Herceptin

Herceptin

trastuzumab

Manufacturer:

Roche

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Trastuzumab.
Description
Active ingredient: trastuzumab.
Sterile product.
IV: 150 mg single dose vial containing powder for concentrate for solution for infusion.
Reconstituted Herceptin concentrate contains 21 mg/ml of trastuzumab.
440 mg multidose vial containing powder for concentrate for solution for infusion.
Solvent vial: water for injection containing 1.1% benzyl alcohol as an antimicrobial preservative (bacteriostatic water for injection).
Reconstituted Herceptin concentrate contains 21 mg/ml of trastuzumab.
SC: Herceptin SC formulation in vial (Herceptin SC Vial): 600 mg/5 ml fixed dose vial containing solution for injection (do not reconstitute or dilute).
Excipients/Inactive Ingredients: IV: Herceptin vial: L-histidine HCl, L-histidine, α,α-trehalose dihydrate, polysorbate 20.
SC: Herceptin SC contains recombinant human hyaluronidase (rHuPH20), an enzyme used to increase the dispersion and absorption of co-administered drugs when administered subcutaneously.
All other excipients described as registered locally.
Action
Pharmacotherapeutic Group: Antineoplastic agent. ATC Code: L01XC03.
Pharmacology: Pharmacodynamics: Mechanism of Action: Trastuzumab is a recombinant humanised monoclonal antibody that selectively targets the extracellular domain of the human epidermal growth factor receptor 2 protein (HER2). The antibody is an IgG1 isotype that contains human framework regions with the complementarity-determining regions of a murine anti-p185 HER2 antibody that binds to human HER2.
The HER2 proto-oncogene or c-erbB2 encodes for a single transmembrane spanning, receptor-like protein of 185 kDa, which is structurally related to the epidermal growth factor receptor. Overexpression of HER2 is observed in 25%-30% of primary breast and 6.8%-42.6 % metastatic gastric cancers. A consequence of HER2 gene amplification is an increase in HER2 protein expression on the surface of these tumour cells, which results in a constitutively activated HER2 protein.
Studies indicate that breast cancer patients whose tumours have amplification or overexpression of HER2 have a shortened disease-free survival compared to patients whose tumours do not have amplification or overexpression of HER2.
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.
SC: The HER2 proto-oncogene or c-erbB2 encodes for a single transmembrane spanning, receptor-like protein of 185 kDa, which is structurally related to the epidermal growth factor receptor. Overexpression of HER2 is observed in 15%-20% of primary breast cancer. The overall rate of HER2 positivity in advanced gastric cancers as observed during screening for study BO18255 is 15% for IHC3+ and IHC2+/FISH+ or 22.1% when applying the broader definition of IHC3+ or FISH+. A consequence of HER2 gene amplification is an increase in HER2 protein expression on the surface of these tumour cells, which results in a constitutively activated HER2 protein.
Clinical/Efficacy Studies: Metastatic Breast Cancer: Herceptin monotherapy has been used in clinical trials for patients with metastatic breast cancer who have tumours that overexpress HER2 and who have failed one or more chemotherapy regimens for their metastatic disease.
Herceptin has also been used in clinical trials in combination with paclitaxel or an anthracycline (doxorubicin or epirubicin) plus cyclophosphamide as first line therapy for patients with metastatic breast cancer who have tumours that overexpress HER2.
Patients who had previously received anthracycline-based adjuvant chemotherapy were treated with paclitaxel (175 mg/m2 infused over 3 hours) with or without Herceptin. Patients could be treated with Herceptin until progression of disease.
Herceptin monotherapy, when used as second- or third-line treatment of women with metastatic breast cancer which overexpresses HER2, results in an overall tumour response rate of 15% and a median survival of 13 months.
The use of Herceptin in combination with paclitaxel as first-line treatment of women with metastatic breast cancer that overexpresses HER2 significantly prolongs the median time to disease progression, compared with patients treated with paclitaxel alone. The increase in median time to disease progression for patients treated with Herceptin and paclitaxel is 3.9 months (6.9 months versus 3.0 months). Tumour response and one year survival rate are also increased for Herceptin in combination with paclitaxel versus paclitaxel alone.
Herceptin has also been studied in a randomised, controlled trial, in combination with docetaxel, as first-line treatment of women with metastatic breast cancer. The combination of Herceptin and docetaxel significantly increased response rate (61% versus 34%) and prolonged the median time to disease progression, (by 5.6 months) compared with patients treated with docetaxel alone. Median survival was also significantly increased in patients receiving the combination, compared with those receiving docetaxel alone (31.2 months versus 22.7 months).
Combination treatment with Herceptin and anastrozole: Herceptin has been studied in combination with anastrozole for first line treatment of metastatic breast cancer in HER2 overexpressing, hormone-receptor [i.e. oestrogen-receptor (ER) and/or progesterone-receptor (PR)] positive patients. Progression free survival was doubled in the Herceptin plus anastrozole arm compared to anastrozole (4.8 months versus 2.4 months). For the other parameters the improvements seen for the combination were; for overall response (16.5% versus 6.7%); clinical benefit rate (42.7% versus 27.9%); time to progression (4.8 months versus 2.4 months). For time to response and duration of response no difference could be recorded between the arms. The median overall survival was extended by 4.6 months for patients in the combination arm. The difference was not statistically significant, however more than half of the patients in the anastrozole alone arm crossed over to a Herceptin containing regimen after progression of disease. Fifty two percent of the patients taking Herceptin plus anastrozole survived for at least 2 years compared to 45% taking anastrozole alone.
Early Breast Cancer: In the adjuvant treatment setting, Herceptin was investigated in 4 large multicentre, randomised phase 3 trials: Study BO16348 was designed to compare one and two years of three-weekly Herceptin treatment versus observation in patients with HER2-positive early breast cancer following surgery, established chemotherapy and radiotherapy (if applicable). In addition, a comparison of two years of Herceptin treatment versus one year of 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 three weeks for either one or two years.
Studies NCCTG N9831 and NSAPB-B31 that comprise the joint analysis were designed to investigate the clinical utility of combining Herceptin IV treatment with paclitaxel following AC chemotherapy; additionally the NCCTG N9831 study investigated adding Herceptin sequentially to AC-paclitaxel chemotherapy in patients with HER2 positive early breast cancer following surgery.
Study BCIRG 006 was designed to investigate combining Herceptin treatment with docetaxel either following AC chemotherapy or in combination with docetaxel and carboplatin in patients with HER2 positive early breast cancer following surgery.
Early breast cancer in the BO16348 study was limited to operable, primary, invasive adenocarcinoma of the breast, with axillary nodes positive or axillary nodes negative tumours of at least 1 cm in diameter.
The efficacy results from the BO16348 study are summarized in the following table: (See Table 1.)

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The efficacy results from the interim efficacy analysis crossed the protocol pre-specified statistical boundary for the comparison of 1-year of Herceptin vs. observation. After a median follow-up of 12 months, the hazard ratio (HR) for disease free survival (DFS) was 0.54 (95% CI 0.44, 0.67) which translates into an absolute benefit, in terms of a 2-year disease-free survival rate, of 7.6 percentage points (85.8% versus 78.2%) in favour of the Herceptin arm.
A final analysis was performed after a median follow-up of 8 years, which showed that 1 year Herceptin treatment is associated with a 24% risk reduction compared to observation only (HR=0.76, 95% CI 0.67, 0.86). This translates into an absolute benefit in terms of an 8 year disease free survival rate of 6.4 percentage points in favour of 1 year Herceptin treatment.
In this final analysis, extending Herceptin treatment for a duration of two 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=0.89 and OS HR=0.98 (0.83, 1.15); p-value= 0.7846]. The rate of asymptomatic cardiac dysfunction was increased in the 2-year treatment arm (8.1% versus 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%).
SC: In this final analysis, extending Herceptin treatment for a duration of two 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% versus 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%).
In the joint analysis of the NCCTG N9831 and NSAPB B31 studies, early breast cancer was limited to women with operable breast cancer at high risk, defined as HER2-positive and axillary lymph node positive or HER2 positive and lymph node negative with high risk features (tumour size > 1 cm and ER negative or tumour size > 2 cm, regardless of hormonal status). Herceptin was administered in combination with paclitaxel, following AC chemotherapy. Paclitaxel was administered as follows: intravenous paclitaxel: 80 mg/m2 as a continuous IV infusion, given every week for 12 weeks, or; intravenous paclitaxel: 175 mg/m2 as a continuous IV infusion, given every 3 weeks for 4 cycles (day 1 of each cycle). (See Table 2.)

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SC: (See Table 3.)

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For the primary endpoint, DFS, the addition of Herceptin to paclitaxel chemotherapy resulted in a 52% decrease in the risk of disease recurrence. The hazard ratio translates into an absolute benefit, in terms of a 3-year disease-free survival rate, of 11.8 percentage points (87.2% versus 75.4%) in favour of the AC→PH (Herceptin) arm.
The pre-planned final analysis of OS from the joint analysis of studies NSABP B-31 and NCCTG N9831 was performed when 707 deaths had occurred (median follow-up 8.3 years in the AC→P H group). Treatment with AC→PH resulted in a statistically significant improvement in OS compared with AC→P (stratified HR=0.64; 95% CI [0.55, 0.74]; log-rank p value < 0.0001). At 8 years, the survival rate was estimated to be 86.9% in the AC→P H arm and 79.4% in the AC→P arm, an absolute benefit of 7.4% (95% CI 4.9%, 10.0%).
The final OS results from the joint analysis of studies NSABP B-31 and NCCTG N9831 are summarized in the following table: (See Table 4.)

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In the BCIRG 006 study HER2 positive, early breast cancer was limited to either lymph node positive or high risk node negative patients, defined as negative (pN0) lymph node involvement, and at least 1 of the following factors: tumour size greater than 2 cm, oestrogen receptor and progesterone receptor negative, histologic and/or nuclear grade 2-3, or age <35 years. Herceptin was administered either in combination with docetaxel, following AC chemotherapy (AC-DH) or in combination with docetaxel and carboplatin (DCarbH).
Docetaxel was administered as follows: intravenously (100 mg/m2 as an IV infusion over 1 hour) given every 3 weeks for 4 cycles (day 2 of first docetaxel cycle, then day 1 of each subsequent cycle), or; intravenously (75 mg/m2 as an IV infusion over 1 hour) given every 3 weeks for 6 cycles (day 2 of cycle 1, then day 1 of each cycle).
Docetaxel therapy was followed by carboplatin (at target AUC = 6 mg/mL/min) administered by IV infusion over 30-60 minutes repeated every 3 weeks for a total of 6 cycles.
The efficacy results from the BCIRG 006 study are summarized in the following tables: (See Table 5 and Table 6.)

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In the BCIRG 006 study for the primary endpoint, DFS, the hazard ratio translates into an absolute benefit, in terms of a 3-year disease-free survival rate, of 5.8 percentage points (86.7% versus 80.9%) in favour of the AC→DH (Herceptin) arm and 4.6 percentage points (85.5% versus 80.9%) in favour of the DCarbH (Herceptin) arm compared to AC→D.
For the secondary endpoint overall survival, treatment with AC→DH reduced the risk of death by 42% when compared to AC→D (hazard ratio 0.58 [95% CI: 0.40, 0.83] p=0.0024, log-rank test) and the risk of death was reduced by 34% for patients treated with DCarbH compared to patients treated with AC→D (hazard ratio 0.66 [95% CI: 0.47, 0.93], p=0.0182). In the BCIRG 006 study at the second interim analysis, 185 randomised patients had died: 80 patients (7.5%) in the AC→D arm, 49 patients (4.6%) in the AC→DH arm, and 56 patients (5.2%) in the DCarbH arm. The median duration of follow-up was 2.9 years in the AC→D arm and 3.0 years in both the AC→DH and DCarbH arms.
In the neoadjuvant-adjuvant treatment setting, Herceptin was evaluated in: Study MO16432 investigated a total of 10 cycles of neoadjuvant chemotherapy [an anthracycline and a taxane (AP+H followed by P+H, followed by CMF+H] concurrently with neoadjuvant-adjuvant Herceptin, or neoadjuvant chemotherapy alone, followed by adjuvant Herceptin for up to a total treatment duration of 1 year) in newly diagnosed locally advanced (Stage III) or inflammatory HER2-positive breast cancer patients.
Study BO22227 was designed to demonstrate non-inferiority of treatment with Herceptin SC versus Herceptin IV based on co-primary PK and efficacy endpoints (trastuzumab Ctrough at pre-dose Cycle 8, and pCR rate at definitive surgery, respectively). Patients with HER2-positive, operable or locally advanced breast cancer (LABC) including inflammatory breast cancer received eight cycles of either Herceptin IV or Herceptin SC concurrently with chemotherapy (docetaxel followed by FEC), followed by surgery, and continued therapy with Herceptin SC or Herceptin IV as originally randomised for an additional 10 cycles for a total of one year of treatment.
The efficacy results from Study MO16432 are summarized in the table as follows. The median duration of follow-up in the Herceptin arm was 3.8 years. (See Table 7.)

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For the primary endpoint, EFS, the addition of Herceptin to the 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% versus 52%) in favour of the Herceptin arm.
In Study BO22227 the analysis of the efficacy co-primary endpoint, pCR, defined as absence of invasive neoplastic cells in the breast, resulted in rates of 40.7% (95% CI: 34.7, 46.9) in the Herceptin IV arm and 45.4% (95% CI: 39.2%, 51.7%) in the Herceptin SC arm, a difference of 4.7% in favour of the Herceptin SC arm. The lower boundary of the one-sided 97.5% confidence interval for the difference in pCR rates was -4.0, whereas the pre-defined non-inferiority margin was -12.5%, establishing the non-inferiority of Herceptin SC for the co-primary endpoint. (See Table 8.)

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Analyses with longer term follow-up of a median duration exceeding 40 months supported the non-inferior efficacy of Herceptin SC compared to Herceptin IV with comparable results of both EFS and OS (3-year EFS rates of 73% in the Herceptin IV arm and 76% in the Herceptin SC arm, and 3-year OS rates of 90% in the Herceptin IV arm and 92% in the Herceptin SC arm).
For non-inferiority of the PK co-primary endpoint, steady-state trastuzumab Ctrough value at the end of treatment Cycle 7, refer to Pharmacokinetics as follows.
The final analysis at a median follow-up exceeding 70 months showed similar EFS and OS between patients who received Herceptin IV and those who received Herceptin SC. The 6-year EFS rate was 65% in both arms (ITT population: HR=0.98 [95% CI: 0.74;1.29]) and the OS rate, 84% in both arms (ITT population: HR=0.94 [95% CI: 0.61;1.45]).
IV: Metastatic Gastric Cancer: The efficacy results from the BO18255 study are summarized in Table 9. Patients with previously untreated for HER2-positive inoperable locally advanced or recurrent and/or metastatic adenocarcinoma of the stomach or gastro-oesophageal junction not amenable to curative therapy were recruited. The primary endpoint was overall survival which was defined as the time from the date of randomization to the date of death from any cause. At the time of the 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.
The overall survival was significantly improved in the Herceptin + capecitabine/5-FU and cisplatin arm compared to the capecitabine/5-FU and cisplatin arm (p = 0.0046, Log-Rank test). The median survival time was 11.1 months with capecitabine/5-FU and cisplatin and 13.8 months with Herceptin + capecitabine/5-FU and cisplatin. The risk of death was decreased by 26% (Hazard Ratio [HR] 0.74 95% CI [0.60-0.91]) for patients in the Herceptin arm compared to the capecitabine/5-FU arm.
Post-hoc subgroup analyses indicate that targeting tumors with higher levels of HER2 protein (IHC 2+/FISH+ and IHC 3+/regardless of the 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 progression free survival was 5.5 months versus 7.6 months, HR 0.64 (95% CI 0.51- 0.79) for capecitabine/5-FU and cisplatin and Herceptin + capecitabine/5-FU and cisplatin respectively.
In a method comparison study a high degree of concordance (>95%) was observed for SISH and FISH techniques for the detection of HER2 gene amplification in gastric cancer patients. (See Table 9.)

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Immunogenocity: In the neoadjuvant-adjuvant EBC study (BO22227), at a median follow-up exceeding 70 months, 10.1% (30/296) of patients treated with Herceptin IV and 15.9% (47/295) of patients receiving Herceptin SC Vial developed antibodies against trastuzumab. Neutralizing anti-trastuzumab antibodies were detected in post-baseline samples in 2 of 30 patients in the Herceptin IV arm and 3 of 47 patients in the Herceptin SC arm.
The clinical relevance of these antibodies is not known. The presence of anti-trastuzumab antibodies had no impact on pharmacokinetics, efficacy [determined by pathological complete response (pCR) and event free survival (EFS)] and safety [determined by occurrence of administration related reactions (ARRs)] of Herceptin IV and Herceptin SC.
Pharmacokinetics: IV formulation: The pharmacokinetics of trastuzumab were evaluated in a population pharmacokinetic model analysis using pooled data from 1,582 subjects from 18 Phase I, II and III trials receiving intravenous Herceptin IV. A two-compartment model with parallel linear and non-linear elimination from the central compartment described the trastuzumab concentration-time profile. Due to the non-linear elimination, total clearance increased with decreasing concentrations. Linear clearance was 0.127 L/day for breast cancer (MBC/EBC) and 0.176 L/day for MGC. The nonlinear elimination parameter values were 8.81 mg/day for the maximum elimination rate (Vmax) and 8.92 mg/L for the Michaelis-Menten constant (Km). The central compartment volume was 2.62 L for patients with breast cancer and 3.63 L for patients with AGC.
The population predicted PK exposures (with 5th - 95th Percentiles) and PK parameter values at clinically relevant concentrations (Cmax and Cmin) for breast cancer and MGC patients treated with the approved Q1W and Q3W dosing regimens are shown in Table 10 (Cycle 1) and Table 11 (steadystate) as follows. (See Table 10 and Table 11.)

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SC: The pharmacokinetics of trastuzumab given as a fixed 600 mg dose of Herceptin SC Vial administered q3w were compared to those of Herceptin IV given as a weight-based 8 mg/kg loading dose followed by 6 mg/kg maintenance doses administered q3w in the phase III study BO22227. The pharmacokinetic results for the co primary PK endpoint, trastuzumab trough concentration at pre dose Cycle 8, showed non inferior trastuzumab exposure for the Herceptin SC arm with fixed 600 mg q3w dosing compared to the Herceptin IV arm with body-weight adjusted q3w dosing. Analysis of Cycle 1 serum trastuzumab trough values confirmed that no loading dose is needed when using the Herceptin SC 600 mg fixed dose, in contrast to when using Herceptin IV weight-based dosing.
The mean observed trastuzumab concentration during the neoadjuvant treatment phase, at the pre-dose Cycle 8 time point, was higher in the Herceptin SC arm than in the Herceptin IV arm of the study, with mean observed values of 78.7 µg/ml (standard deviation: 43.9 µg/ml) as compared to 57.8 µg/ml standard deviation: 30.3 µg/ml). During the adjuvant treatment phase, at the pre-dose Cycle 13 time point, the mean observed trastuzumab trough concentration values, were 90.4 µg/ml (SD: 41.9 µg/ml) and 62.1 µg/ml (SD: 37.1 µg/ml), respectively for the Herceptin SC and Herceptin IV arms of the study. While approximate steady state concentrations with Herceptin IV or Herceptin SC are reached at approximately cycle 8, observed trastuzumab trough concentrations with Herceptin SC tended to increase slightly up to cycle 13. The mean observed trastuzumab trough concentration a pre-dose cycle 18 was: 90.7 µg/ml similar to that of cycle 13, suggesting no further increase after cycle 13.
The median Tmax following Herceptin SC Cycle 7 administration was approximately 3 days, with high variability (range 1-14 days). The mean Cmax was, as expected lower in the Herceptin SC arm (149 µg/ml) than in the Herceptin IV arm (end of infusion value: 221 µg/ml).
The mean observed AUC0-21days value following the Cycle 7 dose was approximately 10% higher with Herceptin SC as compared to Herceptin IV, with mean AUC values of 2268 µg/ml·day and 2056 µg/ml·day respectively. With Herceptin IV and Herceptin SC, body weight had an influence on the pre-dose trastuzumab trough concentration and AUC0-21days values. In patients with body weight (BW), below 51 kg (10th percentile), the mean steady state AUC value of trastuzumab following the Cycle 7 dose was about 80% higher after Herceptin SC than after Herceptin IV treatment whereas in the highest BW group above 90 kg (90th percentile) the mean steady state AUC value was 20% lower after Herceptin SC than after Herceptin IV treatment. Across body weight subsets patients who received Herceptin SC had pre-dose trastuzumab concentration and AUC0-21days values that were comparable to or higher than those observed in patients who received Herceptin IV. Multiple logistic regression analyses showed no correlation of trastuzumab PK to efficacy (pCR) or safety (AE) outcomes, and dose adjustment for body weight is not needed.
A population PK model with parallel linear and nonlinear elimination from the central compartment was constructed using pooled trastuzumab PK data from the phase III study BO22227 of Herceptin SC vs. Herceptin IV, to describe the observed PK concentrations following Herceptin IV or Herceptin SC administration in EBC patients. Bioavailability of trastuzumab given as Herceptin SC was estimated to be 77.1% and the first order absorption rate constant was estimated to be 0.4 day-1. Linear elimination clearance was 0.111 L/day and the central compartment volume (Vc) was 2.91 L. The nonlinear elimination Michaelis-Menten parameters were 11.9 mg/day and 33.9 mg/L for Vmax and Km, respectively. The population predicted PK exposure parameter values (with 5th-95th Percentiles) for the Herceptin SC 600mg q3w regimen in EBC patients is shown in Table 12 as follows. (See Table 12.)

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Trastuzumab washout: Trastuzumab washout time period was assessed following intravenous and subcutaneous administration using the respective population PK models. The results of these simulations indicate that at least 95% of patients will reach serum trastuzumab concentrations that are <1 μg/mL (approximately 3% of the population predicted Cmin,ss, or about 97% washout) by 7 months after the last dose.
IV: In early breast cancer patients administered at an initial loading dose of 8 mg /kg followed by a three weekly maintenance dose of 6 mg/kg for 1 year achieved steady state mean Cmax.
Pharmacokinetics in Special Populations: Detailed pharmacokinetic studies in the geriatric population and those with renal or hepatic impairment have not been carried out.
Renal Impairment: Detailed pharmacokinetic studies in patients with renal impairment have not been carried out. In a population pharmacokinetic analysis, renal impairment was shown not to affect trastuzumab disposition.
Geriatric Population: Age has been shown to have no effect on the disposition of trastuzumab (see Dosage & Administration).
Toxicology: Nonclinical Safety: IV: Intravenous formulation: Trastuzumab was well tolerated in mice (non-binding species) and Macaque monkeys (binding species) in single-dose and repeat-dose toxicity studies of up to 6 months duration, respectively. There was no evidence of acute or chronic toxicity identified.
SC: Trastuzumab was well tolerated in rabbits (non-binding species) and Macaque monkeys (binding species) in single-dose and repeat-dose toxicity studies of up to 6 months duration, respectively. There was no evidence of acute or chronic toxicity identified.
Impairment of Fertility: Reproduction studies have been conducted in cynomolgus monkeys at doses up to 25 times that of the weekly human maintenance dose of 2 mg/kg Herceptin and have revealed no evidence of impaired fertility.
Reproductive Toxicity: Reproduction studies have been conducted in cynomolgus monkeys at doses up to 25 times that of the weekly human maintenance dose of 2 mg/kg Herceptin IV and have revealed no evidence of harm to the foetus. However, when assessing the risk of reproductive toxicity to humans, it is also important to consider the significance of the rodent form of the HER2 receptor in normal embryonic development and the embryonic death in mutant mice lacking this receptor. Placental transfer of trastuzumab during the early (days 20-50 of gestation) and late (days 120-150 of gestation) foetal development period was observed.
Other: Lactation: A study conducted in lactating cynomolgus monkeys at doses 25 times that of the weekly human maintenance dose of 2 mg/kg Herceptin IV demonstrated that trastuzumab is secreted in the milk. The presence of trastuzumab in the serum of infant monkeys was not associated with any adverse effects on their growth or development from birth to 1 month of age.
Indications/Uses
Breast Cancer: Metastatic Breast Cancer (MBC): Herceptin is indicated for the treatment of patients with metastatic breast cancer who have tumours that overexpress HER2: as monotherapy for the treatment of those patients who have received one or more chemotherapy regimens for their metastatic disease; in combination with paclitaxel or docetaxel for the treatment of those patients who have not received chemotherapy for their metastatic disease; in combination with an aromatase inhibitor for the treatment of patients with hormone-receptor positive metastatic breast cancer.
Early Breast Cancer (EBC): Herceptin is indicated for the treatment of patients with HER2 positive early breast cancer: following surgery, chemotherapy (neoadjuvant or adjuvant) and radiotherapy (if applicable); following adjuvant chemotherapy with doxorubicin and cyclophosphamide, in combination with paclitaxel or docetaxel; in combination with adjuvant chemotherapy consisting of docetaxel and carboplatin; in combination with neoadjuvant chemotherapy followed by adjuvant Herceptin, for locally advanced (including inflammatory) breast cancer or tumours >2 cm in diameter.
IV: Metastatic Gastric Cancer (MGC): Herceptin in combination with capecitabine or 5-fluorouracil and cisplatin is indicated for the treatment of patients with Human epidermal growth factor receptor 2 (HER2) positive metastatic adenocarcinoma of the stomach or gastro-esophageal junction who have not received prior anti-cancer treatment for their metastatic disease.
Herceptin should only be used in patients with metastatic gastric cancer whose tumours have HER2 overexpression as defined by immunohistochemistry (IHC2+) and a confirmatory SISH or FISH (fluorescence in situ hybridization) result, or by an IHC 3+ result. Accurate and validated assay methods should be used.
Dosage/Direction for Use
General: HER2 testing is mandatory prior to initiation of Herceptin therapy.
Substitution by any other biological medicinal product requires the consent of the prescribing physician.
Caution should be taken when no switching data are available to support interchangeability of Herceptin and a given biosimilar.
Herceptin should be administered by a qualified health care professional.
It is important to check the product labels to ensure that the drug about to be administered is consistent with what has been prescribed for the patient.
Switching treatment between Herceptin IV and Herceptin SC and vice versa, using a three-weekly (q3w) dosing regimen, was investigated in study MO22982 (see Clinical Trials under Adverse Reactions).
In order to prevent medication errors it is important to check the vial labels to ensure that the drug being prepared and administered is Herceptin (trastuzumab) and not Kadcyla (trastuzumab emtansine).
IV: Herceptin IV should be administered as intravenous infusion.
Do not administer as an intravenous push or bolus.
SC: Herceptin SC (see Special Instructions for Use, Handling and Disposal under Cautions for Usage): Herceptin SC is not to be used for intravenous administration and must be administered as a subcutaneous injection only.
No loading dose is required.
The recommended fixed dose of Herceptin SC is 600 mg irrespective of the patient's body weight. This dose should be administered over 2-5 minutes every three weeks.
The injection site should be alternated between the left and right thigh. New injections should be given at least 1 inch/2.5 cm from the previous site on healthy skin and never into areas where the skin is red, bruised, tender, or hard. During the treatment course with Herceptin SC, other medications for SC administration should preferably be injected at different sites.
MBC and EBC: Weekly schedule: Loading dose: The recommended initial loading dose is 4 mg/kg body weight.
Herceptin administered as a 90-minute IV infusion.
Subsequent doses: The recommended weekly dose of Herceptin is 2 mg/kg body weight. If the prior dose was well tolerated, the dose can be administered as a 30-minute infusion.
Alternative 3-weekly schedule: Initial loading dose of 8 mg/kg body weight, followed by 6 mg/kg body weight 3 weeks later and then 6 mg/kg repeated at 3-weekly intervals administered as infusions over approximately 90 minutes. If the prior dose was well tolerated, the dose can be administered as a 30-minute infusion.
MGC: Three-weekly schedule: Initial loading dose of 8 mg/kg body weight, followed by 6 mg/kg body weight 3 weeks later and then 6 mg/kg repeated at 3-weekly intervals administered as infusions over approximately 90 minutes. If the prior dose was well tolerated, the dose can be administered as a 30-minute infusion.
Breast Cancer (MBC and EBC) and Gastric Cancer (MGC): Duration of treatment: In clinical studies, patients with MBC or metastatic gastric cancer were treated with Herceptin until progression of disease or unmanageable toxicity. Patients with EBC should be treated for 1 year or until disease recurrence or unmanageable toxicity, whichever occurs first. Extending treatment in EBC beyond one year is not recommended (see Pharmacology: Pharmacodynamics: Clinical/Efficacy Studies under Actions).
SC: Duration of treatment: Patients with MBC should be treated with Herceptin until progression of disease or unmanageable toxicity.
Patients with EBC should be treated for 1 year or until disease recurrence or unmanageable toxicity, whichever occurs first. Extending treatment in EBC beyond one year is not recommended (see Pharmacology: Pharmacodynamics: Clinical/Efficacy Studies under Actions).
Missed doses: IV: If the patient misses a dose of Herceptin by one week or less, then the usual maintenance dose of Herceptin (weekly regimen: 2 mg/kg; three-weekly regimen: 6 mg/kg) should be given as soon as possible. Do not wait until the next planned cycle. Subsequent Herceptin maintenance doses (weekly regimen: 2 mg/kg; three-weekly regimen: 6 mg/kg respectively) should then be given according to the original schedule.
If the patient misses a dose of Herceptin by more than one week, a re-loading dose of Herceptin should be given over approximately 90 minutes (weekly regimen: 4 mg/kg; three weekly regimen: 8 mg/kg). Subsequent Herceptin maintenance doses (weekly regimen: 2 mg/kg; three-weekly regimen 6 mg/kg respectively) should then be given according to the original schedule.
SC: If one dose of Herceptin SC is missed, it is recommended to administer the next 600 mg dose (i.e. the missed dose) as soon as possible. The interval between subsequent Herceptin doses should not be less than three weeks.
Dose modification: If the patient develops an infusion-related reaction (IRR), the infusion rate of Herceptin IV may be slowed or interrupted (see Precautions).
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 monitored carefully for complications of neutropenia during this time. The specific instructions to reduce or hold the dose of chemotherapy should be followed.
Special dosage instructions: Geriatric use: Data suggest that the disposition of Herceptin is not altered based on age (see Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions). In clinical trials, patients ≥65 years of age did not receive reduced doses of Herceptin.
Paediatric use: The safety and efficacy of Herceptin in paediatric patients <18 years of age have not been established.
Overdosage
IV: There is no experience with overdosage in human clinical trials. Single doses higher than 10 mg/kg have not been tested.
SC: Single doses of up to 960 mg have been administered with no reported untoward effect.
Contraindications
Herceptin is contraindicated in patients with known hypersensitivity to trastuzumab or to any other component of the product.
Warnings
IV: CARDIOMYOPATHY: Herceptin administration can result in the development of ventricular dysfunction and congestive heart failure. Left ventricular function should be evaluated in all patients prior to and during treatment with Herceptin. Discontinuation of Herceptin treatment should be strongly considered in patients who develop a clinically significant decrease in left ventricular function. The incidence and severity of cardiac dysfunction was particularly high in patients who received Herceptin in combination with anthracyclines and cyclophosphamide.
Special Precautions
General: In order to improve traceability of biological medicinal products, the trade name and batch number of the administered product should be clearly recorded (or stated) in the patient file.
Herceptin therapy should only be initiated under supervision of a physician experienced in the treatment of cancer patients.
Infusion/Administration-related reactions (IRRs/ARRs): IRRs/ARRs may be clinically difficult to distinguish from hypersensitivity reactions.
Pre-medication may be used to reduce risk of occurrence of IRRs/ARRs.
Serious IRRs to Herceptin infusion including dyspnoea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation and respiratory distress, supraventricular tachyarrhythmia and urticaria have been reported (see Adverse Reactions). Patients should be observed for IRRs/ARRs. 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 meperidine or paracetamol, or an antihistamine such as diphenhydramine. Serious reactions have been treated successfully with supportive therapy such as oxygen, beta-agonists and corticosteroids. In rare cases, these reactions are associated with a clinical course culminating in a fatal outcome. 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 not be treated with Herceptin.
IV: IRRs are known to occur with the Herceptin IV formulation.
SC: IRRs/ARRs are known to occur with the administration of Herceptin (see Adverse Reactions).
Pulmonary reactions: Severe pulmonary events have been reported with the use of Herceptin in the post-marketing setting. These events have occasionally resulted in fatal outcome and may occur as part of an IRR 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 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 with Herceptin.
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 taxane following anthracycline (doxorubicin or epirubicin)-containing chemotherapy. This may be moderate to severe and has been associated with death (see Adverse Reactions). 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.
Population pharmacokinetic model simulations indicate that trastuzumab may persist in the circulation for up to 7 months after stopping Herceptin treatment (see Pharmacology: Pharmacokinetics under Actions). 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 7 months 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 exposure to an anthracycline, should undergo baseline cardiac assessment including history and physical examination, and electrocardiogram (ECG) echocardiogram, and/or multigated acquisition scanning (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 LVEF percentage drops 10 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 has declined further, or if clinical 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 unless the benefits for the individual patient are deemed to outweigh the risks.
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 standard medications for heart failure (HF). In the pivotal trials, most patients who developed HF or asymptomatic cardiac dysfunction improved with standard HF treatment consisting of an 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 with Herceptin without additional clinical cardiac events.
Metastatic breast cancer (MBC): Herceptin and anthracyclines should not be given concurrently in the metastatic breast cancer setting.
Early breast cancer (EBC): For patients with EBC, 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.
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 hemodynamic effective pericardial effusion were excluded from adjuvant breast cancer clinical trials with Herceptin.
Adjuvant treatment: Herceptin and anthracyclines should not be given concurrently in the adjuvant treatment setting.
In patients with EBC 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 four 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 (BMI >25kg/m2).
Neoadjuvant-adjuvant treatment: In patients with EBC eligible for neoadjuvant-adjuvant treatment, Herceptin concurrently 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.
Clinical experience in the neoadjuvant-adjuvant setting is limited in patients above 65 years of age.
IV: Benzyl alcohol: Benzyl alcohol, used as a preservative in bacteriostatic water for injection in the 440 mg multidose vial, has been associated with toxicity in neonates and children up to 3 years old. When administering Herceptin to a patient with a known hypersensitivity to benzyl alcohol, Herceptin should be reconstituted with water for injection, and only one dose per Herceptin vial should be used. Any unused portion must be discarded. Sterile water for injection, used to reconstitute the 150mg single dose vial, does not contain benzyl alcohol.
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.
Renal Impairment: In a population pharmacokinetic analysis, renal impairment was shown not to affect trastuzumab disposition.
Use in Children: The safety and efficacy of Herceptin in paediatric patients below the age of 18 have not been established.
Use in Elderly: Data suggest that the disposition of Herceptin is not altered based on age (see Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions).
Use In Pregnancy & Lactation
Females and Males of Reproductive Potential: Fertility: It is not known whether Herceptin can affect reproductive capacity. Animal reproduction studies revealed no evidence of impaired fertility or harm to the foetus (see Pharmacology: Toxicology: Nonclinical Safety: Impairment of Fertility, Reproductive toxicity under Actions).
Contraception: Women of childbearing potential should be advised to use effective contraception during treatment with Herceptin and for 7 months after treatment has concluded (see Pharmacology: Pharmacokinetics under Actions).
Pregnancy: Herceptin should be avoided during pregnancy unless the potential benefit for the mother outweighs the potential risk to the foetus. In the post-marketing setting, cases of foetal renal growth and/or function impairment in association with oligohydramnios, some of which resulted in fatal pulmonary hypoplasia of the foetus, have been reported in pregnant women receiving Herceptin. Women who become pregnant should be advised of the possibility of harm to the foetus. If a pregnant woman is treated with Herceptin, or if a patient becomes pregnant while receiving Herceptin or within 7 months following last dose of Herceptin, close monitoring by a multidisciplinary team is desirable.
Labour and Delivery: No data to report.
Lactation: It is not known whether trastuzumab is secreted 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 (see Pharmacology: Toxicology: Nonclinical Safety: Other under Actions).
Adverse Reactions
Clinical Trials: Table 13 summarizes the adverse drug reactions (ADRs) that have been reported in association with the use of Herceptin alone or in combination with chemotherapy in pivotal clinical trials. All the terms included are based on the highest percentage seen in pivotal clinical trials.
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 13a and 13b.)

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Additional 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 (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 previously mentioned 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 decreased 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 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.
IV: Metastatic 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 Table 14 and Table 15.)

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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 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.
IV: Metastatic 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 16.)

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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.
IV: Metastatic 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.
IV: Metastatic 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 naive 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.
Post Marketing Experience: The following adverse drug reactions have been identified from postmarketing experience with Herceptin (See Table 17.)

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Adverse Events: Table 18 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 18.)

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Drug Interactions
There have been no formal drug interaction studies performed with Herceptin in humans. Clinically significant interactions between Herceptin and the concomitant medication used in clinical trials have not been observed (see Pharmacology: Pharmacokinetics under Actions).
In studies where Herceptin was administered in combination with docetaxel, carboplatin, or anastrozole, the pharmacokinetics of these medications was not altered nor was the pharmacokinetics of Herceptin altered.
Concentrations of paclitaxel and doxorubicin (and their major metabolites 6-α hydroxylpaclitaxel, POH, and doxorubicinol, DOL) were not altered in the presence of trastuzumab. However, trastuzumab may elevate the overall exposure of one doxorubicin metabolite, (7-deoxy-13 dihydro-doxorubicinone, D7D). The bioactivity of D7D and the clinical impact of the elevation of this metabolite is unclear. No changes were observed in trastuzumab concentrations in the presence of paclitaxel and doxorubicin.
The results of a small drug interaction substudy evaluating the pharmacokinetics of capecitabine and cisplatin when used with or without trastuzumab suggested that the exposure to the bioactive metabolites (e.g. 5-FU) of capecitabine was not affected by concurrent use of cisplatin or by concurrent use of cisplatin plus trastuzumab. However, capecitabine itself showed higher concentrations and a longer half-life when combined with trastuzumab. The data also suggested that the pharmacokinetics of cisplatin were not affected by concurrent use of capecitabine or by concurrent use of capecitabine plus trastuzumab.
The administration of concomitant anastrozole did not appear to influence pharmacokinetics of trastuzumab.
Caution For Usage
Special Instructions for Use, Handling and Disposal: Appropriate aseptic technique should be used.
IV: Reconstitution: Herceptin should be carefully handled during reconstitution. Causing excessive foaming during reconstitution or shaking the reconstituted Herceptin solution may result in problems with the amount of Herceptin solution that can be withdrawn from the vial.
Instructions for reconstitution- 440 mg vial: Reconstitution is to be performed with bacteriostatic water for injection, containing 1.1% benzyl alcohol, as supplied. This yields a solution for multiple uses, containing 21 mg/mL trastuzumab, at a pH of approximately 6.0. Use of other reconstitution solvents should be avoided except for water for sterile water for injection in case of a patient with a known hypersensitivity to benzyl alcohol.
1. Using a sterile syringe, slowly inject 20 mL of Bacteriostatic Water for Injection into the vial containing the lyophilized Herceptin, directing the stream into the lyophilized cake.
2. Swirl vial gently to aid reconstitution. DO NOT SHAKE.
Instructions for reconstitution-150 mg vial: 1. Using a sterile syringe, slowly inject 7.2 ml of sterile water for injection into the vial containing the lyophilized Herceptin, directing the stream into the lyophilized cake.
2. Swirl vial gently to aid reconstitution. 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 Herceptin results in a colourless to pale yellow transparent solution and should be essentially free of visible particles.
Dilution of the reconstituted solution: Determine the volume of the solution required: based on a loading dose of 4 mg trastuzumab/kg body weight, or a subsequent weekly dose of 2 mg trastuzumab/kg body weight: (See Equation 1.)

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based on a loading dose of 8 mg trastuzumab/kg body weight, or a subsequent 3 weekly dose of 6 mg trastuzumab/kg body weight: (See Equation 2.)

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The appropriate amount of 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 (see Incompatibilities as follows). The bag should be gently inverted to mix the solution in order to avoid foaming. Care must be taken to ensure the sterility of prepared solutions. Since the medicinal product does not contain any anti-microbial preservative or bacteriostatic agents, aseptic technique must be observed. Parenteral drug products should be inspected visually for particulates and discoloration prior to administration. Once the infusion is prepared it should be administered immediately (see Storage).
SC: The 600 mg/5 ml solution is a ready to use solution for injection which does not need to be diluted.
Herceptin should be inspected visually to ensure there is no particulate matter or discolouration prior to administration.
Herceptin solution for injection is for single-use only.
Once transferred from the vial to the syringe, the medicine should be used immediately, from a microbiological point of view, since the medicine does not contain any antimicrobial-preservative. If not used immediately, preparation should take place in controlled and validated aseptic conditions. Once transferred from the vial to the syringe, the medicinal product is physically and chemically stable for 48 hours at 2°C-8°C and subsequently 6 hours at ambient temperature (do not store above 30°C) in diffused daylight. This exposure time at ambient temperature should not be cumulated to any previous exposure time at room temperature of the medicinal product in the vial (see Storage).
After transfer of the solution to the syringe, it is recommended to replace the transfer needle by a syringe closing cap to avoid drying of the solution in the needle and not compromise the quality of the medicinal product. The hypodermic injection needle must be attached to the syringe immediately prior to administration followed by volume adjustment to 5 ml.
Disposal of unused/expired medicines: The release of pharmaceuticals in the environment should be minimized. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided. Use established "collection systems", if available in the location.
The following points should be strictly adhered to regarding the use and disposal of syringes and other medicinal sharps: Needles and syringes should never be reused.
Place all used needles and syringes into a sharps container (puncture-proof disposable container).
Dispose of the full container according to local requirements.
Incompatibilities: IV: No incompatibilities between Herceptin and polyvinylchloride, polyethylene or polypropylene bags have been observed.
Dextrose (5%) solution should not be used since it causes aggregation of the protein.
Herceptin should not be mixed or diluted with other drugs.
SC: No incompatibilities between Herceptin and polyproplylene syringes have been observed.
Storage
Store vials at 2-8°C.
IV: 440 mg vials (multidose vials): Shelf-life of the reconstituted solution: Reconstituted solutions made with bacteriostatic water for injection for the 440 mg vial of Herceptin, as supplied, are stable for 28 days when stored refrigerated at 2-8°C.
The reconstituted solution contains preservative and is therefore suitable for multiple use.
Any remaining reconstituted solution should be discarded after 28 days.
When administering Herceptin to a patient with a known hypersensitivity to benzyl alcohol (see General/Benzyl alcohol under Precautions), Herceptin should be reconstituted with sterile water for injection. In case Herceptin is reconstituted with sterile water for injection, only one dose per Herceptin vial should be used. The reconstituted solution should be used immediately. Any unused portion must be discarded.
Do not freeze the reconstituted solution.
Shelf-life of the solution for infusion containing the reconstituted product: The infusion solution (0.9% sodium chloride infusion solution) containing the reconstituted product is physically and chemically stable for 24 hours at 2°C - 8°C.
From a microbiological point of view, the Herceptin infusion solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use is the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless reconstitution and dilution have taken place in controlled and validated aseptic conditions.
150 mg vial (single- dose vials): Shelf-life of the reconstituted solution: The reconstituted product is physically and chemically stable for 48 hours at 2°C - 8°C after reconstitution with sterile water for injection.
From a microbiological point of view, the reconstituted solution should be further diluted in infusion solution immediately. If not, in-use storage times and conditions prior to use is the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.
Do not freeze the reconstituted solution.
Shelf-life of the solution for infusion containing the reconstituted product: The infusion solution (0.9% sodium chloride infusion solution) containing the reconstituted product is physically and chemically stable for 24 hours at 2°C - 8°C.
From a microbiological point of view, the Herceptin infusion solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use is the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless reconstitution and dilution have taken place in controlled and validated aseptic conditions.
SC: Store vials at 2°C-8°C (WHO Climatic Zones I-IV). Do not freeze. Store in the original package in order to protect from light.
The vials should not be kept more than 6 hours at ambient temperature (do not store above 30°C).
ATC Classification
L01XC03 - trastuzumab ; Belongs to the class of monoclonal antibodies, other antineoplastic agents. Used in the treatment of cancer.
Presentation/Packing
Infusion (vial) (lyophilised powder is of a white to pale yellow colour; solvent is a clear, colourless liquid) 150 mg x 1's. 440 mg x 1's. Soln for inj (vial) 600 mg/5 mL x 1's.
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