Herzuma Drug Information

Evaluation and Testing

Before Initiating HERZUMA Assess left ventricular ejection fraction (LVEF) prior to initiation of HERZUMA and at regular intervals during treatment. . Verify the pregnancy status of females of reproductive potential prior to the initiation of HERZUMA.

Patient Selection Select patients based on

HER2 protein overexpression or HER2 gene amplification in tumor specimens . 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.

Recommended Dosage

HERZUMA is for intravenous infusion only. Do not administer as an intravenous push or bolus. HERZUMA has different dosage and administration instructions than subcutaneous trastuzumab products.

Do not mix HERZUMA with other drugs. Do not substitute HERZUMA (trastuzumab-pkrb) 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 HERZUMA 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 HERZUMA, administer HERZUMA at 6 mg/kg as an intravenous infusion over 30 to 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 to 90 minutes every three weeks. Extending adjuvant treatment beyond one year is not recommended. Metastatic Breast Cancer Administer HERZUMA, 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 HERZUMA 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 to 90 minutes every three weeks until disease progression.

Important Dosing Considerations Missed Dose

If the patient has missed a dose of HERZUMA by one week or less, then the usual maintenance dose (weekly schedule: 2 mg/kg; once every three week schedule: 6 mg/kg) should be administered as soon as possible. Do not wait until the next planned cycle. Subsequent HERZUMA 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 HERZUMA by more than one week, a re-loading dose of HERZUMA 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 HERZUMA maintenance doses (weekly schedule: 2 mg/kg; once every three week schedule 6 mg/kg) should be administered 7 days or 21 days later according to the weekly or once every three week schedules, respectively.

Dosage Modifications for Adverse Reactions Infusion Reactions Decrease the rate of infusion

for mild or moderate infusion reactions Interrupt the infusion in patients with dyspnea or clinically significant hypotension Discontinue HERZUMA for severe or life-threatening infusion reactions. Cardiomyopathy Assess left ventricular ejection fraction (LVEF) prior to initiation of HERZUMA and at regular intervals during treatment. Withhold HERZUMA 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.

HERZUMA may be resumed if, within 4 to 8 weeks, the LVEF returns to normal limits and the absolute decrease from baseline is ≤ 15%. Permanently discontinue HERZUMA for a persistent (> 8 weeks) LVEF decline or for suspension of HERZUMA dosing on more than 3 occasions for cardiomyopathy.

Preparation Instructions To prevent medication errors, it is important to check the

vial labels to ensure that the drug being prepared and administered is HERZUMA (trastuzumab-pkrb) and not ado-trastuzumab emtansine or fam-trastuzumab deruxtecan. 420 mg Multiple-dose vial Reconstitution Reconstitute each 420 mg vial of HERZUMA with 20 mL of Bacteriostatic Water for Injection (BWFI), USP, containing 1.1% benzyl alcohol as a preservative to yield a multiple-dose solution containing 21 mg/mL trastuzumab-pkrb that delivers 20 mL (420 mg trastuzumab-pkrb). In patients with known hypersensitivity to benzyl alcohol, reconstitute with 20 mL of Sterile Water for Injection (SWFI) without preservative to yield a one-time use solution. Use appropriate aseptic technique when performing the following reconstitution steps: Using a sterile syringe, slowly inject the 20 mL of diluent into the vial containing the lyophilized powder of HERZUMA, which has a cake-like appearance. The stream of diluent should be directed into the cake.

The reconstituted vial yields a solution for multiple-dose use, containing 21 mg/mL trastuzumab-pkrb. 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. Store reconstituted HERZUMA in the refrigerator at 2°C to 8°C (36°F to 46°F); discard unused HERZUMA after 28 days. If HERZUMA is reconstituted with SWFI without preservative, use immediately and discard any unused portion.

Do not freeze. Dilution Determine the dose (mg) of HERZUMA . Calculate the volume of the 21 mg/mL reconstituted HERZUMA 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 HERZUMA 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.

This storage time is additional to the time allowed for the reconstituted vials. Do not freeze. 150 mg Single-dose vial Reconstitution Reconstitute each 150 mg vial of HERZUMA with 7.4 mL of Sterile Water for Injection (SWFI) (not supplied) to yield a single-dose solution containing 21 mg/mL trastuzumab-pkrb that delivers 7.15 mL (150 mg trastuzumab-pkrb). 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 HERZUMA, which has a cake-like appearance. The stream of diluent should be directed into the cake.

The reconstituted vial yields a solution containing 21 mg/mL trastuzumab-pkrb. 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 HERZUMA solution immediately following reconstitution with SWFI, as it contains no preservative and is intended for one-time use only. If not used immediately, store the reconstituted HERZUMA solution for up to 24 hours at 2°C to 8°C (36°F to 46°F); discard any unused HERZUMA after 24 hours.

Do not freeze. Dilution Determine the dose (mg) of HERZUMA . Calculate the volume of the 21 mg/mL reconstituted HERZUMA 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 HERZUMA 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.

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 . 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 . 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

Musculoskeletal Arthralgia 8 6 Back Pain 5 3 Myalgia 4 1 Bone

Pain 3 2 Muscle Spasm 3

Infections Nasopharyngitis 8 3 Urinary tract infection 3 0.8 Gastrointestinal Diarrhea 7

1 Nausea 6 1 Vomiting 3.5

Constipation 2 1 Dyspepsia 2 0.5 Upper abdominal pain 2 1 General

Pyrexia 6

Peripheral edema 5 2 Chills 5 0 Asthenia 4.5 2 Influenza-like illness

2

Respiratory Thoracic Mediastinal Cough 5 2 Influenza 4 0.5 Dyspnea 3 2

URI 3 1 Rhinitis 2

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

Palpitations 3 0.7 Cardiac arrhythmias Higher level grouping term. 3 1 Cardiac

failure (congestive) 2

Skin & Subcutaneous Tissue Rash 4 0.6 Nail Disorders 2 0 Pruritus

2

Clinically relevant adverse reactions in < 1% of patients who received trastuzumab

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 Trastuzumab Beyond One Year Extending adjuvant treatment beyond one year is not recommended . In HERA, a comparison of trastuzumab 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 trastuzumab compared to the 1-year trastuzumab 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 trastuzumab treatment arm (20.4%) compared with the one-year trastuzumab 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 trastuzumab; the median treatment duration was 51 weeks . In NSABP B31, only Grade 3 to 5 adverse events, treatment-related Grade 2 events, and Grade 2 to 5 dyspnea were collected during and for up to 3 months following protocol-specified treatment. The following non-cardiac adverse reactions of Grade 2 to 5 occurred at an incidence of at least 2% greater among patients receiving trastuzumab 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 to 5 non-hematologic toxicities, selected Grade 2 to 5 toxicities associated with taxanes (myalgia, arthralgias, nail changes, motor neuropathy, and sensory neuropathy) and Grade 1 to 5 cardiac toxicities occurring during chemotherapy and/or trastuzumab treatment. The following non-cardiac adverse reactions of Grade 2 to 5 occurred at an incidence of at least 2% greater among patients receiving trastuzumab 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 trastuzumab as part of an adjuvant treatment regimen from 2124 patients receiving at least one dose of study treatment.

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 . In BCIRG006, the toxicity profile was similar to that reported in 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 trastuzumab 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 cancer and in one single-arm study (H0649g) in patients with metastatic breast cancer (n = 222) . Patients received 4 mg/kg initial dose of trastuzumab followed by 2 mg/kg weekly.

In H0648g, 58% of patients received trastuzumab for ≥ 6 months and 9% received trastuzumab for ≥ 12 months, respectively. In H0649g, 31% of patients received trastuzumab for ≥ 6 months and 16% received trastuzumab for ≥ 12 months, respectively. Table 4 shows the adverse reactions (≥ 5%) in patients from H0648g and H0649g.

Table 4: Adverse Reactions Data for trastuzumab single agent were from 4 studies, including 213 patients from H0649g (≥ 5%) in the Trastuzumab Arms in H0648g and H0649g Trastuzumab n = 352 % Trastuzumab + Paclitaxel n = 91 % Paclitaxel n = 95 % Trastuzumab + 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 trastuzumab was evaluated in patients with previously untreated for metastatic gastric or gastroesophageal junction adenocarcinoma in an open label, multi-center trial (ToGA) . Patients were randomized (1:1) to receive trastuzumab in combination with cisplatin and a fluoropyrimidine (FC+H) (n=294) or chemotherapy alone (FC) (n=290). Patients in the trastuzumab plus chemotherapy arm received trastuzumab 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 to 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 trastuzumab treatment was 21 weeks and the median number of trastuzumab infusions administered was eight.

Table 5: Adverse Reactions (All Grades ≥ 5% or Grade 3-4 ≥ 1% between Arms) in ToGA Adverse Reactions Trastuzumab + 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 trastuzumab 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 trastuzumab therapy, the incidence of new-onset dose-limiting myocardial dysfunction was higher among patients receiving trastuzumab and paclitaxel as compared to those receiving paclitaxel alone in NSABP B31 and NCCTG N9831, and in patients receiving one-year trastuzumab 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 NSABP B31, NCCTG N9831, HERA and BCIRG006 For NSABP B31, NCCTG N9831 and HERA, events are counted from the beginning of trastuzumab 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% NSABP B31 & NCCTG N9831 NSABP B31 and NCCTG N9831 regimens: doxorubicin and cyclophosphamide followed by paclitaxel (AC→T) or paclitaxel plus trastuzumab (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% 18.5% 11.2% 37.9% 8.9% AC→T (n = 1170) 11.7% 7.0% 3.0% 22.1% 3.4% HERA Median follow-up duration of 12.6 months in the one-year trastuzumab treatment arm.

Trastuzumab (n = 1678) 8.6% 7.0% 3.8% 22.4% 3.5% Observation (n = 1708) 2.7% 2.0% 1.2% 11.9% 1.2% BCIRG006 BCIRG006 regimens: doxorubicin and cyclophosphamide followed by docetaxel (AC→T) or docetaxel plus trastuzumab (AC→TH); docetaxel and carboplatin plus trastuzumab (TCH). TCH (n = 1056) 8.5% 5.9% 3.3% 34.5% 6.3% AC→TH (n = 1068) 17% 13.3% 9.8% 44.3% 13.2% AC→T (n = 1050) 9.5% 6.6% 3.3% 34% 5.5% 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 trastuzumab + 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 to 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 trastuzumab concurrently with anthracyclines. In ToGA, 5% of patients in the trastuzumab 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 trastuzumab, 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 trastuzumab infusion); permanent discontinuation of trastuzumab 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 trastuzumab 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% ), of selected NCI-CTC Grade 2–5 anemia (12.3% vs. 6.7% ), and of anemia requiring transfusions (0.1% vs. 0 patients ) were increased in patients receiving trastuzumab and chemotherapy compared with those receiving chemotherapy alone. Following the administration of trastuzumab as a single agent (H0649g), the incidence of NCI-CTC Grade 3 anemia was < 1%. In ToGA (metastatic gastric cancer), on the trastuzumab 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 to 5 neutropenia (1.7% vs. 0.8% ) and of selected Grade 2 to 5 neutropenia (6.4% vs. 4.3% ) were increased in patients receiving trastuzumab 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 trastuzumab in combination with myelosuppressive chemotherapy as compared to chemotherapy alone. In ToGA (metastatic gastric cancer) on the trastuzumab 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% ), of selected NCI-CTC Grade 2 to 5 infection/febrile neutropenia (24.3% vs. 13.4% ) and of selected Grade 3 to 5 infection/febrile neutropenia (2.9% vs. 1.4% ) were higher in patients receiving trastuzumab 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 trastuzumab to AC-T but not to TCH. The incidences of NCI-CTC Grade 3 to 4 infection were similar 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 trastuzumab 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 to 5 pulmonary toxicity (14.3% vs. 5.4% ) and of selected NCI-CTC Grade 3 to 5 pulmonary toxicity and spontaneous reported Grade 2 dyspnea (3.4% vs. 0.9% ) was higher in patients receiving trastuzumab and chemotherapy compared with chemotherapy alone.

The most common pulmonary toxicity was dyspnea (NCI-CTC Grade 2 to 5: 11.8% vs. 4.6% ; NCI-CTC Grade 2 to 5: 2.4% vs. 0.2% ). Pneumonitis/pulmonary infiltrates occurred in 0.7% of patients receiving trastuzumab compared with 0.3% of those receiving chemotherapy alone. Fatal respiratory failure occurred in 3 patients receiving trastuzumab, 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 trastuzumab 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 trastuzumab 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 . Thrombosis/Embolism In 4 randomized, controlled clinical trials, the incidence of thrombotic adverse events was higher in patients receiving trastuzumab and chemotherapy compared to chemotherapy alone in three studies (2.6% vs. 1.5%, 2.5% and 3.7% vs. 2.2% and 2.1% vs. 0% ). Diarrhea Among women receiving adjuvant therapy for breast cancer, the incidence of NCI-CTC Grade 2–5 diarrhea (6.7% vs. 5.4% ) and of NCI-CTC Grade 3 to 5 diarrhea (2.2% vs. 0% ), and of Grade 1 to 4 diarrhea (7% vs. 1% ) were higher in patients receiving trastuzumab as compared to controls. In BCIRG006, the incidence of Grade 3 to 4 diarrhea was higher and of Grade 1 to 4 was higher among women receiving trastuzumab. Of patients receiving trastuzumab as a single agent for the treatment of metastatic breast cancer, 25% experienced diarrhea.

An increased incidence of diarrhea was observed in patients receiving trastuzumab in combination with chemotherapy for treatment of metastatic breast cancer. Renal Toxicity In ToGA (metastatic gastric cancer) on the trastuzumab-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 trastuzumab-containing arm compared to 1.7% on the chemotherapy only arm. Treatment discontinuation for renal insufficiency/failure was 2% on the trastuzumab-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 trastuzumab 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 trastuzumab products. 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 Oligohydramnios or oligohydramnios sequence, including pulmonary hypoplasia, skeletal abnormalities, and neonatal death Glomerulopathy Immune thrombocytopenia Tumor lysis syndrome (TLS): Cases of possible TLS have been reported in patients treated with trastuzumab products.

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.

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 . 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.

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. 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. 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 HERZUMA 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-m arketing 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.

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