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As Herceptin is commonly used with other chemotherapeutic agents and radiotherapy it is often difficult to ascertain the causal relationship of an adverse event to a particular drug/radiotherapy.
The corresponding frequency category for each adverse drug reaction is based on the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions should be presented in order of decreasing seriousness. (See Tables 12a and 12b.)
Click on icon to see table/diagram/imageAdditional information for selected adverse drug reactions: Infusion/Administration-related reactions (IRRs/ARRs) and Hypersensitivity: IRRs/ARRs such as chills and/or fever, dyspnoea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation and respiratory distress were seen in all trastuzumab clinical trials and for the IV and the SC formulation (see Precautions).
IRRs/ARRs may be clinically difficult to distinguish from hypersensitivity reactions.
The rate of IRRs/ARRs of all grades varied between studies depending on the indication, whether trastuzumab was given concurrently with chemotherapy or as monotherapy and data collection methodology.
In MBC, the rate of IRRs ranged from 49% to 54% in the trastuzumab containing arm compared to 36% to 58% in the comparator arm (which may have contained other chemotherapy). Severe (grade 3 and above) ranged from 5% to 7% in the trastuzumab containing arm compared to 5 to 6% in the comparator arm.
In EBC, the rate of IRRs/ARRs ranged from 18% to 54% in the trastuzumab containing arm compared to 6% to 50% in the comparator arm (which may have contained other chemotherapy). Severe (grade 3 and above) ranged from 0.5% to 6% in the trastuzumab containing arm compared to 0.3 to 5% in the comparator arm.
In the neoadjuvant-adjuvant EBC treatment setting (BO22227), the rates of IRRs/ARRs were in line with the previous text and were 37.2% in the Herceptin IV arm to 47.8% in the Herceptin SC arm. Severe (grade 3) IRRs/ARRs were 2.0% and 1.7% in the Herceptin IV and Herceptin SC arms, respectively during the treatment phase. There were no grade 4 or 5 IRRs/ARRs.
Anaphylactoid reactions were observed in isolated cases.
Cardiac dysfunction: Congestive heart failure (NYHA Class II-IV) is a common adverse reaction to Herceptin. It has been associated with fatal outcome. Signs and symptoms of cardiac dysfunction such as dyspnoea, orthopnoea, increased cough, pulmonary oedema, S3 gallop, or reduced ventricular ejection fraction, have been observed in patients treated with Herceptin (see Precautions).
Metastatic Breast Cancer: Depending on the criteria used to define cardiac dysfunction, the incidence in the pivotal metastatic trials varied between 9% and 12% in the Herceptin + paclitaxel group, compared with 1% - 4% in the paclitaxel-alone group. For Herceptin monotherapy, the rate was 6% - 9%. The highest rate of cardiac dysfunction was seen in patients receiving concurrent Herceptin + anthracycline/cyclophosphamide (27%), and was significantly higher than in the anthracycline/cyclophosphamide-alone group (7% - 10%). In a subsequent trial with prospective monitoring of cardiac function, the incidence of symptomatic heart failure was 2.2% in patients receiving Herceptin and docetaxel, compared with 0% in patients receiving docetaxel alone. Most of the patients (79%) who developed cardiac dysfunction in these trials experienced an improvement after receiving standard treatment for CHF.
Early Breast Cancer (adjuvant setting): In three pivotal clinical trials of adjuvant trastuzumab given in combination with chemotherapy the incidence of grade 3/4 cardiac dysfunction (symptomatic CHF) was similar in patients who were administered chemotherapy alone and in patients who were administered Herceptin sequentially after a taxane (0.3 - 0.4%). The rate was highest in patients who were administered Herceptin concurrently with a taxane (2.0%). At 3 years, the cardiac event rate in patients receiving AC→P (doxorubicin plus cyclophosphamide followed by paclitaxel) + H (trastuzumab) was estimated at 3.2%, compared with 0.8% in AC→P treated patients. No increase in the cumulative incidence of cardiac events was seen with further follow-up at 5 years.
At 5.5 years, the rates of symptomatic cardiac or LVEF events were 1.0%, 2.3%, and 1.1% in the AC→D (doxorubicin plus cyclophosphamide, followed by docetaxel), AC→DH (doxorubicin plus cyclophosphamide, followed by docetaxel plus trastuzumab), and DCarbH (docetaxel, carboplatin and trastuzumab) treatment arms, respectively. For symptomatic CHF (NCI-CTC Grade 3-4), the 5-year rates were 0.6%, 1.9%, and 0.4% in the AC→D, AC→DH, and DCarbH treatment arms, respectively. The overall risk of developing symptomatic cardiac events was low and similar for patients in the AC→D and DCarbH arms; relative to both the AC→D and DCarbH, arms there was an increased risk of developing a symptomatic cardiac event for patients in the AC→DH arm, being discernable by a continuous increase in the cumulative rate of symptomatic cardiac or LVEF events up to 2.3% compared to approximately 1% in the two comparator arms (AC→D and DCarbH).
When Herceptin was administered after completion of adjuvant chemotherapy NYHA Class III-IV heart failure was observed in 0.6% of patients in the one-year arm after a median follow-up of 12 months. After a median follow-up of 3.6 years the incidence of severe CHF and left ventricular dysfunction after 1 year Herceptin therapy remained low at 0.8% and 9.8%, respectively.
In study BO16348, after a median follow-up of 8 years the incidence of severe CHF (NYHA Class III-IV) in the Herceptin 1 year treatment arm was 0.8%, and the rate of mild symptomatic and asymptomatic left ventricular dysfunction was 4.6%.
Reversibility of severe CHF (defined as a sequence of at least two consecutive LVEF values ≥ 50% after the event) was evident for 71.4% of Herceptin-treated patients. Reversibility of mild symptomatic and asymptomatic left ventricular dysfunction was demonstrated for 79.5% of patients. Approximately 17% of cardiac-dysfunction related events occurred after completion of Herceptin.
In the joint analysis of studies NSABP B-31 and NCCTG N9831, with a median follow-up of 8.1 years for the AC→PH group (doxorubicin plus cyclophosphamide, followed by paclitaxel plus trastuzumab), the per-patient incidence of new onset cardiac dysfunction, as determined by LVEF, remained unchanged compared to the analysis performed at a median follow up of 2.0 years in the AC→PH group: 18.5% of AC→PH patients with an LVEF decrease of ≥10% to below 50%. Reversibility of left ventricular dysfunction was reported in 64.5% of patients who experienced a symptomatic CHF in the AC→PH group being asymptomatic at latest follow up, and 90.3% having full or partial LVEF recovery.
Early Breast Cancer (neoadjuvant-adjuvant setting): In the pivotal trial MO16432, Herceptin was administered concurrently with neoadjuvant chemotherapy containing three cycles of doxorubicin (cumulative dose 180 mg/m2). The incidence of symptomatic cardiac dysfunction was 1.7% in the Herceptin arm. In the pivotal trial BO22227, Herceptin was administered concurrently with neoadjuvant chemotherapy that contained four cycles of epirubicin (cumulative dose 300 mg/m2); at a median follow-up of exceeding 70 months, the incidence of cardiac failure/congestive cardiac failure was 0.3% in the Herceptin IV arm and 0.7% in the Herceptin SC arm. In patients with lower body weights (<59 kg, the lowest body weight quartile) the fixed dose used in the Herceptin SC arm was not associated with an increased risk of cardiac events or significant drop in LVEF.
Advanced Gastric Cancer: In the BO18255 study, at screening, the median LVEF value was 64% (range 48%-90%) in the Fluoropyrimidine/Cisplatin arm (FP) arm and 65% (range 50%-86%) in the Herceptin IV plus Fluoropyrimidine/Cisplatin arm (H+FP) arm.
The majority of the LVEF decreases noted in BO18255 study were asymptomatic, with the exception of one patient in the Herceptin-containing arm whose LVEF decrease coincided with cardiac failure. (See Tables 13 and 14.)
Overall, there were no significant differences in cardiac dysfunction between the treatment arm and the comparator arm.
Haematological toxicity: Breast Cancer: Haematological toxicity is infrequent following the administration of Herceptin IV monotherapy in the metastatic setting, WHO Grade 3 leukopenia, thrombocytopenia and anaemia occurring in < 1% of patients. No WHO Grade 4 toxicities were observed. There was an increase in WHO Grade 3 or 4 haematological toxicity in patients treated with the combination of Herceptin and paclitaxel compared with patients receiving paclitaxel alone (34% versus 21%). Haematological toxicity was also increased in patients receiving Herceptin and docetaxel, compared with docetaxel alone (32% grade 3/4 neutropenia versus 22%, using NCI-CTC criteria). The incidence of febrile neutropenia/neutropenic sepsis was also increased in patients treated with Herceptin plus docetaxel (23% versus 17% for patients treated with docetaxel alone).
Using NCI-CTC criteria, in the BO16348 study, 0.4% of Herceptin-treated patients experienced a shift of 3 or 4 grades from baseline, compared with 0.6% in the observation arm.
Advanced Gastric Cancer: The most frequently reported AEs, of Grade ≥ 3 occurring with an incidence rate of at least 1% by trial treatment, that were categorised under the Blood and Lymphatic System Disorders SOC are shown as follows: See Table 15.
The total percentage of patients who experienced an AE of ≥ grade 3 NCI-CTCAE v3.0 that has been categorised under this SOC were 38% in the FP arm and 40% in the FP + H arm.
Overall, there were no significant differences in haematotoxicity between the treatment arm and the comparator arm.
Hepatic and renal toxicity: Breast Cancer: WHO Grade 3 or 4 hepatic toxicity was observed in 12% of patients following administration of Herceptin IV as single agent, in the metastatic setting. This toxicity was associated with progression of disease in the liver in 60% of these patients.
WHO Grade 3 or 4 hepatic toxicity was less frequently observed among patients receiving Herceptin IV and paclitaxel than among patients receiving paclitaxel alone (7% compared with 15%). No WHO Grade 3 or 4 renal toxicity was observed.
Advanced Gastric Cancer: In the BO18255 study no significant differences in hepatic and renal toxicity were observed between the two treatment arms.
NCI-CTCAE (version 3.0) grade ≥3 renal toxicity was not significantly higher in patients receiving Herceptin IV than those in the F+P arm (3% and 2% respectively).
NCI-CTCAE (version 3.0) grade ≥3 adverse event in the Hepatobiliary Disorders SOC: Hyperbilirubinaemia was the only reported AE and was not significantly higher in patients receiving Herceptin IV than those in the F+P arm (1% and < 1% respectively).
Diarrhoea: Breast Cancer: Of patients treated with Herceptin IV monotherapy in the metastatic setting 27% experienced diarrhoea. An increase in the incidence of diarrhoea, primarily mild to moderate in severity, has also been observed in patients receiving Herceptin in combination with paclitaxel compared with patients receiving paclitaxel alone.
In the BO16348 study, 8% of Herceptin-treated patients experienced diarrhoea during the first year of treatment.
Advanced Gastric Cancer: In the BO18255 study, 109 patients (37%) participating in the Herceptin-containing treatment arm versus 80 patients (28%) in the comparator arm experienced any grade diarrhoea. Using NCI-CTCAE v3.0 severity criteria, the percentage of patients experiencing grade ≥ 3 diarrhoea was 4% in the FP arm versus 9% in the FP+H arm.
Infection: An increased incidence of infections, primarily mild upper respiratory infections of minor clinical significance or catheter infections has been observed in patients treated with Herceptin.
Switching treatment from Herceptin IV to Herceptin SC and vice versa: Study MO22982 investigated switching from Herceptin IV to Herceptin SC, and vice versa, in patients with HER2 positive EBC, with a primary objective to evaluate patient preference for either Herceptin IV infusion or Herceptin SC injection. In this trial, 2 cohorts (one using Herceptin SC Vial and one using Herceptin SC SID) were investigated using a 2-arm, cross-over design with patients being randomized to one of two different q3w Herceptin treatment sequences (Herceptin IV (Cycles 1-4) → Herceptin SC (Cycles 5-8), or Herceptin SC (Cycles 1-4) → Herceptin IV (Cycles 5-8)). Patients were either naïve to Herceptin IV treatment (20.3%) or pre-exposed to Herceptin IV (79.7%) as part of ongoing adjuvant treatment for HER2 positive EBC. Overall, switches from Herceptin IV to Herceptin SC and vice versa were well tolerated. Pre-switch rates (Cycles 1-4) for SAEs, Grade 3 AEs and treatment discontinuations due to AEs were low (<5%) and similar to post-switch rates (Cycles 5-8). No Grade 4 or Grade 5 AEs were reported.
Herceptin SC safety and tolerability in EBC patients: Study MO28048 investigating the safety and tolerability of Herceptin SC as adjuvant therapy enrolled HER2 positive EBC patients in either a Herceptin SC Vial cohort (N=1868 patients, including 20 patients receiving neoadjuvant therapy) or a Herceptin SC SID cohort (N=710 patients, including 21 patients receiving neoadjuvant therapy). The primary analysis included patients with a median follow-up of up to 23.7 months. No new safety signals were observed and results were consistent with the known safety profile for Herceptin IV and Herceptin SC. In addition, treatment of lower body weight patients with Herceptin SC fixed dose in adjuvant EBC was not associated with increased safety risk, AEs and SAEs, compared to the higher body weight patients. The final results of study BO22227 at a median follow-up exceeding 70 months (see Pharmacology: Pharmacodynamics: Clinical/Efficacy Studies under Actions) were also consistent with the known safety profile for Herceptin IV and Herceptin SC, and no new safety signals were observed.
Postmarketing Experience: The following adverse drug reactions have been identified from postmarketing experience with Herceptin (Table 16). (See Table 16.)
Adverse Events: Table 17 as follows indicates adverse events that historically have been reported in patients who have received Herceptin. As no evidence of a causal association has been found between Herceptin and these events, these events are not considered expected for the purposes of regulatory reporting. (See Table 17.)
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