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Herceptin (Trastuzumab) - Side Effects and Adverse Reactions

 
 



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) ]
  • Exacerbation of chemotherapy‑induced neutropenia [ see Warnings and Precautions (5.3) ]
  • Pulmonary toxicity [ see Warnings and Precautions ]

The most common adverse reactions in patients receiving Herceptin 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 ].

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= 3355) or without (n= 3308) 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 Reaction for Study 3, All GradesThe incidence of Grade 3/4 adverse reations was <1% in both arms for each listed term.:
MedDRA (v. 7.1)1 Year HerceptinObservation
Adverse Event Preferred Term(n=1678)(n=1708)
Cardiac
Hypertension64 (4%)35 (2%)
Dizziness60 (4%)29 (2%)
Ejection Fraction Decreased58 (3.5%)11 (0.6%)
Palpitations48 (3%)12 (0.7%)
Cardiac ArrhythmiasHigher level grouping term.40 (3%)17 (1%)
Cardiac Failure Congestive30 (2%)5 (0.3%)
Cardiac Failure9 (0.5%)4 (0.2%)
Cardiac Disorder5 (0.3%)0 (0%)
Ventricular Dysfunction4 (0.2%)0 (0%)
Respiratory Thoracic Mediastinal Disorders
Nasopharyngitis135 (8%)43 (3%)
Cough81 (5%)34 (2%)
Influenza70 (4%)9 (0.5%)
Dyspnea57 (3%)26 (2%)
URI46 (3%)20 (1%)
Rhinitis36 (2%)6 (0.4%)
Pharyngolaryngeal Pain32 (2%)8 (0.5%)
Sinusitis26 (2%)5 (0.3%)
Epistaxis25 (2%)1 (0.06%)
Pulmonary Hypertension4 (0.2%)0 (0%)
Interstitial Pneumonitis4 (0.2%)0 (0%)
Gastrointestinal Disorders
Diarrhea123 (7%)16 (1%)
Nausea108 (6%)19 (1%)
Vomiting58 (3.5%)10 (0.6%)
Constipation33 (2%)17 (1%)
Dyspepsia30 (2%)9 (0.5%)
Upper Abdominal Pain29 (2%)15 (1%)
Musculoskeletal & Connective Tissue Disorders
Arthralgia137 (8%)98 (6%)
Back Pain91 (5%)58 (3%)
Myalgia63 (4%)17 (1%)
Bone Pain49 (3%)26 (2%)
Muscle Spasm46 (3%)3 (0.2%)
Nervous System Disorders
Headache162 (10%)49 (3%)
Paraesthesia29 (2%)11 (0.6%)
Skin & Subcutaneous Tissue Disorders
Rash70 (4%)10 (0.6%)
Nail Disorders43 (2%)0 (0%)
Pruritis40 (2%)10 (0.6%)
General disorders
Pyrexia100 (6%)6 (0.4%)
Edema Peripheral79 (5%)37 (2%)
Chills85 (5%)0 (0%)
Aesthenia75 (4.5%)30 (2%)
Influenza‑like Illness40 (2%)3 (0.2%)
Sudden Death 1 (0.06%)0 (0%)
Infections
Nasopharyngitis135 (8%)43 (3%)
UTI39 (3%)13 (0.8%)
Immune System Disorders
Hypersensitivity10 (0.6%)1 (0.06%)
Autoimmune Thyroiditis4 (0.3%)0 (0%)

The data from Studies 1 and 2 were obtained from 3206 patients enrolled, of which 1635 patients received Herceptin; the median treatment duration was 50 weeks. The median age was 49.0 years (range: 24—80); 84% of patients were White, and 7% were Black, 4% were Hispanic, and 4% were 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 randomized to Herceptin plus chemotherapy as compared to chemotherapy alone: arthralgia (31% vs. 28%), fatigue (28% vs. 22%), infection (22% vs. 14%), hot flashes (17% vs. 15%), anemia (13% vs. 7%), dyspnea (12% vs. 4%), rash/desquamation (11% vs. 7%), neutropenia (7% vs. 5%), headache (6% vs. 4%), and insomnia (3.7% 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 randomized to Herceptin plus chemotherapy as compared to chemotherapy alone: arthralgia (11% vs. 8.4%), myalgia (10% vs. 8%), nail changes (9% vs. 7%), and dyspnea (2.5% vs. 0.1%). 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 5 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), 100% had breast cancer, 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) (Percent of Patients)
Single Agent 1 n = 352Herceptin + Paclitaxel
n = 91
Paclitaxel Alone
n = 95
Herceptin + AC 2
n = 143
AC Alone
n  =  135
Body as a Whole      
   Pain4761625742
   Asthenia4262575455
   Fever3649235634
   Chills324143511
   Headache2636284431
   Abdominal pain2234222318
   Back pain2234302715
   Infection2047274731
   Flu syndrome10125126
   Accidental injury613394
   Allergic reaction38242
Cardiovascular      
   Tachycardia5124105
   Congestive heart failure7111287
Digestive      
   Nausea335197677
   Diarrhea2545294526
   Vomiting2337285349
   Nausea and vomiting81411189
   Anorexia1424163126
Heme & Lymphatic      
   Anemia41493626
   Leukopenia324175234
Metabolic      
   Peripheral edema1022202017
   Edema8108115
Musculoskeletal      
   Bone pain7241877
   Arthralgia6372189
Nervous      
   Insomnia1425132915
   Dizziness1322242418
   Paresthesia948391711
   Depression612132012
   Peripheral neuritis2231622
   Neuropathy113544
Respiratory      
   Cough increased2641224329
   Dyspnea2227264225
   Rhinitis142252216
   Pharyngitis1222143018
   Sinusitis9217136
Skin      
   Rash1838182717
   Herpes simplex212379
   Acne21133<  1
Urogenital      
   Urinary tract infection51814137

1 Data for Herceptin single agent were from 4 studies, including 213 patients from Study 6.
2 Anthracycline (doxorubicin or epirubicin) and cyclophosphamide

The following subsections provide additional detail regarding adverse reactions observed in clinical trials of adjuvant breast, metastatic breast 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, 23 months in the AC‑T arm, 24 months in the AC‑TH arm. In Studies 1 and 2, 6% of patients were not permitted to initiate Herceptin following completion of AC chemotherapy due to cardiac dysfunction (LVEF < 50% or ≥ 15 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 5, Figures 1 and 2).

Table 5 1: Per‑patient Incidence of New Onset Myocardial Dysfunction (by LVEF) Studies 1, 2, 3 and 4
LVEF <50% and Absolute Decrease from BaselineAbsolute LVEF Decrease
LVEF <50%≥10% decrease≥16% decrease<20% and ≥10%≥20%
Studies 1 & 2 2
AC→TH
(n=1606)
22.8%
(366)
18.3%
(294)
11.7%
(188)
33.4%
(536)
9.2%
(148)
AC→T
(n=1488)
9.1%
(136)
5.4%
(81)
2.2%
(33)
18.3%
(272)
2.4%
(36)
Study 3
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 4 3
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)

1 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.
2 Studies 1 and 2 regimens: doxorubicin and cyclophosphamide followed by paclitaxel (AC→T) or paclitaxel plus Herceptin (AC→TH)
3 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
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.

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 (12.5% vs. 6.6% [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%.

Neutropenia

In randomized controlled clinical trials in the adjuvant setting, the incidence of selected NCI‑CTC Grade 4—5 neutropenia (2% vs. 0.7% [Study 2]) and of selected Grade 2—5 neutropenia (7.1% vs. 4.5% [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.

Infection

The overall incidences of infection (46% vs. 30% [Study 5]), of selected NCI‑CTC Grade 2—5 infection/febrile neutropenia (22% vs. 14% [Study 1]) and of selected Grade 3—5 infection/febrile neutropenia (3.3% 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% vs. 5% [Study 1]) and of selected NCI‑CTC Grade 3—5 pulmonary toxicity and spontaneous reported Grade 2 dyspnea (3.4% vs. 1% [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: 12% vs. 4% [Study 1]; NCI‑CTC Grade 2—5: 2.5% vs. 0.1% [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 (3.0% vs. 1.3% [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 (6.2% vs. 4.8% [Study 1]) and of NCI‑CTC Grade 3–5 diarrhea (1.6% 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.

Glomerulopathy

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.

∙ Infusion reaction [ see Warnings and Precautions (5.2) ]

∙ Oligohydramnios [ see Warnings and Precautions (5.6) ]

∙ Glomerulopathy



REPORTS OF SUSPECTED HERCEPTIN SIDE EFFECTS / ADVERSE REACTIONS

Below is a sample of reports where side effects / adverse reactions may be related to Herceptin. The information is not vetted and should not be considered as verified clinical evidence.

Possible Herceptin side effects / adverse reactions in 72 year old female

Reported by a physician from Israel on 2011-10-03

Patient: 72 year old female

Reactions: Glaucoma

Suspect drug(s):
Herceptin



Possible Herceptin side effects / adverse reactions in 49 year old female

Reported by a physician from Japan on 2011-10-07

Patient: 49 year old female weighing 52.0 kg (114.4 pounds)

Reactions: Hypertriglyceridaemia, Hyperuricaemia

Suspect drug(s):
Herceptin
    Dosage: rest by administering 2w a week
    Start date: 2010-04-01

Herceptin
    Indication: Breast Cancer Metastatic
    Start date: 2010-04-07

Xeloda
    Dosage: it was one administering weekly holiday medicine for two weeks.
    Administration route: Oral
    Start date: 2010-03-11
    End date: 2010-05-12

Xeloda
    Dosage: note: it was one administering weekly holiday medicine for two weeks.
    Administration route: Oral
    Indication: Breast Cancer Metastatic

Xeloda
    Dosage: it was one administering weekly holiday medicine for two weeks
    Administration route: Oral
    Start date: 2010-06-01
    End date: 2011-04-25

Xeloda
    Dosage: it was one administering weekly holiday medicine for two weeks
    Administration route: Oral

Other drugs received by patient: Pydoxal; Glycyron; Pravastatin Sodium; Ethyl Icosapentate; Salobel; Bezatol SR; Zetia; Brotizolam



Possible Herceptin side effects / adverse reactions in 62 year old female

Reported by a physician from Japan on 2011-10-11

Patient: 62 year old female weighing 84.0 kg (184.8 pounds)

Reactions: Cerebellar Infarction, Infusion Related Reaction

Adverse event resulted in: hospitalization

Suspect drug(s):
Novorapid
    Dosage: dosage is uncertain
    Indication: Product Used FOR Unknown Indication

Herceptin
    Start date: 2011-07-05
    End date: 2011-07-05

Herceptin
    Dosage: note: dosage is uncertain
    Indication: Breast Cancer
    Start date: 2010-10-25
    End date: 2010-10-25

Herceptin
    Dosage: dosage:uncertain,frequency:unspecified
    Start date: 2011-07-06
    End date: 2011-07-06

Metformin HCL
    Administration route: Oral
    Indication: Product Used FOR Unknown Indication

Aspirin
    Dosage: dosage is uncertain
    Administration route: Oral
    Indication: Product Used FOR Unknown Indication

Herceptin
    Dosage: frequency:1
    Start date: 2010-11-01
    End date: 2011-02-17

Crestor
    Dosage: dosage is uncertain
    Administration route: Oral
    Indication: Product Used FOR Unknown Indication

Other drugs received by patient: Cyclophosphamide; Epirubicin Hydrochloride; Fluorouracil; Paclitaxel



See index of all Herceptin side effect reports >>

Drug label data at the top of this Page last updated: 2008-06-25

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