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Herceptin

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Herceptin

Side Effects
Interactions

SIDE EFFECTS

The following adverse reactions are discussed in greater detail in other sections of the label:

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].

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 Herceptincontaining arm in the absence of disease progression were infection, diarrhea, and febrile neutropenia.

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 Herceptin 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 Study 3, 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 3, All Gradesa

Adverse Reaction 1 Year Herceptin
(n= 1678)
Observation
(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 Arrhythmiasb 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%)
Pruritis 40 (2%) 10 (0.6%)
General Disorders
Pyrexia 100 (6%) 6 (0.4%)
Edema Peripheral 79 (5%) 37 (2%)
Chills 85 (5%) 0 (0%)
Aesthenia 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%)
a The incidence of Grade 3/4 adverse reactions was < 1% in both arms for each listed term.
b Higher level grouping term.

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, 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 Agenta
n = 352
Herceptin + Paclitaxel
n = 91
Paclitaxel Alone
n = 95
Herceptin + ACb
n = 143
ACb 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%
a Data for Herceptin single agent were from 4 studies, including 213 patients from Study 6.
b Anthracycline (doxorubicin or epirubicin) and cyclophosphamide.

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/m o2 r2a lly twice a day on Days 1-14 or 5-fluorouracil 800 mg/m /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

Body System/ Adverse Event Herceptin +FC (N = 294) N (%) FC (N = 290) N (%)
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, 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 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 6a: 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 & 2b,c
  AC→TH 23.1% 18.5% 11.2% 37.9% 8.9%
  (n=1856) (428) (344) (208) (703) (166)
  AC→T 11.7% 7.0% 3.0% 22.1% 3.4%
  (n=1170) (137) (82) (35) (259) (40)
Study 3
  Herceptin 8.6% 7.0% 3.8% 22.4% 3.5%
  (n=1678) (144) (118) (64) (376) (59)
  Observation 2.7% 2.0% 1.2% 11.9% 1.2%
  (n=1708) (46) (35) (20) (204) (21)
Study 4d
  TCH 8.5% 5.9% 3.3% 34.5% 6.3%
  (n=1056) (90) (62) (35) (364) (67)
  AC→TH 17% 13.3% 9.8% 44.3% 13.2%
  (n=1068) (182) (142) (105) (473) (141)
  CA→T 9.5% 6.6% 3.3% 34% 5.5%
  (n=1050) (100) (69) (35) (357) (58)
a 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.
b Studies 1 and 2 regimens: doxorubicin and cyclophosphamide followed by paclitaxel (AC→T) or paclitaxel plus Herceptin (AC→TH).
c Median duration of follow-up for studies 1 and 2 combined was 8.3 years in the AC→TH arm.
d Study 4 regimens: doxorubicin and cyclophosphamide followed by docetaxel (AC→T) or docetaxel plus Herceptin (AC→TH); docetaxel and carboplatin plus Herceptin (TCH).

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

Cumulative Incidence of Time to First LVEF Decline of ≥ 10 Percentage Points - Illustration

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.

Cumulative Incidence of Time to First LVEF Decline of ≥ 10 Percentage Points from Baseline and to Below 50% - Illustration

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

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 -  Illustration

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 infusional toxicity 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. Infusional toxicity occurred in 21% and 35% of patients, and was 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 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 Herceptin-treated patients compared to none in the control arm.

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.

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]) 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 postmarketing 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.

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.

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.

Read the Herceptin (trastuzumab) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

In Study 5, the mean serum trough concentration of trastuzumab was consistently elevated approximately 1.5-fold, when administered in combination with paclitaxel as compared to trough concentrations of trastuzumab when administered in combination with an anthracycline and cyclophosphamide. In other pharmacokinetic studies, where Herceptin was administered in combination with paclitaxel, docetaxel, carboplatin, or doxorubicin, Herceptin did not alter the plasma concentrations of these chemotherapeutic agents, or the metabolites that were analyzed. In a drug interaction substudy conducted in patients in Study 7, the pharmacokinetics of cisplatin, capecitabine and their metabolites were not altered when administered in combination with Herceptin.

Read the Herceptin Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 3/19/2014
This monograph has been modified to include the generic and brand name in many instances.

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