Herceptin: Indications, Dosage, Precautions, Adverse Effects
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Herceptin - Product Information

Manufacture: Roche
Country: Australia
Condition: Breast Cancer, Breast Cancer, Adjuvant, Breast Cancer, Metastatic, Esophageal Carcinoma, Gastric Cancer
Class: HER2 inhibitors
Form: Intravenous (IV), Powder
Ingredients: trastuzumab, histidine hydrochloride, histidine, trehalose dihydrate, polysorbate 20

trastuzumab (rch)

Powder for Intravenous (IV) Infusion

CAS-180288-69-1

HERCEPTIN (trastuzumab) is a recombinant DNA-derived humanized monoclonal antibody that selectively targets the extracellular domain of the human epidermal growth factor receptor 2 protein (HER2). The antibody is an IgG1 kappa that contains human framework regions with the complementarity-determining regions of a murine anti-p185 HER2 antibody that binds to HER2. Trastuzumab is composed of 1,328 amino acids and has a molecular weight of ~148 kDa.

The humanized antibody against HER2 is produced by recombinant mammalian cells (Chinese hamster ovary (rch)) in suspension culture in a nutrient medium and purified by affinity chromatography and ion exchange, including specific viral inactivation and removal procedures.

Description

HERCEPTIN is a sterile, white to pale yellow, preservative-free lyophilized powder for IV infusion.

HERCEPTIN is available as a single-dose vial containing 60 mg or 150 mg of trastuzumab with the following excipients: histidine hydrochloride, histidine, trehalose dihydrate and polysorbate 20.

Reconstitution of the 60 mg vial with 3.0 mL of sterile water for injection yields 3.1 mL of a single-dose solution containing approximately 21 mg/mL trastuzumab, at a pH of approximately 6.0. A volume overage of 7.5% ensures that the labelled dose can be withdrawn from each vial.

Reconstitution of the 150 mg vial with 7.2 mL of sterile water for injection yields 7.4 mL of a single-dose solution containing approximately 21 mg/mL trastuzumab, at a pH of approximately 6.0. A volume overage of 4% ensures that the labelled dose can be withdrawn from each vial.

HERCEPTIN solution for subcutaneous (SC) injection (HERCEPTIN SC) is a colourless to yellowish, clear to opalescent and contains 600 mg/5mL of trastuzumab (see separate HERCEPTIN SC Product Information).

Pharmacology

Pharmacodynamics

The HER2 (or c-erbB2) proto-oncogene encodes for a single transmembrane spanning, receptor-like protein of 185 kDa, which is structurally related to the epidermal growth factor receptor.

Trastuzumab has been shown, both in in-vitro assays and in animals, to inhibit the proliferation of human tumour cells that overexpress HER2. In vitro, trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) has been shown to be preferentially exerted on HER2 overexpressing cancer cells compared with cancer cells that do not overexpress HER2. In animal models in vivo, murine anti-HER2 antibody inhibited the growth of human tumours overexpressing HER2, indicating that the humanized antibody (trastuzumab) is likely also to have anti-proliferative activity in vivo against human breast tumours expressing high levels of HER2.

Pharmacokinetics

The pharmacokinetics of trastuzumab have been studied in patients with breast cancer (metastatic and early) and advanced gastric cancer.

Breast Cancer

Short duration IV infusions of 10, 50, 100, 250, and 500 mg HERCEPTIN once weekly in patients demonstrated non-linear pharmacokinetics where clearance decreased with increased dose.

Steady State Pharmacokinetics in Breast Cancer

A population pharmacokinetic method, using data from Phase I, Phase II and pivotal Phase III studies, was used to estimate the steady state pharmacokinetics in metastatic breast cancer patients. For a typical patient (body weight of 68 kg) the clearance of trastuzumab was 0.241 L/day and volume of distribution of the central (Vc) and peripheral (Vp) compartments were 3.02 L, and 2.68 L respectively, with a corresponding elimination half-life ranging from approximately 28-38 days. These indicate steady state pharmacokinetics should therefore be reached by approximately 27 weeks, with mean predicted AUC at steady state (over a three week period) of 1822mg•day/L with weekly dosing and1912 mg•day/L with 3-weekly (once every three weeks) dosing. The estimated mean peak and trough concentrations were 113 mg/L and 69.9 mg/L (weekly) and 184 mg/L and 52.9 mg/L (3-weekly) respectively. Comparable steady state mean Cmax of 225 μg/mL and mean Cmin of 68.9 μg/mL at day 21 of cycle 18, the last cycle of 1 year of treatment have been reported in early breast cancer patients administered HERCEPTIN 3-weekly.

It is expected that serum trastuzumab levels will fall to less than 5% of the trough levels at steady state approximately 27 weeks (190 days or 5 elimination half-lives) after a dose discontinuation.

Detectable concentrations of the circulating extracellular domain of the HER2 receptor (shed antigen) are found in the serum of some patients with HER2 overexpressing tumours. Determination of shed antigen in baseline serum samples revealed that 64% (286/447) of patients had detectable shed antigen, which ranged as high as 1880 μg/L (median = 11 μg/L). Patients with higher baseline shed antigen levels were more likely to have lower serum trough concentrations of trastuzumab. However, with weekly dosing, most patients with elevated shed antigen levels achieved target serum concentrations of trastuzumab (>20 mg/L) by week 6.

Gastric Cancer

Short duration IV infusions of 8 mg/kg followed by 6 mg/kg HERCEPTIN every 3 weeks in patients with advanced gastric cancer demonstrated concentration-dependent clearance comprised of predominantly linear and non-linear components. At very low serum concentrations (below 10μg/mL) non-linear clearance comprises nearly all of the total clearance (7-fold higher than linear clearance). At higher concentrations (25μg/mL) the non-linear clearance component decreases to approximately one-half of total clearance, whilst at higher concentrations (< 75μg/L) clearance becomes predominantly linear.

Steady State Pharmacokinetics in Advanced Gastric Cancer

A two compartment non-linear population pharmacokinetic model, based on data from the Phase III Study BO18255 (ToGA) was used to estimate the steady state pharmacokinetics in patients with advanced gastric cancer administered HERCEPTIN at a loading dose of 8 mg/kg followed by a 3-weekly maintenance dose of 6 mg/kg. At high serum concentrations, total clearance is dominated by linear clearance and the half-life is approximately 26 days. Steady state Cmin is reached in approximately 168 days, due to the non-linear clearance component. The mean predicted steady-state AUC value (over a period of 3 weeks at steady state) is approximately 1213 mg•day/L, and the mean steady-state Cmax and Cmin values are approximately 132 mg/L and 27.6 mg/L respectively. It is expected that serum trastuzumab levels will fall to less than 5% of the trough levels at steady state, approximately 19 weeks after a dose discontinuation.

There are no data on the level of circulating extracellular domain of the HER2 receptor (shed antigen) in the serum of gastric cancer patients.

Pharmacokinetics in Special Populations

Dedicated pharmacokinetic studies in the elderly and those with renal or hepatic impairment have not been carried out. However, in a population PK analysis, age and renal impairment were not shown to affect trastuzumab disposition. The population PK analysis showed that the estimated creatinine clearance (Cockcroft and Gault) does not correlate with the pharmacokinetics of trastuzumab.

Clinical trials

Early Breast Cancer

Early breast cancer is defined as non-metastatic, primary, invasive carcinoma of the breast.

HERCEPTIN in Combination with Adjuvant Chemotherapy

The use of HERCEPTIN in the setting of early breast cancer (after surgery and in association with chemotherapy and, if applicable, radiotherapy) has been studied in four multicentre randomized phase III trials of patients with HER2 positive breast cancer who have completed surgery. In these clinical trials, early breast cancer was limited to operable, primary adenocarcinoma of the breast with positive axillary nodes or node negative disease with additional indicators of a higher degree of risk. The design of these studies is summarized in Table 1 and efficacy results are presented in Tables 2-5.

Table 1: Clinical Trials in Early Breast Cancer
HERA trial


n = 3386
NSAPB B-31 and NCCTG
N9831 trials (joint
analysis)
n = 3763
BCIRG 006


n = 3222
Eligible patients Node positive or node
negative [n = 1098] and
tumour size >1 cm;
Protocol initially unrestricted
but amended and node
negative patients with
tumours ≤1 cm [n =93, 8.5%]
and node negative patients
with tumours >1 and ≤2 cm [n
= 509,46.4%] were included

Node positive or node
negative [n = 190] and
tumour size

  • >2 cm regardless of
    hormonal status; or
  • >1 cm and ER–ve

[n = 63 node-negative and
tumour size ≤2 cm])

Node positive or node
negative and at least 1 of
the following:

  • tumour size > 2 cm and
    ER and PR -ve, or
  • histologic and/or
    nuclear grade 2-3, or
  • age < 35 years
Herceptin dosage
regimen
Loading dose 8 mg/kg,
followed by 6 mg/kg (q3w)
Loading dose 4 mg/kg,
followed by 2 mg/kg (q1w)
Loading dose 4 mg/kg,
followed by 2 mg/kg
(q1w).
After chemo, 6 mg/kg
(q3w)
Duration
of Herceptin
treatment
1 yr or 2 yrs 52 weeks 52 weeks
Chemotherapy
regimen(s)
Various

AC (q3w) followed by IV
paclitaxel as a continuous
IV infusion (AC→P).

Paclitaxel: 80 mg/m2 q1w
for 12 weeks or 175 mg/m2
q3w for 4 cycles (day 1 of
each cycle)

AC followed by docetaxel
(AC→D) or docetaxel and
carboplatin (DCarb)

Docetaxel (IV infusion
over 60 min):
(AC→D): 100 mg/m2 q3w
for 4 cycles or
(DCarb): 75 mg/m2 q3w
for 6 cycles
Carboplatin (at target
AUC):
6 mg/mL/min (IV infusion
over 30 - 60 min) q3w for
a total of 6 cycles.

Timing of Herceptin
in relation to
chemotherapy
After completion of
(neo)adjuvanta
Concurrent (AC→PH) or
sequential (AC→P→H)
Concurrent (AC→DH and
DCarbH)
Median follow-up 1 year (initial evaluation)
[8 years (follow-up
evaluation)]
2 years 3 years

AC = doxorubicin + cyclophosphamide; q3w = every 3 weeks; q1w = weekly chemo = chemotherapy;

a 89% of subjects received adjuvant chemotherapy; 5% received neoadjuvant chemotherapy and 6% received a combination of neoadjuvant and adjuvant chemotherapy.

The HERA trial was designed to compare 1 and 2 years of 3-weekly HERCEPTIN treatment vs. observation in patients with HER2 positive breast cancer following surgery, established chemotherapy and radiotherapy (if applicable). In addition, a comparison of 2 years HERCEPTIN treatment vs. 1 year HERCEPTIN treatment was performed. Patients assigned to receive HERCEPTIN were given an initial loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks for either 1 or 2 years. The efficacy results from the HERA trial are summarized in the following table:

Table 2: Efficacy Results from the HERA Trial at 12 months1 and 8 years2 of median follow up
Parameter Observation Herceptin
1yr treatment
p-value HR
(95% CI)
Disease free survival
No. of patients with event (1 year1) 12.9% 7.5% <0.0001 0.54 (0.44, 0.67)
No. of patients with event (8 year2) 33.6% 27.7% <0.0001 0.76 (0.67, 0.86)
Overall Survivall
No. of patients with event (1 year1 ) 2.4% 1.8% 0.24 0.75 (0.47, 1.21)
No. of patients with event (8 year2) 20.6% 16.3% 0.0005 0.76 (0.65, 0.88)

HR: Hazard ratio; 1 co-primary endpoint of DFS of 1 year vs. observation met the pre-defined statistical boundary; 2 final analysis (includes crossover of 52% of patients from the observation arm to Herceptin)

The HERA trial included a subgroup of patients (n = 602) with small tumours (<2 cm) and node-negative disease. In this subgroup, the relative risk reduction was similar to the overall trial population (HR = 0.50; 95% CI 0.21 - 1.15). However, the benefit in terms of absolute difference in rate of recurrence after 1 year of follow-up was smaller (2.7% recurrence rate with HERCEPTIN vs. 5.5% with observation).

In the final analysis (8 year median follow up) extending HERCEPTIN treatment for a duration of 2 years did not show additional benefit over treatment for 1 year [DFS HR in the intent to treat (ITT) population of 2 years vs. 1 year = 0.99 (95% CI: 0.87, 1.13); p-value = 0.90 and OS HR = 0.98 (0.83, 1.15); p-value = 0.78]. The rate of asymptomatic cardiac dysfunction was increased in the 2-year treatment arm (8.1% vs. 4.6% in the 1-year treatment arm). More patients experienced at least one grade 3 or 4 adverse event in the 2-year treatment arm (20.4%) compared with the 1-year treatment arm (16.3%).

The efficacy results from the joint analysis of the NCCTG 9831 and NSABP B-31 trials are summarized in the following table:

Table 3: Efficacy Results from NSAPB B-31 and NCCTG N9831 trials (joint analysis)
Parameter AC→P AC→PH p-value HR
(95% CI)
Disease recurrence
Rate (Herceptin vs. observation) 15.5% 8.0% <0.0001 0.48 (0.39,
0.59)
Survival
Deaths (Herceptin vs. observation) 5.5% 3.7% 0.014 0.67 (0.48,
0.92)

A: doxorubicin; C: cyclophosphamide; P: paclitaxel; H: Herceptin; HR: Hazard ratio

The efficacy results from the BCIRG 006 are summarized in the following tables:

Table 4: Overview of Efficacy Analyses BCIRG 006 AC→D versus AC→DH
Parameter AC→D
n = 1073
AC→DH
n = 1074
p-value HR
(95% CI)
Disease-free survival (DFS)
No. patients with event 195 134 <0.0001 0.61 (0.49,
0.77)
Death (OS event)
No. patients with event 80 49 0.0024 0.58 (0.40,0.83)

AC→D = doxorubicin plus cyclophosphamide, followed by docetaxel; AC→DH = doxorubicin plus cyclophosphamide, followed by docetaxel plus trastuzumab; CI = confidence interval

Table 5: Overview of Efficacy Analyses BCIRG 006 AC→D versus DCarbH
Parameter AC→D
n = 1073
DCarbH
n = 1075
p-value HR
(95% CI)
Disease-free survival (DFS)
No. patients with event 195 145 0.0003 0.67 (0.54,
0.83)
Death (OS event)
No. patients with event 80 56 0.00182 0.66 (0.47,0.93)

AC→D = doxorubicin plus cyclophosphamide, followed by docetaxel; DCarbH = docetaxel, carboplatin and trastuzumab; CI = confidence interval

Based on studies to date, the optimal duration of adjuvant trastuzumab therapy is 1 year and may be clarified in further randomized trials. However, extending adjuvant treatment beyond 1 year is not recommended (see DOSAGE AND ADMINISTRATION/Duration of Treatment).

Locally Advanced Breast Cancer

Locally advanced breast cancer is defined as the absence of metastatic disease and meeting one or more of the following criteria: inflammatory breast cancer, a primary tumour that extends to the chest wall or skin, tumour > 5 cm with any positive lymph node(s), any tumour with disease in supraclavicular nodes, infraclavicular nodes or internal mammary nodes, any tumour with axillary lymph nodes fixed to one another or other structures.

HERCEPTIN in Combination with Neoadjuvant-Adjuvant Chemotherapy

The use of HERCEPTIN for the neoadjuvant-adjuvant treatment of locally advanced breast cancer has been studied in Study MO16432 (NOAH), a multicentre randomized trial, designed to investigate the concurrent administration of HERCEPTIN with neoadjuvant chemotherapy, including both an anthracycline and a taxane, followed by adjuvant HERCEPTIN, up to a total treatment duration of 1 year. The trial recruited patients with newly diagnosed locally advanced (Stage III) or inflammatory breast cancer. Patients with HER2+ tumours were randomized to receive either neoadjuvant chemotherapy concurrently with neoadjuvant-adjuvant HERCEPTIN (n = 116), or neoadjuvant chemotherapy alone (n = 118).

HERCEPTIN was administered concurrently with 10 cycles of neoadjuvant chemotherapy as follows;

  • Doxorubicin (60 mg/m2) and paclitaxel (150 mg/m2) in combination with HERCEPTIN (8 mg/kg loading dose, followed by 6 mg/kg maintenance, administered 3-weekly) for 3 cycles, followed by
  • Paclitaxel (175 mg/m2) and HERCEPTIN (6mg/kg, administered 3-weekly) for 4 cycles, followed by
  • CMF on day 1 and 8 every 4 weeks for 3 cycles, in combination with 4 cycles of HERCEPTIN (6mg/kg administered 3-weekly), followed by
  • up to 7 additional cycles of HERCEPTIN (6mg/kg, administered 3-weekly) alone to complete 1 year after starting HERCEPTIN

The primary endpoint for the trial, event-free survival (EFS), was defined as the time from randomization to disease recurrence or progression (local, regional, distant or contralateral), or death of any cause. The efficacy results from NOAH (full analysis population, defined as all patients who were randomized in the trial following the intent-to-treat principle, with the exception of 3 patients whose data could not be evaluated) are summarized in the table below. The median duration of follow-up in the HERCEPTIN arm was 3.8 years.

Table 6: Overview of Efficacy Analyses MO16432 (NOAH)
Parameter Chemo +
Herceptin
n = 115
Chemo only
n = 116
p-value HR
(95% CI)
Event-free survival (EFS)
No. patients with event 46 59 p = 0.0275 0.65 (0.44, 0.96)
Total pathological complete
response
^ (95% CI)
40%
(31.0, 49.6)
20.7%
(13.7, 29.2)
p = 0.0014

^defined as absence of any invasive cancer both in the breast and axillary nodes; HR: hazard ratio

The addition of HERCEPTIN to neoadjuvant chemotherapy, followed by adjuvant HERCEPTIN for a total duration of 52 weeks, resulted in a 35% reduction in the risk of disease recurrence/progression. The hazard ratio translates into an absolute benefit, in terms of 3-year event-free survival rate estimates of 13 percentage points (65 % vs. 52 %) in favour of the HERCEPTIN arm.

To date, results are not available comparing the efficacy of HERCEPTIN administered with chemotherapy in the adjuvant setting with that obtained in the neoadjuvant/adjuvant setting.

Metastatic Breast Cancer

There are no data available to establish the efficacy of HERCEPTIN for the treatment of metastatic disease in patients who have previously received the medicine for the treatment of early disease.

The safety and efficacy of HERCEPTIN has been studied in randomized, controlled clinical trials in combination with chemotherapy (Studies H0648g, M77001 and TaNDEM) and in an open-label monotherapy clinical trial (Study H0649g) for the treatment of metastatic breast cancer. All trials studied patients with metastatic breast cancer whose tumours overexpress HER2. Patients were eligible if they had 2+ or 3+ levels of overexpression based on a 0 - 3+ scale by immunohistochemical (IHC) assessment of tumour tissue or whose tumours have HER2 gene amplification as determined by Fluorescence In Situ Hybridization (FISH) test (see DOSAGE AND ADMINISTRATION, Detection of HER2 Overexpression or HER2 Gene Amplification).

HERCEPTIN in Combination with Chemotherapy

Study H0648g was an open-label, randomized controlled, multinational trial of chemotherapy-alone and in combination with HERCEPTIN. Patients with previously untreated metastatic breast cancer were treated with either an anthracycline (doxorubicin 60 mg/m2 or epirubicin 75 mg/m2) plus cyclophosphamide (600 mg/m2) with or without HERCEPTIN or paclitaxel (175 mg/m2 infused over 3 hours) with or without HERCEPTIN. Patients on HERCEPTIN treatment received 4 mg/kg intravenous loading dose on Day 0, followed by weekly infusions of 2 mg/kg from Day 7, which they could continue to receive until evidence of disease progression. Patients who had previously received anthracycline based adjuvant therapy were treated with paclitaxel whereas those who were anthracycline naïve were treated with an anthracycline + cyclophosphamide.

The prospectively defined, primary intent-to-treat analysis indicated that the combination of HERCEPTIN and chemotherapy significantly prolonged time to disease progression (progression-free survival) compared with chemotherapy-alone as first-line treatment of women with metastatic breast cancer who had tumours that overexpressed HER2. The addition of HERCEPTIN to chemotherapy extended the median time to disease progression by 2.8 months representing a 61% increase (p=0.0001).

Both anthracycline-treated and paclitaxel-treated patients benefited from HERCEPTIN treatment, although the effect appeared to be greater in the paclitaxel stratum. The efficacy of HERCEPTIN treatment was further supported by the secondary endpoints of response rate, duration of response and one-year survival (see Table 7 below).

One-year survival rates (the prospectively defined survival endpoint) were significantly better for the HERCEPTIN + chemotherapy versus chemotherapy-alone (79% vs. 68%; p=0.008). With a median follow-up of approximately two years, overall survival is improved for patients initially treated with HERCEPTIN + chemotherapy compared with those receiving chemotherapy-alone (25.4 vs. 20.3 months; p=0.025) with a relative risk of death of 0.769 (95% CI 0.607 - 0.973; p=0.028).

Figure 1 Survival Time: Anthracycline H0648g : Time t±o H DEReCaEPthTIN (Study H0648g)



Figure 2 Survival Time: Paclitaxel ± H0648g : Time tHoE RDCeEPaTtIhN (Study H0648g)



The relative overall survival advantage with the addition of HERCEPTIN was observed in both subgroups: AC [26.8 months (H + AC) vs. 22.8 months (AC-alone); p=0.052] and paclitaxel [22.1 months (H + P) vs. 18.4 months (P-alone); p=0.273] (see also Figures 1 and 2). The analysis of overall survival was, however, greatly confounded by subsequent HERCEPTIN treatment of each of control arms patients, following disease progression, in the open-label extension study, H0659g (59% of patients in the AC-alone group, and 75% of patients in the paclitaxel-alone group subsequently received HERCEPTIN). Hence, the survival advantage seen above, for HERCEPTIN + chemotherapy treatment versus chemotherapy-alone (which includes patients who subsequently received HERCEPTIN) may underestimate the benefit to patients.

Importantly, the efficacy described above was obtained without a significant negative impact on the quality of life. Global quality of life decreased equally in both the chemotherapy-alone group and the HERCEPTIN + chemotherapy group and was most likely related to the effects of cytotoxic chemotherapy. However, at weeks 20 and 32, the global quality of life score had returned to baseline or better than baseline in the group receiving HERCEPTIN + chemotherapy, while it remained low in the chemotherapy-alone arm (see Figure 3 below).

Figure 3 Changes from Baseline in Health-Related Quality-of-Life Scores in Study H0648g



Study M77001 was a multinational, multi-centre, randomized, controlled trial investigating the safety and efficacy of HERCEPTIN in combination with docetaxel, as first-line treatment in HER2 positive metastatic breast cancer patients. One hundred and eighty six patients received docetaxel (100 mg/m2 infused over 1 hour on Day 2) with or without HERCEPTIN (4 mg/kg loading dose, followed by 2 mg/kg weekly). Sixty percent of patients had received prior anthracycline based adjuvant chemotherapy. HERCEPTIN with docetaxel was shown to be efficacious in patients whether or not they had received prior adjuvant anthracyclines and regardless of their oestrogen and/or progesterone receptor status.

The combination of HERCEPTIN + docetaxel significantly increased response rate (61% vs. 34%) and prolonged the median time to disease progression by 4.9 months compared with patients treated with docetaxel-alone (see Table 7). Median survival was also significantly increased in patients receiving the combination therapy compared with those receiving docetaxel-alone (30.5 months vs. 22.1 months) (see Figure 4).

Figure 4 Survival Time: Docetaxel ± HERCEPTIN (Study M77001)



Table 7: Efficacy Outcomes with Combination Therapy for Metastatic Breast Cancer
H0648g M77001
H +
chemo
Chemo
alone
H + AC AC alone H + P P alone H + D D alone
n = 235 n = 234 n = 143 n = 138 n = 92 n = 96 n = 92 n = 94
Median Time to
Disease
Progression
(months, 95%
CI)
7.4 4.6 7.8 6.1 6.9 3.0 10.6 5.7
(7.0, 9.0) (4.4, 5.4) (7.3, 9.4) (4.9, 7.1) (5.3, 9.9) (2.1, 4.3) (7.6, 12.9) (5, 6.5)
p-value a p=0.0001 p=0.0004 p=0.0001 p=0.0001
Response Rate
(%)
50 32 56 42 41 17 61 34
p-value b p<0.0001 p=0.0197 p=0.0002 p=0.0002
Median
Duration of
Response
(months, 95%
CI)
9.1 6.1 9.1 6.7 10.5 4.5 11.4 5.5
(7.7,11) (5.5,7.8) (7.4,12.2) (5.8, 8.2) (7.3, 12.5) (3.9, 6.4) (8.3, 15.0) (4.4, 6.2)
p-value a p=0.0002 p=0.0047 p=0.0124 p=0.0002
Overall Survival
(months, 95%
CI)
24.8 20.5 33.4 22.8 22.1 18.4 30.5 22.1
(22.3,33.7) (17.9,25.3) (22.8,38.1 (18.3,29.8) (16.9,33.7) (12.7,23.8) (26.8, ne) (17.6, 28.9)
p-value a p=0.0540 p=0.1021 p=0.2597 p=0.0062

H = HERCEPTIN; Chemo = chemotherapy; AC = anthracycline + cyclophosphamide; P = paclitaxel; D = docetaxel

a p = log-rank test; b p = Chi-square test, ne = could not be estimated or not yet reached.

HERCEPTIN in Combination with Anastrozole

The TAnDEM trial was a multi-centre, randomized, open-label, phase III trial comparing HERCEPTIN + anastrozole with anastrozole-alone for the first-line treatment of metastatic breast cancer in HER2 overexpressing, hormone-receptor (i.e. oestrogen-receptor (ER) and/or progesterone-receptor (PR)) positive post-menopausal patients. Two hundred and seven patients were randomized to receive oral anastrozole (1 mg/day) with or without HERCEPTIN (4 mg/kg loading dose, followed by 2 mg/kg weekly). Patients who had received HERCEPTIN for early disease were excluded from this trial.

Median progression free survival (PFS) was doubled in the HERCEPTIN + anastrozole arm compared to the anastrozole-alone arm (4.8 months vs. 2.4 months; p = 0.0016). For the other parameters the improvements seen for HERCEPTIN + anastrozole were; overall response (16.5% vs. 6.7%); clinical benefit rate (42.7% vs. 27.9%); time to progression (4.8 months vs. 2.4 months). For time to response and duration of response no difference could be recorded between the arms. There was no significant difference in overall survival, however more than half of the patients in the anastrozole-alone arm crossed over to a HERCEPTIN-containing regimen after progression of disease.

HERCEPTIN Monotherapy

Study H0649g was a multinational, multi-centre, single arm trial of HERCEPTIN as monotherapy in 222 women with HER2 overexpressing metastatic breast cancer. All patients had relapsed following treatment with the best available agents (e.g. anthracyclines and taxanes) and were heavily pre-treated. Two-thirds of the patients had prior adjuvant chemotherapy and all patients had tumour progression following at least one prior regimen of cytotoxic chemotherapy for metastatic disease. Ninety-four percent of the patients had prior anthracycline therapy, approximately 60% had prior paclitaxel therapy and 26% had prior bone marrow or stem cell transplants. Together with HER2 overexpression, which is associated with poorer clinical outcomes, aggressive disease was also suggested by nodal status at diagnosis and by the disease-free interval. Twenty-seven percent of patients had 10 or more positive nodes at the time of diagnosis. Thirty-eight percent of patients had a disease-free interval of less than one year prior to enrolment.

Patients received an intravenous loading dose of 4 mg/kg HERCEPTIN on Day 0, followed by weekly intravenous infusions of 2 mg/kg until there was evidence of disease progression. Patients who developed progressive disease could stop treatment, continue on the 2 mg/kg weekly dose or receive an increased intravenous dose of 4 mg/kg, as the investigator deemed appropriate. The primary efficacy parameter was tumour response rate.

HERCEPTIN as second- or third-line therapy induced objective, durable tumour responses in women with metastatic breast cancer who had tumours that overexpressed HER2. There were 8 complete responses and 26 partial responses yielding an overall response rate of 15%. The durability of the responses was particularly notable. The median duration of the responses was 9.1 months at the cut-off date for analysis (see Table 8 below).

Table 8: Efficacy Outcomes with Monotherapy Study H0649g
Outcome Measure n Time (months)
Kaplan-Meier Estimate of Median (range)
Duration of response 34 9.1 (2–26+)
Time to disease progression 213 3.1 (0–28+)
Time to Treatment Failure 213 2.4 (0–28+)
Survival Time 213 12.8 (0.5–30+)

The clinical significance of the objective tumour responses in this group of patients was supported by the quality-of-life and survival data. Responders had clinically meaningful improvements in physical function, role function, social function, global quality of life and fatigue scale scores during HERCEPTIN treatment. Most responders were still alive at data cut-off (28/34; 82%). The Kaplan-Meier estimate of median survival for all treated patients at the data cut-off date was 12.8 months.

Evidence of efficacy for HERCEPTIN monotherapy is based upon response rates. No data are available to demonstrate improvement in survival or quality of life.

Advanced Gastric Cancer

Study BO18255 (ToGA) was a randomized, open-label, multicentre phase III trial investigating HERCEPTIN in combination with a fluoropyrimidine and cisplatin (FP) versus chemotherapy alone as first-line therapy in patients with HER2 positive, inoperable, locally advanced or recurrent and/or metastatic adenocarcinoma of the stomach or gastro-oesophageal junction.

Patients were eligible if they had 3+ levels of HER2 overexpression based on a 0 - 3+ scale by IHC assessment of tumour tissue and/or those whose tumours had HER2 gene amplification as determined by a FISH test (see DOSAGE AND ADMINISTRATION, Detection of HER2 Overexpression or HER2 Gene Amplification).

After satisfying the screening eligibility criteria, including assessment of HER2 status, patients were randomly assigned (1:1) to receive either HERCEPTIN (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) + fluoropyrimidine/cisplatin (FP+H) or FP alone. The chemotherapy regimen was chosen between 5-FU/cisplatin and capecitabine/cisplatin at the investigator’s discretion and could be determined on an individual patient basis.

The efficacy results from ToGA are summarized in Table 9. The primary endpoint was overall survival, defined as the time from the date of randomization to the date of death from any cause. At the time of analysis a total of 349 randomized patients had died: 182 patients (62.8%) in the control arm and 167 patients (56.8%) in the treatment arm. The majority of the deaths were due to events related to the underlying cancer.

Overall survival was significantly improved in the FP + H arm compared to the FP arm (p = 0.0046, log-rank test). The median survival time was 11.1 months with FP and 13.8 months with FP + H. The risk of death was decreased by 26% (HR = 0.74; 95% CI 0.60 - 0.91) for patients in the FP + H arm compared to the FP arm.

Post-hoc subgroup analyses indicate that targeting tumours with higher levels of HER2 protein (IHC 2+/FISH+ and IHC 3+/regardless of FISH status) results in a greater treatment effect. The median overall survival for the high HER2 expressing group was 11.8 months versus 16 months, HR = 0.65 (95%CI 0.51 - 0.83) and the median PFS was 5.5 months vs. 7.6 months, HR = 0.64 (95% CI 0.51 - 0.79).

Table 9: Summary of Efficacy from Study BO18255
Herceptin dosage regimen Every 3 weeks
Chemotherapy regimens (FP)
  • Capecitabine: 1000 mg/m2 orally twice daily for 14
    days every 3 weeks for 6 cycles (Days 1 to 15 of
    each cycle).
  • 5-FU: 800 mg/m2/day as a continuous IV infusion
    over 5 days, given every 3 weeks for 6 cycles (Days
    1 to 5 of each cycle). The 5-FU infusion could be
    started at the same time as the cisplatin infusion
    on Day 1.
  • Cisplatin: 80 mg/m2 every 3 weeks for 6 cycles (on
    Day 1 of each cycle) as a 2h IV infusion with
    hydration and premedication (steroids and anti-
    emetics).
Efficacy Parameters FP FP+H HR (95% CI) p-value
n = 290 n = 294
Overall Survival, Median months 11.1 13.8 0.74 (0.60-0.91) 0.0046
Progression-Free Survival, Median months 5.5 6.7 0.71 (0.59-0.85) 0.0002
Time to Disease Progression, Median
months
5.6 7.1 0.70 (0.58-0.85) 0.0003
Overall Response Rate, % 34.5 47.3 1.70a (1.22, 2.38) 0.0017
Duration of Response, Median months 4.8 6.9 0.54 (0.40-0.73) <0.0001

FP: fluoropyrimidine/cisplatin; FP+H: fluoropyrimidine/cisplatin + HERCEPTIN; a Odds ratio Progression-free-survival: time between day of randomization and first documentation of progressive disease (PD) or date of death, whichever occurred first. Time to disease progression: time between randomization and first occurrence of PD. Overall response: occurrence of either a confirmed complete (CR) or a partial (PR) best overall response as determined by RECIST criteria from confirmed radiographic evaluations of target and non-target lesions. Duration of response: time from when response (CR or PR) was first documented to the first documented disease progression. This was only calculated for patients who had a best overall response of CR or PR.

Indications

Early Breast Cancer

HERCEPTIN is indicated for the treatment of HER2-positive early breast cancer following surgery, and in association with chemotherapy and, if applicable, radiotherapy.

Locally Advanced Breast Cancer

HERCEPTIN is indicated for the treatment of HER2-positive locally advanced breast cancer in combination with neoadjuvant chemotherapy followed by adjuvant HERCEPTIN.

Metastatic Breast Cancer

HERCEPTIN is indicated for the treatment of patients with metastatic breast cancer who have tumours that overexpress HER2:

  1. as monotherapy for the treatment of those patients who have received one or more chemotherapy regimens for their metastatic disease;
  2. in combination with taxanes for the treatment of those patients who have not received chemotherapy for their metastatic disease; or
  3. in combination with an aromatase inhibitor for the treatment of post-menopausal patients with hormone-receptor positive metastatic breast cancer.

Advanced Gastric Cancer

HERCEPTIN is indicated in combination with cisplatin and either capecitabine or 5-FU for the treatment of patients with HER2 positive advanced adenocarcinoma of the stomach or gastro-oesophageal junction who have not received prior anti-cancer treatment for their metastatic disease.

Contraindications

HERCEPTIN is contraindicated in patients with known hypersensitivity to trastuzumab, Chinese hamster ovary cell proteins or to any of its excipients.

In the treatment of early or locally advanced breast cancer, HERCEPTIN is contraindicated in patients with a left ventricular ejection fraction of less than 45% and those with symptomatic heart failure.

Precautions

General

HERCEPTIN therapy should only be initiated under the supervision of a physician experienced in the treatment of cancer patients. Usual clinical care should be taken to prevent microbial contamination of the intravenous access sites used to deliver HERCEPTIN therapy. HERCEPTIN should be administered by a healthcare professional prepared to manage anaphylaxis and adequate life support facilities should be available. Treatment may be administered in an outpatient setting.

If HERCEPTIN is used concurrently with cytotoxic chemotherapy, the specific guidelines used to reduce or hold the dose of chemotherapy should be followed. Patients may continue HERCEPTIN therapy during periods of reversible chemotherapy-induced myelosuppression, renal toxicity or hepatic toxicity.

Cardiac Dysfunction

General considerations

Patients treated with HERCEPTIN are at increased risk of developing congestive heart failure (CHF) (New York Heart Association [NYHA] class II-IV) or asymptomatic cardiac dysfunction. These events have been observed in patients receiving HERCEPTIN therapy alone or in combination with a taxane following anthracycline (doxorubicin or epirubicin)–containing chemotherapy. This may be moderate to severe and has been associated with death. In addition, caution should be exercised in treating patients with increased cardiac risk e.g. hypertension, documented coronary artery disease, CHF, diastolic dysfunction, older age.

As the half-life of trastuzumab is approximately 28 – 38 days, trastuzumab may persist in the circulation for up to 27 weeks after stopping HERCEPTIN treatment (see Pharmacokinetics). Patients who receive anthracycline after stopping HERCEPTIN may also be at increased risk of cardiac dysfunction. If possible, physicians should avoid anthracycline-based therapy for up to 27 weeks after stopping HERCEPTIN. If anthracyclines are used, the patient’s cardiac function should be monitored carefully.

Candidates for treatment with HERCEPTIN, especially those with prior anthracycline and cyclophosphamide (AC) exposure, should undergo baseline cardiac assessment including history and physical examination, ECG echocardiogram, and/or MUGA scan. Monitoring may help to identify patients who develop cardiac dysfunction, including signs and symptoms of CHF. Cardiac assessments, as performed at baseline, should be repeated every 3 months during treatment and every 6 months following discontinuation of treatment until 24 months from the last administration of HERCEPTIN.

If left ventricular ejection fraction (LVEF) drops 10 percentage points from baseline and to below 50%, HERCEPTIN should be withheld and a repeat LVEF assessment performed within approximately 3 weeks. If LVEF has not improved, or declined further, or clinically significant CHF has developed, discontinuation of HERCEPTIN should be strongly considered, unless the benefits for the individual patient are deemed to outweigh the risks.

Patients who develop asymptomatic cardiac dysfunction may benefit from more frequent monitoring (e.g. every 6 - 8 weeks). If patients have a continued decrease in left ventricular function, but remain asymptomatic, the physician should consider discontinuing therapy if no clinical benefit of HERCEPTIN therapy has been seen.

The safety of continuation or resumption of HERCEPTIN in patients who experience cardiac dysfunction has not been prospectively studied. If symptomatic cardiac failure develops during HERCEPTIN therapy, it should be treated with the standard medications for this purpose. . In the pivotal trials, most patients who developed heart failure or asymptomatic cardiac dysfunction improved with standard heart failure treatment consisting of angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) and a β-blocker. The majority of patients with cardiac symptoms and evidence of a clinical benefit of HERCEPTIN treatment continued on weekly therapy with HERCEPTIN without additional clinical cardiac events.

Early and Locally Advanced Breast Cancer

For patients with early breast cancer, cardiac assessments, as performed at baseline, should be repeated every 3 months during treatment and every 6 months following discontinuation of treatment until 24 months from the last administration of HERCEPTIN. In patients who receive anthracycline containing chemotherapy further monitoring is recommended, and should occur yearly up to 5 years from the last administration of HERCEPTIN, or longer if a continuous decrease of LVEF is observed.

All patients should have a determination of LVEF prior to treatment. Use of HERCEPTIN is contraindicated in patients with early or locally advanced disease and a LVEF of less than 45% and those with symptomatic heart failure (see CONTRAINDICATIONS). Patients with a LVEF of 45 - 55% at baseline should be monitored regularly for symptoms of heart failure during HERCEPTIN treatment.

Patients with history of myocardial infarction (MI), angina pectoris requiring medication, history of or present CHF (NYHA Class II –IV), other cardiomyopathy, cardiac arrhythmia requiring medication, clinically significant cardiac valvular disease, poorly controlled hypertension (hypertension controlled by standard medication eligible), and haemodynamic effective pericardial effusion were excluded from adjuvant and neoadjuvant breast cancer clinical trials with HERCEPTIN.

Adjuvant treatment

HERCEPTIN and anthracyclines should not be given concurrently in the adjuvant treatment setting.

An increase in the incidence of symptomatic and asymptomatic cardiac events was observed when HERCEPTIN was administered after anthracycline-containing chemotherapy compared to administration with a non-anthracycline regimen of docetaxel and carboplatin. The incidence was more marked when HERCEPTIN was administered concurrently with taxanes than when administered sequentially to taxanes. Regardless of the regimen used, most symptomatic cardiac events occurred within the first 18 months.

Risk factors for a cardiac event, identified in 4 large adjuvant studies, included advanced age (> 50 years), low level of baseline and declining LVEF (< 55%), low LVEF prior to or following the initiation of paclitaxel treatment, HERCEPTIN treatment, and prior or concurrent use of anti-hypertensive medications. In patients receiving HERCEPTIN after completion of adjuvant chemotherapy the risk of cardiac dysfunction was associated with a higher cumulative dose of anthracycline given prior to initiation of HERCEPTIN and a high body mass index (> 25 kg/m2).

Neoadjuvant-adjuvant treatment

HERCEPTIN neoadjuvant-adjuvant treatment concurrent with anthracyclines should be used with caution and only in chemotherapy-naive patients. The maximum cumulative doses of the low-dose anthracycline regimens should not exceed 180 mg/m2 (doxorubicin) or 360 mg/m2 (epirubicin).

If patients have been treated concurrently with low-dose anthracyclines and HERCEPTIN in the neoadjuvant setting, no additional cytotoxic chemotherapy should be given after surgery.

Metastatic breast cancer

HERCEPTIN and anthracyclines should not be given concurrently in the metastatic breast cancer setting.

Advanced Gastric Cancer

In advanced gastric cancer, patients with a history of documented congestive heart failure, angina pectoris requiring medication, evidence of transmural myocardial infarction on ECG, poorly controlled hypertension (systolic BP >180 mmHg or diastolic BP >100 mmHg), clinically significant valvular heart disease, high risk uncontrollable arrhythmias, and baseline LVEF <50% (measured by echocardiography or MUGA) were excluded from Study BO18255 (ToGA) according to the study protocol.

Hypersensitivity Reactions including Anaphylaxis

Severe hypersensitivity reactions have been infrequently reported in patients treated with HERCEPTIN. Signs and symptoms include anaphylaxis, urticaria, bronchospasm, angioedema, and/or hypotension. In some cases, the reactions have been fatal. The onset of symptoms generally occurred during an infusion, but there have also been reports of symptom onset after the completion of an infusion. Reactions were most commonly reported in association with the initial infusion.

Patients should be observed closely for hypersensitivity reactions, HERCEPTIN infusion should be interrupted in all patients with severe hypersensitivity reactions. In the event of a hypersensitivity reaction, appropriate medical therapy should be administered, which may include adrenaline, corticosteroids, antihistamines, bronchodilators and oxygen. Patients should be evaluated and carefully monitored until complete resolution of signs and symptoms.

Infusion-Related Reactions (IRRs)

IRRs are known to occur with the administration of HERCEPTIN (see ADVERSE EFFECTS).

Pre-medication may be used to reduce risk of occurrence of IRRs.

Serious IRRs to HERCEPTIN infusion including dyspnoea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation and respiratory distress and supraventricular tachyarrhythmia have been reported (see ADVERSE EFFECTS).

Patients should be observed for IRRs. Interruption of an IV infusion may help control such symptoms and the infusion may be resumed when symptoms abate. These symptoms can be treated with an analgesic/antipyretic such as paracetamol and an antihistamine. Serious reactions have been treated successfully with supportive therapy such as oxygen, intravenous fluids, beta-agonists and corticosteroids. In rare cases, these reactions are associated with a clinical course culminating in a fatal outcome. In other patients with acute onset of signs and symptoms, initial improvement was followed by clinical deterioration and delayed reactions with rapid clinical deterioration have also been reported. Fatalities have occurred within hours or up to one week following an infusion.

Patients who are experiencing dyspnoea at rest due to complications of advanced malignancy or co-morbidities may be at increased risk of a fatal infusion reaction. Therefore, these patients should be treated with extreme caution and the risk versus the benefit considered for each patient (see Pulmonary Reactions).

Pulmonary Reactions

Severe pulmonary events leading to death have been reported with the use of HERCEPTIN in the post-marketing setting. These events may occur as part of an infusion-related reaction (see Infusion-Related Reactions) or with a delayed onset. In addition, cases of interstitial lung disease including lung infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, respiratory distress, acute pulmonary oedema, pulmonary fibrosis and respiratory insufficiency have been reported.

Risk factors associated with interstitial lung disease include prior or concomitant therapy with other anti-neoplastic therapies known to be associated with it such as taxanes, gemcitabine, vinorelbine and radiation therapy. Patients with dyspnoea at rest due to complications of advanced malignancy and co-morbidities may be at increased risk of pulmonary events. Therefore, these patients should not be treated HERCEPTIN.

Ability to Drive and Use Machines

No studies on the effects on the ability to drive and to use machines have been performed. Patients experiencing infusion-related symptoms should be advised not to drive or use machines until symptoms resolve completely.

Effects on Fertility

A study in female cynomolgus monkeys revealed no evidence of impaired fertility at IV trastuzumab doses up to 25 mg/kg twice weekly, corresponding to serum trough levels (serum Cmin) about 15 times higher than that in humans receiving the recommended weekly dose of 2 mg/kg.

Use in Pregnancy – Category D

HERCEPTIN should be avoided during pregnancy and since trastuzumab may persist in the circulation for up to 7 months, pregnancy should be avoided for 7 months after the last dose of HERCEPTIN, unless the anticipated benefit for the mother outweighs the unknown risk to the foetus.

In the post-marketing setting, cases of foetal renal growth and/or function impairment in association with oligohydramnios, some associated with fatal pulmonary hypoplasia of the foetus, have been reported in pregnant women receiving HERCEPTIN.

Women of childbearing potential should be advised to use effective contraception during treatment with HERCEPTIN and for at least 7 months after treatment has concluded. Women who become pregnant should be advised of the possibility of harm to the foetus. If a pregnant woman is treated with HERCEPTIN, or becomes pregnant within 7 months following the last dose of HERCEPTIN, close monitoring by a multidisciplinary team is desirable.

Use in Lactation

A study conducted in lactating cynomolgus monkeys dosed intravenously with trastuzumab at 25 mg/kg twice weekly (serum Cmin about 15 times higher than that in humans receiving the recommended weekly dose of 2 mg/kg) demonstrated that trastuzumab is excreted in the milk. The presence of trastuzumab in the serum of infant monkeys was not associated with adverse effects on their growth or development from birth to 1 month of age. However, the binding affinity of trastuzumab to epidermal growth factor receptor 2 protein in cynomolgus monkeys is unclear.

It is not known whether trastuzumab is excreted in human milk. As human immunoglobulin G (IgG) is secreted into human milk and the potential for harm to the infant is unknown, breast-feeding should be avoided during HERCEPTIN therapy and for 7 months after the last dose of HERCEPTIN.

Paediatric Use

The safety and efficacy of HERCEPTIN in patients under the age of 18 years have not been established.

Use in the Elderly

Clinical experience is limited in patients above 65 years of age. The risk of cardiac dysfunction may be increased in elderly patients. The reported clinical experience is not adequate to determine whether older patients respond differently from younger patients. Elderly patients did not receive reduced doses of HERCEPTIN in clinical trials. However, greater sensitivity to HERCEPTIN in some older patients cannot be ruled out.

Genotoxicity

Trastuzumab did not induce gene mutations in bacteria, nor did it cause chromosomal damage in vitro (chromosome aberration assay in human lymphocytes) or in vivo (mouse micronucleus test).

Carcinogenicity

No studies on the carcinogenic potential of HERCEPTIN have been conducted to date.

Use in Renal Impairment

Formal PK studies have not been conducted in patients with renal impairment. Based on population PK analysis, renal impairment is not expected to influence trastuzumab exposure, however, limited data from patients with moderate to severe renal impairment were included in the population PK analysis (see Pharmacokinetics).

Use in Hepatic Impairment

The use of HERCEPTIN in patients with hepatic impairment has not been studied.

Interactions with other medicines

No formal drug interaction studies have been performed with HERCEPTIN in humans. Clinically significant interactions with concomitant medication used in clinical trials have not been observed. A comparison of serum levels of HERCEPTIN given in combination with cisplatin, doxorubicin or epirubicin-plus-cyclophosphamide has not suggested the possibility of any interaction.

Administration of paclitaxel in combination with HERCEPTIN resulted in a slightly less than two-fold decrease in trastuzumab clearance in a non-human primate study and a 1.5-fold increase in trastuzumab serum levels in clinical studies. Paclitaxel pharmacokinetics determined during the fourth cycle of the alternative 3-weekly HERCEPTIN regimen (n = 25) were not altered appreciably, relative to parameters determined during the initiation of paclitaxel, prior to introduction of HERCEPTIN. Similarly, docetaxel pharmacokinetics determined during the first dose of HERCEPTIN in the standard weekly regimen (n = 10) were not altered appreciably relative to those determined 2 weeks earlier for docetaxel-alone.

A pharmacokinetic interaction substudy of BO18255 (ToGA) performed in male and female Japanese patients with advanced gastric cancer showed that co-administration of trastuzumab and capecitabine and cisplatin had no significant effects on the pharmacokinetics of the two chemotherapy agents compared with co-administration of the two agents without trastuzumab. The pharmacokinetics of trastuzumab were not evaluated in this study.

The administration of concomitant chemotherapy (either anthracycline or cyclophosphamide) did not appear to influence the pharmacokinetics of trastuzumab.

Adverse effects

The adverse drug reactions listed in this section fall into the following categories: 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 are presented in order of decreasing seriousness.

Presented in Table 10 below are adverse reactions that have been reported in association with the use of HERCEPTIN alone, or in combination with chemotherapy in the below pivotal clinical trials as well as in the post-marketing setting.

Early Breast Cancer

  • BO16348 (HERA): HERCEPTIN arm (n=1678). Control arm (n=1708)
  • B-31/N9831 Joint Analysis: HERCEPTIN arms (n=2345). Control arm (n=1673)
  • BCIRG 006: HERCEPTIN arm (n=2133). Control arm (n=1041)
  • BO16216 (TanDEM): HERCEPTIN arm (n=161). Control arm (n=161)

Locally Advanced Breast Cancer

  • MO16432 (NOAH): HERCEPTIN arm (n=115). Control arm (n=116)

Metastatic Breast Cancer (MBC)

  • H0648g / H0649g: HERCEPTIN arms ( n=469 and n=222 respectively)
  • M77001: HERCEPTIN arm (n=92). Control arm (n=94).

Advanced Gastric Cancer

  • BO18255 (ToGA): HERCEPTIN arm (n=294). Control arm (n=290)

All terms included are based on the highest percentage seen in pivotal clinical trials.

Table 10: Adverse Reactions
System organ class Adverse reaction1 Frequency
Nasopharyngitis Very common
Infection Very common
Neutropenic sepsis Common
Cystitis Common
Herpes zoster Common
Influenza Common
Pharyngitis Common
Sinusitis Common
Skin infection Common
Rhinitis Common
Upper respiratory tract infection Common
Urinary tract infection Common
Erysipelas Common
Cellulitis Common
Sepsis Uncommon
Neoplasms benign,
malignant and unspecified
(incl. Cysts and polyps)
Malignant neoplasm progression Not known
Neoplasm progression Not known
Blood and lymphatic system
disorders
Febrile neutropenia Very common
Anaemia Very common
Thrombocytopenia Very common
White blood cell count decreased /
leukopenia
Very common
Neutropenia Very common
Hypoprothrombinaemia Not known
Immune Thrombocytopenia Not known
Immune system disorders Hypersensitivity Common
2Anaphylactic reaction Not known
2Anaphylactic shock Not known
Metabolism and nutrition
disorders
Weight Decreased/Weight Loss Very common
Weight Increased Very common
Decreased appetite Very common
Anorexia Very common
Hyperkalaemia Not known
Psychiatric disorders Insomnia Very common
Depression Common
Anxiety Common
Thinking abnormal Common
Nervous system disorders Tremor3 Very common
Dizziness Very common
Headache Very common
Dysgeusia Very common
Paraesthesia Very common
Hypoaesthesia Very common
Peripheral neuropathy Common
Hypertonia Common
Somnolence Common
Ataxia Common
Paresis Rare
Brain oedema Not known
Eye disorders Conjunctivitis Very common
Lacrimation increased Very common
Dry eye Common
Papilloedema Not known
Retinal haemorrhage Not known
Ear and Labyrinth Disorders Deafness Uncommon
Cardiac disorders 3Blood pressure decreased Very common
3Blood pressure increased Very common
3Heart beat irregular Very common
3Palpitation Very common
3Cardiac flutter Very common
4Ejection fraction decreased Very common
2Cardiac failure (congestive) Common
2,3Supraventricular tachyarrhythmia Common
Cardiomyopathy Common
Pericardial effusion Uncommon
Cardiogenic shock Not known
Pericarditis Not known
Bradycardia Not known
Gallop rhythm present Not known
Vascular disorders Lymphoedema Very common
Hot flush Very common
2,3Hypotension Common
Hypertension Common
Vasodilatation Common
Respiratory, thoracic and
mediastinal disorders
2,3Wheezing Very common
2Dyspnoea Very common
Cough Very common
Epistaxis Very common
Rhinorrhoea Very common
Oropharyngeal pain Very common
Asthma Common
Lung disorder Common
2Pleural effusion Common
2Pneumonia Common
Pneumonitis Uncommon
2Pulmonary fibrosis Not known
2Respiratory distress Not known
2Respiratory failure Not known
2Lung infiltration Not known
2Acute pulmonary oedema Not known
2Acute respiratory distress syndrome Not known
2Bronchospasm Not known
2Hypoxia Not known
2Oxygen saturation decreased Not known
Laryngeal oedema Not known
2Orthopnoea Not known
Pulmonary oedema Not known
Interstitial lung disease Not known
Gastrointestinal disorders Diarrhoea Very common
Vomiting Very common
Nausea Very common
Lip swelling Very common
Abdominal pain Very common
Stomatitis Very common
Pancreatitis Very common
Constipation Very common
Dyspepsia Very common
Haemorrhoids Common
Dry mouth Common
Hepatobiliary disorders Hepatocellular Injury Common
Hepatitis Common
Liver Tenderness Common
Jaundice Rare
Hepatic Failure Not known
Skin and subcutaneous
disorders
Erythema Very common
Rash Very common
Swelling face3 Very common
Palmar-plantar erythrodysaesthesia
syndrome
Very common
Nail disorder Very common
Alopecia Very common
Dry skin Common
Ecchymosis Common
Hyperhydrosis Common
Maculopapular rash Common
Acne Common
Onychoclasis Common
Pruritus Common
Dermatitis Common
Urticaria Uncommon
Angioedema Not known
Musculoskeletal and
connective tissue disorders
Arthralgia Very common
Muscle tightness Very common
Myalgia Very common
Arthritis Common
Back pain Common
Bone pain Common
Muscle spasms Common
Neck pain Common
Pain in extremity Common
Renal and urinary
conditions
Renal disorder Common
Glomerulonephritis membranous Not known
Glomerulonephropathy Not known
Renal failure Not known
Pregnancy, puerperium and
perinatal disorders
Oligohydramnios Not known
Renal hypoplasia Not known
Pulmonary hypoplasia Not known
Reproductive system and
breast disorders
Breast inflammation/mastitis Common
General disorders and
administration site
conditions
Asthenia Very common
Chest pain Very common
Chills Very common
Fatigue Very common
Influenza-like symptoms Very common
Infusion related reaction Very common
Pain Very common
Pyrexia Very common
Peripheral oedema Very common
Mucosal inflammation Very common
Malaise Common
Oedema Common
Injury, poisoning and
procedural complications
Nail toxicity Very common
Contusion Common

1 Adverse drug reactions (ADRs) were identified as events that occurred with at least a 2% difference compared to the control arm in at least one of the major randomised clinical trials

2 Denotes adverse reactions that have been reported in association with a fatal outcome.

3 Denotes adverse reactions that are reported largely in association with Infusion-related reactions. Specific percentages for these are not available.

4 Observed with combination therapy following anthracyclines and combined with taxanes

The following information is relevant to all indications.

Infusion-Related Reactions (IRRs) and Hypersensitivity

IRRs such as chills and/or fever, dyspnoea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation and respiratory distress were seen in all HERCEPTIN clinical trials (see PRECAUTIONS).

IRRS may be clinically difficult to distinguish from hypersensitivity reactions.

The rate of IRRs of all grades varied between studies depending on the indication, whether HERCEPTIN was given concurrently with chemotherapy or as monotherapy and data collection methodology.

In early breast cancer, the rate of IRRs ranged from 18% to 54% in the HERCEPTIN containing arm compared to 6% to 50% in the comparator arm (which may have contained other chemotherapy). Severe reactions (grade 3 and above) ranged from 0.5% to 6% in the HERCEPTIN containing arm compared to 0.3% to 5 % in the comparator arm.

In metastatic breast cancer, the rate of IRRs ranged from 49% to 54% in the HERCEPTIN containing arm compared to 36% to 58% in the comparator arm (which may have contained other chemotherapy), Severe reactions (grade 3 and above) ranged from 5 % to 7% in the HERCEPTIN containing arm compared to 5% to 6% in the comparator arm.

Anaphylactoid reactions were observed in isolated cases (see PRECAUTIONS).

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 heart failure, such as dyspnoea, orthopnoea, increased cough, pulmonary oedema, and S3 gallop or reduced ventricular ejection fraction, have been observed in patients treated with HERCEPTIN (see PRECAUTIONS).

Locally Advanced Breast Cancer (neoadjuvant –adjuvant setting)

In the clinical trial setting, when HERCEPTIN was administered concurrently with neoadjuvant chemotherapy containing 3-4 cycles of a neoadjuvant anthracycline (cumulative doxorubicin dose 180 mg/m2 or epirubicin dose 360 mg/m2) overall, the incidence of symptomatic cardiac dysfunction was up to 1.7 % in the HERCEPTIN arm.

Early Breast Cancer (adjuvant setting)

In 3 pivotal clinical trials of adjuvant HERCEPTIN 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 to 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 (HERCEPTIN) 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 HERCEPTIN) 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 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 1 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.

After a median follow-up of 8 years the incidence of severe CHF (NYHA Class III & IV) following 1 year of HERCEPTIN therapy (combined analysis of the two HERCEPTIN treatment arms) 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 HERCEPTIN-treated 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): in patients with a symptomatic CHF event, while data are missing for 22.6%, 64.5% were known to recover, and 12.9% experienced no recovery. The median time to first recovery by LVEF status occurred at 8.3 months (range 1 – 104 months); 90.3% experienced a full or partial LVEF recovery.

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 subgroup, compared with 1% - 4% for the paclitaxel-alone subgroup. For HERCEPTIN monotherapy, the rate was 6 - 9%. The highest rate of cardiac dysfunction was seen in patients receiving concurrent HERCEPTIN + anthracycline / cyclophosphamide (27%), significantly higher than in the anthracycline / cyclophosphamide-alone subgroup (7 - 10%). In study M77001 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 heart failure.

Advanced Gastric Cancer

In Study BO18255 (ToGA), at screening, the median LVEF value was 64% (range 48% - 90%) in the fluoropyrimidine/cisplatin (FP) arm and 65% (range 50% - 86%) in the HERCEPTIN + FP arm.

The majority of the LVEF decreases noted in Study BO18255 (ToGA) were asymptomatic, with the exception of 1 patient in the HERCEPTIN arm whose LVEF decrease coincided with cardiac failure.

Table 11: Summary of LVEF Change from baseline (Study BO18255)
LVEF Decrease#:
Lowest Post-screening Value
FP
(n = 290)
(% patients in each treatment
arm)
FP + H
(n = 294)
(% patients in each treatment arm)
LVEF decrease ≥10% to <50% 1.1% 4.6%
Absolute Value <50% 1.1% 5.9%
LVEF decrease ≥ 10% to ≥ 50% 11.8% 16.5%

FP: fluoropyrimidine/cisplatin; FP+H: fluoropyrimidine/cisplatin + HERCEPTIN; #Only includes patients whose method of assessment at that visit is the same as at their initial assessments (FP: n = 187 and FP + H: n = 237).

Table 12: Cardiac Adverse Events (Study BO18255)
FP
(n = 290)
(% patients in each treatment
arm)
FP+H
(n = 294)
(% patients in each treatment
arm)
Total Cardiac Events 6% 6%
≥ Grade 3 NCI CTCAE v3.0 3% a 1% b

FP: fluoropyrimidine/cisplatin; FP+H: fluoropyrimidine/cisplatin + HERCEPTIN; a 9 patients experienced 9 Events; b 4 patients experienced 5 Events

Overall, there were no significant differences in cardiotoxicity between the treatment arm and the comparator arm.

Haematological Toxicity

Breast Cancer

Monotherapy– Study H0649g

Haematological toxicity is infrequent following the administration of HERCEPTIN as monotherapy in the metastatic setting, WHO Grade 3 leucopenia, thrombocytopenia and anaemia occurring in <1% of patients. No WHO Grade 4 toxicities were observed.

Combination Therapy – Studies H0648g and M77001

WHO Grade 3 or 4 haematological toxicity was observed in 63% of patients treated with HERCEPTIN and an anthracycline/cyclophosphamide compared to an incidence of 62% in patients treated with the anthracycline/cyclophosphamide combination without HERCEPTIN.

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% vs. 21%). Haematological toxicity was also increased in patients receiving HERCEPTIN and docetaxel, compared with docetaxel-alone (32% grade 3/4 neutropenia vs. 22%, using NCI-CTC criteria). The incidence of febrile neutropenia/neutropenic sepsis was also increased in patients treated with HERCEPTIN + docetaxel (23% vs. 17% for patients treated with docetaxel-alone).

Early Setting – HERA Trial

Using NCI-CTC criteria, in the BO16348 (HERA) trial, 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 adverse events categorized under the Blood and Lymphatic System Disorders SOC (Grade ≥3) are shown below by trial treatment.

Table 13: Frequently reported adverse events grade ≥ 3 in blood and lymphatic System Disorders (SOC)
FP
(n = 290)
(% patients in each treatment
arm)
FP+H
(n = 294)
(% patients in each treatment
arm)
Neutropenia 30% 27%
Anaemia 10% 12%
Febrile
neutropenia
3% 5%
Thrombocytopenia 3% 5%

FP: fluoropyrimidine/cisplatin; FP+H: fluoropyrimidine/cisplatin + HERCEPTIN

The total percentage of patients who experienced an adverse event of ≥ Grade 3 NCI CTCAE v3.0 categorized 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

Monotherapy– Study H0649g

WHO Grade 3 or 4 hepatic toxicity was observed in 12% of patients following administration of HERCEPTIN as monotherapy in the metastatic setting. This toxicity was associated with progression of disease in the liver in 60% of these patients. No WHO Grade 3 or 4 renal toxicity was observed.

Combination Therapy – Study H0648g

WHO Grade 3 or 4 hepatic toxicity was observed in 6% of patients treated with HERCEPTIN and an anthracycline/cyclophosphamide compared with an incidence of 8% in patients treated with the anthracycline/cyclophosphamide combination without HERCEPTIN. No WHO Grade 3 or 4 renal toxicity was observed.

WHO Grade 3 or 4 hepatic toxicity was less frequently observed among patients receiving HERCEPTIN and paclitaxel than among patients receiving paclitaxel-alone (7% vs.15%). No WHO Grade 3 or 4 renal toxicity was observed.

Advanced Gastric Cancer

In Study BO18255 (ToGA) no significant differences in hepatic and renal toxicity were observed between the two treatment arms.

NCI-CTCAE (v3.0) grade ≥ 3 renal toxicity was not significantly higher in patients receiving HERCEPTIN than those in the fluoropyrimidine/cisplatin arm (3% and 2% respectively).

NCI-CTCAE (v3.0) grade ≥ 3 adverse events in the Hepatobiliary Disorders SOC: Hyperbilirubinaemia was the only reported adverse event and was not significantly higher in patients receiving HERCEPTIN than those in the fluoropyrimidine/cisplatin arm (1% and <1% respectively).

Diarrhoea

Breast Cancer

Monotherapy– Study H0649g

Of patients treated with HERCEPTIN monotherapy in the metastatic setting, 27% experienced diarrhoea.

Combination Therapy – Studies H0648g and M77001

An increase in the incidence of diarrhoea, primarily mild to moderate in severity, has been observed in patients receiving HERCEPTIN in combination with chemotherapy compared with patients receiving chemotherapy-alone or HERCEPTIN-alone.

Early Setting – HERA Study

In the HERA trial, 8% of HERCEPTIN treated patients experienced diarrhoea during the first year of treatment.

Advanced Gastric Cancer

In Study BO18255 (ToGA), 109 patients (37%) in the HERCEPTIN treatment arm versus 80 patients (28%) in the comparator arm experienced any grade diarrhoea. Four percent (4%) of patients in the fluoropyrimidine/cisplatin arm experienced Grade ≥ 3 diarrhoea vs. 9% in the HERCEPTIN arm.

Infection

An increased incidence of infections, primarily mild upper respiratory infections of minor clinical significance or catheter infections, has been observed primarily in patients treated with HERCEPTIN + chemotherapy compared with patients receiving chemotherapy-alone or HERCEPTIN-alone.

Laboratory Abnormalities

Febrile neutropenia occurs very commonly. Commonly occurring adverse reactions include anaemia, leukopenia, thrombocytopenia and neutropenia. The frequency of occurrence of hypoprothrombinemia is not known.

Immunogenicity

In a neoadjuvant-adjuvant breast cancer trial, 7.1% of patients treated with HERCEPTIN developed antibodies against trastuzumab (regardless of antibody presence at baseline).

The clinical relevance of these antibodies is not known. However the pharmacokinetics, efficacy [determined by pathological complete response (pCR)] or safety [determined by the occurrence of administration related reaction (ARRs)] of trastuzumab did not appear to be adversely affected by these antibodies.

Dosage and administration

HER2 testing is mandatory prior to initiation of HERCEPTIN therapy (refer to Detection of HER2 Protein Overexpression and Gene Amplification below).

In order to prevent medication errors it is important to check the vial labels to ensure the medicine being prepared and administered is HERCEPTIN (trastuzumab) and not KADCYLA (trastuzumab emtansine).

It is important to check the labels to ensure the correct formulation (intravenous or subcutaneous) is being administered to the patient as was prescribed. Limited information is currently available on switches from one formulation to the other. Switching patients from SC to IV formulation has not been studied.

In order to improve traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded in the patient medical record. Substitution by any other biological medicinal product requires the consent of the prescribing physician.

Recommended Dosage

Early Breast Cancer

Three-weekly schedule: the recommended initial loading dose is 8 mg/kg body weight, followed by a maintenance dose of 6 mg/kg body weight administered at 3 weekly intervals.

Weekly schedule: the recommended initial loading dose is 4 mg/kg body weight, followed by a maintenance dose of 2 mg/kg body weight administered at weekly intervals.

Locally Advanced Breast Cancer

Three-weekly schedule: the recommended initial loading dose is 8 mg/kg body weight, followed by a maintenance dose of 6 mg/kg body weight administered at 3 weekly intervals.

Metastatic Breast Cancer

Three-weekly schedule: the recommended initial loading dose is 8 mg/kg body weight, followed by a maintenance dose of 6 mg/kg body weight administered at 3 weekly intervals.

Weekly schedule: the recommended initial loading dose is 4 mg/kg body weight, followed by a maintenance dose of 2 mg/kg body weight administered at weekly intervals.

Advanced Gastric Cancer

Three-weekly schedule: the recommended initial loading dose is 8 mg/kg body weight, followed by a maintenance dose of 6 mg/kg body weight administered at 3-weekly intervals.

Refer to the CLINICAL TRIALS section (including Table 2 for early breast cancer) for the sequence and dosing of chemotherapy medicines used in the supporting pivotal trials. Refer also to the currently approved product information for the chemotherapy partners.

Administration

HERCEPTIN IV solution is not to be used for subcutaneous administration and must be administered as an IV infusion. Do not administer as an IV push or bolus.

HERCEPTIN IV loading doses should be administered over approximately 90 minutes. If the loading dose was well tolerated, subsequent doses can be administered as a 30 minute infusion.

Patients should be observed for fever and chills or other infusion-associated symptoms (see ADVERSE EFFECTS). Interruption of the infusion and/or medication may help to control such symptoms. The infusion may be resumed when symptoms abate.

Duration of Treatment

Patients with early or locally advanced breast cancer should be treated for 1 year or until disease recurrence, whichever occurs first. However, extending adjuvant treatment beyond one year is not recommended (see CLINICAL TRIALS, Early breast cancer).

Patients with metastatic breast cancer and advanced gastric cancer should be treated until progression of disease.

Missed Doses

If the patient has missed a dose of HERCEPTIN by one week or less, then the usual maintenance dose of HERCEPTIN (weekly regimen: 2 mg/kg; 3-weekly: 6 mg/kg) should be administered as soon as possible (do not wait until the next planned cycle). Subsequent maintenance doses should then 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 regimen: 4 mg/kg; 3-weekly: 8 mg/kg) as soon as possible. Subsequent maintenance doses (weekly regimen: 2 mg/kg; 3-weekly: 6 mg/kg) should be administered 7 days or 21 days later according to the weekly or three-weekly schedules, respectively.

Dose Reduction

No reductions in the dose of HERCEPTIN were made during clinical trials. Patients may continue HERCEPTIN therapy during periods of reversible, chemotherapy-induced myelosuppression, but they should be carefully monitored for complications of neutropenia during this time. The specific instructions to reduce or hold the dose of chemotherapy should be followed.

Use in Elderly: In clinical trials, elderly patients did not receive reduced doses of trastuzumab. Age has been shown to have no effect on the disposition of trastuzumab (see PHARMACOKINETICS, Pharmacokinetics in Special Populations).

Detection of HER2 Protein Overexpression or HER2 Gene Amplification

HERCEPTIN should only be used in patients whose tumours have HER2 protein overexpression or HER2 gene amplification.

To ensure accurate and reproducible results, testing must be performed in a specialized laboratory, which can ensure validation of the testing procedures.

HER2 protein overexpression should be detected using an immunohistochemistry (IHC)-based assessment of fixed tumour blocks. HER2 gene amplification should be detected using in situ hybridization (ISH) of fixed tumour blocks. Examples of ISH include fluorescence in situ hybridization (FISH), chromogenic in situ hybridization (CISH) and silver in situ hybridization (SISH).

For any other method to be used for the assessment of HER2 protein or gene expression, the test method must be precise and accurate enough to demonstrate overexpression of HER2 (it must be able to distinguish between moderate (congruent with 2+) and strong (congruent with 3+) HER2 overexpression).

For full instructions on the use of these assays and interpretation of the results please refer to the package inserts of validated FISH, CISH and SISH assays. Official recommendations on HER2 testing may also apply.

Breast Cancer

HERCEPTIN treatment is only appropriate if there is strong HER2 overexpression, as described by a 3+ score by IHC or a positive ISH result. For patients with an intensity score of 2+ on IHC, confirmation of HER2 positive status by ISH is mandatory.

Advanced Gastric Cancer

HERCEPTIN treatment is only appropriate if there is HER2 overexpression, as described by a 3+ IHC score. For cases with a score of less than 3+ by IHC, confirmation of HER2 positive status by ISH is mandatory.

Bright-field ISH technology is recommended for advanced gastric cancer samples to enable evaluation of tumour histology and morphology in parallel. Either FISH or SISH are recommended for detecting HER2 gene amplification in advanced gastric cancer tissue.

Preparation for IV infusion

Reconstituting the Powder

Appropriate aseptic technique should be used.

HERCEPTIN should be carefully handled during reconstitution. Causing excessive foaming during reconstitution or shaking the reconstituted HERCEPTIN may result in problems with the amount of HERCEPTIN that can be withdrawn from the vial.

Each 60 mg vial should be reconstituted with 3.0 mL of sterile water for injections as the solvent. The use of other solvents should be avoided. The resultant solution is 3.1 mL of approximately 21 mg/mL trastuzumab. A 7.5% overage is included to ensure withdrawal of the labelled dose of 60 mg.

Each 150 mg vial should be reconstituted with 7.2 mL of sterile water for injections as the solvent. The use of other solvents should be avoided. The resultant solution is 7.4 mL of approximately 21 mg/mL trastuzumab. A 4% overage is included to ensure withdrawal of the labelled dose of 150 mg.

Instructions for Reconstitution

  1. Using a sterile syringe, slowly inject 7.2 mL (for 150 mg vial) or 3.0 mL (for 60 mg vial) of sterile water for injections in the vial containing the lyophilized HERCEPTIN, directing the stream into the lyophilized cake.
  2. Swirl vial gently to aid reconstitution. HERCEPTIN may be sensitive to shear-induced stress, e.g. agitation or rapid expulsion from a syringe. DO NOT SHAKE.

Slight foaming of the product upon reconstitution is not unusual. Allow the vial to stand undisturbed for approximately 5 minutes. The reconstituted preparation results in a colourless to pale yellow transparent solution and should be essentially free of visible particulates.

Instructions for Dilution

Weekly Regimen: Determine the volume of the reconstituted solution required based on a loading dose of trastuzumab 4 mg/kg body weight, or a maintenance dose of trastuzumab 2 mg/kg body weight:



Three-Weekly Regimen: Determine the volume of the reconstituted solution required based on a loading dose of trastuzumab 8 mg/kg body weight, or subsequent every 3 weeks dose of 6 mg/kg body weight:



Preparation and Stability of the Admixture

The appropriate amount of the reconstituted solution should be withdrawn from the vial and added to an infusion bag containing 250 mL of 0.9% sodium chloride.

Dextrose (5%) solution should not be used since it causes aggregation of the protein. HERCEPTIN SHOULD NOT BE MIXED OR DILUTED WITH OTHER MEDICINES. No incompatibilities between HERCEPTIN and polyvinylchloride, polyethylene or polypropylene bags have been observed.

The infusion bag should be gently inverted to mix the solution in order to avoid foaming. Parenteral drug products should be inspected visually for particulates and discoloration prior to administration.

From a microbiological point of view, the HERCEPTIN infusion solution should be used immediately. If diluted aseptically, it may be stored for 24 hours when refrigerated at 2 to 8°C.

Overdosage

There is no experience with overdosage in human clinical trials. Single doses higher than 10 mg/kg have not been tested.

Treatment of overdose should consist of general supportive measures.

For information on the management of overdose, contact the Poisons Information Centre (in Australia call 13 11 26; in New Zealand call 0800 767 766).

Presentation and storage conditions

HERCEPTIN powder for IV infusion is available as:

  • single-dose 60 mg vial or
  • single-dose 150 mg vial

The contents of the sterile vial appear as a lyophilized, white to pale yellow powder. The reconstituted HERCEPTIN solution contains approximately 21 mg/mL of trastuzumab.

Storage

Store HERCEPTIN 60 mg and 150 mg vials at 2 to 8°C. Refrigerate. Do not freeze. Do not use beyond the expiration date stamped on the vial.

Reconstituted Solution

A vial of HERCEPTIN reconstituted with sterile Water for Injections without preservative should be used immediately and any unused portion must be discarded. Product is for single use in one patient only. Do not freeze the reconstituted solution.

Diluted Solution for Infusion

From a microbiological point of view, the HERCEPTIN infusion solution should be diluted and used immediately. The product is not intended to be stored after dilution. Solutions of HERCEPTIN for infusion are physically and chemically stable in polyvinylchloride, polyethylene or polypropylene bags containing 0.9% sodium chloride at 2 to 8°C for 24 hours. Diluted HERCEPTIN has been shown to be stable for up to 24 hours at temperatures up to 30°C.

Disposal of Medicines

The release of medicines into the environment should be minimized. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided. Unused or expired medicine should be returned to a pharmacy for disposal.

Name and address of the sponsor

Roche Products Pty Limited

ABN 70 000 132 865

4–10 Inman Road

Dee Why NSW 2099


Medical enquiries: 1800 233 950

Poison schedule of the medicine

Schedule 4 – Prescription Only Medicine

Date of first inclusion in the australian register of therapeutic goods (the artg)

14 September 2000