Herceptin Hylecta

1 INDICATIONS AND USAGE HERCEPTIN HYLECTA is a combination of trastuzumab, a HER2/neu receptor antagonist, and hyaluronidase, an endoglycosidase, indicated in adults for: The treatment of HER2-overexpressing breast cancer. ( 1.1 , 1.2 ) Select patients for therapy based on an FDA-authorized companion diagnostic for trastuzumab. ( 1 , 2.2 ) 1.1 Adjuvant Breast Cancer HERCEPTIN HYLECTA is indicated for adjuvant treatment of adults with HER2 overexpressing node positive or node negative (ER/PR negative or with one high risk feature [see Clinical Studies (14.1) ] ) breast cancer: as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel as part of a treatment regimen with docetaxel and carboplatin as a single agent following multi-modality anthracycline based therapy. Select patients for therapy based on an FDA-authorized companion diagnostic for trastuzumab [see Dosage and Administration (2.2) ] . 1.2 Metastatic Breast Cancer HERCEPTIN HYLECTA is indicated in adults: In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer As a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease. Select patients for therapy based on an FDA-authorized companion diagnostic for trastuzumab [see Dosage and Administration (2.2) ] .

2 DOSAGE AND ADMINISTRATION For subcutaneous use only. HERCEPTIN HYLECTA has different dosage and administration instructions than intravenous trastuzumab products. Do not administer intravenously. ( 2.3 ) Do not substitute HERCEPTIN HYLECTA for or with ado-trastuzumab emtansine. ( 2.3 ) Perform HER2 testing using FDA-authorized tests by laboratories with demonstrated proficiency. ( 1 , 2.2 ) The recommended dose of HERCEPTIN HYLECTA is 600 mg/10,000 units (600 mg trastuzumab and 10,000 units hyaluronidase) administered subcutaneously over approximately 2-5 minutes once every three weeks. ( 2.3 ) 2.1 Evaluation and Testing Before Initiating HERCEPTIN HYLECTA Verify the pregnancy status of females of reproductive potential prior to the initiation of HERCEPTIN HYLECTA [see Use in Specific Populations (8.1 , 8.3) ] . 2.2 Patient Selection Select patients based on HER2 protein overexpression or HER2 gene amplification in tumor specimens [see Indications and Usage (1) and Clinical Studies (14) ] . Assessment of HER2 protein overexpression and HER2 gene amplification should be performed using FDA-authorized tests specific for breast cancer by laboratories with demonstrated proficiency. Information on the FDA-authorized tests for the detection of HER2 protein overexpression and HER2 gene amplification is available at: http://www.fda.gov/CompanionDiagnostics. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. 2.3 Recommended Dosage HERCEPTIN HYLECTA is for subcutaneous use only. HERCEPTIN HYLECTA has different dosage and administration instructions than intravenous trastuzumab products. Do not administer intravenously. Do not substitute HERCEPTIN HYLECTA for or with ado-trastuzumab emtansine. The recommended dose of HERCEPTIN HYLECTA is 600 mg/10,000 units (600 mg trastuzumab and 10,000 units hyaluronidase) administered subcutaneously over approximately 2-5 minutes once every three weeks. No loading dose is required. No dose adjustments for patient body weight or for different concomitant chemotherapy regimens are required. Duration of treatment Patients with adjuvant breast cancer should be treated with HERCEPTIN HYLECTA for 52 weeks or until disease recurrence, whichever occurs first; extending treatment in adjuvant breast cancer beyond one year is not recommended. Patients with metastatic breast cancer (MBC) should be treated with HERCEPTIN HYLECTA until progression of disease. Missed Dose If one dose is missed, it is recommended to administer the next 600 mg/10,000 units dose (i.e. the missed dose) as soon as possible. The interval between subsequent HERCEPTIN HYLECTA doses should not be less than three weeks. 2.4 Dosage Modification for Adverse Reactions Cardiomyopathy [see Boxed Warning , Warnings and Precautions (5.1) ] Assess left ventricular ejection fraction (LVEF) prior to initiation of HERCEPTIN HYLECTA and at regular intervals during treatment. Withhold HERCEPTIN HYLECTA dosing for at least 4 weeks for either of the following: ≥16% absolute decrease in LVEF from pre-treatment values LVEF below institutional limits of normal and ≥10% absolute decrease in LVEF from pretreatment values. HERCEPTIN HYLECTA may be resumed if, within 4–8 weeks, the LVEF returns to normal limits and the absolute decrease from baseline is ≤15%. Permanently discontinue HERCEPTIN HYLECTA for a persistent (>8 weeks) LVEF decline or for suspension of HERCEPTIN HYLECTA dosing on more than 3 occasions for cardiomyopathy. 2.5 Administration and Storage To prevent medication errors, it is important to check the vial labels to ensure that the drug being prepared and administered is HERCEPTIN HYLECTA and not ado-trastuzumab emtansine or intravenous trastuzumab. HERCEPTIN HYLECTA should be administered by a healthcare professional. Parenteral drug products sho…

5 WARNINGS AND PRECAUTIONS Exacerbation of Chemotherapy-Induced Neutropenia. ( 5.4 , 6.1 ) Hypersensitivity and Administration-Related Reactions (ARRs): Severe ARRs, including anaphylaxis, have been reported with HERCEPTIN HYLECTA. Monitor patients for systemic hypersensitivity reactions. Permanently discontinue HERCEPTIN HYLECTA in patients who experience anaphylaxis or severe hypersensitivity reactions. ( 5.5 ) 5.1 Cardiomyopathy HERCEPTIN HYLECTA can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death [see Boxed Warning: Cardiomyopathy ] . HERCEPTIN HYLECTA can also cause asymptomatic decline in LVEF. There is a 4–6 fold increase in the incidence of symptomatic myocardial dysfunction among patients receiving trastuzumab as a single agent or in combination therapy compared with those not receiving trastuzumab. The highest absolute incidence occurs when trastuzumab is administered with an anthracycline. The incidence of symptomatic myocardial dysfunction for intravenous trastuzumab and HERCEPTIN HYLECTA was similar in clinical trials [see Adverse Reactions (6) ]. Withhold HERCEPTIN HYLECTA for ≥16% absolute decrease in LVEF from pre-treatment values or an LVEF value below institutional limits of normal and ≥10% absolute decrease in LVEF from pretreatment values [see Dosage and Administration (2.4) ] . The safety of continuation or resumption of HERCEPTIN HYLECTA in patients with HERCEPTIN HYLECTA induced left ventricular cardiac dysfunction has not been studied. Patients who receive anthracycline after stopping HERCEPTIN HYLECTA may also be at increased risk of cardiac dysfunction [see Drug Interactions (7) and Clinical Pharmacology (12.3) ] . Cardiac Monitoring Conduct thorough cardiac assessment, including history, physical examination, and determination of LVEF by echocardiogram or MUGA scan. The following schedule is recommended: Baseline LVEF measurement immediately prior to initiation of HERCEPTIN HYLECTA LVEF measurements every 3 months during and upon completion of HERCEPTIN HYLECTA Repeat LVEF measurement at 4 week intervals if HERCEPTIN HYLECTA is withheld for significant left ventricular cardiac dysfunction [see Dosage and Administration (2.4) ] LVEF measurements every 6 months for at least 2 years following completion of HERCEPTIN HYLECTA as a component of adjuvant therapy. HERCEPTIN HYLECTA In the HannaH study, the overall percentage of patients with at least one cardiac disorder was similar in both study arms: 15% (44/297) of patients in the HERCEPTIN HYLECTA arm and 14% (42/298) of patients in the intravenous trastuzumab arm. The most frequent cardiac adverse reactions were left ventricular dysfunction [3.4% (10/297) and 4.0% (12/298)], tachycardia [2% (6/297) and 3% (9/298)] and palpitations [2% (6/297) and 1.3% (4/298)] in the HERCEPTIN HYLECTA arm and the intravenous trastuzumab arm, respectively. The incidence of cardiac failure and congestive cardiac failure was 1% (3/297) in the HERCEPTIN HYLECTA arm and <1% (1/298) in the intravenous trastuzumab arm. The proportion of patients in each treatment arm with a significant decrease in LVEF defined as a drop of ≥10% points to an LVEF of <50% was comparable between treatment arms [3.8% (11/297) in the HERCEPTIN HYLECTA arm and 4.2% (12/298) in the intravenous trastuzumab arm]. In patients with lower body weights (<59 kg, the lowest body weight quartile) the fixed-dose used in the HERCEPTIN HYLECTA arm was not associated with an increased risk of cardiac events or significant drop in LVEF. In the SafeHER study, in patients treated with HERCEPTIN HYLECTA , 17% (323/1864) reported a cardiac disorder during the treatment period. Decreased ejection fraction, reported in 4.5% (84/1864) of the patients was the most frequently reported cardiac disorder. Congestive cardiac failure was reported in <1% (10/1864) of patients and <1% (4/1864) of patients reported cardiac failure during the treatm…

4 CONTRAINDICATIONS None. None. ( 4 )

7 DRUG INTERACTIONS Anthracyclines Patients who receive anthracycline after stopping HERCEPTIN HYLECTA may be at increased risk of cardiac dysfunction because of HERCEPTIN HYLECTA's estimated long washout period [see Clinical Pharmacology (12.3) ] . If possible, avoid anthracycline-based therapy for up to 7 months after stopping HERCEPTIN HYLECTA. If anthracyclines are used, closely monitor the patient's cardiac function.

8.1 Pregnancy If HERCEPTIN HYLECTA is administered during pregnancy, or if a patient becomes pregnant while receiving HERCEPTIN HYLECTA or within 7 months following the last dose of HERCEPTIN HYLECTA, health care providers and patients should immediately report HERCEPTIN HYLECTA exposure to Genentech at 1-888-835-2555. Risk Summary HERCEPTIN HYLECTA can cause fetal harm when administered to a pregnant woman. In post-marketing reports and published literature, use of trastuzumab during pregnancy resulted in cases of oligohydramnios and of oligohydramnios sequence, manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death [see Data ]. Apprise the patient of the potential risks to a fetus. There are clinical considerations if HERCEPTIN HYLECTA is used in a pregnant woman or if a patient becomes pregnant within 7 months following the last dose of HERCEPTIN HYLECTA [see Clinical Considerations ]. The 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% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Monitor women who received HERCEPTIN HYLECTA during pregnancy or within 7 months prior to conception for oligohydramnios. If oligohydramnios occurs, perform fetal/neonatal testing that is appropriate for gestational age and consistent with community standards of care. Data Human Data In post-marketing reports and published literature, use of trastuzumab during pregnancy resulted in cases of oligohydramnios and of oligohydramnios sequence. Fetal manifestations included 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 most reported cases, amniotic fluid index increased after use of trastuzumab was stopped. In reported cases where Herceptin therapy was resumed after amniotic index improved, oligohydramnios recurred. Animal Data HERCEPTIN HYLECTA for subcutaneous injection contains trastuzumab and hyaluronidase [see Description (11) ] . 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 2 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 >7,200 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 a daily dose of 360,000 U/kg, which is >1,200 times higher than the human dose. In a 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 >3,600 times higher than the human dose. The study found no adverse effects on sexual maturation, learning and memory or fertility of the offspring.

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) ] Adjuvant Breast Cancer Most common adverse reactions (≥10%) for HERCEPTIN HYLECTA are fatigue, arthralgia, diarrhea, injection site reaction, upper respiratory tract infection, rash, myalgia, nausea, headache, edema, flushing, pyrexia, cough, and pain in extremity. ( 6.1 ) Metastatic Breast Cancer (based on intravenous trastuzumab) Most common adverse reactions (≥10%) are fever, chills, headache, infection, congestive heart failure, insomnia, cough, and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of HERCEPTIN HYLECTA administered subcutaneously has been established in the HannaH and SafeHER studies conducted in patients with HER2 overexpressing breast cancer. The safety of intravenous trastuzumab has been established in studies H0648g and H0649g conducted in patients with HER2 overexpressing metastatic breast cancer. Adjuvant Breast Cancer HannaH HannaH was a randomized, open-label study to compare the pharmacokinetics, efficacy, and safety of HERCEPTIN HYLECTA compared to intravenous trastuzumab in women with HER2-positive breast cancer. Patients randomized to the HERCEPTIN HYLECTA arm received a dose of 600 mg HERCEPTIN HYLECTA every 3 weeks throughout the treatment phase. Patients were treated for 8 cycles in combination with chemotherapy (docetaxel followed by 5FU, epirubicin and cyclophosphamide), then underwent surgery, and continued HERCEPTIN HYLECTA to complete 18 cycles of therapy. The median age of patients was 50 (range: 25-81 years), all patients were female, and a majority of patients were white (67%). The median number of HERCEPTIN HYLECTA cycles received was 18 (range 1-18). The most common adverse reactions of any grade (occurring in ≥10% of patients) with HERCEPTIN HYLECTA were alopecia (63%), nausea (49%), ARRs (48%), neutropenia (44%), diarrhea (34%), asthenia (25%), fatigue (24%), vomiting (23%), myalgia (21%), decreased appetite (20%), stomatitis (19%), arthralgia (18%), headache (17%), rash (16%), constipation (14%), radiation skin injury (14%), pyrexia (12%), cough (12%), anemia (11%), dyspnea (11%), incision site pain (11%), peripheral sensory neuropathy (11%), leukopenia (10%), mucosal inflammation (10%), hot flush (10%), upper respiratory tract infection (10%). The most common Grade ≥3 adverse reactions (occurring in >1% of patients) in the HERCEPTIN HYLECTA arm were neutropenia (30%), febrile neutropenia (6%), leukopenia (4%), diarrhea (3%), hypertension (2%), irregular menstruation (2%), alopecia (1%), nausea (1%), granulocytopenia (1%), vomiting (1%), amenorrhea (1%), and cellulitis (1%). Adverse reactions leading to interruption of any study drug in the HERCEPTIN HYLECTA arm occurred in 34% of patients; 31% of patients had these events during the neoadjuvant phase of the study with concurrent chemotherapy and 9% of patients had these events during the adjuvant phase. Overall, the most common (≥ 1%) were neutropenia (21%), leukopenia (2.4%), ALT increase (1.7%), pyrexia (1.7%), anemia (1%), bronchitis (1%), and left ventricular dysfunction (1%). Adverse reactions that led to discontinuation of any study drug in the HERCEPTIN HYLECTA arm (>1 patient)…