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BOXED WARNINGS: Left Ventricular Dysfunction and Embryo-Fetal Toxicity

• PERJETA can result in subclinical and clinical cardiac failure manifesting as decreased left ventricular ejection fraction (LVEF) and congestive heart failure (CHF). Evaluate cardiac function prior to and during treatment. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function
• Exposure to PERJETA can result in embryo-fetal death and birth defects. Advise patients of these risks and the need for effective contraception
  • Based on its mechanism of action and findings in animal studies, PERJETA can cause fetal harm when administered to a pregnant woman. PERJETA is a HER2/neu receptor antagonist. Cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death have been reported with use of another HER2/neu receptor antagonist (trastuzumab) during pregnancy. 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 death at exposures 2.5 to 20 times the exposure in humans at the recommended dose, based on C_max
  • Verify the pregnancy status of females of reproductive potential prior to the initiation of PERJETA. Advise pregnant women and females of reproductive potential that exposure to PERJETA in combination with trastuzumab during pregnancy or within 7 months prior to conception can result in fetal harm, including embryo-fetal death or birth defects. 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
  • 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, healthcare providers and patients should immediately report PERJETA exposure to Genentech at 1-888-835-2555

Additional Important Safety Information

PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients

Left Ventricular Dysfunction (LVD)

• Assess LVEF prior to initiation of PERJETA and at regular intervals during treatment to ensure that LVEF is within normal limits. If LVEF declines and has not improved, or has declined further at the subsequent assessment, discontinuation of PERJETA and trastuzumab should be strongly considered
• In the CLEOPATRA study, for patients with MBC, PERJETA in combination with trastuzumab and docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in LVEF compared to placebo in combination with trastuzumab and docetaxel. LVD occurred in 4% of patients in the PERJETA-treated group and in 8% of patients in the placebo-treated group. Symptomatic LVSD (CHF) occurred in 1% of patients in the PERJETA-treated group and in 2% of patients in the placebo-treated group
• Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of decreased LVEF
• In the NeoSphere study, for patients treated in the neoadjuvant setting, the incidence of LVSD was higher in the PERJETA-treated groups compared to the trastuzumab and docetaxel–treated group. An increased incidence of LVEF declines was observed in patients treated with PERJETA in combination with trastuzumab and docetaxel. In the overall treatment period, LVEF decline >10% and a drop to <50% occurred in 2% of patients treated with neoadjuvant trastuzumab and docetaxel as compared to 8% of patients treated with neoadjuvant PERJETA in combination with trastuzumab and docetaxel. LVD occurred in 0.9% of patients treated with neoadjuvant trastuzumab and docetaxel as compared to 3% of patients treated with neoadjuvant PERJETA in combination with trastuzumab and docetaxel. Symptomatic LVSD occurred in 0.9% of patients treated with neoadjuvant PERJETA in combination with trastuzumab and in no patients in the other 3 arms. LVEF recovered to ≥50% in all patients
• In the TRYPHAENA study, for patients treated in the neoadjuvant setting, in the overall treatment period, LVEF decline ˃10% and a drop to <50% occurred in 7% of patients treated with PERJETA plus trastuzumab and 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), followed by PERJETA plus trastuzumab and docetaxel; in 16% of patients treated with PERJETA plus trastuzumab and docetaxel following FEC; and in 11% of patients treated with PERJETA in combination with docetaxel, carboplatin, and trastuzumab (TCH). LVD occurred in 6% of patients treated with PERJETA plus trastuzumab and FEC, followed by PERJETA plus trastuzumab and docetaxel; in 4% of patients treated with PERJETA plus trastuzumab and docetaxel following FEC; and in 3% of patients treated with PERJETA in combination with TCH. Symptomatic LVSD occurred in 4% of patients treated with PERJETA plus trastuzumab and docetaxel following FEC, in 1% of patients treated with PERJETA in combination with TCH, and in none of the patients treated with PERJETA plus trastuzumab and FEC, followed by PERJETA plus trastuzumab and docetaxel. LVEF recovered to ≥50% in all but 1 patient
• In patients receiving neoadjuvant PERJETA in the BERENICE study, in the neoadjuvant period, LVEF decline ≥10% and a drop to <50% as measured by ECHO/MUGA assessment occurred in 7% of patients treated with PERJETA plus trastuzumab and paclitaxel following dose-dense doxorubicin and cyclophosphamide (ddAC), and in 2% of patients treated with PERJETA plus trastuzumab and docetaxel following FEC. Ejection fraction decrease (asymptomatic LVD) occurred in 7% of patients treated with PERJETA plus trastuzumab and paclitaxel following ddAC and in 4% of the patients treated with PERJETA plus trastuzumab and docetaxel following FEC in the neoadjuvant period. Symptomatic LVSD (New York Heart Association [NYHA] Class III/IV CHF) occurred in 2% of patients treated with PERJETA plus trastuzumab and paclitaxel following ddAC and in none of the patients treated with PERJETA plus trastuzumab and docetaxel following FEC in the neoadjuvant period
• In the APHINITY study, for patients treated in the adjuvant setting, the incidence of symptomatic heart failure (NYHA Class III/IV) with a LVEF decline ≥10% and a drop to <50% was <1% (0.6% of PERJETA-treated patients vs 0.2% of placebo-treated patients). Of the patients who experienced symptomatic heart failure, 47% of PERJETA-treated patients and 67% of placebo-treated patients had recovered (defined as 2 consecutive LVEF measurements above 50%) at the data cutoff. The majority of the events (86%) were reported in anthracycline-treated patients. Asymptomatic or mildly symptomatic (NYHA Class II) declines in LVEF ≥10% and a drop to <50% were reported in 3% of PERJETA-treated patients and 3% of placebo-treated patients, of whom 80% of PERJETA-treated patients and 81% of placebo-treated patients recovered at the data cutoff

Infusion-Related Reactions

• PERJETA has been associated with infusion reactions,  including fatal events
• In the CLEOPATRA study, on the first day, when only PERJETA was administered, the overall frequency of infusion reactions was 13% in the PERJETA-treated group and 10% in the placebo-treated group. Less than 1% were Grade 3 or 4. The most common infusion reactions (≥1.0%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting. During the second cycle, when all drugs were administered on the same day, the most common infusion reactions in the PERJETA-treated group (≥1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting
• In the NeoSphere, TRYPHAENA, and APHINITY studies, PERJETA was administered on the same day as the other study treatment drugs. For APHINITY, infusion-related reactions occurred in 21% of patients on the first day of PERJETA administration (in combination with trastuzumab and chemotherapy) and in 18% of patients in the placebo arm. The incidence of Grades 3-4 National Cancer Institute–Common Terminology Criteria for Adverse Events (NCI-CTCAE v4.0) reactions was 1% for the PERJETA arm and 0.7% for the placebo arm
• Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of PERJETA. If a significant infusion reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions

Hypersensitivity Reactions/Anaphylaxis

• In the CLEOPATRA study, the overall frequency of hypersensitivity reaction/anaphylaxis was 11% in the PERJETA-treated group and 9% in the placebo-treated group. The incidence of Grades 3-4 hypersensitivity reaction/anaphylaxis was 2% in the PERJETA-treated group and 3% in the placebo-treated group according to NCI-CTCAE v3.0. Overall, 4 patients in the PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis
• In the NeoSphere, TRYPHAENA, BERENICE, and APHINITY studies, hypersensitivity/anaphylaxis events were consistent with those observed in CLEOPATRA. In NeoSphere, 2 patients in the PERJETA and docetaxel–treated group experienced anaphylaxis. In APHINITY, the overall frequency of hypersensitivity/anaphylaxis was 5% in the PERJETA-treated group vs 4% in the placebo-treated group. The incidence was highest in the PERJETA plus TCH–treated group (8%), of which 1% were NCI-CTCAE (v4.0) Grades 3-4
• Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity, including anaphylaxis and fatal events, have been observed in patients treated with PERJETA. Angioedema has been described in post-marketing reports. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use  PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients

Most Common Adverse Reactions

Neoadjuvant Treatment of Breast Cancer

• The most common adverse reactions (>30%) with PERJETA in combination with trastuzumab and docetaxel administered for 4 cycles were alopecia, neutropenia, diarrhea, and nausea. The most common NCI-CTCAE v3.0 Grades 3-4 adverse reactions (>2%) were neutropenia, febrile neutropenia, leukopenia, and diarrhea
• The most common adverse reactions (>30%) with PERJETA in combination with trastuzumab and docetaxel administered for 3 cycles following 3 cycles of FEC were diarrhea, nausea, alopecia, neutropenia, vomiting, and fatigue. The most common NCI-CTCAE v3.0 Grades 3-4 adverse reactions (>2%) were neutropenia, leukopenia, febrile neutropenia, diarrhea, left ventricular dysfunction, anemia, dyspnea, nausea, and vomiting
• The most common adverse reactions (>30%) with PERJETA in combination with TCH administered for 6 cycles were diarrhea, alopecia, neutropenia, nausea, fatigue, vomiting, anemia, and thrombocytopenia. The most common NCI-CTCAE v3.0 Grades 3-4 adverse reactions (>2%) were neutropenia, febrile neutropenia, anemia, leukopenia, diarrhea, thrombocytopenia, vomiting, fatigue, alanine aminotransferase (ALT) increased, hypokalemia, and hypersensitivity 
• The most common adverse reactions (>30%) with PERJETA in combination with trastuzumab and paclitaxel administered for 4 cycles following 4 cycles of ddAC were nausea, diarrhea, alopecia, fatigue, constipation, peripheral neuropathy, and headache.  The most common Grades 3-4 adverse reactions (>2%) were neutropenia, febrile neutropenia, neutrophil count decreased, white blood cell count decreased, anemia, diarrhea, peripheral neuropathy, ALT increased, and nausea
• The most common adverse reactions (>30%) with PERJETA in combination with trastuzumab and docetaxel administered for 4 cycles following 4 cycles of FEC were diarrhea, nausea, alopecia, asthenia, constipation, fatigue, mucosal inflammation, vomiting, myalgia, and anemia. The most common Grades 3-4 adverse reactions (>2%) were febrile neutropenia, diarrhea, neutropenia, neutrophil count decreased, stomatitis, fatigue, vomiting, mucosal inflammation, neutropenic sepsis, and anemia

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. The most common Grades 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%)

Metastatic Breast Cancer

• 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 Grades 3-4 adverse reactions (>2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue

You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at 1-888-835-2555.

Please see full Prescribing Information for additional Important Safety Information, including BOXED WARNINGS.