Side Effects of Herceptin (trastuzumab)

Herceptin (trastuzumab) is a monoclonal antibody that is part of a chemotherapy regimen that is used to prevent recurrence of breast cancer, and for the treatment of breast cancer that has spread beyond the breast (metastasized).

A cancer cell has various receptors on its surface. Chemicals bind to these receptors and cause changes within the cancer cell. One of the receptors that occurs in about one-third of all breast cancers is called HER2.

HER2 is known to control the growth and development of the cancer cells, and the production of new cancer cells. If HER2 receptors are present in large numbers on the cancer cells (often referred to as overexpression of HER2), then the cancer cells may multiply and grow quickly.

Normally, the immune system produces antibodies that will detect and attack HER2 receptors to slow the growth of cancer cells; however, if HER2 is present in large numbers, the immune system may be unable to control HER2. Herceptin is thought to block the HER2 receptors when there is overexpression, thereby blocking growth of the cancer.

Common side effects of Herceptin include

• diarrhea,
• prickling or burning sensation in the skin,
• upper respiratory or a catheter-related infection,
• increased cough,
• nausea and vomiting,
• rash,
• infusion-related reactions including mild to moderate chills and/or fever,
• insomnia,
• weight loss,
• inflammation of the mouth and lips,
• shortness of breath,
• distortion of taste,
• fatigue,
• pain,
• cough, and
• dizziness.

Other side effects of Herceptin include

• bone pain,
• joint pain,
• muscle pain,
• increased heart rate,
• swelling (edema),
• acne, and
• headache.

Serious side effects of Herceptin include

• heart failure,
• pulmonary toxicity,
• serious allergic reactions,
• fetal toxicity,
• decreased red and/or white blood cells,
• herpes simplex infections,
• urinary tract infections (UTIs),
• depression,
• neutropenia,
• anemia,
• leukopenia,
• sepsis, and
• glomerulonephritis.

Drug interactions of Herceptin include paclitaxel, which may increase blood levels of Herceptin.

Herceptin can cause fetal harm when administered to pregnant women and should not be administered during pregnancy.

It is unknown if Herceptin is excreted in breast milk. Breastfeeding mothers should decide whether to stop nursing or discontinue the drug.

WARNING

• Trastuzumab can cause heart failure, especially when it is combined with cyclophosphamide and anthracycline-containing chemotherapy regimens. Left ventricular function should be monitored prior to and during treatment.
• It should be stopped in patients receiving adjuvant therapy, and withheld in patients with metastatic cancer if the function of the heart decreases significantly.

Common side effects include:

• Diarrhea (25% of patients)
• A prickling or burning sensation in the skin (9% of patients)
• Either an upper respiratory or a catheter-related infection (26% of patients)
• Increased cough (26% of patients)
• Nausea and vomiting (23%-33% of patients)
• Rash (18% of patients)
• infusion-related side effects including mild to moderate chills and/or fever (40% of patients)
• Insomnia
• Weight loss
• Stomatitis
• Shortness of breath
• Distortion of taste
• Fatigue
• Pain
• Cough
• Dizziness

Other side effects include:

• Bone pain
• Joint pain
• Muscle pain
• Increased heart rate
• Body swelling (edema)
• Acne
• Headache

Possible serious side effects include:

• Heart failure
• Pulmonary toxicity
• Serious allergic reactions
• Fetal toxicity
• Decreased red and/or white blood cells,
• Herpes simplex infections
• Urinary tract infections
• Depression
• Neutropenia
• Anemia
• Leukopenia
• Sepsis
• Glomerulonephritis

Trastuzumab can cause serious and fatal infusion reactions and pulmonary toxicity. Symptoms usually occur during treatment or within 24 hours of treatment. The infusion should be interrupted if patients develop shortness of breath or significant reduction in blood pressure, and patients should be monitored until symptoms completely resolve.

Trastuzumab should be stopped if any of the following occurs:

• Anaphylaxis
• Angioedema
• Interstitial pneumonia
• Acute respiratory distress syndrome

Use of trastuzumab during pregnancy can cause oligohydramnios and oligohydramnios sequence, manifesting as pulmonary hypoplasia, skeletal abnormalities, and death of the baby.

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

• Cardiomyopathy
• Infusion Reactions
• Embryo-Fetal Toxicity
• Pulmonary Toxicity
• Exacerbation of Chemotherapy-Induced Neutropenia

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.

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 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 3^a, All Grades^b

• 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)

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

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^a : Per-patient Incidence of New Onset Myocardial Dysfunction (by LVEF) Studies 1, 2, 3 and 4

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 NCICTC 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.

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.

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
• Oligohydramnios or oligohydramnios sequence, including pulmonary hypoplasia, skeletal abnormalities, and neonatal death
• Glomerulopathy
• Immune thrombocytopenia
• Tumor lysis syndrome (TLS): Cases of possible TLS have been reported in patients treated with Herceptin. Patients with significant tumor burden (e.g. bulky metastases) may be at a higher risk. Patients could present with hyperuricemia, hyperphosphatemia, and acute renal failure which may represent possible TLS. Providers should consider additional monitoring and/or treatment as clinically indicated.

• 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.
• 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.