Ontruzant

1 INDICATIONS AND USAGE Ontruzant is a HER2/neu receptor antagonist indicated in adults for: The treatment of HER2-overexpressing breast cancer. ( 1.1 , 1.2 ) The treatment of HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma. ( 1.3 ) Select patients for therapy based on an FDA-approved companion diagnostic for a trastuzumab product ( 1 , 2.2 ). 1.1 Adjuvant Breast Cancer Ontruzant is indicated in adults for adjuvant treatment of 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-approved companion diagnostic for a trastuzumab product [see Dosage and Administration (2.2) ] . 1.2 Metastatic Breast Cancer Ontruzant 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-approved companion diagnostic for a trastuzumab product [see Dosage and Administration (2.2) ] . 1.3 Metastatic Gastric Cancer Ontruzant is indicated in adults, in combination with cisplatin and capecitabine or 5-fluorouracil, for the treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease. Select patients for therapy based on an FDA-approved companion diagnostic for a trastuzumab product [see Dosage and Administration (2.2) ] .

2 DOSAGE AND ADMINISTRATION For intravenous (IV) infusion only. Do not administer as an IV push or bolus. Ontruzant has different dosage and administration instructions than subcutaneous trastuzumab products. ( 2.3 ) Do not substitute Ontruzant (trastuzumab-dttb) for or with ado-trastuzumab emtansine or fam-trastuzumab deruxtecan. ( 2.3 ) Perform HER2 testing using FDA-approved tests by laboratories with demonstrated proficiency. ( 1 , 2.2 ) Adjuvant Treatment of HER2-Overexpressing Breast Cancer ( 2.2 ) Administer at either: Initial dose of 4 mg/kg over 90 minute IV infusion, then 2 mg/kg over 30 minute IV infusion weekly for 12 weeks (with paclitaxel or docetaxel) or 18 weeks (with docetaxel and carboplatin). One week after the last weekly dose of Ontruzant, administer 6 mg/kg as an IV infusion over 30 to 90 minutes every three weeks to complete a total of 52 weeks of therapy, or Initial dose of 8 mg/kg over 90 minutes IV infusion, then 6 mg/kg over 30 to 90 minutes IV infusion every three weeks for 52 weeks. Metastatic HER2-Overexpressing Breast Cancer ( 2.3 ) Initial dose of 4 mg/kg as a 90 minute IV infusion followed by subsequent weekly doses of 2 mg/kg as 30 minute IV infusions. Metastatic HER2-Overexpressing Gastric Cancer ( 2.3 ) Initial dose of 8 mg/kg over 90 minutes IV infusion, followed by 6 mg/kg over 30 to 90 minutes IV infusion every 3 weeks. 2.1 Evaluation and Testing Before Initiating Ontruzant Assess left ventricular ejection fraction (LVEF) prior to initiation of Ontruzant and at regular intervals during treatment. [see Boxed Warning , Dosage and Administration (2.5) , Warnings and Precautions (5.1) ]. Verify the pregnancy status of females of reproductive potential prior to the initiation of Ontruzant [see Warnings and Precautions (5.3) , 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-approved tests specific for breast or gastric cancers 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. Assessment of HER2 protein overexpression and HER2 gene amplification in metastatic gastric cancer should be performed using FDA-approved tests specifically for gastric cancers due to differences in gastric vs. breast histopathology, including incomplete membrane staining and more frequent heterogeneous expression of HER2 seen in gastric cancers. 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 Ontruzant is for intravenous infusion only. Do not administer as an intravenous push or bolus. Ontruzant has different dosage and administration instructions than subcutaneous trastuzumab products. Do not mix Ontruzant with other drugs. Do not substitute Ontruzant (trastuzumab-dttb) for or with ado-trastuzumab emtansine or fam-trastuzumab deruxtecan. Adjuvant Treatment of Breast Cancer: Administer according to one of the following doses and schedules for a total of 52 weeks of Ontruzant therapy: During and following paclitaxel, docetaxel, or docetaxel and carboplatin: Initial dose of 4 mg/kg as an intravenous infusion over 90 minutes then at 2 mg/kg as an intravenous infusion over 30 minutes weekly during chemotherapy for the first 12 weeks (paclitaxel or docetaxel) or 18 weeks (docetaxel and carboplatin). One week following the last weekly dose of Ontruzant, administer Ontruzant at 6 mg/kg as an intravenous infusion over 30 to 90 minutes every three weeks. As a single a…

5 WARNINGS AND PRECAUTIONS Exacerbation of Chemotherapy-Induced Neutropenia. ( 5.5 , 6.1 ) 5.1 Cardiomyopathy Trastuzumab products can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death [see Boxed Warning: Cardiomyopathy ] . Trastuzumab products can also cause asymptomatic decline in left ventricular ejection fraction (LVEF). There is a 4 to 6 fold increase in the incidence of symptomatic myocardial dysfunction among patients receiving trastuzumab products as a single agent or in combination therapy compared with those not receiving trastuzumab products. The highest absolute incidence occurs when a trastuzumab product is administered with an anthracycline. Withhold Ontruzant 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 (2.5) ] . The safety of continuation or resumption of trastuzumab products in patients with trastuzumab product-induced left ventricular cardiac dysfunction has not been studied. Patients who receive anthracycline after stopping trastuzumab products 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 Ontruzant LVEF measurements every 3 months during and upon completion of Ontruzant Repeat LVEF measurement at 4 week intervals if Ontruzant is withheld for significant left ventricular cardiac dysfunction [see Dosage and Administration (2.5) ] LVEF measurements every 6 months for at least 2 years following completion of Ontruzant as a component of adjuvant therapy. In NSABPB31, 15% (158/1031) of patients discontinued trastuzumab due to clinical evidence of myocardial dysfunction or significant decline in LVEF after a median follow-up duration of 8.7 years in the AC-TH (anthracycline, cyclophosphamide, paclitaxel, and trastuzumab) arm. In HERA (one-year trastuzumab treatment), the number of patients who discontinued trastuzumab due to cardiac toxicity at 12.6 months median duration of follow-up was 2.6% (44/1678). In BCIRG006, a total of 2.9% (31/1056) of patients in the TCH (docetaxel, carboplatin, trastuzumab) arm (1.5% during the chemotherapy phase and 1.4% during the monotherapy phase) and 5.7% (61/1068) of patients in the AC-TH arm (1.5% during the chemotherapy phase and 4.2% during the monotherapy phase) discontinued trastuzumab due to cardiac toxicity. Among 64 patients receiving adjuvant chemotherapy (NSABP B31 and NCCTG N9831) who developed congestive heart failure, one patient died of cardiomyopathy, one patient died suddenly without documented etiology, and 33 patients were receiving cardiac medication at last follow-up. Approximately 24% of the surviving patients had recovery to a normal LVEF (defined as ≥ 50%) and no symptoms on continuing medical management at the time of last follow-up. Incidence of congestive heart failure (CHF) is presented in Table 1. The safety of continuation or resumption of trastuzumab products in patients with trastuzumab product-induced left ventricular cardiac dysfunction has not been studied. Table 1 Incidence of Congestive Heart Failure in Adjuvant Breast Cancer Studies Incidence of Congestive Heart Failure % (n) Study Regimen Trastuzumab Control NSABP B31 & NCCTG N9831 Median follow-up duration for NSABP B31 & NCCTG N9831 combined was 8.3 years in the AC → paclitaxel+trastuzumab arm. AC Anthracycline (doxorubicin) and cyclophosphamide. → Paclitaxel + Trastuzumab 3.2% (64/2000) Includes 1 patient with fatal cardiomyopathy and 1 patient with sudden death without documented etiology. 1.3% (21/1655) HERA Includes NYHA II-I…

4 CONTRAINDICATIONS None. None. ( 4 )

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

8.1 Pregnancy Risk Summary Trastuzumab products can cause fetal harm when administered to a pregnant woman. In post-marketing reports and published literature, use of trastuzumab products 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 a trastuzumab product is used in a pregnant woman or if a patient becomes pregnant within 7 months following the last dose of a trastuzumab product (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 Ontruzant 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 products 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 trastuzumab was stopped. In reported cases where trastuzumab therapy was resumed after amniotic index improved, oligohydramnios recurred. Animal Data In studies where 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.

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) ] Infusion Reactions [see Warnings and Precautions (5.2) ] Embryo-Fetal Toxicity [see Warnings and Precautions (5.3) ] Pulmonary Toxicity [see Warnings and Precautions (5.4) ] Exacerbation of Chemotherapy-induced Neutropenia [see Warnings and Precautions (5.5) ] Adjuvant Breast Cancer Most common adverse reactions (≥ 5%) are headache, diarrhea, nausea, and chills. ( 6.1 ) Metastatic Breast Cancer Most common adverse reactions (≥ 10%) are fever, chills, headache, infection, congestive heart failure, insomnia, cough, and rash. ( 6.1 ) Metastatic Gastric Cancer Most common adverse reactions (≥ 10%) are neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Organon LLC, a subsidiary of Organon & Co., at 1-844-674-3200 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 most common adverse reactions in patients receiving trastuzumab products in the adjuvant and metastatic breast cancer setting are fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia. Adverse reactions requiring interruption or discontinuation of trastuzumab product treatment include CHF, significant decline in left ventricular cardiac function, severe infusion reactions, and pulmonary toxicity [see Dosage and Administration (2.5) ] . In the metastatic gastric cancer setting, the most common adverse reactions (≥ 10%) that were increased (≥ 5% difference) in the trastuzumab arm as compared to the chemotherapy alone arm were neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia. The most common adverse reactions which resulted in discontinuation of treatment on the trastuzumab-containing arm in the absence of disease progression were infection, diarrhea, and febrile neutropenia. Adjuvant Breast Cancer The information below reflects exposure to one-year trastuzumab therapy across three randomized, open-label studies, NSABP B31, NCCTG N9831, and HERA, with (n = 3678) or without (n = 3363) trastuzumab in the adjuvant treatment of breast cancer. HERA Table 3 reflects exposure to trastuzumab in 1678 patients in HERA; the median treatment duration was 51 weeks and median number of infusions was 18 [see Clinical Studies (14.1) ] . Table 3 Adverse Reactions (≥1%) in HERA (All Grades) The incidence of Grade 3 or higher adverse reactions was <1% in both arms for each listed term. Adverse Reactions Trastuzumab (n = 1678) % Observation (n = 1708) % Nervous System Headache 10 3 Paresthesia 2 0.6 Musculoskeletal Arthralgia 8 6 Back pain 5 3 Myalgia 4 1 Bone pain 3 2 Muscle spasm 3 0.2 Infections Nasopharyngitis 8 3 Urinary tract infection 3 0.8 Gastrointestinal Diarrhea 7 1 Nausea 6 1 Vomiting 3.5 0.6 Constipation 2 1 Dyspepsia 2 0.5 Upper abdominal pain 2 1 General Pyrexia 6 0.4 Peripheral edema 5 2 Chills 5 0 Asthenia 4.5 2 Influenza-like illness 2 0.2 Respiratory Thoracic Mediastinal Cough 5 2 Influenza 4 0.5 Dyspnea 3 2 URI 3 1 Rhinitis 2 0.4 Pharyngolaryngeal pain 2 0.5 Sinusitis 2 0.3 Epistaxis 2 0.06 Cardiac Hypertension 4 2 Dizziness 4 2 Ejection fraction decreased 3.5 0.6 Palpitations 3 0.7 Cardiac arrhythmias Higher level grouping term. 3 1 Cardiac failure (congestive) 2 0.3 Skin & Subcutaneous Tissue Rash 4 0.6 Nail dis…