Data from FDA - Curated by EPG Health - Last updated 12 April 2018

Indication(s)

1 INDICATIONS AND USAGE Herceptin is a HER2/neu receptor antagonist indicated 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, 2.1). 1.1 Adjuvant Breast Cancer Herceptin is indicated 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 (2.1)]. 1.2 Metastatic Breast Cancer Herceptin is indicated: 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 (2.1)]. 1.3 Metastatic Gastric Cancer Herceptin is indicated, 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 (2.1)].

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contraindications
4 CONTRAINDICATIONS None. None. (4)
Adverse reactions
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)] 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 (2.3)]. 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 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. Adjuvant Breast Cancer Studies The data below reflect 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. The data summarized in Table 3 below, from Study 3, reflect exposure to Herceptin in 1678 patients; the median treatment duration was 51 weeks and median number of infusions was 18. Among the 3386 patients enrolled in the observation and one-year Herceptin arms of Study 3 at a median duration of follow-up of 12.6 months in the Herceptin arm, the median age was 49 years (range: 21 to 80 years), 83% of patients were Caucasian, and 13% were Asian. Table 3: Adverse Reactions for Study 3Median follow-up duration of 12.6 months in the one-year Herceptin treatment arm., All GradesThe incidence of Grade 3 or higher adverse reactions was <1% in both arms for each listed term. One Year Herceptin Observation Adverse Reaction (n = 1678) (n = 1708) Cardiac Hypertension 64 (4%) 35 (2%) Dizziness 60 (4%) 29 (2%) Ejection Fraction Decreased 58 (3.5%) 11 (0.6%) Palpitations 48 (3%) 12 (0.7%) Cardiac ArrhythmiasHigher level grouping term. 40 (3%) 17 (1%) Cardiac Failure Congestive 30 (2%) 5 (0.3%) Cardiac Failure 9 (0.5%) 4 (0.2%) Cardiac Disorder 5 (0.3%) 0 (0%) Ventricular Dysfunction 4 (0.2%) 0 (0%) Respiratory Thoracic Mediastinal Disorders Cough 81 (5%) 34 (2%) Influenza 70 (4%) 9 (0.5%) Dyspnea 57 (3%) 26 (2%) URI 46 (3%) 20 (1%) Rhinitis 36 (2%) 6 (0.4%) Pharyngolaryngeal Pain 32 (2%) 8 (0.5%) Sinusitis 26 (2%) 5 (0.3%) Epistaxis 25 (2%) 1 (0.06%) Pulmonary Hypertension 4 (0.2%) 0 (0%) Interstitial Pneumonitis 4 (0.2%) 0 (0%) Gastrointestinal Disorders Diarrhea 123 (7%) 16 (1%) Nausea 108 (6%) 19 (1%) Vomiting 58 (3.5%) 10 (0.6%) Constipation 33 (2%) 17 (1%) Dyspepsia 30 (2%) 9 (0.5%) Upper Abdominal Pain 29 (2%) 15 (1%) Musculoskeletal & Connective Tissue Disorders Arthralgia 137 (8%) 98 (6%) Back Pain 91 (5%) 58 (3%) Myalgia 63 (4%) 17 (1%) Bone Pain 49 (3%) 26 (2%) Muscle Spasm 46 (3%) 3 (0.2%) Nervous System Disorders Headache 162 (10%) 49 (3%) Paraesthesia 29 (2%) 11 (0.6%) Skin & Subcutaneous Tissue Disorders Rash 70 (4%) 10 (0.6%) Nail Disorders 43 (2%) 0 (0%) Pruritus 40 (2%) 10 (0.6%) General disorders Pyrexia 100 (6%) 6 (0.4%) Edema Peripheral 79 (5%) 37 (2%) Chills 85 (5%) 0 (0%) Asthenia 75 (4.5%) 30 (2%) Influenza-like Illness 40 (2%) 3 (0.2%) Sudden Death 1 (0.06%) 0 (0%) Infections Nasopharyngitis 135 (8%) 43 (3%) UTI 39 (3%) 13 (0.8%) Immune System Disorders Hypersensitivity 10 (0.6%) 1 (0.06%) Autoimmune Thyroiditis 4 (0.3%) 0 (0%) In Study 3, a comparison of 3-weekly Herceptin treatment for two years versus one year was also performed. The rate of asymptomatic cardiac dysfunction was increased in the 2-year Herceptin treatment arm (8.1% versus 4.6% in the one-year Herceptin treatment arm). 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%). The safety data from Studies 1 and 2 were obtained from 3655 patients, of whom 2000 received Herceptin; the median treatment duration was 51 weeks. The median age was 49 years (range: 24–80); 84% of patients were White, 7% Black, 4% Hispanic, and 3% Asian. In Study 1, 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. 15.0%), 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. 3.0%), edema (4.7% vs. 2.7%), and insomnia (4.3% vs. 1.5%). The majority of these events were Grade 2 in severity. In Study 2, 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. Safety data from Study 4 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 every three week dosing in the monotherapy period. Among these patients, the median age was 49 years (range 22 to 74 years). In Study 4, the toxicity profile was similar to that reported in Studies 1, 2, and 3 with the exception of a low incidence of CHF in the TCH arm. Metastatic Breast Cancer Studies The data below reflect exposure to Herceptin in one randomized, open-label study, Study 5, of chemotherapy with (n = 235) or without (n = 234) trastuzumab in patients with metastatic breast cancer, and one single-arm study (Study 6; n = 222) in patients with metastatic breast cancer. Data in Table 4 are based on Studies 5 and 6. Among the 464 patients treated in Study 5, the median age was 52 years (range: 25–77 years). Eighty-nine percent were White, 5% Black, 1% Asian, and 5% other racial/ethnic groups. All patients received 4 mg/kg initial dose of Herceptin followed by 2 mg/kg weekly. The percentages of patients who received Herceptin treatment for ≥ 6 months and ≥ 12 months were 58% and 9%, respectively. Among the 352 patients treated in single agent studies (213 patients from Study 6), the median age was 50 years (range 28–86 years), 86% were White, 3% were Black, 3% were Asian, and 8% in other racial/ethnic groups. Most of the patients received 4 mg/kg initial dose of Herceptin followed by 2 mg/kg weekly. The percentages of patients who received Herceptin treatment for ≥ 6 months and ≥ 12 months were 31% and 16%, respectively. Table 4: Per-Patient Incidence of Adverse Reactions Occurring in ≥5% of Patients in Uncontrolled Studies or at Increased Incidence in the Herceptin Arm (Studies 5 and 6) Single AgentData for Herceptin single agent were from 4 studies, including 213 patients from Study 6. n = 352 Herceptin + Paclitaxel n = 91 Paclitaxel Alone n = 95 Herceptin + ACAnthracycline (doxorubicin or epirubicin) and cyclophosphamide. n = 143 AC Alone n = 135 Body as a Whole 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% Cardiovascular Tachycardia 5% 12% 4% 10% 5% Congestive heart failure 7% 11% 1% 28% 7% Digestive Nausea 33% 51% 9% 76% 77% Diarrhea 25% 45% 29% 45% 26% Vomiting 23% 37% 28% 53% 49% Nausea and vomiting 8% 14% 11% 18% 9% Anorexia 14% 24% 16% 31% 26% Heme & Lymphatic Anemia 4% 14% 9% 36% 26% Leukopenia 3% 24% 17% 52% 34% Metabolic Peripheral edema 10% 22% 20% 20% 17% Edema 8% 10% 8% 11% 5% Musculoskeletal Bone pain 7% 24% 18% 7% 7% Arthralgia 6% 37% 21% 8% 9% 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% 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% Urogenital Urinary tract infection 5% 18% 14% 13% 7% Metastatic Gastric Cancer The data below are based on the exposure of 294 patients to Herceptin in combination with a fluoropyrimidine (capecitabine or 5-FU) and cisplatin (Study 7). In the Herceptin plus chemotherapy arm, the initial dose of Herceptin 8 mg/kg was administered on Day 1 (prior to chemotherapy) followed by 6 mg/kg every 21 days until disease progression. Cisplatin was administered at 80 mg/m2 on Day 1 and the fluoropyrimidine was administered as either capecitabine 1000 mg/m2 orally twice a day on Days 1-14 or 5-fluorouracil 800 mg/m2/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; median number of Herceptin infusions administered was eight. Table 5: Study 7: Per Patient Incidence of Adverse Reactions of All Grades (Incidence ≥ 5% between Arms) or Grade 3 /4 (Incidence > 1% between Arms) and Higher Incidence in Herceptin Arm Herceptin + FC (N = 294) N (%) FC (N = 290) N (%) Body System/ Adverse Event All Grades Grades 3/4 All Grades Grades 3/4 Investigations Neutropenia 230 (78) 101 (34) 212 (73) 83 (29) Hypokalemia 83 (28) 28 (10) 69 (24) 16 (6) Anemia 81 (28) 36 (12) 61 (21) 30 (10) Thrombocytopenia 47 (16) 14 (5) 33 (11) 8 (3) Blood and Lymphatic System Disorders Febrile Neutropenia — 15 ( 5) — 8 (3) Gastrointestinal Disorders Diarrhea 109 (37) 27 (9) 80 (28) 11 (4) Stomatitis 72 (24) 2 (1) 43 (15) 6 (2) Dysphagia 19 (6) 7 (2) 10 (3) 1 (≤ 1) Body as a Whole Fatigue 102 (35) 12 (4) 82 (28) 7 (2) Fever 54 (18) 3 (1) 36 (12) 0 (0) Mucosal Inflammation 37 (13) 6 (2) 18 (6) 2 (1) Chills 23 (8) 1 (≤ 1) 0 (0) 0 (0) Metabolism and Nutrition Disorders Weight Decrease 69 (23) 6 (2) 40 (14) 7 (2) Infections and Infestations Upper Respiratory Tract Infections 56 (19) 0 (0) 29 (10) 0 (0) Nasopharyngitis 37 (13) 0 (0) 17 (6) 0 (0) Renal and Urinary Disorders Renal Failure and Impairment 53 (18) 8 (3) 42 (15) 5 (2) Nervous System Disorders Dysgeusia 28 (10) 0 (0) 14 (5) 0 (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 Study 3, 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 Studies 1 and 2, 7.9 years in the AC-T arm, 8.3 years in the AC-TH arm. In Studies 1 and 2, 6% of all randomized patients with post-AC LVEF evaluation were not permitted to initiate Herceptin following completion of AC chemotherapy due to cardiac dysfunction (LVEF < LLN or ≥ 16 point decline in LVEF from baseline to end of AC). 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 Studies 1 and 2, and in patients receiving one-year Herceptin monotherapy compared to observation in Study 3 (see Table 6, Figures 1 and 2). The per-patient 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 also 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 For Studies 1, 2 and 3, events are counted from the beginning of Herceptin treatment. For Study 4, events are counted from the date of randomization.: Per-patient Incidence of New Onset Myocardial Dysfunction (by LVEF) Studies 1, 2, 3 and 4 LVEF < 50% and Absolute Decrease from Baseline Absolute LVEF Decrease LVEF < 50% ≥ 10% decrease ≥ 16% decrease < 20% and ≥ 10% ≥ 20% Studies 1 & 2Studies 1 and 2 regimens: doxorubicin and cyclophosphamide followed by paclitaxel (AC→T) or paclitaxel plus Herceptin (AC→TH). , Median duration of follow-up for Studies 1 and 2 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) Study 3Median 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) Study 4Study 4 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 Studies 1 and 2: 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 Study 3: 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 Study 4: 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 treatment emergent 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 Study 7, 5.0% 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. 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% [Study 5]), of selected NCI-CTC Grade 2–5 anemia (12.3% vs. 6.7% [Study 1]), and of anemia requiring transfusions (0.1% vs. 0 patients [Study 2]) were increased in patients receiving Herceptin and chemotherapy compared with those receiving chemotherapy alone. Following the administration of Herceptin as a single agent (Study 6), the incidence of NCI-CTC Grade 3 anemia was < 1%. In Study 7 (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% [Study 2]) and of selected Grade 2–5 neutropenia (6.4% vs. 4.3% [Study 1]) 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 Study 7 (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% [Study 5]), of selected NCI-CTC Grade 2–5 infection/febrile neutropenia (24.3% vs. 13.4% [Study 1]) and of selected Grade 3–5 infection/febrile neutropenia (2.9% vs. 1.4%) [Study 2]) 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 Study 4, 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% [Study 1]) and of selected NCI-CTC Grade 3–5 pulmonary toxicity and spontaneous reported Grade 2 dyspnea (3.4% vs. 0.9% [Study 2]) 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% [Study 1]; NCI-CTC Grade 2–5: 2.4% vs. 0.2% [Study 2]). 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 Study 3, 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% [Study 1], 2.5% and 3.7% vs. 2.2% [Study 4] and 2.1% vs. 0% [Study 5]). Diarrhea Among women receiving adjuvant therapy for breast cancer, the incidence of NCI-CTC Grade 2–5 diarrhea (6.7% vs. 5.4% [Study 1]) and of NCI-CTC Grade 3–5 diarrhea (2.2% vs. 0% [Study 2]), and of Grade 1–4 diarrhea (7% vs. 1% [Study 3; one-year Herceptin treatment at 12.6 months median duration of follow-up]) were higher in patients receiving Herceptin as compared to controls. In Study 4, 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 Study 7 (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 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Among 903 women with metastatic breast cancer, human anti-human antibody (HAHA) to Herceptin was detected in one patient using an enzyme-linked immunosorbent assay (ELISA). This patient did not experience an allergic reaction. Samples for assessment of HAHA were not collected in studies of adjuvant breast cancer. The incidence of antibody formation is highly dependent on the sensitivity and the specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Herceptin with the incidence of antibodies to other products may be misleading. 6.3 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 Figure 1 Figure 2 Figure 3

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION For intravenous (IV) infusion only. Do not administer as an IV push or bolus. (2.2) Do not substitute Herceptin (trastuzumab) for or with ado-trastuzumab emtansine. (2.2) Perform HER2 testing using FDA-approved tests by laboratories with demonstrated proficiency. (1, 2.1) 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/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 ( 2.2 ) 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 ( 2.2 ) 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 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. 2.2 Recommended Doses and Schedules Do not administer as an intravenous push or bolus. Do not mix Herceptin with other drugs. Do not substitute Herceptin (trastuzumab) for or with ado-trastuzumab emtansine. Adjuvant Treatment, 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/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 [see Dosage and Administration (2.3)]. Extending adjuvant treatment beyond one year is not recommended [see Adverse Reactions (6.1)]. Metastatic Treatment, 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 [see Dosage and Administration (2.3)]. 2.3 Important Dosing Considerations If the patient has missed a dose of Herceptin by one week or less, then the usual maintenance dose (weekly schedule: 2 mg/kg; three-weekly 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 three-weekly 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; three-weekly 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 three-weekly schedules, respectively. 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. 2.4 Preparation for Administration 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. 420 mg Multiple-dose vial Reconstitution Reconstitute each 420 mg vial of Herceptin 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 that delivers 20 mL (420 mg trastuzumab). In patients with known hypersensitivity to benzyl alcohol, reconstitute with 20 mL of Sterile Water for Injection (SWFI) without preservative to yield a single 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 cake of Herceptin. The stream of diluent should be directed into the lyophilized cake. The reconstituted vial yields a solution for multiple-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. Store reconstituted Herceptin in the refrigerator at 2°C to 8° C (36°F to 46°F); discard unused Herceptin after 28 days. If Herceptin is reconstituted with SWFI without preservative, use immediately and discard any unused portion. Do not freeze. Dilution Determine the dose (mg) of Herceptin [see Dosage and Administration (2.2)]. Calculate the volume of the 21 mg/mL reconstituted Herceptin solution needed, withdraw this amount from the vial 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. Do not freeze. 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 150 mg Herceptin, directing the diluent stream into the lyophilized 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 (2.1)]. Calculate the volume of the 21 mg/mL reconstituted Herceptin solution needed. Withdraw this amount from the vial 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.
Use in special populations
8 USE IN SPECIFIC POPULATIONS Females and Males of Reproductive Potential: Verify the pregnancy status of females prior to initiation of Herceptin (8.3). 8.1 Pregnancy Pregnancy Exposure Registry and Pharmacovigilance Program There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Herceptin during pregnancy. Encourage women who receive Herceptin during pregnancy or within 7 months prior to conception to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 or visiting http://www.motherpregnancyregistry.com/. In addition, there is a pregnancy pharmacovigilance program for Herceptin. If Herceptin is administered during pregnancy, or if a patient becomes pregnant while receiving Herceptin or within 7 months following the last dose of Herceptin, health care providers and patients should immediately report Herceptin exposure to Genentech at 1-888-835-2555. Risk Summary Herceptin can cause fetal harm when administered to a pregnant woman. In post-marketing reports, use of Herceptin 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 is used in a pregnant woman or if a patient becomes pregnant within 7 months following the last dose of Herceptin [see Clinical Considerations]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Monitor women who received Herceptin during pregnancy or within 7 months prior to conception for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. Data Human Data In post-marketing reports, use of Herceptin during pregnancy resulted in cases of oligohydramnios and of oligohydramnios sequence, manifesting in the fetus as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. These case reports described oligohydramnios in pregnant women who received Herceptin either alone or in combination with chemotherapy. In some case reports, amniotic fluid index increased after Herceptin was stopped. In one case, Herceptin therapy resumed after amniotic index improved and 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. 8.2 Lactation Risk Summary There is no information regarding the presence of trastuzumab in human milk, the effects on the breastfed infant, or the effects on milk production. Published data suggest human IgG is present in human milk but does not enter the neonatal and infant circulation in substantial amounts. Trastuzumab was present in the milk of lactating Cynomolgus monkeys but not associated with neonatal toxicity [see Data]. Consider the developmental and health benefits of breastfeeding along with the mother's clinical need for Herceptin treatment and any potential adverse effects on the breastfed child from Herceptin or from the underlying maternal condition. This consideration should also take into account the trastuzumab wash out period of 7 months [see Clinical Pharmacology (12.3)]. Data In lactating Cynomolgus monkeys, trastuzumab was present in breast milk at about 0.3% of maternal serum concentrations after pre- (beginning Gestation Day 120) and post-partum (through Post-partum Day 28) doses of 25 mg/kg administered twice weekly (25 times the recommended weekly human dose of 2 mg/kg of Herceptin). Infant monkeys with detectable serum levels of trastuzumab did not exhibit any adverse effects on growth or development from birth to 1 month of age. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to the initiation of Herceptin. Contraception Females Herceptin can cause embryo-fetal harm when administered during pregnancy. Advise females of reproductive potential to use effective contraception during treatment with Herceptin and for 7 months following the last dose of Herceptin [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)]. 8.4 Pediatric Use The safety and effectiveness of Herceptin in pediatric patients have not been established. 8.5 Geriatric Use Herceptin has been administered to 386 patients who were 65 years of age or over (253 in the adjuvant treatment and 133 in metastatic breast cancer treatment settings). The risk of cardiac dysfunction was increased in geriatric patients as compared to younger patients in both those receiving treatment for metastatic disease in Studies 5 and 6, or adjuvant therapy in Studies 1 and 2. Limitations in data collection and differences in study design of the 4 studies of Herceptin in adjuvant treatment of breast cancer preclude a determination of whether the toxicity profile of Herceptin in older patients is different from younger patients. The reported clinical experience is not adequate to determine whether the efficacy improvements (ORR, TTP, OS, DFS) of Herceptin treatment in older patients is different from that observed in patients < 65 years of age for metastatic disease and adjuvant treatment. In Study 7 (metastatic gastric cancer), of the 294 patients treated with Herceptin, 108 (37%) were 65 years of age or older, while 13 (4.4%) were 75 and over. No overall differences in safety or effectiveness were observed.

Interactions

7 DRUG INTERACTIONS Patients who receive anthracycline after stopping Herceptin may be at increased risk of cardiac dysfunction because of trastuzumab's long washout period based on population PK analysis [see Clinical Pharmacology (12.3)]. If possible, physicians should avoid anthracycline-based therapy for up to 7 months after stopping Herceptin. If anthracyclines are used, the patient's cardiac function should be monitored carefully.

More information

Category Value
Authorisation number BLA103792
Agency product number P188ANX8CK
Orphan designation No
Product NDC 50242-333,50242-134,50242-132
Date Last Revised 11-05-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 1922509
Storage and handling 16.2 Storage Store Herceptin vials in the refrigerator at 2°C to 8°C (36°F to 46°F) until time of reconstitution.
Marketing authorisation holder Genentech, Inc.
Warnings WARNING: CARDIOMYOPATHY, INFUSION REACTIONS, EMBRYO-FETAL TOXICITY, and PULMONARY TOXICITY Cardiomyopathy Herceptin administration can result in sub-clinical and clinical cardiac failure. The incidence and severity was highest in patients receiving Herceptin with anthracycline-containing chemotherapy regimens. Evaluate left ventricular function in all patients prior to and during treatment with Herceptin. Discontinue Herceptin treatment in patients receiving adjuvant therapy and withhold Herceptin in patients with metastatic disease for clinically significant decrease in left ventricular function [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)]. Infusion Reactions; Pulmonary Toxicity Herceptin administration can result in serious and fatal infusion reactions and pulmonary toxicity. Symptoms usually occur during or within 24 hours of Herceptin administration. Interrupt Herceptin infusion for dyspnea or clinically significant hypotension. Monitor patients until symptoms completely resolve. Discontinue Herceptin for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome [see Warnings and Precautions (5.2, 5.4)]. Embryo Fetal Toxicity Exposure to Herceptin during pregnancy can result in oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Advise patients of these risks and the need for effective contraception [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1, 8.3)]. WARNING: CARDIOMYOPATHY, INFUSION REACTIONS, EMBRYO-FETAL TOXICITY, and PULMONARY TOXICITY See full prescribing information for complete boxed warning Cardiomyopathy: Herceptin can result in subclinical and clinical cardiac failure manifesting as CHF, and decreased LVEF, with greatest risk when administered concurrently with anthracyclines. Evaluate cardiac function prior to and during treatment. Discontinue Herceptin for cardiomyopathy. (2.3, 5.1) Infusion Reactions, Pulmonary Toxicity: Discontinue Herceptin for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome. (5.2, 5.4) Embryo-Fetal Toxicity: Exposure to Herceptin during pregnancy can result in oligohydramnios, in some cases complicated by pulmonary hypoplasia and neonatal death. Advise patients of these risks and the need for effective contraception. (5.3, 8.1, 8.3)