 26 2 3 0 26 0 Asthenia 18 0 21 2 3 0 16 2 Pyrexia 10 0 17 0 8 0 9 0 Edema peripheral 10 0 3 0 0.9 0 5 0 Skin and subcutaneous tissue disorders Alopecia 66 0 65 0 3 0 67 0 Rash 21 2 26 0.9 11 0 29 1 Gastrointestinal disorders Diarrhea 34 4 46 6 28 0 54 4 Nausea 36 0 39 0 14 0 36 1 Stomatitis 7 0 18 0 5 0 10 0 Vomiting 12 0 13 0 5 0 16 2 Blood and lymphatic system disorders Neutropenia 64 59 50 45 0.9 0.9 65 57 Leukopenia 21 11 9 5 0 0 14 9 Nervous system disorders Dysgeusia 10 0 15 0 5 0 7 0 Headache 11 0 11 0 14 0 13 0 Peripheral Sensory Neuropathy 12 0.9 8 0.9 2 0 11 0 Musculoskeletal and connective tissue disorders Myalgia 22 0 22 0 9 0 21 0 Arthralgia 8 0 10 0 5 0 10 0 Metabolism and nutrition disorders Decreased appetite 7 0 14 0 2 0 15 0 Psychiatric disorders Insomnia 11 0 8 0 4 0 9 0 The following adverse reactions were reported in < 10% of patients receiving neoadjuvant treatment and occurred more frequently in PERJETA-treated groups in NeoSphere: (Ptz=pertuzumab; H=trastuzumab; D=docetaxel) Blood and lymphatic system disorders: Anemia (7% in the H+D arm, 3% in the Ptz+H+D arm, 5% in the Ptz+H arm and 9% in the Ptz+D arm), Febrile neutropenia (7% in the H+D arm, 8% in the Ptz+H+D arm, 0% in the Ptz+H arm and 7% in the Ptz+D arm) Nervous system disorders: Dizziness (4% in the H+D arm, 3% in the Ptz+H+D arm, 6% in the Ptz+H arm and 3% in the Ptz+D arm) Infections and infestations: Upper respiratory tract infection (3% in the H+D arm, 5% in the Ptz+H+D arm, 2% in the Ptz+H arm and 7% in the Ptz+D arm) Eye disorders: Lacrimation increased (2% in the H+D arm, 4% in the Ptz+H+D arm, 0.9% in the Ptz+H arm, and 4% in the Ptz+D arm) Neoadjuvant Treatment of Breast Cancer (TRYPHAENA) In TRYPHAENA, when PERJETA was 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 NCI-CTCAE (version 3) Grade 3 – 4 adverse reactions (> 2%) were neutropenia, leukopenia, febrile neutropenia, diarrhea, left ventricular dysfunction, anemia, dyspnea, nausea, and vomiting. Similarly, when PERJETA was 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 NCI-CTCAE (version 3) Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, anemia, leukopenia, diarrhea, thrombocytopenia, vomiting, fatigue, ALT increased, hypokalemia, and hypersensitivity. 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. Table 4 reports the adverse reactions that occurred in patients who received neoadjuvant treatment with PERJETA for breast cancer in TRYPHAENA. Table 4 Summary of Adverse Reactions Occurring in ≥ 10% of Patients Receiving Neoadjuvant Treatment with PERJETA in TRYPHAENA Body System/Adverse Reactions PERJETA + trastuzumab + FEC followed by PERJETA + trastuzumab + docetaxel PERJETA + trastuzumab + docetaxel following FEC PERJETA + TCH n=72 n=75 n=76 Frequency rate % Frequency rate % Frequency rate % All Grades % Grades 3 – 4 % All Grades % Grades 3 – 4 % All Grades % Grades 3 – 4 % FEC=5-fluorouracil, epirubicin, cyclophosphamide, TCH=docetaxel, carboplatin, trastuzumab General disorders and administration site conditions Fatigue 36 0 36 0 42 4 Mucosal inflammation 24 0 20 0 17 1 Pyrexia 17 0 9 0 16 0 Asthenia 10 0 15 1 13 1 Edema peripheral 11 0 4 0 9 0 Skin and subcutaneous tissue disorders Alopecia 49 0 52 0 55 0 Rash 19 0 11 0 21 1 Palmar-Plantar Erythrodysaesthesia Syndrome 7 0 11 0 8 0 Dry skin 6 0 9 0 11 0 Gastrointestinal disorders Diarrhea 61 4 61 5 72 12 Nausea 53 0 53 3 45 0 Vomiting 40 0 36 3 39 5 Dyspepsia 25 1 8 0 22 0 Constipation 18 0 23 0 16 0 Stomatitis 14 0 17 0 12 0 Blood and lymphatic system disorders Neutropenia 51 47 47 43 49 46 Leukopenia 22 19 16 12 17 12 Anemia 19 1 9 4 38 17 Febrile neutropenia 18 18 9 9 17 17 Thrombocytopenia 7 0 1 0 30 12 Immune system disorders Hypersensitivity 10 3 1 0 12 3 Nervous system disorders Headache 22 0 15 0 17 0 Dysgeusia 11 0 13 0 21 0 Dizziness 8 0 8 1 16 0 Neuropathy peripheral 6 0 1 0 11 0 Musculoskeletal and connective tissue disorders Myalgia 17 0 11 1 11 0 Arthralgia 11 0 12 0 7 0 Respiratory, thoracic, and mediastinal disorders Dyspnea 13 0 8 3 11 1 Epistaxis 11 0 11 0 16 1 Cough 10 0 5 0 12 0 Oropharyngeal pain 8 0 7 0 12 0 Metabolism and nutrition disorders Decreased appetite 21 0 11 0 21 0 Eye disorders Lacrimation increased 13 0 5 0 8 0 Psychiatric disorders Insomnia 11 0 13 0 21 0 Investigations ALT increased 7 0 3 0 11 4 The following selected adverse reactions were reported in < 10% of patients receiving neoadjuvant treatment in TRYPHAENA: (Ptz=pertuzumab; H=trastuzumab; D=docetaxel; FEC= fluorouracil, epirubicin, and cyclophosphamide; TCH=docetaxel, carboplatin, and trastuzumab) Skin and subcutaneous tissue disorders: Nail disorder (10% in the Ptz+H+FEC/Ptz+H+D arm, 7% in the FEC/Ptz+H+D arm, and 9% in the Ptz+TCH arm), Paronychia (0% in the Ptz+H+FEC/Ptz+H+D arm, and 1% in both the FEC/Ptz+H+D and Ptz+TCH arms), Pruritus (3% in the Ptz+H+FEC/Ptz+H+D arm, 4% in the FEC/Ptz+H+D arm, and 4% in the Ptz+TCH arm) Infections and infestations: Upper respiratory tract infection (8.3% in the Ptz+H+FEC/Ptz+H+D arm, 4.0% in the FEC/Ptz+H+D arm, and 2.6% in the Ptz+TCH arm), Nasopharyngitis (6.9% in the Ptz+H+FEC/Ptz+H+D arm, 6.7% in the FEC/Ptz+H+D arm, and 7.9% in the Ptz+TCH arm) Neoadjuvant Treatment of Breast Cancer (BERENICE) In BERENICE, when PERJETA was 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, neutrophil count decreased, white blood cell count decreased, anemia, diarrhea, peripheral neuropathy, alanine aminotransferase increased and nausea. When PERJETA was 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, neutrophil count decreased, stomatitis, fatigue, vomiting, mucosal inflammation, neutropenic sepsis and anemia. 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 neuropathy peripheral, ejection fraction decreased, diarrhea, neutropenia and infusion related reaction. Table 5 reports the adverse reactions that occurred in patients who received neoadjuvant treatment with PERJETA for breast cancer in BERENICE. Table 5 Summary of Adverse Reactions Occurring in ≥ 10% of Patients Receiving Neoadjuvant Treatment with PERJETA in BERENICE Body System/Adverse Reactions PERJETA + trastuzumab + paclitaxel following ddAC PERJETA + trastuzumab + docetaxel following FEC n=199 n=198 Frequency rate % Frequency rate % All Grades % Grades 3 – 4 % All Grades % Grades 3 – 4 % ddAC = dose-dense doxorubicin, cyclophosphamide, FEC=5-fluorouracil, epirubicin, cyclophosphamide 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 Edema peripheral 9 0 12 1 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 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 Abdominal pain upper 6 0 13 0 Abdominal pain 5 0 10 0 Gastroesophageal reflux disease 12 0 2 0 Blood and lymphatic system disorders Anemia 27 3 30 3 Neutropenia 22 12 16 9 Febrile neutropenia 7 7 17 17 Nervous system disorders Headache 30 0.5 14 0.5 Dysgeusia 20 0 19 0.5 Neuropathy peripheral 42 3 26 0.5 Paresthesia 15 0 9 0 Dizziness 12 0 8 0 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 Infections and infestations Urinary tract infection 11 1 2 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 Eye disorders Lacrimation increased 9 0 18 0 Psychiatric disorders Insomnia 19 0 13 0 Vascular disorders Hot flush 19 0 13 0 Investigations White blood cell count decreased 11 4 3 2 Injury, poisoning and procedural complications Infusion related reaction 16 1 13 1 The following selected adverse reactions were reported in < 10% of patients receiving neoadjuvant treatment in BERENICE: (Ptz=pertuzumab; H=trastuzumab; P=paclitaxel; ddAC=dose-dense doxorubicin and cyclophosphamide; D=docetaxel; FEC= fluorouracil, epirubicin, and cyclophosphamide) Skin and Subcutaneous tissue disorders: Pruritus (9% in the ddAC/Ptz+H+P arm, and 8% in the FEC/Ptz+H+D arm), Nail disorder (7% in the ddAC/Ptz+H+P arm, and 10% in the FEC/Ptz+H+D arm) Infections and infestations: Upper respiratory tract infection (7% in the ddAC/Ptz+H+P arm, and 2% in the FEC/Ptz+H+D arm), nasopharyngitis (7% in the ddAC/Ptz+H+P arm, and 9% in the FEC/Ptz+H+D arm), paronychia (0.5% in the ddAC/Ptz+H+P arm, and 1% in the FEC/Ptz+H+D arm) Adjuvant Treatment of Breast Cancer (APHINITY) The adverse reactions described in Table 6 were identified in 4769 patients with HER2-positive early breast cancer treated in APHINITY. Patients were randomized to receive either PERJETA in combination with trastuzumab and chemotherapy or placebo in combination with trastuzumab and chemotherapy. Adverse reactions resulting in permanent discontinuation of any study therapy were 13% for patients in the PERJETA-treated group and 12% for patients in the placebo-treated group. Adverse reactions resulting in permanent discontinuation of PERJETA or placebo was 7% and 6%, respectively. 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. Table 6 reports the adverse reactions that occurred in at least 10% of patients in the PERJETA-treated group. 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. The incidence of diarrhea, all Grades, was higher when chemotherapy was administered with targeted therapy (61% in the PERJETA-treated group vs. 34% in the placebo-treated group), and was higher when administered with non-anthracycline based therapy (85% in the PERJETA-treated group vs. 62% in the placebo-treated group) than with anthracycline based therapy (67% in the PERJETA-treated group vs. 41% in the placebo-treated group). The incidence of diarrhea during the period that targeted therapy was administered without chemotherapy was 18% in the PERJETA-treated group vs. 9% in the placebo-treated group. The median duration of all Grades diarrhea was 8 days for the PERJETA-treated group vs. 6 days for the placebo-treated group. The median duration of Grade ≥3 diarrhea was 20 days for the PERJETA-treated group vs. 8 days for the placebo-treated group. More patients required hospitalization for diarrhea as a serious adverse event in the PERJETA-treated group (2.4%) than in the placebo-treated group (0.7%). Table 6 Summary of Adverse Reactions Occurring in ≥ 10% of Patients Receiving Adjuvant Treatment with PERJETA in APHINITY Body System/ Adverse Reactions PERJETA + trastuzumab + chemotherapy n=2364 Frequency rate % Placebo + trastuzumab + chemotherapy n=2405 Frequency rate % All Grades % Grades 3 – 4 % All Grades % Grades 3 – 4 % 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 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 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 Blood and lymphatic system disorders Anemia 28 7 23 5 Neutropenia 25 16 23 16 Febrile neutropeniaIn 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 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 Infections and infestations Nasopharyngitis 13 <0.1 12 0.1 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 Metabolism and nutrition disorders Decreased appetite 24 0.8 20 0.4 Vascular disorders Hot flush 20 0.2 21 0.4 Eye disorders Lacrimation increased 13 0 13 <0.1 Psychiatric disorders Insomnia 17 0.3 17 <0.1 Investigations Neutrophil count decreased 14 10 14 10 Injury, poisoning and procedural complications Radiation skin injury 13 0.3 11 0.3 For the adverse reactions that were reported in ≥10% of patients with at least 5% difference between the PERJETA-treated group and the placebo-treated group in APHINITY, the breakdown per chemotherapy regimen is provided: (Ptz=pertuzumab; H=trastuzumab; AC=anthracyclines; TCH=docetaxel, carboplatin, and trastuzumab) Gastrointestinal disorders: Diarrhea (67% in the Ptz+H+AC chemo arm, 85% in the Ptz+TCH arm, 41% in the Pla+H+AC chemo arm, 62% in the Pla+TCH arm) Skin and subcutaneous disorders: Rash (26% in the Ptz+H+AC chemo arm, 25% in the Ptz+TCH arm, 21% in the Pla+H+AC chemo arm, 19% in the Pla+TCH arm), Pruritus (14% in the Ptz+H+AC chemo arm, 15% in the Ptz+TCH arm, 9% in the Pla+H+AC chemo arm, 9% in the Pla+TCH arm) The following clinically relevant adverse reactions were reported in < 10% of patients in the PERJETA-treated group in APHINITY: Blood and lymphatic system disorders: Leukopenia (9% in the PERJETA-treated group vs. 9% in the placebo-treated group) Infections and infestations: Upper respiratory tract infection (8% in the PERJETA-treated group vs. 7% in the placebo-treated group), paronychia (4% in the PERJETA-treated group vs. 2% in the placebo-treated group) Adverse Reactions Reported in Patients Receiving PERJETA and Trastuzumab After Discontinuation of Chemotherapy In the APHINITY study, during the targeted treatment alone phase, all adverse reactions in the PERJETA treatment group occurred in < 10% of patients with the exception of diarrhea (18%), arthralgia (15%), radiation skin injury (12%), and hot flush (12%). 6.2 Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to pertuzumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. Patients in CLEOPATRA were tested at multiple time-points for antibodies to PERJETA. 3% (13/389) of patients in the PERJETA-treated group and 7% (25/372) of patients in the placebo-treated group tested positive for anti-PERJETA antibodies. Of these 38 patients, none experienced anaphylactic/hypersensitivity reactions that were clearly related to the anti-drug antibodies (ADA). The presence of pertuzumab in patient serum at the levels expected at the time of ADA sampling can interfere with the ability of this assay to detect anti-pertuzumab antibodies. In addition, the assay may be detecting antibodies to trastuzumab. As a result, data may not accurately reflect the true incidence of anti-pertuzumab antibody development. In the neoadjuvant period of BERENICE, 0.3% (1/383) of patients treated with PERJETA tested positive for anti-PERJETA antibodies. This patient did not experience any anaphylactic/hypersensitivity reactions.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION For intravenous infusion only. Do not administer as an intravenous push or bolus. (2.4) 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. (2.2) MBC: Administer PERJETA, trastuzumab, and docetaxel by intravenous infusion every 3 weeks. (2.2) Neoadjuvant: Administer PERJETA, trastuzumab, and chemotherapy by intravenous infusion preoperatively every 3 weeks for 3 to 6 cycles. (2.2) Adjuvant: Administer PERJETA, trastuzumab, and chemotherapy by intravenous infusion postoperatively every 3 weeks for a total of 1 year (up to 18 cycles). (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 Recommended Doses and Schedules 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. PERJETA, trastuzumab, and taxane should be administered sequentially. PERJETA and trastuzumab can be given in any order. Taxane should be administered after PERJETA and trastuzumab. An observation period of 30 to 60 minutes is recommended after each PERJETA infusion and before commencement of any subsequent infusion of trastuzumab or taxane [see Warnings and Precautions (5.3)]. In patients receiving an anthracycline-based regimen, PERJETA and trastuzumab should be administered following completion of the anthracycline. Metastatic Breast Cancer (MBC) When administered with PERJETA, the recommended initial dose of docetaxel is 75 mg/m2 administered as an intravenous infusion. The dose may be escalated to 100 mg/m2 administered every 3 weeks if the initial dose is well tolerated. Neoadjuvant Treatment of Breast Cancer PERJETA should be administered every 3 weeks for 3 to 6 cycles as part of one of the following treatment regimens for early breast cancer [see Clinical Studies (14.2)]: Four preoperative cycles of PERJETA in combination with trastuzumab and docetaxel followed by 3 postoperative cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC) as given in NeoSphere Three or four preoperative cycles of FEC alone followed by 3 or 4 preoperative cycles of PERJETA in combination with docetaxel and trastuzumab as given in TRYPHAENA and BERENICE, respectively Six preoperative cycles of PERJETA in combination with docetaxel, carboplatin, and trastuzumab (TCH) (escalation of docetaxel above 75 mg/m2 is not recommended) as given in TRYPHAENA Four preoperative cycles of dose-dense doxorubicin and cyclophosphamide (ddAC) alone followed by 4 preoperative cycles of PERJETA in combination with paclitaxel and trastuzumab as given in BERENICE Following surgery, patients should continue to receive PERJETA and trastuzumab to complete 1 year of treatment (up to 18 cycles). Adjuvant Treatment of Breast Cancer PERJETA should be administered in combination with trastuzumab 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 as given in APHINITY. PERJETA and trastuzumab should start on Day 1 of the first taxane-containing cycle [see Clinical Studies (14.3)]. 2.3 Dose Modification For delayed or missed doses, if the time between two sequential infusions is less than 6 weeks, the 420 mg dose of PERJETA should be administered. Do not wait until the next planned dose. If the time between two sequential infusions is 6 weeks or more, the initial dose of 840 mg PERJETA should be re-administered as a 60-minute intravenous infusion followed every 3 weeks thereafter by a dose of 420 mg administered as an intravenous infusion over 30 to 60 minutes. PERJETA should be discontinued if trastuzumab treatment is discontinued. Dose reductions are not recommended for PERJETA. For chemotherapy dose modifications, see relevant prescribing information. Left Ventricular Ejection Fraction (LVEF): Assess left ventricular ejection fraction (LVEF) prior to initiation of PERJETA and at regular intervals during treatment as indicated in Table 1. The recommendations on dose modifications in the event of LVEF dysfunction are also indicated in Table 1 [see Warnings and Precautions (5.1)]. Table 1 Dose Modifications for Left Ventricular Dysfunction Pre-treatment LVEF: Monitor LVEF every: Withhold PERJETA and trastuzumab for at least 3 weeks for an LVEF decrease to: Resume PERJETA and trastuzumab 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 ~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)]. 2.4 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. Withdraw the appropriate volume of PERJETA solution from the vial(s). Dilute into a 250 mL 0.9% sodium chloride PVC or non-PVC polyolefin 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 at 2°C to 8°C for up to 24 hours. Dilute with 0.9% Sodium Chloride injection only. Do not use dextrose (5%) solution.
Use in special populations
8 USE IN SPECIFIC POPULATIONS Females and Males of Reproductive Potential: Verify the pregnancy status of females prior to initiation of PERJETA. (8.3) 8.1 Pregnancy Pregnancy Exposure Registry and Pharmacovigilance Program There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to PERJETA during pregnancy. Encourage women who receive PERJETA in combination with trastuzumab during pregnancy or within 7 months prior to conception, to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 or visiting http://www.motherpregnancyregistry.com/. In addition, there is a pregnancy pharmacovigilance program for PERJETA. If PERJETA is administered during pregnancy, or if a patient becomes pregnant while receiving PERJETA or within 7 months following the last dose of PERJETA in combination with trastuzumab, health care providers and patients should immediately report PERJETA exposure to Genentech at 1-888-835-2555. Risk Summary Based on its mechanism of action and findings in animal studies, PERJETA can cause fetal harm when administered to a pregnant woman. There are no available data on the use of PERJETA in pregnant women. However, in post-marketing reports, use of another HER2/neu receptor antagonist (trastuzumab) during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. In an animal reproduction study, administration of pertuzumab to pregnant cynomolgus monkeys during the period of organogenesis resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal deaths at clinically relevant exposures that were 2.5 to 20-fold greater than exposures in humans receiving the recommended dose, based on Cmax [see Data]. Apprise the patient of the potential risks to a fetus. There are clinical considerations if PERJETA in combination with trastuzumab is used during pregnancy or within 7 months prior to conception [see Clinical Considerations]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Monitor women who received PERJETA in combination with trastuzumab during pregnancy or within 7 months prior to conception for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. Data Animal Data Pregnant cynomolgus monkeys were treated on Gestational Day (GD)19 with loading doses of 30 to 150 mg/kg pertuzumab, followed by bi-weekly doses of 10 to 100 mg/kg. These dose levels resulted in clinically relevant exposures of 2.5 to 20-fold greater than exposures in humans receiving the recommended dose, based on Cmax. Intravenous administration of pertuzumab from GD19 through GD50 (period of organogenesis) was embryotoxic, with dose-dependent increases in embryo-fetal death between GD25 to GD70. The incidences of embryo-fetal loss were 33, 50, and 85% for dams treated with bi-weekly pertuzumab doses of 10, 30, and 100 mg/kg, respectively (2.5 to 20-fold greater than the recommended human dose, based on Cmax). At Caesarean section on GD100, oligohydramnios, decreased relative lung and kidney weights, and microscopic evidence of renal hypoplasia consistent with delayed renal development were identified in all pertuzumab dose groups. Pertuzumab exposure was reported in offspring from all treated groups, at levels of 29% to 40% of maternal serum levels at GD100. 8.2 Lactation Risk Summary There is no information regarding the presence of pertuzumab in human milk, the effects on the breastfed infant or the effects on milk production. Published data suggest that human IgG is present in human milk but does not enter the neonatal and infant circulation in substantial amounts. Consider the developmental and health benefits of breast feeding along with the mother's clinical need for PERJETA treatment and any potential adverse effects on the breastfed child from PERJETA or from the underlying maternal condition. This consideration should also take into account the elimination half-life of pertuzumab and the trastuzumab wash out period of 7 months. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to the initiation of PERJETA. Contraception Females Based on the mechanism of action and animal data, PERJETA can cause embryo-fetal harm when administered during pregnancy. Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose of PERJETA in combination with trastuzumab [see Use in Specific Populations (8.1)]. 8.4 Pediatric Use The safety and effectiveness of PERJETA have not been established in pediatric patients. 8.5 Geriatric Use In studies in the indicated populations, CLEOPATRA, NeoSphere, TRYPHAENA, BERENICE, and APHINITY, 464 patients who received PERJETA were ≥ 65 years of age and 47 were ≥ 75 years of age. The most common (≥ 10%) Grade 3-4 adverse reactions in both age groups were neutropenia (22% ≥ 65 years, 23% ≥ 75 years), febrile neutropenia (12% ≥ 65 years, 13% ≥ 75 years), diarrhea (15% ≥ 65 years, 17% ≥ 75 years) and anemia (15% ≥ 75 years). The incidence of the following all grade adverse events was at least 5% higher in patients aged ≥ 65 years of age, compared to patients aged < 65 years of age: decreased appetite (13% higher), anemia (7% higher), weight decreased (7% higher), asthenia (7% higher), dysgeusia (7% higher), neuropathy peripheral and hypomagnesemia (both 5% higher). No overall differences in efficacy of PERJETA were observed in patients aged ≥ 65 and <65 years of age. There are too few patients aged ≥ 75 years to draw conclusions on efficacy in this age group. Based on a population pharmacokinetic analysis, no significant difference was observed in the pharmacokinetics of pertuzumab between patients < 65 years (n=306) and patients ≥ 65 years (n=175). 8.6 Renal Impairment Dose adjustments of PERJETA are not needed in patients with mild (creatinine clearance [CLcr] 60 to 90 mL/min) or moderate (CLcr 30 to 60 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CLcr less than 30 mL/min) because of the limited pharmacokinetic data available [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of pertuzumab.

Interactions

7 DRUG INTERACTIONS No drug-drug interactions were observed between pertuzumab and trastuzumab, or between pertuzumab and docetaxel, paclitaxel, or carboplatin.

More information

Category Value
Authorisation number BLA125409
Agency product number K16AIQ8CTM
Orphan designation No
Product NDC 50242-145
Date Last Revised 19-12-2017
Type HUMAN PRESCRIPTION DRUG
Storage and handling Store vials in a refrigerator at 2°C to 8°C (36°F to 46°F) until time of use. Keep vial in the outer carton in order to protect from light. DO NOT FREEZE. DO NOT SHAKE.
Marketing authorisation holder Genentech, Inc.
Warnings WARNING: LEFT VENTRICULAR DYSFUNCTION and EMBRYO-FETAL TOXICITY Left Ventricular Dysfunction: PERJETA can result in subclinical and clinical cardiac failure manifesting as decreased LVEF and CHF. Evaluate cardiac function prior to and during treatment. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function [see Dosage and Administration (2.3), Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. Embryo-fetal Toxicity: Exposure to PERJETA can result in embryo-fetal death and birth defects. Advise patients of these risks and the need for effective contraception [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1) (8.3)]. WARNING: LEFT VENTRICULAR DYSFUNCTION and EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning. Left Ventricular Dysfunction: PERJETA can result in subclinical and clinical cardiac failure manifesting as decreased LVEF and CHF. Evaluate cardiac function prior to and during treatment. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function. (2.3, 5.1, 6.1) Embryo-fetal Toxicity: Exposure to PERJETA can result in embryo-fetal death and birth defects. Advise patients of these risks and the need for effective contraception. (5.2, 8.1, 8.3)