CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. PHESGO is contraindicated in patients with known hypersensitivity to pertuzumab, or trastuzumab, or hyaluronidase, or to any of its excipients.. PHESGO is contraindicated in patients with known hypersensitivity to pertuzumab, or trastuzumab, or hyaluronidase, or to any of its excipients. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. PHESGO is combination of pertuzumab, trastuzumab, and hyaluronidase.Pertuzumab is recombinant humanized monoclonal antibody that targets the extracellular dimerization domain (Subdomain II) of the human epidermal growth factor receptor protein (HER2). Pertuzumab is produced by recombinant DNA technology in mammalian cell (Chinese Hamster Ovary) culture. Pertuzumab has an approximate molecular weight of 148 kDa.Trastuzumab is humanized IgG1 kappa monoclonal antibody that selectively binds with high affinity to the extracellular domain of the human epidermal growth factor receptor protein, HER2. Trastuzumab is produced by recombinant DNA technology in mammalian cell (Chinese Hamster Ovary) culture. Trastuzumab has molecular weight of approximately 148 kDa.Hyaluronidase (recombinant human) is an endoglycosidase used to increase the dispersion and absorption of co-administered drugs when administered subcutaneously. It is glycosylated single-chain protein produced by mammalian (Chinese Hamster Ovary) cells containing DNA plasmid encoding for soluble fragment of human hyaluronidase (PH20). Hyaluronidase (recombinant human) has molecular weight of approximately 61 kDa.PHESGO (pertuzumab, trastuzumab, and hyaluronidase-zzxf) injection is sterile, preservative-free, clear to opalescent, and colorless to slightly brownish solution supplied in single-dose vials for subcutaneous administration.PHESGO injection is supplied as two different configurations:PHESGO is supplied in 15 mL single-dose vial containing 1,200 mg of pertuzumab, 600 mg of trastuzumab, and 30,000 units of hyaluronidase, and ,-trehalose (397 mg), L-histidine (6.75 mg), L-histidine hydrochloric monohydrate (53.7 mg), L-methionine (22.4 mg), polysorbate 20 (6 mg), and sucrose (685 mg) with pH of 5.5.PHESGO is supplied in 10 mL single-dose vial containing 600 mg of pertuzumab, 600 mg of trastuzumab, and 20,000 units of hyaluronidase, and ,-trehalose (397 mg), L-histidine (4.4 mg), L-histidine hydrochloric monohydrate (36.1 mg), L-methionine (14.9 mg), polysorbate 20 (4 mg), and sucrose (342 mg) with pH of 5.5.. PHESGO is supplied in 15 mL single-dose vial containing 1,200 mg of pertuzumab, 600 mg of trastuzumab, and 30,000 units of hyaluronidase, and ,-trehalose (397 mg), L-histidine (6.75 mg), L-histidine hydrochloric monohydrate (53.7 mg), L-methionine (22.4 mg), polysorbate 20 (6 mg), and sucrose (685 mg) with pH of 5.5.. PHESGO is supplied in 10 mL single-dose vial containing 600 mg of pertuzumab, 600 mg of trastuzumab, and 20,000 units of hyaluronidase, and ,-trehalose (397 mg), L-histidine (4.4 mg), L-histidine hydrochloric monohydrate (36.1 mg), L-methionine (14.9 mg), polysorbate 20 (4 mg), and sucrose (342 mg) with pH of 5.5.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. For subcutaneous use in the thigh only.PHESGO has different dosage and administration instructions than intravenous pertuzumab and trastuzumab products.Do not administer intravenously. (2.2)Perform HER2 testing using FDA-approved tests by laboratories with demonstrated proficiency. (1, 2.1)The initial dose of PHESGO is 1,200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase administered subcutaneously over approximately minutes, followed every weeks by dose of 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase administered subcutaneously over approximately minutes. (2.2)Neoadjuvant: administer PHESGO by subcutaneous injection every weeks and chemotherapy by intravenous infusion preoperatively for to cycles. (2.2)Adjuvant: administer PHESGO by subcutaneous injection every weeks and chemotherapy by intravenous infusion postoperatively for total of year (up to 18 cycles). (2.2)MBC: administer PHESGO by subcutaneous injection and docetaxel by intravenous infusion every weeks. (2.2). For subcutaneous use in the thigh only.. PHESGO has different dosage and administration instructions than intravenous pertuzumab and trastuzumab products.. Do not administer intravenously. (2.2). Perform HER2 testing using FDA-approved tests by laboratories with demonstrated proficiency. (1, 2.1). The initial dose of PHESGO is 1,200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase administered subcutaneously over approximately minutes, followed every weeks by dose of 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase administered subcutaneously over approximately minutes. (2.2). Neoadjuvant: administer PHESGO by subcutaneous injection every weeks and chemotherapy by intravenous infusion preoperatively for to cycles. (2.2). Adjuvant: administer PHESGO by subcutaneous injection every weeks and chemotherapy by intravenous infusion postoperatively for total of year (up to 18 cycles). (2.2). MBC: administer PHESGO by subcutaneous injection and docetaxel by intravenous infusion every weeks. (2.2). 2.1Patient 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.. 2.2Important Dosage and Administration Information. PHESGO is for subcutaneous use only in the thigh. Do not administer intravenously.PHESGO has different dosage and administration instructions than intravenous pertuzumab, intravenous trastuzumab, and subcutaneous trastuzumab when administered alone.Do not substitute PHESGO for or with pertuzumab, trastuzumab, ado-trastuzumab emtansine, or fam-trastuzumab deruxtecan.PHESGO must always be administered by healthcare professional.In patients receiving an anthracycline-based regimen for early breast cancer, administer PHESGO following completion of the anthracycline.In patients receiving PHESGO for early breast cancer with docetaxel or paclitaxel, administer docetaxel or paclitaxel after PHESGO.In patients receiving PHESGO for metastatic breast cancer with docetaxel, administer docetaxel after PHESGO.Observe patients for minimum of 30 minutes after initial dose of PHESGO and 15 minutes after each maintenance dose of PHESGO for signs or hypersensitivity symptoms or administration-related reactions. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use [see Warnings and Precautions (5.5)]. 2.3Recommended Doses and Schedules. The recommended dosage and administration schedule for PHESGO are shown in Table 1.Table 1: Recommended Dosage and Administration ScheduleDoseStrengthAdministration InstructionsInitial dose1,200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase in 15 mLAdminister subcutaneously over approximately minutes(1,200 mg, 600 mg, and 30,000 units/15 mL)Maintenance dose (administer every weeks)600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase in 10 mL(600 mg, 600 mg, and 20,000 units/10 mL)Administer subcutaneously over approximately minutes every weeksNo dose adjustments for PHESGO are required for patient body weight or for concomitant chemotherapy regimen.Patients currently receiving intravenous pertuzumab and trastuzumab can transition to PHESGO. In patients receiving intravenous pertuzumab and trastuzumab with 6 weeks since their last dose, administer PHESGO as maintenance dose of 600 mg pertuzumab/600 mg trastuzumab and every weeks for subsequent administrations. In patients receiving intravenous pertuzumab and trastuzumab with >= weeks since their last dose, administer PHESGO as an initial dose of 1,200 mg pertuzumab/600 mg trastuzumab, followed by maintenance dose of 600 mg pertuzumab/600 mg trastuzumab every weeks for subsequent administrations. Neoadjuvant Treatment of Breast CancerAdminister PHESGO every weeks for to cycles as part of treatment regimen for early breast cancer [see Clinical Studies (14.2)].Refer to the prescribing information for pertuzumab, administered in combination with trastuzumab and chemotherapy, for recommended dose and dosage modifications.Following surgery, patients should continue to receive PHESGO to complete year of treatment (up to 18 cycles) or until disease recurrence or unmanageable toxicity, whichever occurs first, as part of complete regimen for early breast cancer.. Adjuvant Treatment of Breast CancerAdminister PHESGO every weeks for total of year (up to 18 cycles) or until disease recurrence or unmanageable toxicity, whichever occurs first, as part of complete regimen for early breast cancer, including standard anthracycline- and/or taxane-based chemotherapy. Start PHESGO on Day of the first taxane-containing cycle [see Clinical Studies (14.2)].. Metastatic Breast Cancer (MBC)When administered with PHESGO, the recommended initial dose of docetaxel is 75 mg/m2 administered as an intravenous infusion. The dose may be escalated to 100 mg/m2 administered every weeks if the initial dose is well tolerated. Administer PHESGO until disease progression or unmanageable toxicity, whichever occurs first.. 2.4Dose Modification. Dose Modification for delayed or missed dosesFor delayed or missed doses of PHESGO, if the time between two sequential injections is less than weeks, administer the maintenance dose of 600 mg, 600 mg, and 20,000 units/10 mL. Do not wait until the next planned dose.If the time between two sequential injections is weeks or more, re-administer the initial dose of 1,200 mg, 600 mg, and 30,000 units/15 mL, followed every weeks thereafter by maintenance dose of 600 mg, 600 mg, and 20,000 units/10 mL.For chemotherapy dose modifications, see relevant prescribing information.. Cardiomyopathy [see Boxed Warning, Warnings and Precautions (5.1)] Assess left ventricular ejection fraction (LVEF) prior to initiation of PHESGO and at regular intervals during treatment as indicated in Table 2.The recommendations on dose modifications in the event of LVEF dysfunction are indicated in Table [see Warnings and Precautions (5.1)]. Table 2: Dose Modifications for Left Ventricular DysfunctionPre-treatment LVEF:Monitor LVEF every:Withhold PHESGO for at least weeks for an LVEF decrease to:Resume PHESGO after weeks if LVEF has recovered to:Early Breast Cancer>= 55%For patients receiving anthracycline-based chemotherapy, LVEF of >= 50% is required after completion of anthracyclines, before starting PHESGO ~12 weeks (once during neoadjuvant therapy)<50% with fall of >=10%-points below pre-treatment valueEither>=50%<10% points below pre-treatment valueMetastatic Breast Cancer>= 50%~12 weeksEitherEither<40%40%-45% with fall of >=10%-points below pre-treatment value>45%40%-45% with fall of <10%-points below pre-treatment valueIf after repeat assessment within approximately weeks, the LVEF has not improved, has declined further, and/or the patient is symptomatic, permanently discontinue PHESGO [see Warnings and Precautions (5.1)].. Hypersensitivity and Administration-Related ReactionsDiscontinue the injection immediately if the patient experiences serious hypersensitivity reaction (e.g. anaphylaxis) [see Warnings and Precautions (5.5)].. 2.5Preparation for Administration. To prevent medication errors, it is important to check the vial labels to ensure that the drug being prepared and administered is PHESGO and not intravenous pertuzumab, or intravenous trastuzumab, or subcutaneous trastuzumab.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use vial if particulates or discoloration is present. Do not shake. Discard any unused portion remaining in the vial.For both the initial and maintenance dose, each corresponding PHESGO vial is ready-to-use for one subcutaneous injection and should not be diluted.A syringe, transfer needle, and an injection needle are needed to withdraw PHESGO solution from the vial and inject it subcutaneously. PHESGO may be injected using 25G-27G (3/8-5/8) hypodermic injection needles.To avoid needle clogging, attach the hypodermic injection needle to the syringe immediately prior to administration followed by volume adjustment to 15 mL (initial dose) and 10 mL (maintenance dose). If the dose is not to be administered immediately, and the solution of PHESGO has been withdrawn from the vial into the syringe, replace the transfer needle with syringe closing cap. Label the syringe with the peel-off sticker and store the syringe in the refrigerator [2C to 8C (36F to 46F)] for up to 24 hours and at room temperature [20C to 25C (68F to 77F)] for up to hours and avoid unnecessary storage.PHESGO is compatible with stainless steel, polypropylene, polycarbonate, polyethylene, polyurethane, polyvinyl chloride and fluorinated ethylene polypropylene.. AdministrationAdminister PHESGO 1,200 mg, 600 mg, 30,000 units/15 mL subcutaneously over approximately minutesAdminister PHESGO 600 mg, 600 mg, 20,000 units/10 mL subcutaneously over approximately minutesThe subcutaneous injection site should be alternated between the left and right thigh only. New injections should be given at least inch (2.5 cm) from the previous site on healthy skin and never into areas where the skin is red, bruised, tender, or hard. Do not split the dose between two syringes or between two sites of administration. During the treatment course with PHESGO, other medications for subcutaneous administration should preferably be injected at different sites.. Administer PHESGO 1,200 mg, 600 mg, 30,000 units/15 mL subcutaneously over approximately minutes. Administer PHESGO 600 mg, 600 mg, 20,000 units/10 mL subcutaneously over approximately minutes.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. CardiomyopathyAdvise patients to contact health care professional immediately for any of the following: new onset or worsening shortness of breath, cough, swelling of the ankles/legs, swelling of the face, palpitations, weight gain of more than pounds in 24 hours, dizziness or loss of consciousness [see Warnings and Precautions (5.1)].. Advise patients to contact health care professional immediately for any of the following: new onset or worsening shortness of breath, cough, swelling of the ankles/legs, swelling of the face, palpitations, weight gain of more than pounds in 24 hours, dizziness or loss of consciousness [see Warnings and Precautions (5.1)].. Embryo-Fetal ToxicityAdvise pregnant women and females of reproductive potential that exposure to PHESGO during pregnancy or within months prior to conception can result in fetal harm. Advise female patients to contact their healthcare provider with known or suspected pregnancy [see Use in Specific Populations (8.1)].Advise women who are exposed to PHESGO during pregnancy or within months prior to conception that there is pregnancy pharmacovigilance program that monitors pregnancy outcomes. Encourage these patients to report their pregnancy to Genentech [see Use in Specific Populations (8.1)].Advise females of reproductive potential to use effective contraception during treatment and for months following the last dose of PHESGO [see Use in Specific Populations (8.3)].. Advise pregnant women and females of reproductive potential that exposure to PHESGO during pregnancy or within months prior to conception can result in fetal harm. Advise female patients to contact their healthcare provider with known or suspected pregnancy [see Use in Specific Populations (8.1)].. Advise women who are exposed to PHESGO during pregnancy or within months prior to conception that there is pregnancy pharmacovigilance program that monitors pregnancy outcomes. Encourage these patients to report their pregnancy to Genentech [see Use in Specific Populations (8.1)].. Advise females of reproductive potential to use effective contraception during treatment and for months following the last dose of PHESGO [see Use in Specific Populations (8.3)].. Hypersensitivity and Administration-Related ReactionsAdvise patients to contact their healthcare provider immediately and to report any symptoms of hypersensitivity and administration-related reactions including dizziness, nausea, chills, fever, vomiting, diarrhea, urticaria, angioedema, breathing problems, or chest pain [see Warnings and Precautions (5.5)].. Advise patients to contact their healthcare provider immediately and to report any symptoms of hypersensitivity and administration-related reactions including dizziness, nausea, chills, fever, vomiting, diarrhea, urticaria, angioedema, breathing problems, or chest pain [see Warnings and Precautions (5.5)].

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed in greater detail in other sections of the label:Cardiomyopathy [see Warnings and Precautions (5.1)] Embryo-Fetal Toxicity [see Warnings and Precautions (5.2)] Pulmonary Toxicity [see Warnings and Precautions (5.3)] Exacerbation of Chemotherapy-Induced Neutropenia [see Warnings and Precautions (5.4)] Hypersensitivity and Administration-Related Reactions [see Warnings and Precautions (5.5)] Cardiomyopathy [see Warnings and Precautions (5.1)] Embryo-Fetal Toxicity [see Warnings and Precautions (5.2)] Pulmonary Toxicity [see Warnings and Precautions (5.3)] Exacerbation of Chemotherapy-Induced Neutropenia [see Warnings and Precautions (5.4)] Hypersensitivity and Administration-Related Reactions [see Warnings and Precautions (5.5)] Neoadjuvant and Adjuvant Treatment of Breast CancerThe most common adverse reactions (>30%) with PHESGO were alopecia, nausea, diarrhea, anemia, and asthenia. (6.1)Metastatic Breast Cancer (based on intravenous pertuzumab) The most common adverse reactions (> 30%) with pertuzumab in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. The most common adverse reactions (>30%) with PHESGO were alopecia, nausea, diarrhea, anemia, and asthenia. (6.1). The most common adverse reactions (> 30%) with pertuzumab in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. (6.1). 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. Neoadjuvant and Adjuvant Treatment of Breast CancerThe safety of PHESGO was evaluated in an open-label, multicenter, randomized study (FeDeriCa) conducted in 500 patients with HER2 overexpressing early breast cancer [see Clinical Studies (14.2)].Patients were randomized to receive either PHESGO (1,200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase/15 mL) followed every weeks by maintenance dose of 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase/10 mL or the recommended dosages for intravenous pertuzumab and intravenous trastuzumab. Patients were randomized to receive cycles of neoadjuvant chemotherapy with concurrent administration of cycles of either PHESGO or intravenous pertuzumab and trastuzumab during cycles 5-8, followed by surgery. Following surgery, patients continued therapy with PHESGO or intravenous pertuzumab and trastuzumab (intravenous or subcutaneously administered) as treated prior to surgery, for an additional 14 cycles, to complete 18 cycles. The median duration of treatment for PHESGO was 24 weeks (range: 0-42 weeks).Serious adverse reactions occurred in 16% of patients who received PHESGO. Serious adverse reactions in 1% of patients included febrile neutropenia (4%), neutropenic sepsis (1%), and neutrophil count decreased (1%). One fatal adverse reaction occurred in 1/248 (0.4%) of patients, which was due to acute myocardial infarction, and occurred prior to the start of HER2 targeted treatment with PHESGO.Adverse reactions resulting in permanent discontinuation of any study drug occurred in 8% of patients on the PHESGO arm. Adverse reactions which resulted in permanent discontinuation of PHESGO were ejection fraction decreased (1.2%), cardiac failure (0.8%), and pneumonitis/pulmonary fibrosis (0.8%).Dosage interruptions due to an adverse reaction occurred in 40% of patients who received PHESGO. Adverse reactions which required dosage interruption in 1% of patients who received PHESGO included neutropenia (8%), neutrophil count decreased (4%), and diarrhea (7%).Tables summarizes the adverse reactions in FeDeriCa.Table 3: Adverse Reactions (>= 5%) in Patients Who Received PHESGO in FeDeriCaBody System/Adverse ReactionsPHESGO(n=248)Intravenous pertuzumab plus intravenous or subcutaneous trastuzumab(n=252)All Grades%Grades - 4%All Grades%Grades - 4%Skin and subcutaneous tissue disordersAlopecia770710.4Dry skin150.4130Rash160.4210Nail discoloration9060Erythema9050Dermatitis7060Nail disorder7070.4Palmar-plantar erythrodysesthesia syndrome60.850.4Gastrointestinal disordersNausea602611.6Diarrhea607574.8Stomatitis250.8240.8Constipation220210Vomiting200.8191.2Dyspepsia140120Hemorrhoids904.00Abdominal pain upper8060Abdominal pain90.460Blood and lymphatic system disordersAnemia361.6434.4Neutropenia22142714Leukopenia92.4142Febrile neutropenia7766General disorders and administration site conditionsAsthenia310.4322.4Fatigue292242Mucosal inflammation150.8201.2Injection site reaction1500.80Pyrexia130160.4Edema peripheral80100Malaise7060.4Influenza-like illness503.60Nervous system disordersDysgeusia170140Peripheral sensory neuropathy160.8140.4Headache170250.8Neuropathy peripheral120.4152Paresthesia100.880Dizziness130110InvestigationsWeight decreased110.860.8Musculoskeletal and connective tissue disordersMyalgia250.4190.4Arthralgia240280.4Back pain1004.80Bone pain7050Pain in extremity6080Muscle spasms6070Musculoskeletal pain60.480Respiratory, thoracic and mediastinal disorderCough150.4130Epistaxis120140.4Dyspnea101.250Rhinorrhea704.40Infections and infestationsUpper respiratory tract infection11080.8Nasopharyngitis90100Paronychia70.43.60Urinary tract infection70.450Injury, poisoning and procedural complicationsProcedural pain130100Radiation skin injury190.4190.4Infusion related reaction3.60150.8Metabolism and nutrition disordersDecreased appetite170.8190.4Hypokalemia71.680Psychiatric disordersInsomnia170130.4Eye disordersLacrimation increased50.460Dry eye50.43.20Vascular disordersHot flush120130Clinically relevant adverse reactions in 5% of patients who received PHESGO include ejection fraction decreased (3.6%) and pruritus (3.2%).Table summarizes the laboratory abnormalities in FeDeriCa.Table 4: Select Laboratory Abnormalities (>=5%) that Worsened from Baseline in Patients Who Received PHESGO in FeDeriCa The denominator used to calculate the rate varied from 163 to 252 based on the number of patients with baseline value and at least one post-treatment value. Laboratory AbnormalityPHESGO(n=248)Intravenous pertuzumab plus intravenous or subcutaneous trastuzumab(n=252)All Grades%Grades - 4%All Grades%Grades - 4%HematologyHemoglobin (low)902.8924.4Lymphocytes, Absolute (low)89378836Total Leukocyte Count (low)82257825Neutrophils, Total Absolute (low)68306733Platelet (low)270280.4ChemistryCreatinine (high)840870.4Alanine aminotransferase (high)581.6682.4Aspartate aminotransferase (high)500.8580.8Potassium (low)175.2172.8Albumin (low)160200.4Potassium (high)131.290Sodium (low)130.4101.6Bilirubin (high)9090.4Glucose (low)9090.4Sodium (high)70.8100.8. Other Clinical Trials ExperienceThe safety of the addition of intravenous pertuzumab to trastuzumab in combination with chemotherapy has been established in studies conducted in patients with HER2 overexpressing early breast cancer. The following adverse reactions have been reported following administration of intravenous pertuzumab and trastuzumab: diarrhea, alopecia, nausea, fatigue, neutropenia, vomiting, peripheral neuropathy, constipation, anemia, asthenia, mucosal inflammation, myalgia, and thrombocytopenia. Refer to the Prescribing Information for pertuzumab for more information.The safety of intravenous pertuzumab, trastuzumab and docetaxel has been established in patients with HER2 overexpressing metastatic breast cancer. The following adverse reactions have been reported following administration of intravenous pertuzumab and trastuzumab: diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. Refer to the Prescribing Information for pertuzumab for more information.. 6.2 Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity with PHESGO. 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 PHESGO and intravenous pertuzumab and trastuzumab in the FeDeriCa study with the incidence of antibodies in other studies or to other products may be misleading.In the FeDeriCa study, the incidence of treatment-emergent anti-pertuzumab and anti-trastuzumab antibodies in most patients completing 1-4 cycles of therapy was 3% (7/237) and 0.4% (1/237), respectively, in patients treated with intravenous pertuzumab and trastuzumab. The incidence of treatment-emergent anti-pertuzumab, anti-trastuzumab, and anti-recombinant human hyaluronidase PH20 antibodies in most patients completing 1-4 cycles of therapy was 4.8% (11/231), 0.9% (2/232), and 0.9% (2/225), respectively, in patients treated with PHESGO. Among patients who tested positive to anti-pertuzumab antibodies, neutralizing anti-pertuzumab antibodies were detected in one patient treated with intravenous pertuzumab and trastuzumab and in one patient treated with PHESGO. Among patients who tested positive to anti-trastuzumab antibodies, neutralizing anti-trastuzumab antibodies were detected in one patient treated with PHESGO.The clinical relevance of the development of anti-pertuzumab, anti-trastuzumab or anti-recombinant human hyaluronidase PH20 antibodies after treatment with PHESGO is unknown.. 6.3 Postmarketing Experience. The following adverse reactions have been identified with the use of intravenous pertuzumab and trastuzumab. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.GlomerulopathyImmune thrombocytopeniaTumor lysis syndrome (TLS): Patients with significant tumor burden (e.g. bulky metastases) may be at higher risk. Patients could present with hyperuricemia, hyperphosphatemia, and acute renal failure which may represent possible TLS. Providers should consider additional monitoring and/or treatment as clinically indicated.. Glomerulopathy. Immune thrombocytopenia. Tumor lysis syndrome (TLS): Patients with significant tumor burden (e.g. bulky metastases) may be at higher risk. Patients could present with hyperuricemia, hyperphosphatemia, and acute renal failure which may represent possible TLS. Providers should consider additional monitoring and/or treatment as clinically indicated.

BOXED WARNING SECTION.

WARNING: CARDIOMYOPATHY, EMBRYO-FETAL TOXICITY, and PULMONARY TOXICITY. WARNING: CARDIOMYOPATHY, EMBRYO-FETAL TOXICITY, and PULMONARY TOXICITYSee full prescribing information for complete boxed warning.Cardiomyopathy: PHESGO administration can result in subclinical and clinical cardiac failure manifesting as CHF, and decreased LVEF, with greatest risk when administered concurrently with anthracyclines. Evaluate cardiac function prior to and during treatment. Discontinue PHESGO for cardiomyopathy. (2.3, 5.1)Embryo-fetal Toxicity: Exposure to PHESGO 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)Pulmonary Toxicity: Discontinue PHESGO for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome. (5.3). CardiomyopathyPHESGO 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 [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].. Embryo-fetal ToxicityExposure 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 [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1), (8.3)]. Pulmonary ToxicityPHESGO 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 [see Warnings and Precautions (5.3)].

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. PHESGO contains pertuzumab, trastuzumab, and hyaluronidase.. PertuzumabStudies have not been performed to evaluate the carcinogenicity or mutagenic potential of pertuzumab. No specific fertility studies in animals have been performed to evaluate the effect of pertuzumab.No adverse effects on male and female reproductive organs were observed in repeat-dose toxicity studies of up to six months duration in cynomolgus monkeys.. TrastuzumabTrastuzumab has not been tested for carcinogenicity potential.No evidence of mutagenic activity was observed when trastuzumab was tested in the standard Ames bacterial and human peripheral blood lymphocyte mutagenicity assays at concentrations of up to 5000 mcg/mL. In an in vivo micronucleus assay, no evidence of chromosomal damage to mouse bone marrow cells was observed following bolus intravenous doses of up to 118 mg/kg of trastuzumab.A fertility study was conducted in female cynomolgus monkeys at doses up to 25 times the weekly recommended human dose of mg/kg of intravenous trastuzumab and has revealed no evidence of impaired fertility, as measured by menstrual cycle duration and female sex hormone levels.. HyaluronidaseHyaluronidases are found in most tissues of the body. Long-term animal studies have not been performed to assess the carcinogenic or mutagenic potential of hyaluronidase. In addition, when subcutaneous hyaluronidase (recombinant human) was administered to cynomolgus monkeys for 39 weeks at dose levels up to 220,000 U/kg, which is >223 and 335, based on loading and maintenance doses, respectively, times higher than the human dose, no evidence of toxicity to the male or female reproductive system was found through periodic monitoring of in-life parameters, e.g., semen analyses, hormone levels, menstrual cycles, and also from gross pathology, histopathology and organ weight data.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Pertuzumab targets the extracellular dimerization domain (subdomain II) of HER2 and, thereby, blocks ligand-dependent heterodimerization of HER2 with other HER family members, including EGFR, HER3 and HER4. As result, pertuzumab inhibits ligand-initiated intracellular signaling through two major signaling pathways, mitogen-activated protein (MAP) kinase and phosphoinositide 3-kinase (PI3K). Inhibition of these signaling pathways can result in cell growth arrest and apoptosis, respectively.Trastuzumab binds to subdomain IV of the extracellular domain of the HER2 protein to inhibit the ligand-independent, HER2 mediated cell proliferation and PI3K signaling pathway in human tumor cells that overexpress HER2.Both pertuzumab and trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) have been shown to be preferentially exerted on HER2 overexpressing cancer cells compared with cancer cells that do not overexpress HER2.While pertuzumab alone inhibited the proliferation of human tumor cells, the combination of pertuzumab and trastuzumab augmented anti-tumor activity in HER2-overexpressing xenograft models.Hyaluronan is polysaccharide found in the extracellular matrix of the subcutaneous tissue. It is depolymerized by the naturally occurring enzyme hyaluronidase. Unlike the stable structural components of the interstitial matrix, hyaluronan has half-life of approximately 0.5 days. Hyaluronidase increases permeability of the subcutaneous tissue by depolymerizing hyaluronan. In the doses administered, hyaluronidase in PHESGO acts transiently and locally.The effects of hyaluronidase are reversible and permeability of the subcutaneous tissue is restored within 24 to 48 hours.Hyaluronidase has been shown to increase the absorption rate of trastuzumab product into the systemic circulation when given in the subcutis of Gottingen Minipigs.. 12.2 Pharmacodynamics. Cardiac ElectrophysiologyThe effect of intravenous pertuzumab with an initial dose of 840 mg followed by maintenance dose of 420 mg every three weeks on QTc interval was evaluated in subgroup of 20 patients with HER2-positive breast cancer (NCT00567190). No large changes in the mean QT interval (i.e., greater than 20 ms) from placebo based on Fridericia correction method were detected in the trial. small increase in the mean QTc interval (i.e., less than 10 ms) cannot be excluded because of the limitations of the trial design.The effects of trastuzumab on electrocardiographic (ECG) endpoints, including QTc interval duration, were evaluated in patients with HER2 positive solid tumors. Trastuzumab had no clinically relevant effect on the QTc interval duration and there was no apparent relationship between serum trastuzumab concentrations and change in QTcF interval duration in patients with HER2 positive solid tumors.. 12.3 Pharmacokinetics. The pharmacokinetics (PK) of pertuzumab and trastuzumab was characterized in the FeDeriCa study following subcutaneous administration of PHESGO (1200 mg pertuzumab/600 mg trastuzumab initial dose followed by 600 mg pertuzumab/600 mg trastuzumab every weeks) and intravenous administration of pertuzumab and trastuzumab (840 mg pertuzumab/8 mg/kg trastuzumab initial dose followed by 420 mg pertuzumab/6 mg/kg trastuzumab every weeks). The pharmacokinetic parameters of pertuzumab and trastuzumab are described in Table 5. Trastuzumab is estimated to reach concentrations that are 1 mcg/mL by months in at least 95% patients.Pertuzumab Cycle Ctrough (i.e., pre-dose cycle 8) showed non-inferiority of pertuzumab within PHESGO (88.7 mcg/mL) to intravenous pertuzumab (72.4 mcg/mL), with geometric mean ratio of 1.22 (90% CI: 1.14-1.31). Trastuzumab Cycle Ctrough showed non-inferiority of trastuzumab within PHESGO (58.7 mcg/mL) to intravenous trastuzumab (44.1 mcg/mL), with geometric mean ratio of 1.33 (90% CI: 1.24-1.43). [see Clinical Studies (14.2)].A population PK analysis reported that, following subcutaneous administration of PHESGO, the mean Cycle Cmax and AUC0-21 days of pertuzumab were 34% lower and 5% higher, respectively, than that following intravenous administration of pertuzumab. The mean Cycle Cmax and AUC0-21 days of trastuzumab were 31% lower and 9% higher, respectively, than that following intravenous administration of trastuzumab.Table 5: PK Parameters of Pertuzumab and Trastuzumab Following Subcutaneous Administration of PHESGO Parameters represented as population mean (intersubject variability) unless otherwise specified PertuzumabParameters obtained from FeDeriCa population PK model unless otherwise specified TrastuzumabParameters obtained from subcutaneous trastuzumab population PK model unless otherwise specified Absorption Absolute Bioavailability0.7 (18)0.8 (13) First-order absorption rate, ka (day-1)0.4 (8) Residual standard error 0.4 (2.9) Tmax (day)4 (1 21) Median (range) values from FeDeriCa study (1- 22) Distribution Volume of Central Compartment (L)2.8 (35)2.9 (19)Elimination Linear Elimination Clearance (L/day)0.2 (24)0.1 (30) Non-linear Elimination Vmax (mg/day)N/A12 (20) Non-linear Elimination Km (mg/L)N/A34 (39). Specific PopulationsLean body weight and baseline serum albumin level were included as significant covariates in the pertuzumab population PK model. However, no dose adjustments based on body weight or baseline albumin level are needed, as the exposure changes are not considered clinically relevant.Body weight showed statistically significant influence on trastuzumab PK. In patients with body weight 58 kg, mean Cycle AUC0-21 days of trastuzumab was about 34% higher after PHESGO than after intravenous trastuzumab treatment, whereas in the highest BW group (> 77 kg) Cycle AUC0-21 days was 24% lower after PHESGO than after intravenous trastuzumab treatment. However, no body weight-based dose adjustments are needed, as the exposure changes are not considered clinically relevant.No clinically significant differences in the pharmacokinetics of pertuzumab and trastuzumab were observed based on age (25 to 80 years), race (Asian and non-Asian) and renal impairment (creatinine clearance determined by Cockcroft-Gault 30 mL/min or greater). The effects of hepatic impairment on the pharmacokinetics of pertuzumab and trastuzumab are unknown.. Drug Interaction StudiesThere have been no formal drug interaction studies performed with PHESGO in humans. Clinically significant interactions among pertuzumab, trastuzumab, and concomitant medications used in clinical trials have not been observed.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Neoadjuvant and Adjuvant Treatment of Breast Cancer. The effectiveness of PHESGO for use in combination with chemotherapy has been established for the treatment of patients with HER2-positive early breast cancer. Use of PHESGO for this indication is supported by evidence from adequate and well-controlled studies conducted with intravenous pertuzumab and intravenous trastuzumab administered in combination with chemotherapy in adults with HER2-overexpressing early breast cancer (NCT00545688, NCT00976989, NCT02132949, NCT01358877) and additional pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety profiles between PHESGO and intravenous pertuzumab and intravenous trastuzumab in FeDeriCa [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. FeDeriCaThe FeDeriCa study (NCT03493854) was an open-label, multicenter, randomized study conducted in 500 patients with operable or locally advanced (including inflammatory) HER2-positive breast cancer with tumor size 2 cm or node-positive. HER2 overexpression was defined as IHC 3+ in 10% of immunoreactive cells or HER2 gene amplification by ISH (ratio of HER2 gene signals to centromere 17 signals >= 2.0) using an FDA-approved test. Patients were randomized to receive cycles of neoadjuvant chemotherapy with concurrent administration of cycles of either PHESGO or intravenous pertuzumab and trastuzumab during cycles 5-8, followed by surgery. Investigators selected one of two of the following neoadjuvant chemotherapy regimens for individual patients:4 cycles of doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) every weeks followed by paclitaxel (80 mg/m2) weekly for 12 weeks4 cycles of doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) every weeks followed by cycles of docetaxel (75 mg/m2 for the first cycle and then 100 mg/m2 at subsequent cycles at the investigators discretion) every weeksFollowing surgery, patients continued therapy with PHESGO or intravenous pertuzumab and trastuzumab as treated prior to surgery, for an additional 14 cycles, to complete 18 cycles of anti-HER2 therapy. Patients also received adjuvant radiotherapy and endocrine therapy as per investigators discretion. In adjuvant period, substitution of intravenous trastuzumab for subcutaneous trastuzumab was permitted at investigator discretion. Patients received HER2-targeted therapy every weeks according to Table as follows:Table 6: Dosing and Administration of PHESGO, Intravenous Pertuzumab, Intravenous Trastuzumab, and Subcutaneous TrastuzumabMedicationAdministrationDoseInitialMaintenancePHESGOSubcutaneously1200 mg/600 mg600mg/600 mgPertuzumabIntravenously840 mg420 mgTrastuzumabIntravenously8 mg/kg6 mg/kgTrastuzumab-oyskSubcutaneouslyIn adjuvant period substitution of intravenous trastuzumab for subcutaneous trastuzumab was permitted at investigator discretion 600 mgFeDeriCa was designed to demonstrate non-inferiority of the Cycle (i.e., pre-dose Cycle 8) pertuzumab serum Ctrough from PHESGO pertuzumab to the intravenous pertuzumab (primary endpoint) [see Clinical Pharmacology 12.3]. Secondary endpoints included Cycle serum trastuzumab Ctrough, efficacy (pathological complete response [pCR], defined as the absence of invasive neoplastic cells in the breast and in the axillary lymph nodes), and safety. The median age was 51 years (range: 25-81), and the majority of patients were White (66%). The majority of patients had hormone receptor-positive disease (61%) or node-positive disease (58%).The pCR rate was 59.7% (95% CI: 53.3, 65.8) in the PHESGO arm and 59.5% (95% CI: 53.2, 65.6) in the intravenous pertuzumab and trastuzumab arm.Table 7: Summary of Pathological Complete Response (pCR) (FeDeriCa)PHESGOn=248Intravenous pertuzumab trastuzumabn=252pCR (ypT0/is, ypN0)148 (59.7%)150 (59.5%) Exact 95% CI for pCR RateConfidence interval for one sample binomial using Pearson-Clopper method (53.3%, 65.8%)(53.2%, 65.6%) Difference in pCR rate (SC minus IV arm)0.15% 95% CI for the difference in pCRHauck-Anderson continuity correction has been used in this calculation rate(-8.7%; 9.0%). cycles of doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) every weeks followed by paclitaxel (80 mg/m2) weekly for 12 weeks. cycles of doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) every weeks followed by cycles of docetaxel (75 mg/m2 for the first cycle and then 100 mg/m2 at subsequent cycles at the investigators discretion) every weeks. 14.2 Metastatic Breast Cancer. The effectiveness of PHESGO for use in combination with docetaxel has been established for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. Use of PHESGO for this indication is supported by evidence from adequate and well-controlled studies conducted with intravenous pertuzumab and intravenous trastuzumab administered in combination with chemotherapy in adults with HER2-overexpressing metastatic breast cancer (NCT00567190) and additional pharmacokinetic and safety data that demonstrated comparable pharmacokinetics and safety profiles between PHESGO and intravenous pertuzumab and intravenous trastuzumab in FeDeriCa [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)]. 14.3 Patient Experience. The PHranceSCa study (NCT03674112) was randomized, multi-center, open-label cross-over trial conducted in 160 patients with HER2-positive breast cancer undergoing adjuvant treatment. All patients completed neoadjuvant treatment with pertuzumab, trastuzumab and chemotherapy and had surgery before randomization. Following randomization, 80 patients in arm received cycles of intravenous pertuzumab and trastuzumab followed by cycles of PHESGO and 80 patients in arm received cycles of PHESGO followed by cycles of intravenous pertuzumab and trastuzumab. All patients received 18 total cycles of HER2-targeted therapy. After Cycle 6, 136 out of 160 patients (85%) reported preferring subcutaneous administration of PHESGO over intravenous pertuzumab and trastuzumab and the most common reason was that administration required less time in the clinic. After Cycle 6, 22 out of 160 patients (14%) reported preferring intravenous pertuzumab and trastuzumab over PHESGO and the most common reason was feels more comfortable during administration. Two out of 160 patients (1%) had no preference for the route of administration. All 160 patients (100%) completed the preference questionnaire.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. Neoadjuvant and Adjuvant Treatment of Breast CancerThe safety of PHESGO was evaluated in an open-label, multicenter, randomized study (FeDeriCa) conducted in 500 patients with HER2 overexpressing early breast cancer [see Clinical Studies (14.2)].Patients were randomized to receive either PHESGO (1,200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase/15 mL) followed every weeks by maintenance dose of 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase/10 mL or the recommended dosages for intravenous pertuzumab and intravenous trastuzumab. Patients were randomized to receive cycles of neoadjuvant chemotherapy with concurrent administration of cycles of either PHESGO or intravenous pertuzumab and trastuzumab during cycles 5-8, followed by surgery. Following surgery, patients continued therapy with PHESGO or intravenous pertuzumab and trastuzumab (intravenous or subcutaneously administered) as treated prior to surgery, for an additional 14 cycles, to complete 18 cycles. The median duration of treatment for PHESGO was 24 weeks (range: 0-42 weeks).Serious adverse reactions occurred in 16% of patients who received PHESGO. Serious adverse reactions in 1% of patients included febrile neutropenia (4%), neutropenic sepsis (1%), and neutrophil count decreased (1%). One fatal adverse reaction occurred in 1/248 (0.4%) of patients, which was due to acute myocardial infarction, and occurred prior to the start of HER2 targeted treatment with PHESGO.Adverse reactions resulting in permanent discontinuation of any study drug occurred in 8% of patients on the PHESGO arm. Adverse reactions which resulted in permanent discontinuation of PHESGO were ejection fraction decreased (1.2%), cardiac failure (0.8%), and pneumonitis/pulmonary fibrosis (0.8%).Dosage interruptions due to an adverse reaction occurred in 40% of patients who received PHESGO. Adverse reactions which required dosage interruption in 1% of patients who received PHESGO included neutropenia (8%), neutrophil count decreased (4%), and diarrhea (7%).Tables summarizes the adverse reactions in FeDeriCa.Table 3: Adverse Reactions (>= 5%) in Patients Who Received PHESGO in FeDeriCaBody System/Adverse ReactionsPHESGO(n=248)Intravenous pertuzumab plus intravenous or subcutaneous trastuzumab(n=252)All Grades%Grades - 4%All Grades%Grades - 4%Skin and subcutaneous tissue disordersAlopecia770710.4Dry skin150.4130Rash160.4210Nail discoloration9060Erythema9050Dermatitis7060Nail disorder7070.4Palmar-plantar erythrodysesthesia syndrome60.850.4Gastrointestinal disordersNausea602611.6Diarrhea607574.8Stomatitis250.8240.8Constipation220210Vomiting200.8191.2Dyspepsia140120Hemorrhoids904.00Abdominal pain upper8060Abdominal pain90.460Blood and lymphatic system disordersAnemia361.6434.4Neutropenia22142714Leukopenia92.4142Febrile neutropenia7766General disorders and administration site conditionsAsthenia310.4322.4Fatigue292242Mucosal inflammation150.8201.2Injection site reaction1500.80Pyrexia130160.4Edema peripheral80100Malaise7060.4Influenza-like illness503.60Nervous system disordersDysgeusia170140Peripheral sensory neuropathy160.8140.4Headache170250.8Neuropathy peripheral120.4152Paresthesia100.880Dizziness130110InvestigationsWeight decreased110.860.8Musculoskeletal and connective tissue disordersMyalgia250.4190.4Arthralgia240280.4Back pain1004.80Bone pain7050Pain in extremity6080Muscle spasms6070Musculoskeletal pain60.480Respiratory, thoracic and mediastinal disorderCough150.4130Epistaxis120140.4Dyspnea101.250Rhinorrhea704.40Infections and infestationsUpper respiratory tract infection11080.8Nasopharyngitis90100Paronychia70.43.60Urinary tract infection70.450Injury, poisoning and procedural complicationsProcedural pain130100Radiation skin injury190.4190.4Infusion related reaction3.60150.8Metabolism and nutrition disordersDecreased appetite170.8190.4Hypokalemia71.680Psychiatric disordersInsomnia170130.4Eye disordersLacrimation increased50.460Dry eye50.43.20Vascular disordersHot flush120130Clinically relevant adverse reactions in 5% of patients who received PHESGO include ejection fraction decreased (3.6%) and pruritus (3.2%).Table summarizes the laboratory abnormalities in FeDeriCa.Table 4: Select Laboratory Abnormalities (>=5%) that Worsened from Baseline in Patients Who Received PHESGO in FeDeriCa The denominator used to calculate the rate varied from 163 to 252 based on the number of patients with baseline value and at least one post-treatment value. Laboratory AbnormalityPHESGO(n=248)Intravenous pertuzumab plus intravenous or subcutaneous trastuzumab(n=252)All Grades%Grades - 4%All Grades%Grades - 4%HematologyHemoglobin (low)902.8924.4Lymphocytes, Absolute (low)89378836Total Leukocyte Count (low)82257825Neutrophils, Total Absolute (low)68306733Platelet (low)270280.4ChemistryCreatinine (high)840870.4Alanine aminotransferase (high)581.6682.4Aspartate aminotransferase (high)500.8580.8Potassium (low)175.2172.8Albumin (low)160200.4Potassium (high)131.290Sodium (low)130.4101.6Bilirubin (high)9090.4Glucose (low)9090.4Sodium (high)70.8100.8. Other Clinical Trials ExperienceThe safety of the addition of intravenous pertuzumab to trastuzumab in combination with chemotherapy has been established in studies conducted in patients with HER2 overexpressing early breast cancer. The following adverse reactions have been reported following administration of intravenous pertuzumab and trastuzumab: diarrhea, alopecia, nausea, fatigue, neutropenia, vomiting, peripheral neuropathy, constipation, anemia, asthenia, mucosal inflammation, myalgia, and thrombocytopenia. Refer to the Prescribing Information for pertuzumab for more information.The safety of intravenous pertuzumab, trastuzumab and docetaxel has been established in patients with HER2 overexpressing metastatic breast cancer. The following adverse reactions have been reported following administration of intravenous pertuzumab and trastuzumab: diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. Refer to the Prescribing Information for pertuzumab for more information.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Injection: PHESGO is clear to opalescent, and colorless to slightly brownish solution provided as:1,200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase/15 mL (80 mg, 40 mg, and 2,000 units/mL) of solution in single-dose vial600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase/10 mL (60 mg, 60 mg, and 2,000 units/mL) of solution in single-dose vial. 1,200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase/15 mL (80 mg, 40 mg, and 2,000 units/mL) of solution in single-dose vial. 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase/10 mL (60 mg, 60 mg, and 2,000 units/mL) of solution in single-dose vial. Injection:1,200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase/15 mL (80 mg, 40 mg, and 2,000 units/mL) of solution in single-dose vial. (3)600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase/10 mL (60 mg, 60 mg, and 2,000 units/mL) of solution in single-dose vial. (3). 1,200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase/15 mL (80 mg, 40 mg, and 2,000 units/mL) of solution in single-dose vial. (3). 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase/10 mL (60 mg, 60 mg, and 2,000 units/mL) of solution in single-dose vial. (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Patients who receive anthracycline after stopping PHESGO may be at increased risk of cardiac dysfunction because of PHESGOs long washout period [see Clinical Pharmacology (12.3)]. If possible, avoid anthracycline-based therapy for up to months after stopping PHESGO. If anthracyclines are used, carefully monitor the patients cardiac function.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. PHESGO can cause embryo-fetal harm when administered during pregnancy.. Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to the initiation of PHESGO.. Contraception. FemalesAdvise females of reproductive potential to use effective contraception during treatment and for months following the last dose of PHESGO [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)].

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the total number of patients in the FeDeriCa study (n=500) treated with PHESGO, 11% were 65 and over, while 1.6% were 75 and over. Clinical studies of PHESGO did not include sufficient numbers of patients age 65 years and older to determine whether they respond differently from younger patients.In the intravenous trastuzumab trials, the risk of cardiac dysfunction was increased in geriatric patients as compared to younger patients, in both those receiving treatment for adjuvant therapy or metastatic disease. Other differences in safety or effectiveness were not observed between elderly patients and younger patients. In the intravenous pertuzumab in combination with trastuzumab trials, the risk of decreased appetite, anemia, weight decreased, asthenia, dysgeusia, neuropathy peripheral and hypomagnesemia was increased in patients 65 years of age and older compared to patients less than 65 years of age.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1How Supplied. PHESGO (pertuzumab, trastuzumab, and hyaluronidase-zzxf) injection is sterile, preservative-free, clear to opalescent, and colorless to slightly brownish solution in single-dose vials for subcutaneous administration supplied as each carton containing one single-dose vial:1,200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase/15 mL (80 mg, 40 mg, and 2,000 units/mL) (NDC 50242-245-01).600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase/10 mL (60 mg, 60 mg, 2,000 units/mL) (NDC 50242-260-01).. 1,200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase/15 mL (80 mg, 40 mg, and 2,000 units/mL) (NDC 50242-245-01).. 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase/10 mL (60 mg, 60 mg, 2,000 units/mL) (NDC 50242-260-01).. 16.2Storage and Handling. Store PHESGO vials in the refrigerator at 2C to 8C (36F to 46F) in the original carton to protect from light.Do not freeze. Do not shake.

IMMUNOGENICITY.

6.2 Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity with PHESGO. 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 PHESGO and intravenous pertuzumab and trastuzumab in the FeDeriCa study with the incidence of antibodies in other studies or to other products may be misleading.In the FeDeriCa study, the incidence of treatment-emergent anti-pertuzumab and anti-trastuzumab antibodies in most patients completing 1-4 cycles of therapy was 3% (7/237) and 0.4% (1/237), respectively, in patients treated with intravenous pertuzumab and trastuzumab. The incidence of treatment-emergent anti-pertuzumab, anti-trastuzumab, and anti-recombinant human hyaluronidase PH20 antibodies in most patients completing 1-4 cycles of therapy was 4.8% (11/231), 0.9% (2/232), and 0.9% (2/225), respectively, in patients treated with PHESGO. Among patients who tested positive to anti-pertuzumab antibodies, neutralizing anti-pertuzumab antibodies were detected in one patient treated with intravenous pertuzumab and trastuzumab and in one patient treated with PHESGO. Among patients who tested positive to anti-trastuzumab antibodies, neutralizing anti-trastuzumab antibodies were detected in one patient treated with PHESGO.The clinical relevance of the development of anti-pertuzumab, anti-trastuzumab or anti-recombinant human hyaluronidase PH20 antibodies after treatment with PHESGO is unknown.

INDICATIONS & USAGE SECTION.

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

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere is no information regarding the presence of pertuzumab, trastuzumab or hyaluronidase 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. Trastuzumab was present in the milk of lactating cynomolgus monkeys but not associated with neonatal toxicity (see Data). Consider the developmental and health benefits of breast feeding along with the mothers clinical need for PHESGO treatment and any potential adverse effects on the breastfed child from PHESGO 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 months [see Clinical Pharmacology (12.3)].. DataIn lactating cynomolgus monkeys, trastuzumab was present in breast milk at about 0.3% of maternal serum concentrations after pre- (beginning Gestation Day 120) and post-partum (through Post-partum Day 28) doses of 25 mg/kg administered twice weekly (25 times the recommended weekly human dose of mg/kg of intravenous trastuzumab). Infant monkeys with detectable serum levels of trastuzumab did not exhibit any adverse effects on growth or development from birth to month of age.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Pertuzumab targets the extracellular dimerization domain (subdomain II) of HER2 and, thereby, blocks ligand-dependent heterodimerization of HER2 with other HER family members, including EGFR, HER3 and HER4. As result, pertuzumab inhibits ligand-initiated intracellular signaling through two major signaling pathways, mitogen-activated protein (MAP) kinase and phosphoinositide 3-kinase (PI3K). Inhibition of these signaling pathways can result in cell growth arrest and apoptosis, respectively.Trastuzumab binds to subdomain IV of the extracellular domain of the HER2 protein to inhibit the ligand-independent, HER2 mediated cell proliferation and PI3K signaling pathway in human tumor cells that overexpress HER2.Both pertuzumab and trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) have been shown to be preferentially exerted on HER2 overexpressing cancer cells compared with cancer cells that do not overexpress HER2.While pertuzumab alone inhibited the proliferation of human tumor cells, the combination of pertuzumab and trastuzumab augmented anti-tumor activity in HER2-overexpressing xenograft models.Hyaluronan is polysaccharide found in the extracellular matrix of the subcutaneous tissue. It is depolymerized by the naturally occurring enzyme hyaluronidase. Unlike the stable structural components of the interstitial matrix, hyaluronan has half-life of approximately 0.5 days. Hyaluronidase increases permeability of the subcutaneous tissue by depolymerizing hyaluronan. In the doses administered, hyaluronidase in PHESGO acts transiently and locally.The effects of hyaluronidase are reversible and permeability of the subcutaneous tissue is restored within 24 to 48 hours.Hyaluronidase has been shown to increase the absorption rate of trastuzumab product into the systemic circulation when given in the subcutis of Gottingen Minipigs.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. PHESGO contains pertuzumab, trastuzumab, and hyaluronidase.. PertuzumabStudies have not been performed to evaluate the carcinogenicity or mutagenic potential of pertuzumab. No specific fertility studies in animals have been performed to evaluate the effect of pertuzumab.No adverse effects on male and female reproductive organs were observed in repeat-dose toxicity studies of up to six months duration in cynomolgus monkeys.. TrastuzumabTrastuzumab has not been tested for carcinogenicity potential.No evidence of mutagenic activity was observed when trastuzumab was tested in the standard Ames bacterial and human peripheral blood lymphocyte mutagenicity assays at concentrations of up to 5000 mcg/mL. In an in vivo micronucleus assay, no evidence of chromosomal damage to mouse bone marrow cells was observed following bolus intravenous doses of up to 118 mg/kg of trastuzumab.A fertility study was conducted in female cynomolgus monkeys at doses up to 25 times the weekly recommended human dose of mg/kg of intravenous trastuzumab and has revealed no evidence of impaired fertility, as measured by menstrual cycle duration and female sex hormone levels.. HyaluronidaseHyaluronidases are found in most tissues of the body. Long-term animal studies have not been performed to assess the carcinogenic or mutagenic potential of hyaluronidase. In addition, when subcutaneous hyaluronidase (recombinant human) was administered to cynomolgus monkeys for 39 weeks at dose levels up to 220,000 U/kg, which is >223 and 335, based on loading and maintenance doses, respectively, times higher than the human dose, no evidence of toxicity to the male or female reproductive system was found through periodic monitoring of in-life parameters, e.g., semen analyses, hormone levels, menstrual cycles, and also from gross pathology, histopathology and organ weight data.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 20 mL Vial Carton. NDC 50242-245-01 Phesgo(TM)(pertuzumab, trastuzumab,and hyaluronidase-zzxf)Injection1,200 mg, 600 mg, and30,000 units/15 mL (80 mg, 40 mg, and 2,000 units/mL)For subcutaneous injectionover minutesSingle-Dose VialDiscard Unused Portion1 vial Rx only Genentech10220690. PRINCIPAL DISPLAY PANEL 20 mL Vial Carton.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of PHESGO in pediatric patients have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Cardiac ElectrophysiologyThe effect of intravenous pertuzumab with an initial dose of 840 mg followed by maintenance dose of 420 mg every three weeks on QTc interval was evaluated in subgroup of 20 patients with HER2-positive breast cancer (NCT00567190). No large changes in the mean QT interval (i.e., greater than 20 ms) from placebo based on Fridericia correction method were detected in the trial. small increase in the mean QTc interval (i.e., less than 10 ms) cannot be excluded because of the limitations of the trial design.The effects of trastuzumab on electrocardiographic (ECG) endpoints, including QTc interval duration, were evaluated in patients with HER2 positive solid tumors. Trastuzumab had no clinically relevant effect on the QTc interval duration and there was no apparent relationship between serum trastuzumab concentrations and change in QTcF interval duration in patients with HER2 positive solid tumors.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics (PK) of pertuzumab and trastuzumab was characterized in the FeDeriCa study following subcutaneous administration of PHESGO (1200 mg pertuzumab/600 mg trastuzumab initial dose followed by 600 mg pertuzumab/600 mg trastuzumab every weeks) and intravenous administration of pertuzumab and trastuzumab (840 mg pertuzumab/8 mg/kg trastuzumab initial dose followed by 420 mg pertuzumab/6 mg/kg trastuzumab every weeks). The pharmacokinetic parameters of pertuzumab and trastuzumab are described in Table 5. Trastuzumab is estimated to reach concentrations that are 1 mcg/mL by months in at least 95% patients.Pertuzumab Cycle Ctrough (i.e., pre-dose cycle 8) showed non-inferiority of pertuzumab within PHESGO (88.7 mcg/mL) to intravenous pertuzumab (72.4 mcg/mL), with geometric mean ratio of 1.22 (90% CI: 1.14-1.31). Trastuzumab Cycle Ctrough showed non-inferiority of trastuzumab within PHESGO (58.7 mcg/mL) to intravenous trastuzumab (44.1 mcg/mL), with geometric mean ratio of 1.33 (90% CI: 1.24-1.43). [see Clinical Studies (14.2)].A population PK analysis reported that, following subcutaneous administration of PHESGO, the mean Cycle Cmax and AUC0-21 days of pertuzumab were 34% lower and 5% higher, respectively, than that following intravenous administration of pertuzumab. The mean Cycle Cmax and AUC0-21 days of trastuzumab were 31% lower and 9% higher, respectively, than that following intravenous administration of trastuzumab.Table 5: PK Parameters of Pertuzumab and Trastuzumab Following Subcutaneous Administration of PHESGO Parameters represented as population mean (intersubject variability) unless otherwise specified PertuzumabParameters obtained from FeDeriCa population PK model unless otherwise specified TrastuzumabParameters obtained from subcutaneous trastuzumab population PK model unless otherwise specified Absorption Absolute Bioavailability0.7 (18)0.8 (13) First-order absorption rate, ka (day-1)0.4 (8) Residual standard error 0.4 (2.9) Tmax (day)4 (1 21) Median (range) values from FeDeriCa study (1- 22) Distribution Volume of Central Compartment (L)2.8 (35)2.9 (19)Elimination Linear Elimination Clearance (L/day)0.2 (24)0.1 (30) Non-linear Elimination Vmax (mg/day)N/A12 (20) Non-linear Elimination Km (mg/L)N/A34 (39). Specific PopulationsLean body weight and baseline serum albumin level were included as significant covariates in the pertuzumab population PK model. However, no dose adjustments based on body weight or baseline albumin level are needed, as the exposure changes are not considered clinically relevant.Body weight showed statistically significant influence on trastuzumab PK. In patients with body weight 58 kg, mean Cycle AUC0-21 days of trastuzumab was about 34% higher after PHESGO than after intravenous trastuzumab treatment, whereas in the highest BW group (> 77 kg) Cycle AUC0-21 days was 24% lower after PHESGO than after intravenous trastuzumab treatment. However, no body weight-based dose adjustments are needed, as the exposure changes are not considered clinically relevant.No clinically significant differences in the pharmacokinetics of pertuzumab and trastuzumab were observed based on age (25 to 80 years), race (Asian and non-Asian) and renal impairment (creatinine clearance determined by Cockcroft-Gault 30 mL/min or greater). The effects of hepatic impairment on the pharmacokinetics of pertuzumab and trastuzumab are unknown.. Drug Interaction StudiesThere have been no formal drug interaction studies performed with PHESGO in humans. Clinically significant interactions among pertuzumab, trastuzumab, and concomitant medications used in clinical trials have not been observed.

POSTMARKETING EXPERIENCE SECTION.

6.3 Postmarketing Experience. The following adverse reactions have been identified with the use of intravenous pertuzumab and trastuzumab. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.GlomerulopathyImmune thrombocytopeniaTumor lysis syndrome (TLS): Patients with significant tumor burden (e.g. bulky metastases) may be at higher risk. Patients could present with hyperuricemia, hyperphosphatemia, and acute renal failure which may represent possible TLS. Providers should consider additional monitoring and/or treatment as clinically indicated.. Glomerulopathy. Immune thrombocytopenia. Tumor lysis syndrome (TLS): Patients with significant tumor burden (e.g. bulky metastases) may be at higher risk. Patients could present with hyperuricemia, hyperphosphatemia, and acute renal failure which may represent possible TLS. Providers should consider additional monitoring and/or treatment as clinically indicated.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Pharmacovigilance ProgramThere is pregnancy pharmacovigilance program for PHESGO. If PHESGO is administered during pregnancy, or if patient becomes pregnant while receiving PHESGO or within months following the last dose of PHESGO, health care providers and patients should immediately report PHESGO exposure to Genentech at 1-888-835-2555.. Risk SummaryPHESGO can cause fetal harm when administered to 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 (see Data). 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 fetus. There are clinical considerations if PHESGO is used during pregnancy or within 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 ReactionsMonitor women who received PHESGO during pregnancy or within 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. Human DataIn post-marketing reports, use of trastuzumab during pregnancy resulted in cases of oligohydramnios and of oligohydramnios sequence, manifesting in the fetus as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. These case reports described oligohydramnios in pregnant women who received trastuzumab either alone or in combination with chemotherapy. In some case reports, amniotic fluid index increased after trastuzumab was stopped. In one case, trastuzumab therapy resumed after amniotic index improved and oligohydramnios recurred.. Animal DataPHESGO for subcutaneous injection contains pertuzumab, trastuzumab, and hyaluronidase [see Description (11)].. Pertuzumab: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%. 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.. Trastuzumab:In studies where intravenous trastuzumab was administered to pregnant cynomolgus monkeys during the period of organogenesis at doses up to 25 mg/kg given twice weekly (up to 25 times the recommended weekly human dose of mg/kg), trastuzumab crossed the placental barrier during the early (Gestation Days 20 to 50) and late (Gestation Days 120 to 150) phases of gestation. The resulting concentrations of trastuzumab in fetal serum and amniotic fluid were approximately 33% and 25%, respectively, of those present in the maternal serum but were not associated with adverse developmental effects.. Hyaluronidase:In an embryo-fetal study, mice have been dosed daily by subcutaneous injection during the period of organogenesis with hyaluronidase (recombinant human) at dose levels up to 2,200,000 U/kg, which is >2,400 and 3,600, based on loading and maintenance doses, respectively, times higher than the human dose. The study found no evidence of teratogenicity. Reduced fetal weight and increased numbers of fetal resorptions were observed, with no effects found at daily dose of 360,000 U/kg, which is >400 and 600, based on loading and maintenance doses, respectively, times higher than the human dose.In peri-and post-natal reproduction study, mice have been dosed daily by subcutaneous injection, with hyaluronidase (recombinant human) from implantation through lactation and weaning at dose levels up to 1,100,000 U/kg, which is >1,200 and 1,800, based on loading and maintenance doses, respectively, times higher than the human dose. The study found no adverse effects on sexual maturation, learning and memory or fertility of the offspring.

SPL UNCLASSIFIED SECTION.

CardiomyopathyPHESGO 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 [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].

STORAGE AND HANDLING SECTION.

16.2Storage and Handling. Store PHESGO vials in the refrigerator at 2C to 8C (36F to 46F) in the original carton to protect from light.Do not freeze. Do not shake.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Females and Males of Reproductive Potential: Verify the pregnancy status of females prior to initiation of PHESGO. (8.3). 8.1 Pregnancy. Pregnancy Pharmacovigilance ProgramThere is pregnancy pharmacovigilance program for PHESGO. If PHESGO is administered during pregnancy, or if patient becomes pregnant while receiving PHESGO or within months following the last dose of PHESGO, health care providers and patients should immediately report PHESGO exposure to Genentech at 1-888-835-2555.. Risk SummaryPHESGO can cause fetal harm when administered to 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 (see Data). 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 fetus. There are clinical considerations if PHESGO is used during pregnancy or within 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 ReactionsMonitor women who received PHESGO during pregnancy or within 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. Human DataIn post-marketing reports, use of trastuzumab during pregnancy resulted in cases of oligohydramnios and of oligohydramnios sequence, manifesting in the fetus as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. These case reports described oligohydramnios in pregnant women who received trastuzumab either alone or in combination with chemotherapy. In some case reports, amniotic fluid index increased after trastuzumab was stopped. In one case, trastuzumab therapy resumed after amniotic index improved and oligohydramnios recurred.. Animal DataPHESGO for subcutaneous injection contains pertuzumab, trastuzumab, and hyaluronidase [see Description (11)].. Pertuzumab: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%. 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.. Trastuzumab:In studies where intravenous trastuzumab was administered to pregnant cynomolgus monkeys during the period of organogenesis at doses up to 25 mg/kg given twice weekly (up to 25 times the recommended weekly human dose of mg/kg), trastuzumab crossed the placental barrier during the early (Gestation Days 20 to 50) and late (Gestation Days 120 to 150) phases of gestation. The resulting concentrations of trastuzumab in fetal serum and amniotic fluid were approximately 33% and 25%, respectively, of those present in the maternal serum but were not associated with adverse developmental effects.. Hyaluronidase:In an embryo-fetal study, mice have been dosed daily by subcutaneous injection during the period of organogenesis with hyaluronidase (recombinant human) at dose levels up to 2,200,000 U/kg, which is >2,400 and 3,600, based on loading and maintenance doses, respectively, times higher than the human dose. The study found no evidence of teratogenicity. Reduced fetal weight and increased numbers of fetal resorptions were observed, with no effects found at daily dose of 360,000 U/kg, which is >400 and 600, based on loading and maintenance doses, respectively, times higher than the human dose.In peri-and post-natal reproduction study, mice have been dosed daily by subcutaneous injection, with hyaluronidase (recombinant human) from implantation through lactation and weaning at dose levels up to 1,100,000 U/kg, which is >1,200 and 1,800, based on loading and maintenance doses, respectively, times higher than the human dose. The study found no adverse effects on sexual maturation, learning and memory or fertility of the offspring.. 8.2 Lactation. Risk SummaryThere is no information regarding the presence of pertuzumab, trastuzumab or hyaluronidase 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. Trastuzumab was present in the milk of lactating cynomolgus monkeys but not associated with neonatal toxicity (see Data). Consider the developmental and health benefits of breast feeding along with the mothers clinical need for PHESGO treatment and any potential adverse effects on the breastfed child from PHESGO 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 months [see Clinical Pharmacology (12.3)].. DataIn lactating cynomolgus monkeys, trastuzumab was present in breast milk at about 0.3% of maternal serum concentrations after pre- (beginning Gestation Day 120) and post-partum (through Post-partum Day 28) doses of 25 mg/kg administered twice weekly (25 times the recommended weekly human dose of mg/kg of intravenous trastuzumab). Infant monkeys with detectable serum levels of trastuzumab did not exhibit any adverse effects on growth or development from birth to month of age.. 8.3 Females and Males of Reproductive Potential. PHESGO can cause embryo-fetal harm when administered during pregnancy.. Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to the initiation of PHESGO.. Contraception. FemalesAdvise females of reproductive potential to use effective contraception during treatment and for months following the last dose of PHESGO [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)].. 8.4 Pediatric Use. The safety and effectiveness of PHESGO in pediatric patients have not been established.. 8.5 Geriatric Use. Of the total number of patients in the FeDeriCa study (n=500) treated with PHESGO, 11% were 65 and over, while 1.6% were 75 and over. Clinical studies of PHESGO did not include sufficient numbers of patients age 65 years and older to determine whether they respond differently from younger patients.In the intravenous trastuzumab trials, the risk of cardiac dysfunction was increased in geriatric patients as compared to younger patients, in both those receiving treatment for adjuvant therapy or metastatic disease. Other differences in safety or effectiveness were not observed between elderly patients and younger patients. In the intravenous pertuzumab in combination with trastuzumab trials, the risk of decreased appetite, anemia, weight decreased, asthenia, dysgeusia, neuropathy peripheral and hypomagnesemia was increased in patients 65 years of age and older compared to patients less than 65 years of age.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Exacerbation of Chemotherapy-Induced Neutropenia. (5.4)Hypersensitivity and Administration-Related Reactions (ARRs): Monitor patients for systemic hypersensitivity reactions. Permanently discontinue PHESGO in patients who experience anaphylaxis or severe hypersensitivity reactions. (5.5). Exacerbation of Chemotherapy-Induced Neutropenia. (5.4). Hypersensitivity and Administration-Related Reactions (ARRs): Monitor patients for systemic hypersensitivity reactions. Permanently discontinue PHESGO in patients who experience anaphylaxis or severe hypersensitivity reactions. (5.5). 5.1Cardiomyopathy. PHESGO can cause hypertension, arrhythmias, left ventricular cardiac dysfunction, disabling cardiac failure, cardiomyopathy, and cardiac death [see Boxed Warning: Cardiomyopathy]. PHESGO can cause asymptomatic decline in LVEF.An increased incidence of LVEF decline has been observed in patients treated with intravenous pertuzumab, intravenous trastuzumab, and docetaxel. 4-6 fold increase in the incidence of symptomatic myocardial dysfunction has been reported among patients receiving trastuzumab, with the highest absolute incidence occurring when trastuzumab was administered with an anthracycline.Patients who receive anthracycline after stopping PHESGO may also be at increased risk of cardiac dysfunction [see Drug Interactions (7) and Clinical Pharmacology (12.2)]. Cardiac MonitoringPrior to initiation of PHESGO, conduct thorough cardiac assessment, including history, physical examination, and determination of LVEF by echocardiogram or MUGA scan.During treatment with PHESGO, assess LVEF at regular intervals [see Dosage and Administration (2.4)]. If after repeat assessment within approximately weeks, the LVEF has not improved, has declined further, and/or the patient is symptomatic, permanently discontinue PHESGO.Following completion of PHESGO, continue to monitor for cardiomyopathy and assess LVEF measurements every months for at least years as component of adjuvant therapy.. PHESGOIn the FeDeriCa study, the percentage of patients with at least one cardiac disorder was 22% in the PHESGO arm. The most frequent cardiac adverse reaction in the PHESGO arm was ejection fraction decreased.The incidence of cardiac failure (NYHA Class III/IV) with LVEF decline >= 10% and drop to less than 50% was 0.8% in the PHESGO arm. Confirmed asymptomatic or mildly symptomatic (NYHA Class II) declines in LVEF >= 10% and drop to less than 50% was 1.2% in the PHESGO arm [see Adverse Reactions (6.1)].PHESGO and/or intravenous pertuzumab and trastuzumab have not been studied in patients with pretreatment LVEF value of 55% (EBC) or <50% (MBC); prior history of CHF, conditions that could impair left ventricular function such as uncontrolled hypertension, recent myocardial infarction, serious cardiac arrhythmia requiring treatment or cumulative prior anthracycline exposure to 360 mg/m2 of doxorubicin or its equivalent.. 5.2Embryo-Fetal Toxicity. PHESGO can cause fetal harm when administered to 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 Cmax.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 months prior to conception can result in fetal harm. Advise females of reproductive potential to use effective contraception during treatment and for months following the last dose of PHESGO [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.3)]. 5.3Pulmonary 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.. 5.4Exacerbation 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.. 5.5Hypersensitivity 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 severe or of fatal ARR.In the FeDeriCa study, the incidence of hypersensitivity was 1.2% in the PHESGO arm. Administration-related reactions occurred in 21% of patients who received PHESGO. In the PHESGO arm, the most common administration-related reactions 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 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 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 or hypersensitivity reactions, consider pre-medication with an analgesic, antipyretic, or an antihistamine prior to readministration of PHESGO [see Adverse Reactions (6.1)].PHESGO is contraindicated in patients with known hypersensitivity to pertuzumab, trastuzumab, hyaluronidase or to any of its excipients [see Contraindications (4)].