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BOXED WARNINGS: Cardiomyopathy, Embryo-Fetal Toxicity, and Pulmonary Toxicity

• PHESGO administration can result in subclinical and clinical cardiac failure. The incidence and severity was highest in patients receiving PHESGO with anthracycline-containing chemotherapy regimens. Evaluate cardiac function prior to and during treatment with PHESGO. Discontinue PHESGO treatment in patients receiving adjuvant therapy and withhold PHESGO in patients with metastatic disease for clinically significant decrease in left ventricular function

• Exposure to PHESGO can result in embryo-fetal death and birth defects, including oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Advise patients of these risks and the need for effective contraception

• PHESGO administration can result in serious and fatal pulmonary toxicity. Discontinue PHESGO for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome. Monitor patients until symptoms completely resolve

Contraindications

PHESGO is contraindicated in patients with known hypersensitivity to pertuzumab, or trastuzumab, or hyaluronidase, or to any of its excipients.

Additional Important Safety Information

Cardiomyopathy

• PHESGO administration can result in subclinical and clinical cardiac failure. The incidence and severity was highest in patients receiving PHESGO with anthracycline-containing chemotherapy regimens. An increased incidence of left ventricular ejection fraction (LVEF) decline has been observed in patients treated with intravenous pertuzumab, intravenous trastuzumab, and docetaxel

• PHESGO can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death

• PHESGO can also cause asymptomatic decline in LVEF

• Patients who receive anthracycline after stopping PHESGO may also be at increased risk of cardiac dysfunction

• Discontinue PHESGO treatment in patients receiving adjuvant therapy and withhold PHESGO in patients with metastatic disease for clinically significant decrease in left ventricular function

Cardiac Monitoring

• Evaluate cardiac function prior to and during treatment. For adjuvant breast cancer therapy, also evaluate cardiac function after completion of PHESGO

• Conduct thorough cardiac assessment, including history, physical examination, and determination of LVEF by echocardiogram or MUGA scan

• Monitor frequently for decreased left ventricular function during and after PHESGO treatment

• Monitor more frequently if PHESGO is withheld for significant left ventricular cardiac dysfunction

Embryo-Fetal Toxicity

• PHESGO can cause fetal harm when administered to a pregnant woman. In post-marketing reports, use of intravenous 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 intravenous 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 PHESGO. Advise pregnant women and females of reproductive potential that exposure to PHESGO during pregnancy or within 7 months prior to conception can result in fetal harm. Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose of PHESGO

• There is a pregnancy pharmacovigilance program for PHESGO. If PHESGO is administered during pregnancy, or if a patient becomes pregnant while receiving PHESGO or within 7 months following the last dose of PHESGO, health care providers and patients should immediately report PHESGO exposure to Genentech at 1-888-835-2555

Pulmonary Toxicity

• PHESGO can cause serious and fatal pulmonary toxicity. These adverse reactions have been reported with intravenous trastuzumab

• Pulmonary toxicity includes dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, and pulmonary fibrosis. Patients with symptomatic intrinsic lung disease or with extensive tumor involvement of the lungs, resulting in dyspnea at rest, appear to have more severe toxicity

Exacerbation of Chemotherapy-Induced Neutropenia

• PHESGO may exacerbate chemotherapy-induced neutropenia. In randomized controlled clinical trials with intravenous trastuzumab, Grade 3-4 neutropenia and febrile neutropenia were higher in patients receiving trastuzumab in combination with myelosuppressive chemotherapy as compared to those who received chemotherapy alone. The incidence of septic death was similar among patients who received trastuzumab and those who did not

Hypersensitivity and Administration-Related Reactions

• Severe administration-related reactions (ARRs), including hypersensitivity, anaphylaxis, and events with fatal outcomes, have been associated with intravenous pertuzumab and trastuzumab. Patients experiencing dyspnea at rest due to complications of advanced malignancy and comorbidities may be at increased risk of a severe or of a fatal ARR

• In the FeDeriCa study the incidence of hypersensitivity was 1.2% in the PHESGO arm. ARRs occurred in 21% of patients who received PHESGO. In the PHESGO arm, the most common ARRs were injection site reaction (15%) and injection site pain (2%).

• Closely monitor patients during and for 30 minutes after the injection of initial dose and during and for 15 minutes following subsequent injections of maintenance dose of PHESGO. If a significant injection-related reaction occurs, slow down or pause the injection and administer appropriate medical therapies. Evaluate and carefully monitor patients until complete resolution of signs and symptoms

• Permanently discontinue treatment with PHESGO in patients who experience anaphylaxis or severe injection-related reactions. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. For patients experiencing reversible Grade 1 or 2 hypersensitivity reactions, consider pre-medication with an analgesic, antipyretic, or an antihistamine prior to readministration of PHESGO

Most Common Adverse Reactions

Early Breast Cancer

The most common adverse reactions (>30%) with PHESGO were alopecia, nausea, diarrhea, anemia, and asthenia.

Metastatic Breast Cancer (based on IV 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.

You are encouraged to report side effects to Genentech and the FDA. 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.