Trastuzumab

1 INDICATIONS AND USAGE Herceptin 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 Herceptin ( 1 , 2.2 ). 1.1 Adjuvant Breast Cancer Herceptin 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 Herceptin [see Dosage and Administration (2.2) ] . 1.2 Metastatic Breast Cancer Herceptin 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 Herceptin [see Dosage and Administration (2.2) ] . 1.3 Metastatic Gastric Cancer Herceptin 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 Herceptin [see Dosage and Administration (2.2) ] .

2 DOSAGE AND ADMINISTRATION For intravenous (IV) infusion only. Do not administer as an IV push or bolus. Herceptin has different dosage and administration instructions than subcutaneous trastuzumab products. ( 2.3 ) Do not substitute Herceptin (trastuzumab) 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 minutes IV infusion, then 2 mg/kg over 30 minutes 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 Herceptin, administer 6 mg/kg as an IV infusion over 30–90 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 30–90 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 minutes IV infusion followed by subsequent weekly doses of 2 mg/kg as 30 minutes 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 Herceptin Assess left ventricular ejection fraction (LVEF) prior to initiation of Herceptin 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 Herceptin [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 Herceptin is for intravenous infusion only. Do not administer as an intravenous push or bolus. Herceptin has different dosage and administration instructions than subcutaneous trastuzumab products. Do not mix Herceptin with other drugs. Do not substitute Herceptin (trastuzumab) 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 Herceptin therapy: During and following paclitaxel, docetaxel, or docetaxel/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 Herceptin, administer Herceptin at 6 mg/kg as an intravenous infusion over 30–90 minutes every three weeks. As a single agent within three weeks following completion of multi-modality, anthracycline-based chemotherapy regimens: Initial dose at 8 mg/kg as an intravenous infusion over 90 minutes Subsequent doses at 6 mg/kg as an intravenous infusion over 30–90 minutes every three weeks. Extending adjuvant treatment beyond one year is not recommended [see Adverse Reactions (6.1) ] . Metastatic Breast Cancer Administer Herceptin, alone or in combination with paclitaxel, at an initial dose of 4 mg/kg as a 90-minute intravenous infusion followed by subsequent once weekly doses of 2 mg/kg as 30-minute intravenous infusions until disease progression. Metastatic Gastric Cancer Administer Herceptin at an initial dose of 8 mg/kg as a 90-minute intravenous infusion followed by subsequent doses of 6 mg/kg as an intravenous infusion over 30–90 minutes every three weeks until disease progression . 2.4 Important Dosing Considerations Missed Dose If the patient has missed a dose of Herceptin by one week or less, then the usual maintenance dose (weekly schedule: 2 mg/kg; once every three weeks schedule: 6 mg/kg) should be administered as soon as possible. Do not wait until the next planned cycle. Subsequent Herceptin maintenance doses should be administered 7 days or 21 days later according to the weekly or once every three week schedules, respectively. If the patient has missed a dose of Herceptin by more than one week, a re-loading dose of Herceptin should be administered over approximately 90 minutes (weekly schedule: 4 mg/kg; once every three week schedule: 8 mg/kg) as soon as possible. Subsequent Herceptin maintenance doses (weekly schedule: 2 mg/kg; three-weekly schedule 6 mg/kg) should be administered 7 days or 21 days later according to the weekly or once every three week schedules, respectively. 2.5 Dosage Modifications for Adverse Reactions Infusion Reactions [See Boxed Warning , Warnings and Precautions (5.2) ] Decrease the rate of infusion for mild or moderate infusion reactions Interrupt the infusion in patients with dyspnea or clinically significant hypotension Discontinue Herceptin for severe or life-threatening infusion reactions. Cardiomyopathy [See Boxed Warning , Warnings and Precautions (5.1) ] Assess left ventricular ejection fraction (LVEF) prior to initiation of Herceptin and at regular intervals during treatment. Withhold Herceptin 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 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 for a persistent (> 8 weeks) LVEF decline or for suspension of Herceptin dosing on more than 3 occasions for cardiomyopathy. 2.6 Preparation Instructions To prevent medication errors, it is important to check the vial labels to ensure that the drug being prepared and administered is Herceptin (trastuzumab) and not ado-trastuzumab emtansine or fam-trastuzumab deruxtecan. 150 mg Single-dose vial Reconstitution Reconstitute each 150 mg vial of Herceptin with 7.4 mL of Sterile Water for Injection (SWFI) (not supplied) to yield a single-dose solution containing 21 mg/mL trastuzumab that delivers 7.15 mL (150 mg trastuzumab). Use appropriate aseptic technique when performing the following reconstitution steps: Using a sterile syringe, slowly inject 7.4 mL of SWFI (not supplied) into the vial containing the lyophilized powder of Herceptin, which has a cake-like appearance. The stream of diluent should be directed into the cake. The reconstituted vial yields a solution for single-dose use, containing 21 mg/mL trastuzumab. Swirl the vial gently to aid reconstitution. DO NOT SHAKE . Slight foaming of the product may be present upon reconstitution. Allow the vial to stand undisturbed for approximately 5 minutes. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Inspect visually for particulates and discoloration. The solution should be free of visible particulates, clear to slightly opalescent and colorless to pale yellow. Use the Herceptin solution immediately following reconstitution with SWFI, as it contains no preservative and is intended for single-dose only. If not used immediately, store the reconstituted Herceptin solution for up to 24 hours at 2°C to 8°C (36°F to 46°F) ; discard any unused Herceptin after 24 hours. Do not freeze . Dilution Determine the dose (mg) of Herceptin [see Dosage and Administration (2.3) ] . Calculate the volume of the 21 mg/mL reconstituted Herceptin solution needed. Withdraw this amount from the vial using a sterile needle and syringe and add it to an infusion bag containing 250 mL of 0.9% Sodium Chloride Injection, USP. DO NOT USE DEXTROSE (5%) SOLUTION. Gently invert the bag to mix the solution. The solution of Herceptin for infusion diluted in polyvinylchloride or polyethylene bags containing 0.9% Sodium Chloride Injection, USP, should be stored at 2°C to 8°C (36°F to 46°F) for no more than 24 hours prior to use. Discard after 24 hours. This storage time is additional to the time allowed for the reconstituted vials. Do not freeze .

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 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 most common adverse reactions in patients receiving Herceptin 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 Herceptin 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 Herceptin 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 Herceptin-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 Herceptin therapy across three randomized, open-label studies, Studies 1, 2, and 3, with (n = 3678) or without (n = 3363) trastuzumab in the adjuvant treatment of breast cancer. HERA Table 3 reflects exposure to Herceptin 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 Herceptin (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 disorders 2 0 Pruritus 2 0.6 Clinically relevant adverse reactions in < 1% of patients who received Herceptin in HERA included hypersensitivity (0.6%), cardiac failure (0.5%), cardiac disorder (0.3%), interstitial pneumonitis (0.2%), pulmonary hypertension (0.2%), ventricular disorder (0.2%), autoimmune thyroiditis (0.3%), and sudden death (0.06%). Adjuvant Treatment of Breast Cancer with Herceptin Beyond One Year Extending adjuvant treatment beyond one year is not recommended [see Dosage and Administration (2.2) ]. In HERA, a comparison of Herceptin administered once every 3 weeks for two years versus one year was performed. The rate of asymptomatic cardiac dysfunction was increased in the 2-year Herceptin compared to the 1-year Herceptin treatment arm (8.1% versus 4.6%, respectively). More patients experienced at least one adverse reaction of Grade 3 or higher in the 2-year Herceptin treatment arm (20.4%) compared with the one-year Herceptin treatment arm (16.3%). NSABP B31 and NCCTG N9831 The safety data from NSABP B31 and NCCTG N9831 were obtained from 3655 patients, of whom 2000 received Herceptin; the median treatment duration was 51 weeks [see Clinical Studies (14.1) ]. In NSABP B31, only Grade 3–5 adverse events, treatment-related Grade 2 events, and Grade 2–5 dyspnea were collected during and for up to 3 months following protocol-specified treatment. The following non-cardiac adverse reactions of Grade 2–5 occurred at an incidence of at least 2% greater among patients receiving Herceptin plus chemotherapy as compared to chemotherapy alone: fatigue (29.5% vs. 22.4%), infection (24.0% vs. 12.8%), hot flashes (17.1% vs. 15%), anemia (12.3% vs. 6.7%), dyspnea (11.8% vs. 4.6%), rash/desquamation (10.9% vs. 7.6%), leukopenia (10.5% vs. 8.4%), neutropenia (6.4% vs. 4.3%), headache (6.2% vs. 3.8%), pain (5.5% vs. 3%), edema (4.7% vs. 2.7%), and insomnia (4.3% vs. 1.5%). The majority of these events were Grade 2 in severity. In NCCTG N9831, data collection was limited to the following investigator-attributed treatment-related adverse reactions: NCI-CTC Grade 4 and 5 hematologic toxicities, Grade 3–5 non-hematologic toxicities, selected Grade 2–5 toxicities associated with taxanes (myalgia, arthralgias, nail changes, motor neuropathy, and sensory neuropathy) and Grade 1–5 cardiac toxicities occurring during chemotherapy and/or Herceptin treatment. The following non-cardiac adverse reactions of Grade 2–5 occurred at an incidence of at least 2% greater among patients receiving Herceptin plus chemotherapy as compared to chemotherapy alone: arthralgia (12.2% vs. 9.1%), nail changes (11.5% vs. 6.8%), dyspnea (2.4% vs. 0.2%), and diarrhea (2.2% vs. 0%). The majority of these events were Grade 2 in severity. BCIRG006 Safety data from BCIRG006 reflect exposure to Herceptin as part of an adjuvant treatment regimen from 2124 patients receiving at least one dose of study treatment [AC-TH: n = 1068; TCH: n = 1056]. The overall median treatment duration was 54 weeks in both the AC-TH and TCH arms. The median number of infusions was 26 in the AC-TH arm and 30 in the TCH arm, including weekly infusions during the chemotherapy phase and once every three week dosing in the monotherapy period [see Clinical Studies (14.1) ]. In BCIRG006, the toxicity profile was similar to that reported in Studies NSABP B31, NCCTG N9831, and HERA with the exception of a lower incidence of CHF in the TCH arm. Metastatic Breast Cancer Studies The safety of Herceptin was evaluated in one randomized, open-label study (H0648g) of chemotherapy with (n = 235) or without (n = 234) intravenous trastuzumab in patients with metastatic breast cancerand in one single-arm study (H0649g); in patients with metastatic breast cancer (n=222) [see Clinical Studies (14.1) ]. Patients received 4 mg/kg initial dose of Herceptin followed by 2 mg/kg weekly. In H0648g, 58% of patients received Herceptin for ≥ 6 months and 9% received Herceptin ≥ 12 months, respectively. In H0649g, 31% of patients received Herceptin for ≥ 6 months and 16% received Herceptin for ≥ 12 months, respectively. Table 4 shows the adverse reactions ( ≥ 5%) in patients from H0648g and H0649g. Table 4: Adverse Reactions ≥ (5%) in the Herceptin Arms in H0648g and H0649g Herceptin Data for Herceptin single agent were from 4 studies, including 213 patients from H0649g. n = 352 % Herceptin + Paclitaxel n = 91 % Paclitaxel n = 95 % Herceptin + AC Anthracycline (doxorubicin or epirubicin) and cyclophosphamide. n = 143 % AC n = 135 % General Pain 47 61 62 57 42 Asthenia 42 62 57 54 55 Fever 36 49 23 56 34 Chills 32 41 4 35 11 Headache 26 36 28 44 31 Abdominal pain 22 34 22 23 18 Back pain 22 34 30 27 15 Infection 20 47 27 47 31 Flu syndrome 10 12 5 12 6 Accidental injury 6 13 3 9 4 Allergic reaction 3 8 2 4 2 Gastrointestinal Nausea 33 51 9 76 77 Diarrhea 25 45 29 45 26 Vomiting 23 37 28 53 49 Anorexia 14 24 16 31 26 Nausea and vomiting 8 14 11 18 9 Respiratory Cough increased 26 41 22 43 29 Dyspnea 22 27 26 42 25 Rhinitis 14 22 5 22 16 Pharyngitis 12 22 14 30 18 Sinusitis 9 21 7 13 6 Skin Rash 18 38 18 27 17 Herpes simplex 2 12 3 7 9 Acne 2 11 3 3 < 1 Nervous Insomnia 14 25 13 29 15 Dizziness 13 22 24 24 18 Paresthesia 9 48 39 17 11 Depression 6 12 13 20 12 Peripheral neuritis 2 23 16 2 2 Neuropathy 1 13 5 4 4 Metabolic Peripheral edema 10 22 20 20 17 Edema 8 10 8 11 5 Cardiovascular Congestive heart failure 7 11 1 28 7 Tachycardia 5 12 4 10 5 Musculoskeletal Bone pain 7 24 18 7 7 Arthralgia 6 37 21 8 9 Urogenital Urinary tract infection 5 18 14 13 7 Blood and Lymphatic Anemia 4 14 9 36 26 Leukopenia 3 24 17 52 34 Metastatic Gastric Cancer The safety of Herceptin was evaluated in patients with previously untreated for metastatic gastric or gastroesophageal junction adenocarcinoma in an open label, multi-center trial (ToGA) [see Clinical Studies (14.3) ]. Patients were randomized (1:1) to receive Herceptin in combination with cisplatin and a fluoropyrimidine (FC+H) (n=294) or chemotherapy alone (FC) (n=290) Patients in the Herceptin plus chemotherapy arm received Herceptin 8 mg/kg administered on Day 1 (prior to chemotherapy) followed by 6 mg/kg every 21 days until disease progression. Cisplatin was administered at 80 mg/m 2 on Day 1 and the fluoropyrimidine was administered as either capecitabine 1000 mg/m 2 orally twice a day on Days 1–14 or 5-fluorouracil 800 mg/m 2 /day as a continuous intravenous infusion Days 1 through 5. Chemotherapy was administered for six 21-day cycles. Median duration of Herceptin treatment was 21 weeks and the median number of Herceptin infusions administered was eight. Table 5: Adverse Reactions (All Grades ≥ 5% or Grade 3-4 ≥ 1% between Arms) in ToGA Adverse Reactions Herceptin +FC (N = 294) % FC (N = 290) % All Grades Grades 3-4 All Grades Grades 3-4 Investigations Neutropenia 78 34 73 29 Hypokalemia 28 10 24 6 Anemia 28 12 21 10 Thrombocytopenia 16 5 11 3 Blood and Lymphatic System Disorders Febrile Neutropenia — 5 — 3 Gastrointestinal Disorders Diarrhea 37 9 28 4 Stomatitis 24 1 15 2 Dysphagia 6 2 3 < 1 General Fatigue 35 4 28 2 Fever 18 1 12 0 Mucosal Inflammation 13 2 6 1 Chills 8 < 1 0 0 Metabolism and Nutrition Disorders Weight Decrease 23 2 14 2 Infections and Infestations Upper Respiratory Tract Infections 19 0 10 0 Nasopharyngitis 13 0 6 0 Renal and Urinary Disorders Renal Failure and Impairment 18 3 15 2 Nervous System Disorders Dysgeusia 10 0 5 0 The following subsections provide additional detail regarding adverse reactions observed in clinical trials of adjuvant breast cancer, metastatic breast cancer, metastatic gastric cancer, or post-marketing experience. Cardiomyopathy Serial measurement of cardiac function (LVEF) was obtained in clinical trials in the adjuvant treatment of breast cancer. In HERA, the median duration of follow-up was 12.6 months (12.4 months in the observation arm; 12.6 months in the 1-year Herceptin arm); and in NSABP B31 and NCCTG N9831, 7.9 years in the AC-T arm, 8.3 years in the AC-TH arm. Following initiation of Herceptin therapy, the incidence of new-onset dose-limiting myocardial dysfunction was higher among patients receiving Herceptin and paclitaxel as compared to those receiving paclitaxel alone in NSABP B31 and NCCTG N9831, and in patients receiving one-year Herceptin monotherapy compared to observation in HERA (see Table 6 , Figures 1 and 2 ). The incidence of new-onset cardiac dysfunction, as measured by LVEF, remained similar when compared to the analysis performed at a median follow-up of 2.0 years in the AC-TH arm. This analysis showed evidence of reversibility of left ventricular dysfunction, with 64.5% of patients who experienced symptomatic CHF in the AC-TH group being asymptomatic at latest follow-up, and 90.3% having full or partial LVEF recovery. Table 6: Myocardial Dysfunction (by LVEF) in Studies 1, 2, 3 and 4 For Studies 1, 2 and 3, events are counted from the beginning of Herceptin treatment. For BCIRG006, events are counted from the date of randomization. Study and Arm LVEF < 50% and Decrease from Baseline LVEF Decrease LVEF < 50% ≥ 10% decrease ≥ 16% decrease < 20% and ≥ 10% ≥ 20% Studies 1 & 2 NSABP B31 and NCCTG N9831 regimens: doxorubicin and cyclophosphamide followed by paclitaxel (AC→T) or paclitaxel plus Herceptin (AC→TH). , Median duration of follow-up for NSABP B31 and NCCTG N9831 combined was 8.3 years in the AC→TH arm. AC→TH (n = 1856) 23.1% (428) 18.5% (344) 11.2% (208) 37.9% (703) 8.9% (166) AC→T (n = 1170) 11.7% (137) 7.0% (82) 3.0% (35) 22.1% (259) 3.4% (40) HERA Median follow-up duration of 12.6 months in the one-year Herceptin treatment arm. Herceptin (n = 1678) 8.6% (144) 7.0% (118) 3.8% (64) 22.4% (376) 3.5% (59) Observation (n = 1708) 2.7% (46) 2.0% (35) 1.2% (20) 11.9% (204) 1.2% (21) BCIRG006 BCIRG006 regimens: doxorubicin and cyclophosphamide followed by docetaxel (AC→T) or docetaxel plus Herceptin (AC→TH); docetaxel and carboplatin plus Herceptin (TCH). TCH (n = 1056) 8.5% (90) 5.9% (62) 3.3% (35) 34.5% (364) 6.3% (67) AC→TH (n = 1068) 17% (182) 13.3% (142) 9.8% (105) 44.3% (473) 13.2% (141) AC→T (n = 1050) 9.5% (100) 6.6% (69) 3.3% (35) 34% (357) 5.5% (58) Figure 1 NSABP B31 and NCCTG N9831: Cumulative Incidence of Time to First LVEF Decline of ≥ 10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event Time 0 is initiation of paclitaxel or Herceptin + paclitaxel therapy. Figure 2 HERA: Cumulative Incidence of Time to First LVEF Decline of ≥ 10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event Time 0 is the date of randomization. Figure 3 BCIRG006: Cumulative Incidence of Time to First LVEF Decline of ≥ 10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event Time 0 is the date of randomization. The incidence of congestive heart failure among patients in the metastatic breast cancer trials was classified for severity using the New York Heart Association classification system (I–IV, where IV is the most severe level of cardiac failure) (see Table 2 ). In the metastatic breast cancer trials, the probability of cardiac dysfunction was highest in patients who received Herceptin concurrently with anthracyclines. In ToGA, 5% of patients in the Herceptin plus chemotherapy arm compared to 1.1% of patients in the chemotherapy alone arm had LVEF value below 50% with a ≥ 10% absolute decrease in LVEF from pretreatment values. Figure 1 Figure 2 Figure 3 Infusion Reactions During the first infusion with Herceptin, the symptoms most commonly reported were chills and fever, occurring in approximately 40% of patients in clinical trials. Symptoms were treated with acetaminophen, diphenhydramine, and meperidine (with or without reduction in the rate of Herceptin infusion); permanent discontinuation of Herceptin for infusion reactions was required in < 1% of patients. Other signs and/or symptoms may include nausea, vomiting, pain (in some cases at tumor sites), rigors, headache, dizziness, dyspnea, hypotension, elevated blood pressure, rash, and asthenia. Infusion reactions occurred in 21% and 35% of patients, and were severe in 1.4% and 9% of patients, on second or subsequent Herceptin infusions administered as monotherapy or in combination with chemotherapy, respectively. In the post-marketing setting, severe infusion reactions, including hypersensitivity, anaphylaxis, and angioedema have been reported. Anemia In randomized controlled clinical trials, the overall incidence of anemia (30% vs. 21% [H0648g]), of selected NCI-CTC Grade 2–5 anemia (12.3% vs. 6.7% [NSABP B31]), and of anemia requiring transfusions (0.1% vs. 0 patients [NCCTG N9831]) were increased in patients receiving Herceptin and chemotherapy compared with those receiving chemotherapy alone. Following the administration of Herceptin as a single agent (H0649g), the incidence of NCI-CTC Grade 3 anemia was < 1%. In ToGA (metastatic gastric cancer), on the Herceptin containing arm as compared to the chemotherapy alone arm, the overall incidence of anemia was 28% compared to 21% and of NCI- CTC Grade 3/4 anemia was 12.2% compared to 10.3%. Neutropenia In randomized controlled clinical trials in the adjuvant setting, the incidence of selected NCI-CTC Grade 4–5 neutropenia (1.7% vs. 0.8% [NCCTG N9831]) and of selected Grade 2–5 neutropenia (6.4% vs. 4.3% [NSABP B31]) were increased in patients receiving Herceptin and chemotherapy compared with those receiving chemotherapy alone. In a randomized, controlled trial in patients with metastatic breast cancer, the incidences of NCI-CTC Grade 3/4 neutropenia (32% vs. 22%) and of febrile neutropenia (23% vs. 17%) were also increased in patients randomized to Herceptin in combination with myelosuppressive chemotherapy as compared to chemotherapy alone. In ToGA (metastatic gastric cancer) on the Herceptin containing arm as compared to the chemotherapy alone arm, the incidence of NCI-CTC Grade 3/4 neutropenia was 36.8% compared to 28.9%; febrile neutropenia 5.1% compared to 2.8%. Infection The overall incidences of infection (46% vs. 30% [H0648g]), of selected NCI-CTC Grade 2–5 infection/febrile neutropenia (24.3% vs. 13.4% [NSABP B31]) and of selected Grade 3–5 infection/febrile neutropenia (2.9% vs. 1.4% [NCCTG N9831]) were higher in patients receiving Herceptin and chemotherapy compared with those receiving chemotherapy alone. The most common site of infections in the adjuvant setting involved the upper respiratory tract, skin, and urinary tract. In BCIRG006, the overall incidence of infection was higher with the addition of Herceptin to AC-T but not to TCH [44% (AC-TH), 37% (TCH), 38% (AC-T)]. The incidences of NCI-CTC Grade 3–4 infection were similar [25% (AC-TH), 21% (TCH), 23% (AC-T)] across the three arms. In a randomized, controlled trial in treatment of metastatic breast cancer, the reported incidence of febrile neutropenia was higher (23% vs. 17%) in patients receiving Herceptin in combination with myelosuppressive chemotherapy as compared to chemotherapy alone. Pulmonary Toxicity Adjuvant Breast Cancer Among women receiving adjuvant therapy for breast cancer, the incidence of selected NCI-CTC Grade 2–5 pulmonary toxicity (14.3% vs. 5.4% [NSABP B31]) and of selected NCI-CTC Grade 3–5 pulmonary toxicity and spontaneous reported Grade 2 dyspnea (3.4% vs. 0.9% [NCCTG N9831]) was higher in patients receiving Herceptin and chemotherapy compared with chemotherapy alone. The most common pulmonary toxicity was dyspnea (NCI-CTC Grade 2–5: 11.8% vs. 4.6% [NSABP B31]; NCI-CTC Grade 2–5: 2.4% vs. 0.2% [NCCTG N9831]). Pneumonitis/pulmonary infiltrates occurred in 0.7% of patients receiving Herceptin compared with 0.3% of those receiving chemotherapy alone. Fatal respiratory failure occurred in 3 patients receiving Herceptin, one as a component of multi-organ system failure, as compared to 1 patient receiving chemotherapy alone. In HERA, there were 4 cases of interstitial pneumonitis in the one-year Herceptin treatment arm compared to none in the observation arm at a median follow-up duration of 12.6 months. Metastatic Breast Cancer Among women receiving Herceptin for treatment of metastatic breast cancer, the incidence of pulmonary toxicity was also increased. Pulmonary adverse events have been reported in the post-marketing experience as part of the symptom complex of infusion reactions. Pulmonary events include bronchospasm, hypoxia, dyspnea, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, and acute respiratory distress syndrome. For a detailed description, see Warnings and Precautions (5.4) . Thrombosis/Embolism In 4 randomized, controlled clinical trials, the incidence of thrombotic adverse events was higher in patients receiving Herceptin and chemotherapy compared to chemotherapy alone in three studies (2.6% vs. 1.5% [NSABP B31], 2.5% and 3.7% vs. 2.2% [BCIRG006] and 2.1% vs. 0% [H0648g]). Diarrhea Among women receiving adjuvant therapy for breast cancer, the incidence of NCI-CTC Grade 2–5 diarrhea (6.7% vs. 5.4% [NSABP B31]) and of NCI-CTC Grade 3–5 diarrhea (2.2% vs. 0% [NCCTG N9831]), and of Grade 1–4 diarrhea (7% vs. 1% [HERA; one-year Herceptin treatment at 12.6 months median duration of follow-up]) were higher in patients receiving Herceptin as compared to controls. In BCIRG006, the incidence of Grade 3–4 diarrhea was higher [5.7% AC-TH, 5.5% TCH vs. 3.0% AC-T] and of Grade 1–4 was higher [51% AC-TH, 63% TCH vs. 43% AC-T] among women receiving Herceptin. Of patients receiving Herceptin as a single agent for the treatment of metastatic breast cancer, 25% experienced diarrhea. An increased incidence of diarrhea was observed in patients receiving Herceptin in combination with chemotherapy for treatment of metastatic breast cancer. Renal Toxicity In ToGA (metastatic gastric cancer) on the Herceptin-containing arm as compared to the chemotherapy alone arm the incidence of renal impairment was 18% compared to 14.5%. Severe (Grade 3/4) renal failure was 2.7% on the Herceptin-containing arm compared to 1.7% on the chemotherapy only arm. Treatment discontinuation for renal insufficiency/failure was 2% on the Herceptin-containing arm and 0.3% on the chemotherapy only arm. In the post-marketing setting, rare cases of nephrotic syndrome with pathologic evidence of glomerulopathy have been reported. The time to onset ranged from 4 months to approximately 18 months from initiation of Herceptin therapy. Pathologic findings included membranous glomerulonephritis, focal glomerulosclerosis, and fibrillary glomerulonephritis. Complications included volume overload and congestive heart failure. 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of Herceptin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Infusion reaction [see Warnings and Precautions (5.2) ] Oligohydramnios or oligohydramnios sequence, including pulmonary hypoplasia, skeletal abnormalities, and neonatal death [see Warnings and Precautions (5.3) ] Glomerulopathy [see Adverse Reactions (6.1) ] Immune thrombocytopenia Tumor lysis syndrome (TLS): Cases of possible TLS have been reported in patients treated with Herceptin. Patients with significant tumor burden (e.g. bulky metastases) may be at a 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.

12.3 Pharmacokinetics The pharmacokinetics of trastuzumab was evaluated in a pooled population pharmacokinetic (PK) model analysis of 1,582 subjects with primarily breast cancer and metastatic gastric cancer (MGC) receiving intravenous Herceptin. Total trastuzumab clearance increases with decreasing concentrations due to parallel linear and non-linear elimination pathways. Although the average trastuzumab exposure was higher following the first cycle in breast cancer patients receiving the once every three week schedule compared to the weekly schedule of Herceptin, the average steady-state exposure was essentially the same at both dosages. The average trastuzumab exposure following the first cycle and at steady state as well as the time to steady state was higher in breast cancer patients compared to MGC patients at the same dosage; however, the reason for this exposure difference is unknown. Additional predicted trastuzumab exposure and PK parameters following the first Herceptin cycle and at steady state exposure are described in Tables 7 and 8 , respectively. Population PK based simulations indicate that following discontinuation of Herceptin, concentrations in at least 95% of breast cancer and MGC patients will decrease to approximately 3% of the population predicted steady-state trough serum concentration (approximately 97% washout) by 7 months [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1 , 8.3) ] . Table 7 Population Predicted Cycle 1 PK Exposures (Median with 5 th – 95 th Percentiles) in Breast Cancer and MGC Patients Schedule Primary tumor type N C min (µg/mL) C max (µg/mL) AUC 0-21days (µg.day/mL) 8 mg/kg + 6 mg/kg q3w Breast cancer 1195 29.4 (5.8 - 59.5) 178 (117 - 291) 1373 (736 - 2245) MGC 274 23.1 (6.1 - 50.3) 132 (84.2 - 225) 1109 (588 - 1938) 4 mg/kg + 2 mg/kg qw Breast cancer 1195 37.7 (12.3 - 70.9) 88.3 (58 - 144) 1066 (586 - 1754) Table 8 Population Predicted Steady State PK Exposures (Median with 5 th - 95 th Percentiles) in Breast Cancer and MGC Patients Schedule Primary tumor type N C min,ss Steady-state trough serum concentration of trastuzumab (µg/mL) C max,ss Maximum steady-state serum concentration of trastuzumab (µg/mL) AUC ss, 0-21 days (µg.day/mL) Time to steady-state (week) Total CL range at steady-state (L/day) 8 mg/kg + 6 mg/kg q3w Breast cancer 1195 47.4 (5 - 115) 179 (107 - 309) 1794 (673 - 3618) 12 0.173 - 0.283 MGC 274 32.9 (6.1 - 88.9) 131 (72.5 - 251) 1338 (557 - 2875) 9 0.189 - 0.337 4 mg/kg + 2 mg/kg qw Breast cancer 1195 66.1 (14.9 - 142) 109 (51.0 - 209) 1765 (647 - 3578) 12 0.201 - 0.244 Specific Populations Based on a population pharmacokinetic analysis, no clinically significant differences were observed in the pharmacokinetics of trastuzumab based on age (< 65 (n = 1294); ≥ 65 (n = 288)), race (Asian (n = 264); non-Asian (n = 1324)) and renal impairment (mild (creatinine clearance [CLcr] 60 to 90 mL/min) (n = 636) or moderate (CLcr 30 to 60 mL/min) (n = 133)). The pharmacokinetics of trastuzumab in patients with severe renal impairment, end-stage renal disease with or without hemodialysis, or hepatic impairment is unknown. Drug Interaction Studies There have been no formal drug interaction studies performed with Herceptin in humans. Clinically significant interactions between Herceptin and concomitant medications used in clinical trials have not been observed. Paclitaxel and doxorubicin : Concentrations of paclitaxel and doxorubicin and their major metabolites (i.e., 6-α hydroxyl-paclitaxel [POH], and doxorubicinol [DOL], respectively) were not altered in the presence of trastuzumab when used as combination therapy in clinical trials. Trastuzumab concentrations were not altered as part of this combination therapy. Docetaxel and carboplatin: When Herceptin was administered in combination with docetaxel or carboplatin, neither the plasma concentrations of docetaxel or carboplatin nor the plasma concentrations of trastuzumab were altered. Cisplatin and capecitabine : In a drug interaction substudy conducted in patients in ToGA, the pharmacokinetics of cisplatin, capecitabine and their metabolites were not altered when administered in combination with Herceptin.