Breast cancer
Metastatic breast cancer
Zercepac is indicated for the treatment of adult patients with HER2 positive metastatic breast cancer
(MBC):

• as monotherapy for the treatment of those patients who have received at least two chemotherapy

regimens for their metastatic disease. Prior chemotherapy must have included at least an
Anthracycline and a Taxane unless patients are unsuitable for these treatments. Hormone receptor
positive patients must also have failed hormonal therapy, unless patients are unsuitable for these
treatments.
• in combination with Paclitaxel for the treatment of those patients who have not received
chemotherapy for their metastatic disease and for whom an Anthracycline is not suitable.
• in combination with 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 postmenopausal patients with
hormone-receptor positive MBC, not previously treated with Trastuzumab.

Early breast cancer
Zercepac is indicated for the treatment of adult patients with HER2 positive early breast cancer (EBC).
• following surgery, chemotherapy (neoadjuvant or adjuvant) and radiotherapy (if applicable) (see
section 5.1).
• 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 Zercepac therapy, for locally
advanced (including inflammatory) disease or tumours > 2cm in diameter (see sections 4.4 and 5.1).

Zercepac should only be used in patients with metastatic or early breast cancer whose tumours have
either HER2 overexpression or HER2 gene amplification as determined by an accurate and validated
assay (see sections 4.4 and 5.1).

Metastatic gastric cancer
Zercepac in combination with Capecitabine or 5-Fluorouracil and Cisplatin is indicated for the
treatment of adult patients with HER2 positive metastatic adenocarcinoma of the stomach or gastrooesophageal
junction who have not received prior anti-cancer treatment for their metastatic disease.

Zercepac should only be used in patients with metastatic gastric cancer (MGC) whose tumours have
HER2 overexpression as defined by IHC2+ and a confirmatory SISH or FISH result, or by an IHC 3+
result. Accurate and validated assay methods should be used (see sections 4.4 and 5.1).

HER2 testing is mandatory prior to initiation of therapy (see sections 4.4 and 5.1). Zercepac treatment should only be initiated by a physician experienced in the administration of cytotoxic chemotherapy
(see section 4.4) and should be administered by a healthcare professional only.

Zercepac intravenous formulation is not intended for subcutaneous administration and should be
administered via an intravenous infusion only.
In order to prevent medication errors, it is important to check the vial labels to ensure that the medicinal
product being prepared and administered is Zercepac (Trastuzumab) and not Kadcyla (Trastuzumab
emtansine).

Posology
Metastatic breast cancer
Three-weekly schedule
The recommended initial loading dose is 8mg/kg body weight. The recommended maintenance dose at
three-weekly intervals is 6mg/kg body weight, beginning three weeks after the loading dose.

Weekly schedule
The recommended initial loading dose of Zercepac is 4mg/kg body weight. The recommended weekly
maintenance dose of Zercepac is 2mg/kg body weight, beginning one week after the loading dose.
Administration in combination with Paclitaxel or Docetaxel
In the pivotal trials (H0648g, M77001), Paclitaxel or Docetaxel was administered the day following the
first dose of Trastuzumab (for dose, see the Summary of Product Characteristics (SmPC) for Paclitaxel
or Docetaxel) and immediately after the subsequent doses of Trastuzumab if the preceding dose of
Trastuzumab was well tolerated.

Administration in combination with an aromatase inhibitor
In the pivotal trial (BO16216) Trastuzumab and Anastrozole were administered from day 1. There were
no restrictions on the relative timing of Trastuzumab and Anastrozole at administration (for dose, see
the SmPC for Anastrozole or other aromatase inhibitors).

Early breast cancer
Three-weekly and weekly schedule
As a three-weekly regimen the recommended initial loading dose of Zercepac is 8mg/kg body weight.
The recommended maintenance dose of Zercepac at three-weekly intervals is 6mg/kg body weight,
beginning three weeks after the loading dose.

As a weekly regimen (initial loading dose of 4mg/kg followed by 2mg/kg every week) concomitantly
with Paclitaxel following chemotherapy with Doxorubicin and Cyclophosphamide.
See section 5.1 for chemotherapy combination dosing.

Metastatic gastric cancer
Three-weekly schedule
The recommended initial loading dose is 8mg/kg body weight. The recommended maintenance dose at
three-weekly intervals is 6mg/kg body weight, beginning three weeks after the loading dose.

Breast cancer and gastric cancer
Duration of treatment
Patients with MBC or MGC should be treated with Zercepac until progression of disease.
Patients with EBC should be treated with Zercepac for 1 year or until disease recurrence, whichever
occurs first; extending treatment in EBC beyond one year is not recommended (see section 5.1).

Dose reduction
No reductions in the dose of Zercepac were made during clinical trials. Patients may continue therapy
during periods of reversible, chemotherapy-induced myelosuppression but they should be monitored
carefully for complications of neutropenia during this time. Refer to the SmPC for Paclitaxel, Docetaxel
or aromatase inhibitor for information on dose reduction or delays.

If left ventricular ejection fraction (LVEF) percentage drops ≥ 10 points from baseline AND to below
50%, treatment should be suspended and a repeat LVEF assessment performed within approximately
3 weeks. If LVEF has not improved, or has declined further, or if symptomatic congestive heart failure
(CHF) has developed, discontinuation of Zercepac should be strongly considered, unless the benefits
for the individual patient are deemed to outweigh the risks. All such patients should be referred for
assessment by a cardiologist and followed up.

Missed doses
If the patient has missed a dose of Zercepac by one week or less, then the usual maintenance dose
(weekly regimen: 2mg/kg; three-weekly regimen: 6mg/kg) should be administered as soon as possible.
Do not wait until the next planned cycle. Subsequent maintenance doses should 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 Zercepac by more than one week, a re-loading dose of Zercepac
should be administered over approximately 90 minutes (weekly regimen: 4mg/kg; three-weekly
regimen: 8mg/kg) as soon as possible. Subsequent Zercepac maintenance doses (weekly regimen:
2mg/kg; three-weekly regimen 6mg/kg respectively) should be administered 7 days or 21 days later
according to the weekly or three-weekly schedules respectively.

Special populations
Dedicated pharmacokinetic studies in the elderly and those with renal or hepatic impairment have not
been carried out. In a population pharmacokinetic analysis, age and renal impairment were not shown
to affect Trastuzumab disposition.

Paediatric population
There is no relevant use of Zercepac in the paediatric population.

Method of administration
Zercepac is for intravenous use only. The loading dose should be administered as a 90-minute
intravenous infusion. Do not administer as an intravenous push or bolus. Zercepac intravenous infusion
should be administered by a healthcare provider prepared to manage anaphylaxis and an emergency kit
should be available. Patients should be observed for at least six hours after the start of the first infusion and for two hours after the start of the subsequent infusions for symptoms like fever and chills or other infusion-related symptoms (see sections 4.4 and 4.8). Interruption or slowing the rate of the infusion may help control such symptoms. The infusion may be resumed when symptoms abate.

If the initial loading dose was well tolerated, the subsequent doses can be administered as a 30-minute
infusion.

For instructions on reconstitution of Zercepac intravenous formulation before administration, see
section 6.6.

Traceability
In order to improve traceability of biological medicinal products, the trade name and the batch number
of the administered product should be clearly recorded.
HER2 testing must be performed in a specialised laboratory which can ensure adequate validation of
the testing procedures (see section 5.1).
Currently no data from clinical trials are available on re-treatment of patients with previous exposure
to Zercepac in the adjuvant setting.

Cardiac dysfunction
General considerations
Patients treated with Zercepac are at increased risk for developing CHF (New York Heart Association
[NYHA] Class II-IV) or asymptomatic cardiac dysfunction. These events have been observed in
patients receiving Trastuzumab therapy alone or in combination with Paclitaxel or Docetaxel,
particularly following Anthracycline (Doxorubicin or Epirubicin) containing chemotherapy. These may
be moderate to severe and have been associated with death (see section 4.8). In addition, caution should
be exercised in treating patients with increased cardiac risk, e.g. hypertension, documented coronary
artery disease, CHF, LVEF of <55%, older age.

All candidates for treatment with Zercepac, but especially those with prior Anthracycline and
Cyclophosphamide (AC) exposure, should undergo baseline cardiac assessment including history and
physical examination, electrocardiogram (ECG), echocardiogram, and/or multigated acquisition
(MUGA) scan or magnetic resonance imaging. Monitoring may help to identify patients who develop
cardiac dysfunction. 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 Zercepac. A careful risk-benefit assessment should be made before deciding to
treat with Zercepac.

Trastuzumab may persist in the circulation for up to 7 months after stopping Zercepac treatment based
on population pharmacokinetic analysis of all available data (see section 5.2). Patients who receive
Anthracyclines after stopping Zercepac may possibly be at increased risk of cardiac dysfunction. If
possible, physicians should avoid Anthracycline-based therapy for up to 7 months after stopping
Zercepac. If Anthracyclines are used, the patient’s cardiac function should be monitored carefully.

Formal cardiological assessment should be considered in patients in whom there are cardiovascular
concerns following baseline screening. In all patients cardiac function should be monitored during
treatment (e.g. every 12 weeks). Monitoring may help to identify patients who develop cardiac dysfunction. 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 Zercepac therapy has been seen.

dysfunction. 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
Zercepac therapy has been seen.

If symptomatic cardiac failure develops during Zercepac therapy, it should be treated with standard
medicinal products for CHF. Most patients who developed CHF or asymptomatic cardiac dysfunction
in pivotal trials improved with standard CHF treatment consisting of an angiotensin-converting enzyme
(ACE) inhibitor or angiotensin receptor blocker (ARB) and a beta-blocker. The majority of patients
with cardiac symptoms and evidence of a clinical benefit of Trastuzumab treatment continued on
therapy without additional clinical cardiac events.

Metastatic breast cancer
Zercepac and Anthracyclines should not be given concurrently in combination in the MBC setting.
Patients with MBC who have previously received Anthracyclines are also at risk of cardiac dysfunction
with Zercepac treatment, although the risk is lower than with concurrent use of Zercepac and
Anthracyclines.

Early breast cancer
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 Zercepac. In patients who receive Anthracycline-containing
chemotherapy further monitoring is recommended, and should occur yearly up to 5 years from the last
administration of Zercepac, or longer if a continuous decrease of LVEF is observed.

Patients with history of myocardial infarction (MI), angina pectoris requiring medical treatment, history
of or existing CHF (NYHA Class II –IV), LVEF of <55%, other cardiomyopathy, cardiac arrhythmia
requiring medical treatment, clinically significant cardiac valvular disease, poorly controlled
hypertension (hypertension controlled by standard medical treatment eligible), and hemodynamic
effective pericardial effusion were excluded from adjuvant and neoadjuvant EBC pivotal trials with
Trastuzumab and therefore treatment cannot be recommended in such patients.

Adjuvant treatment
Zercepac and Anthracyclines should not be given concurrently in combination in the adjuvant treatment
setting.
In patients with EBC an increase in the incidence of symptomatic and asymptomatic cardiac events was
observed when Trastuzumab was administered after Anthracycline-containing chemotherapy compared
to administration with a non-Anthracycline regimen of Docetaxel and Carboplatin and was more
marked when Trastuzumab 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. In one of the 3 pivotal studies conducted in which a median follow-up of
5.5 years was available (BCIRG006) a continuous increase in the cumulative rate of symptomatic
cardiac or LVEF events was observed in patients who were administered Trastuzumab concurrently
with a Taxane following Anthracycline therapy up to 2.37% compared to approximately 1% in the two
comparator arms (Anthracycline plus Cyclophosphamide followed by Taxane and Taxane, Carboplatin
and Trastuzumab).

Risk factors for a cardiac event identified in four large adjuvant studies included advanced age
(>50 years), low LVEF (<55%) at baseline, prior to or following the initiation of Paclitaxel treatment,
decline in LVEF by 10-15 points, and prior or concurrent use of anti-hypertensive medicinal products.
In patients receiving Trastuzumab after completion of adjuvant chemotherapy, the risk of cardiac
dysfunction was associated with a higher cumulative dose of Anthracycline given prior to initiation of
Trastuzumab and a body mass index (BMI) >25 kg/m2.

Neoadjuvant-adjuvant treatment
In patients with EBC eligible for neoadjuvant-adjuvant treatment, Zercepac should be used concurrently
with Anthracyclines only in chemotherapy-naive patients and only with low-dose Anthracycline
regimens i.e. maximum cumulative doses of Doxorubicin 180 mg/m2 or Epirubicin 360 mg/m2.

If patients have been treated concurrently with a full course of low-dose Anthracyclines and Zercepac
in the neoadjuvant setting, no additional cytotoxic chemotherapy should be given after surgery. In other
situations, the decision on the need for additional cytotoxic chemotherapy is determined based on
individual factors.

Experience of concurrent administration of Trastuzumab with low dose Anthracycline regimens is
currently limited to two trials (MO16432 and BO22227).

In the pivotal trial MO16432, Trastuzumab 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 Trastuzumab arm.

In the pivotal trial BO22227, Trastuzumab 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 congestive cardiac failure was 0.3% in the
Trastuzumab intravenous arm.

Clinical experience is limited in patients above 65 years of age.

Infusion-related reactions (IRRs) and hypersensitivity

Serious IRRs to Trastuzumab infusion including dyspnoea, hypotension, wheezing, hypertension,
bronchospasm, supraventricular tachyarrhythmia, reduced oxygen saturation, anaphylaxis, respiratory
distress, urticaria and angioedema have been reported (see section 4.8). Pre-medication may be used to
reduce risk of occurrence of these events. The majority of these events occur during or within 2.5 hours
of the start of the first infusion. Should an infusion reaction occur the infusion should be discontinued
or the rate of infusion slowed and the patient should be monitored until resolution of all observed
symptoms (see section 4.2). These symptoms can be treated with an analgesic/antipyretic such as
Meperidine or Paracetamol, or an antihistamine such as Diphenhydramine. The majority of patients
experienced resolution of symptoms and subsequently received further infusions of Trastuzumab.
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 experiencing dyspnoea at rest due to complications of advanced malignancy and
comorbidities may be at increased risk of a fatal infusion reaction. Therefore, these patients should not
be treated with Zercepac (see section 4.3).

Initial improvement followed by clinical deterioration and delayed reactions with rapid clinical
deterioration have also been reported. Fatalities have occurred within hours and up to one week
following infusion. On very rare occasions, patients have experienced the onset of infusion symptoms
and pulmonary symptoms more than six hours after the start of the Trastuzumab infusion. Patients
should be warned of the possibility of such a late onset and should be instructed to contact their
physician if these symptoms occur.

Pulmonary events
Severe pulmonary events have been reported with the use of Trastuzumab in the post-marketing setting 

(see section 4.8). These events have occasionally been fatal. 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. These events may occur as part of an infusion-related reaction or
with a delayed onset. Patients experiencing dyspnoea at rest due to complications of advanced
malignancy and comorbidities may be at increased risk of pulmonary events. Therefore, these patients
should not be treated with Zercepac (see section 4.3). Caution should be exercised for pneumonitis,
especially in patients being treated concomitantly with Taxanes.

No formal drug interaction studies have been performed. Clinically significant interactions between
Zercepac and the concomitant medicinal products used in clinical trials have not been observed.

Effect of Trastuzumab on the pharmacokinetics of other antineoplastic agents
Pharmacokinetic data from studies BO15935 and M77004 in women with HER2-positive MBC
suggested that exposure to Paclitaxel and Doxorubicin (and their major metabolites 6-α hydroxyl-
Paclitaxel, POH, and Doxorubicinol, DOL) was not altered in the presence of Trastuzumab (8 mg/kg
or 4 mg/kg IV loading dose followed by 6 mg/kg q3w or 2 mg/kg q1w IV, respectively).

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 was unclear.

Data from study JP16003, a single-arm study of Trastuzumab (4 mg/kg IV loading dose and 2 mg/kg
IV weekly) and Docetaxel (60 mg/m2 IV) in Japanese women with HER2- positive MBC, suggested
that concomitant administration of Trastuzumab had no effect on the single dose pharmacokinetics of
Docetaxel. Study JP19959 was a substudy of BO18255 (ToGA) performed in male and female Japanese
patients with advanced gastric cancer to study the pharmacokinetics of Capecitabine and Cisplatin when
used with or without Trastuzumab. The results of this substudy 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.

Pharmacokinetic data from Study H4613g/GO01305 in patients with metastatic or locally advanced
inoperable HER2-positive cancer suggested that Trastuzumab had no impact on the PK of Carboplatin.

Effect of antineoplastic agents on Trastuzumab pharmacokinetics
By comparison of simulated serum Trastuzumab concentrations after Trastuzumab monotherapy
(4 mg/kg loading/2 mg/kg q1w IV) and observed serum concentrations in Japanese women with HER2-
positive MBC (study JP16003) no evidence of a PK effect of concurrent administration of Docetaxel
on the pharmacokinetics of Trastuzumab was found.

Comparison of PK results from two Phase II studies (BO15935 and M77004) and one Phase III study
(H0648g) in which patients were treated concomitantly with Trastuzumab and Paclitaxel and two
Phase II studies in which Trastuzumab was administered as monotherapy (W016229 and MO16982),
in women with HER2-positive MBC indicates that individual and mean Trastuzumab trough serum
concentrations varied within and across studies but there was no clear effect of the concomitant
administration of Paclitaxel on the pharmacokinetics of Trastuzumab. Comparison of Trastuzumab PK
data from Study M77004 in which women with HER2-positive MBC were treated concomitantly with
Trastuzumab, Paclitaxel and Doxorubicin to Trastuzumab PK data in studies where Trastuzumab was
administered as monotherapy (H0649g) or in combination with Anthracycline plus Cyclophosphamide

or Paclitaxel (Study H0648g), suggested no effect of Doxorubicin and Paclitaxel on the
pharmacokinetics of Trastuzumab.

Pharmacokinetic data from Study H4613g/GO01305 suggested that Carboplatin had no impact on the
PK of Trastuzumab.

The administration of concomitant Anastrozole did not appear to influence the pharmacokinetics of
Trastuzumab.

Women of childbearing potential
Women of childbearing potential should be advised to use effective contraception during treatment with
Zercepac and for 7 months after treatment has concluded (see section 5.2).
Pregnancy
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 Trastuzumab intravenous formulation and have revealed
no evidence of impaired fertility or harm to the foetus. Placental transfer of Trastuzumab during the
early (days 20–50 of gestation) and late (days 120-150 of gestation) foetal development period was
observed. It is not known whether Trastuzumab can affect reproductive capacity. As animal
reproduction studies are not always predictive of human response, Trastuzumab 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 associated with fatal pulmonary hypoplasia of the foetus, have been
reported in pregnant women receiving Trastuzumab. Women who become pregnant should be advised
of the possibility of harm to the foetus. If a pregnant woman is treated with Zercepac, or if a patient
becomes pregnant while receiving Zercepac or within 7 months following the last dose of Zercepac,
close monitoring by a multidisciplinary team is desirable.

Breastfeeding
A study conducted in lactating Cynomolgus monkeys at doses 25 times that of the weekly human
maintenance dose of 2 mg/kg Trastuzumab intravenous formulation 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. It is not known
whether Trastuzumab is secreted in human milk. As human IgG1 is secreted into human milk, and the
potential for harm to the infant is unknown, women should not breast-feed during Zercepac therapy and
for 7 months after the last dose.

Fertility
There is no fertility data available.

Zercepac has minor influence on the ability to drive or use machines (see section 4.8).
Dizziness and somnolence may occur during treatment with Zercepac (see section 4.8). Patients
experiencing infusion-related symptoms (see section 4.4) should be advised not to drive and use
machines until symptoms abate.

Summary of the safety profile
Amongst the most serious and/or common adverse reactions reported in Trastuzumab usage to date are
cardiac dysfunction, infusion-related reactions, haematotoxicity (in particular neutropenia), infections
and pulmonary adverse reactions.

Tabulated list of adverse reactions
In this section, the following categories of frequency have been used: 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 1 are adverse reactions that have been reported in association with the use of
intravenous Trastuzumab alone or in combination with chemotherapy in pivotal clinical trials and in
the post-marketing setting.

All the terms included are based on the highest percentage seen in pivotal clinical trials. In addition,
terms reported in the post marketing setting are included in Table 1.

Table 1 Undesirable effects reported with intravenous Trastuzumab monotherapy or in combination
with chemotherapy in pivotal clinical trials (N = 8386) and in post-marketing

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

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

*          Observed with combination therapy following Anthracyclines and combined with Taxanes

Description of selected adverse reactions
Cardiac dysfunction
Congestive heart failure (NYHA Class II – IV) is a common adverse reaction associated with the use
of Trastuzumab and has been associated with a fatal outcome (see section 4.4). 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 Trastuzumab (see
section 4.4).

In 3 pivotal clinical trials of adjuvant Trastuzumab given in combination with chemotherapy, the
incidence of grade 3/4 cardiac dysfunction (specifically symptomatic Congestive Heart Failure) was
similar in patients who were administered chemotherapy alone (i.e. did not receive Trastuzumab) and
in patients who were administered Trastuzumab sequentially after a Taxane (0.3-0.4%). The rate was
highest in patients who were administered Trastuzumab concurrently with a Taxane (2.0%). In the
neoadjuvant setting, the experience of concurrent administration of Trastuzumab and low dose
Anthracycline regimen is limited (see section 4.4).

When Trastuzumab 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. In study BO16348, after a median follow-up of 8 years the incidence of severe CHF (NYHA
Class III & IV) in the Trastuzumab 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 Trastuzumab-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 Trastuzumab.

In the pivotal metastatic trials of intravenous Trastuzumab, the incidence of cardiac dysfunction varied
between 9% and 12% when it was combined with Paclitaxel compared with 1%-4% for Paclitaxel alone.
For monotherapy, the rate was 6% – 9%. The highest rate of cardiac dysfunction was seen in patients
receiving Trastuzumab concurrently with Anthracycline/Cyclophosphamide (27%), and was
significantly higher than for Anthracycline/Cyclophosphamide alone (7%-10%). In a subsequent trial
with prospective monitoring of cardiac function, the incidence of symptomatic CHF was 2.2% in
patients receiving Trastuzumab 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.

Infusion reactions, allergic-like reactions and hypersensitivity
It is estimated that approximately 40% of patients who are treated with Trastuzumab will experience
some form of infusion-related reaction. However, the majority of infusion-related reactions are mild to
moderate in intensity (NCI-CTC grading system) and tend to occur earlier in treatment, i.e. during
infusions one, two and three and lessen in frequency in subsequent infusions. Reactions include chills,

fever, dyspnoea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation,
respiratory distress, rash, nausea, vomiting and headache (see section 4.4). The rate of infusion-related
reactions of all grades varied between studies depending on the indication, the data collection
methodology, and whether Trastuzumab was given concurrently with chemotherapy or as monotherapy.

Severe anaphylactic reactions requiring immediate additional intervention can occur usually during
either the first or second infusion of Trastuzumab (see section 4.4) and have been associated with a fatal
outcome.

Anaphylactoid reactions have been observed in isolated cases.

Haematotoxicity
Febrile neutropenia, leukopenia, anaemia, thrombocytopenia and neutropenia occurred very commonly.
The frequency of occurrence of hypoprothrombinaemia is not known. The risk of neutropenia may be
slightly increased when Trastuzumab is administered with Docetaxel following Anthracycline therapy.

Pulmonary events
Severe pulmonary adverse reactions occur in association with the use of Trastuzumab and have been
associated with a fatal outcome. These include, but are not limited to, pulmonary infiltrates, acute
respiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, respiratory distress, acute
pulmonary oedema and respiratory insufficiency (see section 4.4).
Details of risk minimisation measures that are consistent with the EU Risk Management Plan are
presented in (section 4.4) Warnings and Precautions.
Immunogenicity

In the neoadjuvant-adjuvant EBC study (BO22227), at a median follow-up exceeding 70 months, 10.1%
(30/296) of patients treated with Trastuzumab intravenous developed antibodies against Trastuzumab.
Neutralizing anti-Trastuzumab antibodies were detected in post-baseline samples in 2 of 30 patients in
the Trastuzumab intravenous 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 Trastuzumab intravenous.

There are no immunogenicity data available for Trastuzumab in gastric cancer.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare
professionals are asked to report any suspected adverse reactions via The National Pharmacovigilance
Centre (NPC).

To report any side effect(s) in Saudi Arabia, please contact:

The National Pharmacovigilance Centre (NPC)
• SFDA Call Centre: 19999
• E-mail: npc.drug@sfda.gov.sa
• Website: https://ade.sfda.gov.sa/

There is no experience with overdose in human clinical trials. Single doses of Zercepac alone greater
than 10 mg/kg have not been administered in the clinical trials; a maintenance dose of 10 mg/kg q3w
following a loading dose of 8 mg/kg has been studied in a clinical trial with metastatic gastric cancer
patients. Doses up to this level were well tolerated.

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC03

Zercepac is a biosimilar medicinal product. Detailed information is available on the website of the
European Medicines Agency http://www.ema.europa.eu. 

Trastuzumab is a recombinant humanised IgG1 monoclonal antibody against the human epidermal
growth factor receptor 2 (HER2). Overexpression of HER2 is observed in 20%-30% of primary breast
cancers. Studies of HER2-positivity rates in gastric cancer (GC) using immunohistochemistry (IHC)
and fluorescence in situ hybridization (FISH) or chromogenic in situ hybridization (CISH) have shown
that there is a broad variation of HER2-positivity ranging from 6.8% to 34.0% for IHC and 7.1% to
42.6% for FISH. Studies indicate that breast cancer patients whose tumours overexpress HER2 have a
shortened disease-free survival compared to patients whose tumours do not overexpress HER2. The
extracellular domain of the receptor (ECD, p105) can be shed into the blood stream and measured in
serum samples.

Mechanism of action
Trastuzumab binds with high affinity and specificity to sub-domain IV, a juxta-membrane region of
HER2’s extracellular domain. Binding of Trastuzumab to HER2 inhibits ligand-independent HER2
signalling and prevents the proteolytic cleavage of its extracellular domain, an activation mechanism of
HER2. As a result, Trastuzumab has been shown, in both in vitro assays and in animals, to inhibit the
proliferation of human tumour cells that overexpress HER2. Additionally, Trastuzumab is a potent
mediator of antibody-dependent cell-mediated cytotoxicity (ADCC). In vitro, Trastuzumab-mediated
ADCC has been shown to be preferentially exerted on HER2 overexpressing cancer cells compared
with cancer cells that do not overexpress HER2.

Detection of HER2 overexpression or HER2 gene amplification
Detection of HER2 overexpression or HER2 gene amplification in breast cancer
Zercepac should only be used in patients whose tumours have HER2 overexpression or HER2 gene
amplification as determined by an accurate and validated assay. HER2 overexpression should be
detected using an immunohistochemistry (IHC)-based assessment of fixed tumour blocks (see
section 4.4). HER2 gene amplification should be detected using fluorescence in situ hybridisation
(FISH) or chromogenic in situ hybridisation (CISH) of fixed tumour blocks. Patients are eligible for
Zercepac treatment if they show strong HER2 overexpression as described by a 3+ score by IHC or a
positive FISH or CISH result.

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

The recommended scoring system to evaluate the IHC staining patterns is as stated in Table 2:

Table 2 Recommended scoring system to evaluate the IHC staining patterns in breast cancer

In general, FISH is considered positive if the ratio of the HER2 gene copy number per tumour cell to the chromosome 17 copy number is greater than or equal to 2, or if there are more than 4 copies of the HER2 gene per tumour cell if no chromosome 17 control is used.

In general, FISH is considered positive if the ratio of the HER2 gene copy number per tumour cell to
the chromosome 17 copy number is greater than or equal to 2, or if there are more than 4 copies of the
HER2 gene per tumour cell if no chromosome 17 control is used.

In general, CISH is considered positive if there are more than 5 copies of the HER2 gene per nucleus
in greater than 50% of tumour cells.

For full instructions on assay performance and interpretation please refer to the package inserts of
validated FISH and CISH assays. Official recommendations on HER2 testing may also apply.

For any other method that may be used for the assessment of HER2 protein or gene expression, the
analyses should only be performed by laboratories that provide adequate state-of-the-art performance
of validated methods. Such methods must clearly be precise and accurate enough to demonstrate
overexpression of HER2 and must be able to distinguish between moderate (congruent with 2+) and
strong (congruent with 3+) overexpression of HER2.

Detection of HER2 over expression or HER2 gene amplification in gastric cancer
Only an accurate and validated assay should be used to detect HER2 over expression or HER2 gene
amplification. IHC is recommended as the first testing modality and in cases where HER2 gene
amplification status is also required, either a silver-enhanced in situ hybridization (SISH) or a FISH
technique must be applied. SISH technology is however, recommended to allow for the parallel
evaluation of tumour histology and morphology. To ensure validation of testing procedures and the
generation of accurate and reproducible results, HER2 testing must be performed in a laboratory staffed
by trained personnel. Full instructions on assay performance and results interpretation should be taken
from the product information leaflet provided with the HER2 testing assays used.

In the ToGA (BO18255) trial, patients whose tumours were either IHC3+ or FISH positive were defined
as HER2 positive and thus included in the trial. Based on the clinical trial results, the beneficial effects
were limited to patients with the highest level of HER2 protein overexpression, defined by a 3+ score
by IHC, or a 2+ score by IHC and a positive FISH result.

In a method comparison study (study D008548) a high degree of concordance (>95%) was observed
for SISH and FISH techniques for the detection of HER2 gene amplification in gastric cancer patients.

HER2 over expression should be detected using an immunohistochemistry (IHC)-based assessment of
fixed tumour blocks; HER2 gene amplification should be detected using in situ hybridisation using
either SISH or FISH on fixed tumour blocks.

The recommended scoring system to evaluate the IHC staining patterns is as stated in Table 3:

In general, SISH or FISH is considered positive if the ratio of the HER2 gene copy number per tumour
cell to the chromosome 17 copy number is greater than or equal to 2.

Clinical efficacy and safety
Metastatic breast cancer
Trastuzumab has been used in clinical trials as monotherapy for patients with MBC who have tumours
that overexpress HER2 and who have failed one or more chemotherapy regimens for their metastatic
disease (Trastuzumab alone).

Trastuzumab has also been used in combination with Paclitaxel or Docetaxel for the treatment of
patients who have not received chemotherapy for their metastatic disease. Patients who had previously
received Anthracycline-based adjuvant chemotherapy were treated with Paclitaxel (175 mg/m2 infused
over 3 hours) with or without Trastuzumab. In the pivotal trial of Docetaxel (100 mg/m2 infused over
1 hour) with or without Trastuzumab, 60% of the patients had received prior Anthracycline-based
adjuvant chemotherapy. Patients were treated with Trastuzumab until progression of disease.

The efficacy of Trastuzumab in combination with Paclitaxel in patients who did not receive prior
adjuvant Anthracyclines has not been studied. However, Trastuzumab plus Docetaxel was efficacious
in patients whether or not they had received prior adjuvant Anthracyclines.

The test method for HER2 overexpression used to determine eligibility of patients in the pivotal
Trastuzumab monotherapy and Trastuzumab plus Paclitaxel clinical trials employed
immunohistochemical staining for HER2 of fixed material from breast tumours using the murine
monoclonal antibodies CB11 and 4D5. These tissues were fixed in formalin or Bouin’s fixative. This
investigative clinical trial assay performed in a central laboratory utilised a 0 to 3+ scale. Patients
classified as staining 2+ or 3+ were included, while those staining 0 or 1+ were excluded. Greater than
70% of patients enrolled exhibited 3+ overexpression. The data suggest that beneficial effects were
greater among those patients with higher levels of overexpression of HER2 (3+).

The main test method used to determine HER2 positivity in the pivotal trial of Docetaxel, with or
without Trastuzumab, was immunohistochemistry. A minority of patients was tested using fluorescence

in-situ hybridisation (FISH). In this trial, 87% of patients entered had disease that was IHC3+, and 95%
of patients entered had disease that was IHC3+ and/or FISH-positive.

Weekly dosing in metastatic breast cancer
The efficacy results from the monotherapy and combination therapy studies are summarised in Table 4:
Table 4 Efficacy results from the monotherapy and combination therapy studies

TTP = time to progression; “ne” indicates that it could not be estimated or it was not yet reached.

1.              Study H0649g: IHC3+ patient subset

2.              Study H0648g: IHC3+ patient subset

3.              Study M77001: Full analysis set (intent-to-treat), 24 months results

Combination treatment with Trastuzumab and Anastrozole
Trastuzumab has been studied in combination with Anastrozole for first line treatment of MBC in HER2
overexpressing, hormone-receptor (i.e. oestrogen-receptor (ER) and/or progesterone-receptor (PR))
positive postmenopausal patients. Progression free survival was doubled in the Trastuzumab 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 Trastuzumab containing regimen after progression of disease.

Three -weekly dosing in metastatic breast cancer
The efficacy results from the non-comparative monotherapy and combination therapy studies are
summarised in Table 5:

TTP = time to progression; “ne” indicates that it could not be estimated or it was not yet reached.

1.              Study WO16229: loading dose 8 mg/kg, followed by 6 mg/kg 3-weekly schedule

2.              Study MO16982: loading dose 6 mg/kg weekly x 3; followed by 6 mg/kg 3-weekly schedule

3.              Study BO15935

4.              Study MO16419

Sites of progression
The frequency of progression in the liver was significantly reduced in patients treated with the
combination of Trastuzumab and Paclitaxel, compared to Paclitaxel alone (21.8% versus 45.7%;
p=0.004). More patients treated with Trastuzumab and Paclitaxel progressed in the central nervous
system than those treated with Paclitaxel alone (12.6% versus 6.5%; p=0.377).

Early breast cancer (adjuvant setting)
Early breast cancer is defined as non-metastatic primary invasive carcinoma of the breast.

In the adjuvant treatment setting, Trastuzumab was investigated in 4 large multicentre, randomised,
trials.
• Study BO16348 was designed to compare one and two years of three-weekly Trastuzumab
treatment versus observation in patients with HER2 positive EBC following surgery, established
chemotherapy and radiotherapy (if applicable). In addition, comparison of two years of
Trastuzumab treatment versus one year of Trastuzumab treatment was performed. Patients assigned
to receive Trastuzumab were given an initial loading dose of 8 mg/kg, followed by 6 mg/kg every
three weeks for either one or two years.
• The NSABP B-31 and NCCTG N9831 studies that comprise the joint analysis were designed to
investigate the clinical utility of combining Trastuzumab treatment with Paclitaxel following AC
chemotherapy, additionally the NCCTG N9831 study also investigated adding Trastuzumab
sequentially to AC→P chemotherapy in patients with HER2 positive EBC following surgery.
• The BCIRG 006 study was designed to investigate combining Trastuzumab treatment with
Docetaxel either following AC chemotherapy or in combination with Docetaxel and Carboplatin in
patients with HER2 positive EBC following surgery.

Early breast cancer in the HERA trial was limited to operable, primary, invasive adenocarcinoma of the
breast, with axillary nodes positive or axillary nodes negative if tumours at least 1 cm in diameter.

In the joint analysis of the NSABP B-31 and NCCTG N9831 studies, EBC 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).

In the BCIRG 006 study HER2 positive, EBC was defined as either lymph node positive or high risk
node negative patients with no (pN0) lymph node involvement, and at least 1 of the following factors:
tumour size greater than 2 cm, oestrogen receptor and progesterone receptor negative, histological
and/or nuclear grade 2-3, or age <35 years.

The efficacy results from the BO16348 trial following 12 months* and 8 years** median follow-up are
summarized in Table 6:
Table 6 Efficacy results from study BO16348

*Co-primary endpoint of DFS of 1 year versus observation met the pre-defined statistical boundary

**Final analysis (including crossover of 52% of patients from the observation arm to Trastuzumab)

*** There is a discrepancy in the overall sample size due to a small number of patients who were randomized after the cut-off date for the 12-month median follow-up analysis

The efficacy results from the interim efficacy analysis crossed the protocol pre-specified statistical
boundary for the comparison of 1-year of Trastuzumab versus 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 Trastuzumab arm.

A final analysis was performed after a median follow-up of 8 years, which showed that 1 year
Trastuzumab 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 Trastuzumab treatment.

In this final analysis, extending Trastuzumab 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
versus 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 NSABP B-31 and NCCTG N9831 studies Trastuzumab was administered in combination with
Paclitaxel, following AC chemotherapy.

Doxorubicin and Cyclophosphamide were administered concurrently as follows:
 intravenous push Doxorubicin, at 60 mg/m2, given every 3 weeks for 4 cycles.
 intravenous Cyclophosphamide, at 600 mg/m2 over 30 minutes, given every 3 weeks for 4 cycles.
Paclitaxel, in combination with Trastuzumab, was administered as follows:
 intravenous Paclitaxel - 80 mg/m2 as a continuous intravenous infusion, given every week for
12 weeks.
or
 intravenous Paclitaxel - 175 mg/m2 as a continuous intravenous infusion, given every 3 weeks for
4 cycles (day 1 of each cycle).

The efficacy results from the joint analysis of the NSABP B-31 and NCCTG 9831 trials at the time of
the definitive analysis of DFS* are summarized in Table 7. The median duration of follow up was
1.8 years for the patients in the AC→P arm and 2.0 years for patients in the AC→PH arm.

Table 7 Summary of efficacy results from the joint analysis of the NSABP B-31 and NCCTG N9831
trials at the time of the definitive DFS analysis*

A: Doxorubicin; C: Cyclophosphamide; P: Paclitaxel; H: Trastuzumab

* At median duration of follow up of 1.8 years for the patients in the AC→P arm and 2.0 years for patients in the AC→PH arm

** p value for OS did not cross the pre-specified statistical boundary for comparison of AC→PH vs. AC→P

For the primary endpoint, DFS, the addition of Trastuzumab 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 3-year disease-free survival rate estimates of 11.8 percentage points (87.2% versus 75.4%) in
favour of the AC→PH (Trastuzumab) arm.

At the time of a safety update after a median of 3.5-3.8 years follow up, an analysis of DFS reconfirms
the magnitude of the benefit shown in the definitive analysis of DFS. Despite the cross-over to
Trastuzumab in the control arm, the addition of Trastuzumab to Paclitaxel chemotherapy resulted in a
52% decrease in the risk of disease recurrence. The addition of Trastuzumab to Paclitaxel chemotherapy
also resulted in a 37% decrease in the risk of death.

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→PH 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 Table 8 below:
Table 8 Final overall survival analysis from the joint analysis of trials NSABP B-31 and NCCTG N9831

A: Doxorubicin; C: Cyclophosphamide; P: Paclitaxel; H: Trastuzumab

DFS analysis was also performed at the final analysis of OS from the joint analysis of studies NSABP
B-31 and NCCTG N9831. The updated DFS analysis results (stratified HR = 0.61; 95% CI [0.54, 0.69])
showed a similar DFS benefit compared to the definitive primary DFS analysis, despite 24.8% patients
in the AC→P arm who crossed over to receive Trastuzumab. At 8 years, the disease-free survival rate
was estimated to be 77.2% (95% CI: 75.4, 79.1) in the AC→PH arm, an absolute benefit of 11.8%
compared with the AC→P arm.

In the BCIRG 006 study Trastuzumab 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:
• intravenous Docetaxel - 100 mg/m2 as an intravenous infusion over 1 hour, given every 3 weeks
for 4 cycles (day 2 of first Docetaxel cycle, then day1 of each subsequent cycle)
or
• intravenous Docetaxel - 75 mg/m2 as an intravenous infusion over 1 hour, given every 3 weeks for
6 cycles (day 2 of cycle 1, then day 1 of each subsequent cycle)
which was followed by:
• Carboplatin – at target AUC = 6 mg/mL/min administered by intravenous infusion over
30-60 minutes repeated every 3 weeks for a total of six cycles

Trastuzumab was administered weekly with chemotherapy and 3 weekly thereafter for a total of
52 weeks.

The efficacy results from the BCIRG 006 are summarized in Tables 9 and 10. The median duration of
follow up was 2.9 years in the AC→D arm and 3.0 years in each of the AC→DH and DCarbH arms.

Table 9 Overview of efficacy analyses BCIRG 006 AC→D versus AC→DH

AC→D = Doxorubicin plus Cyclophosphamide, followed by Docetaxel; AC→DH = Doxorubicin plus Cyclophosphamide, followed by Docetaxel plus Trastuzumab; CI = confidence interval

Table 10 Overview of efficacy analyses BCIRG 006 AC→D versus DCarbH

AC→D = Doxorubicin plus Cyclophosphamide, followed by Docetaxel; DCarbH = Docetaxel, Carboplatin and Trastuzumab; CI = confidence interval

In the BCIRG 006 study for the primary endpoint, DFS, the hazard ratio translates into an absolute
benefit, in terms of 3-year disease-free survival rate estimates of 5.8 percentage points (86.7% versus
80.9%) in favour of the AC→DH (Trastuzumab) arm and 4.6 percentage points (85.5% versus 80.9%)
in favour of the DCarbH (Trastuzumab) arm compared to AC→D.

In study BCIRG 006, 213/1075 patients in the DCarbH (TCH) arm, 221/1074 patients in the AC→DH
(AC→TH) arm, and 217/1073 in the AC→D (AC→T) arm had a Karnofsky performance status ≤90
(either 80 or 90). No disease-free survival (DFS) benefit was noticed in this subgroup of patients (hazard
ratio = 1.16, 95% CI [0.73, 1.83] for DCarbH (TCH) versus AC→D (AC→T); hazard ratio 0.97, 95%
CI [0.60, 1.55] for AC→DH (AC→TH) versus AC→D).

In addition a post-hoc exploratory analysis was performed on the data sets from the joint analysis (JA)
NSABP B-31/NCCTG N9831* and BCIRG006 clinical studies combining DFS events and
symptomatic cardiac events and summarised in Table 11:

Table 11 Post-hoc exploratory analysis results from the joint analysis NSABP B-31/NCCTG N9831*
and BCIRG006 clinical studies combining DFS events and symptomatic cardiac events

A: Doxorubicin; C: Cyclophosphamide; P: Paclitaxel; D: Docetaxel; Carb: Carboplatin; H: Trastuzumab

CI = confidence interval

*At the time of the definitive analysis of DFS. Median duration of follow up was 1.8 years in the AC→P
arm and 2.0 years in the AC→PH arm
** Median duration of long term follow-up for the Joint Analysis clinical studies was 8.3 years (range:
0.1 to 12.1) for the AC→PH arm and 7.9 years (range: 0.0 to 12.2) for the AC→P arm; Median duration
of long term follow-up for the BCIRG 006 study was 10.3 years in both the AC→D arm (range: 0.0 to
12.6) arm and the DCarbH arm (range: 0.0 to 13.1), and was 10.4 years (range: 0.0 to 12.7) in the
AC→DH arm

Early breast cancer (neoadjuvant-adjuvant setting)
So far, no results are available which compare the efficacy of Trastuzumab administered with
chemotherapy in the adjuvant setting with that obtained in the neo-adjuvant/adjuvant setting.

In the neoadjuvant-adjuvant treatment setting, study MO16432, a multicentre randomised trial, was
designed to investigate the clinical efficacy of concurrent administration of Trastuzumab with
neoadjuvant chemotherapy including both an Anthracycline and a Taxane, followed by adjuvant
Trastuzumab, up to a total treatment duration of 1 year. The study recruited patients with newly
diagnosed locally advanced (Stage III) or inflammatory EBC. Patients with HER2+ tumours were
randomised to receive either neoadjuvant chemotherapy concurrently with neoadjuvant-adjuvant
Trastuzumab, or neoadjuvant chemotherapy alone.

In study MO16432, Trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg maintenance every
3 weeks) was administered concurrently with 10 cycles of neoadjuvant chemotherapy as follows:
• Doxorubicin 60 mg/m2 and Paclitaxel 150 mg/m2, administered 3-weekly for 3 cycles, which
was followed by
• Paclitaxel 175 mg/m2 administered 3-weekly for 4 cycles, which was followed by
• CMF on day 1 and 8 every 4 weeks for 3 cycles, which was followed after surgery by
• additional cycles of adjuvant Trastuzumab (to complete 1 year of treatment)

The efficacy results from Study MO16432 are summarized in Table 12. The median duration of followup
in the Trastuzumab arm was 3.8 years.

Table 12 Efficacy results from MO16432

* defined as absence of any invasive cancer both in the breast and axillary nodes

An absolute benefit of 13 percentage points in favour of the Trastuzumab arm was estimated in terms
of 3-year event-free survival rate (65% versus 52%).

Metastatic gastric cancer
Trastuzumab has been investigated in one randomised, open-label phase III trial ToGA (BO18255) in
combination with chemotherapy versus chemotherapy alone.
Chemotherapy was administered as follows:
• Capecitabine - 1000 mg/m2 orally twice daily for 14 days every 3 weeks for 6 cycles (evening of
day 1 to morning of day 15 of each cycle)
or
• intravenous 5-Fluorouracil - 800 mg/m2/day as a continuous intravenous infusion over 5 days,
given every 3 weeks for 6 cycles (days 1 to 5 of each cycle)
Either of which was administered with:
• Cisplatin - 80 mg/m2 every 3 weeks for 6 cycles on day 1 of each cycle.

The efficacy results from study BO18225 are summarized in Table 13:
Table 13 Efficacy results from BO18225

FP + H: Fluoropyrimidine/Cisplatin + Trastuzumab

FP: Fluoropyrimidine/Cisplatin

a Odds ratio

Patients were recruited to the trial who were 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. 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.

Post-hoc subgroup analyses indicate that positive treatment effects are limited to targeting tumours with
higher levels of HER2 protein (IHC 2+/FISH+ or IHC 3+). 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
FP versus FP + H, respectively. For overall survival, the HR was 0.75 (95% CI 0.51-1.11) in the
IHC 2+/FISH+ group and the HR was 0.58 (95% CI 0.41-0.81) in the IHC 3+/FISH+ group.

In an exploratory subgroup analysis performed in the TOGA (BO18255) trial there was no apparent
benefit on overall survival with the addition of Trastuzumab in patients with ECOG PS 2 at baseline
[HR 0.96 (95% CI 0.51-1.79)], non-measurable [HR 1.78 (95% CI 0.87-3.66)] and locally advanced
disease [HR 1.20 (95% CI 0.29-4.97)].

Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with
Trastuzumab in all subsets of the paediatric population for breast and gastric cancer (see section 4.2 for
information on paediatric use).

The pharmacokinetics of Trastuzumab were evaluated in a population pharmacokinetic model analysis
using pooled data from 1,582 subjects, including patients with HER2 positive MBC, EBC, AGC or
other tumour types, and healthy volunteers, in 18 Phase I, II and III trials receiving Trastuzumab
intravenous. A two-compartment model with parallel linear and non-linear elimination from the central
compartment described the Trastuzumab concentration-time profile. Due to non-linear elimination,
total clearance increased with decreasing concentration. Therefore, no constant value for half-life of
Trastuzumab can be deduced. The t1/2 decreases with decreasing concentrations within a dosing interval
(see Table 16). MBC and EBC patients had similar PK parameters (e.g. clearance (CL), the central
compartment volume (Vc)) and population-predicted steady-state exposures (Cmin, Cmax and AUC).
Linear clearance was 0.136 L/day for MBC, 0.112 L/day for EBC and 0.176 L/day for AGC. The nonlinear
elimination parameter values were 8.81 mg/day for the maximum elimination rate (Vmax) and
8.92 mcg/mL for the Michaelis-Menten constant (Km) for the MBC, EBC, and AGC patients. The
central compartment volume was 2.62 L for patients with MBC and EBC and 3.63 L for patients with
AGC. In the final population PK model, in addition to primary tumour type, body-weight, serum
aspartate aminotransferase and albumin were identified as a statistically significant covariates affecting
the exposure of Trastuzumab. However, the magnitude of effect of these covariates on Trastuzumab
exposure suggests that these covariates are unlikely to have a clinically meaningful effect on
Trastuzumab concentrations.

The population predicted PK exposure values (median with 5th - 95th percentiles) and PK parameter
values at clinically relevant concentrations (Cmax and Cmin) for MBC, EBC and AGC patients treated
with the approved q1w and q3w dosing regimens are shown in Table 14 (Cycle 1), Table 15 (steadystate),
and Table 16 (PK parameters).

Table 14 Population predicted cycle 1 PK exposure values (median with 5th - 95th percentiles) for
Trastuzumab intravenous dosing regimens in MBC, EBC and AGC patients

Table 15 Population predicted steady state PK exposure values (median with 5th - 95th percentiles) for Trastuzumab intravenous dosing regimens in MBC, EBC and AGC patients

*Cmin,ss – Cmin at steady state

**Cmax,ss = Cmax at steady state

*** time to 90% of steady-state

Table 16 Population predicted PK parameter values at steady state for Trastuzumab intravenous dosing regimens in MBC, EBC and AGC patients

Trastuzumab washout
Trastuzumab washout period was assessed following q1w or q3w intravenous administration using the
population PK model. The results of these simulations indicate that at least 95% of patients will reach
concentrations that are <1 mcg/mL (approximately 3% of the population predicted Cmin,ss, or about 97%
washout) by 7 months.

Circulating shed HER2 ECD
The exploratory analyses of covariates with information in only a subset of patients suggested that
patients with greater shed HER2-ECD level had faster nonlinear clearance (lower Km) (P <0.001). There
was a correlation between shed antigen and SGOT/AST levels; part of the impact of shed antigen on
clearance may have been explained by SGOT/AST levels.

Baseline levels of the shed HER2-ECD observed in MGC patients were comparable to those in MBC
and EBC patients and no apparent impact on Trastuzumab clearance was observed.

There was no evidence of acute or multiple dose-related toxicity in studies of up to 6 months, or
reproductive toxicity in teratology, female fertility or late gestational toxicity/placental transfer studies.
Zercepac is not genotoxic. A study of trehalose, a major formulation excipient did not reveal any
toxicities.

No long-term animal studies have been performed to establish the carcinogenic potential of Zercepac,
or to determine its effects on fertility in males.

L-histidine hydrochloride monohydrate
L-histidine
α, α-trehalose dihydrate
Polysorbate 20

This medicinal product must not be mixed or diluted with other medicinal products except those
mentioned under section 6.6.
Do not dilute with glucose solutions since these cause aggregation of the protein.

Store in a refrigerator (2°C - 8°C). Store in the original carton in order to protect from light.
For storage conditions of the reconstituted and diluted medicinal product, see section 6.3.

One 20ml clear glass type I vial with bromobutyl rubber stopper containing 150mg of Trastuzumab.
Each carton contains one vial.

Zercepac is provided in sterile, preservative-free, non-pyrogenic, single use vials.
Since the medicinal product does not contain any anti-microbial preservative or bacteriostatic agents,
appropriate aseptic technique should be used for reconstitution and dilution procedures. Care must be
taken to ensure the sterility of prepared solutions.

Aseptic preparation, handling and storage:
The infusion preparation should be:
• performed by trained personnel in accordance with good practice rules especially with respect to
the aseptic preparation of parenteral products.
• prepared in a laminar flow hood or biological safety cabinet using standard precautions for the
safe handling of intravenous agents.
• followed by adequate storage of the prepared solution for intravenous infusion to ensure
maintenance of the aseptic conditions.

Instructions for aseptic reconstitution:
1) Using a sterile syringe, slowly inject 7.2 mL of sterile water for injection (not supplied) in the
vial containing the lyophilized Zercepac, directing the stream into the lyophilised cake. Use of
other reconstitution solvents should be avoided.
2) Swirl the 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 Zercepac results in a colourless to pale yellow
transparent solution and should be essentially free of visible particulates.

This yields a 7.5ml solution for single-dose use, containing approximately 21 mg/mL Trastuzumab, at
a pH of approximately 6.0. A volume overage of 5% ensures that the labelled dose of 150 mg can be
withdrawn from each vial.

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

The reconstituted solution should not be frozen.

Instructions for aseptic 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:

Volume (ml) =  Body weight (kg) x dose (4 mg/kg for loading or 2 mg/kg for maintenance)

21 (mg/mL, concentration of reconstituted solution)

· 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:

Volume (mL) =    Body weight (kg) x dose (8 mg/kg for loading or 6 mg/kg for maintenance)

21 (mg/mL, concentration of reconstituted solution)

The appropriate amount of solution should be withdrawn from the vial and added to an infusion bag
containing 250ml of 9 mg/ml (0.9%) sodium chloride solution. Do not use with glucose-containing
solutions (see section 6.2). The bag should be gently inverted to mix the solution in order to avoid
foaming.

Parenteral medicinal products should be inspected visually for particulate matter and discoloration prior
to administration.

No incompatibilities between Zercepac and polyethylene or polypropylene bags have been observed.

Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.