Herzuma

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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This medicinal product is subject to additional monitoring. This will allow quick identification of 

new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 

See section 4.8 for how to report adverse reactions. 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Herzuma 150 mg powder for concentrate for solution for infusion 

Herzuma 420 mg powder for concentrate for solution for infusion 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

Herzuma 150 mg powder for concentrate for solution for infusion 

 

One vial contains 150 mg of trastuzumab, a humanised IgG1 monoclonal antibody produced by 

mammalian (Chinese hamster ovary) cell suspension culture and purified by affinity and ion exchange 

chromatography including specific viral inactivation and removal procedures.  

  

Herzuma 420 mg powder for concentrate for solution for infusion 

 

One vial contains 420 mg of trastuzumab, a humanised IgG1 monoclonal antibody produced by 

mammalian (Chinese hamster ovary) cell suspension culture and purified by affinity and ion exchange 

chromatography including specific viral inactivation and removal procedures.  

 

The reconstituted Herzuma solution contains 21 mg/mL of trastuzumab.  

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 
 

Powder for concentrate for solution for infusion.  

 

White to pale yellow lyophilised powder. 

 

 

4. CLINICAL PARTICULARS 
 

4.1 Therapeutic indications 
 

Breast cancer  

 

Metastatic breast cancer 

 

Herzuma 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.  

 



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- 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  

 

Herzuma 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 Herzuma therapy, for 
locally advanced (including inflammatory) disease or tumours > 2 cm in diameter (see sections 

4.4 and 5.1). 

 

Herzuma 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  

 

Herzuma 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 gastro-esophageal 

junction who have not received prior anti-cancer treatment for their metastatic disease.  

 

Herzuma 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). 

 

4.2 Posology and method of administration 

 

HER2 testing is mandatory prior to initiation of therapy (see sections 4.4 and 5.1). Herzuma 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.   

  

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 Herzuma (trastuzumab) and not Kadcyla 

(trastuzumab emtansine). 

 

Posology 

 

Metastatic breast cancer 

 

Three-weekly schedule  

 

The recommended initial loading dose is 8 mg/kg body weight. The recommended maintenance dose 

at three-weekly intervals is 6 mg/kg body weight, beginning three weeks after the loading dose.  

 

Weekly schedule  

 



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The recommended initial loading dose of Herzuma is 4 mg/kg body weight. The recommended weekly 

maintenance dose of Herzuma is 2 mg/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 Herzuma is 8 mg/kg body weight. 

The recommended maintenance dose of Herzuma at three-weekly intervals is 6 mg/kg body weight, 

beginning three weeks after the loading dose. 

 

As a weekly regimen (initial loading dose of 4 mg/kg followed by 2 mg/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 8 mg/kg body weight. The recommended maintenance dose 

at three-weekly intervals is 6 mg/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 Herzuma until progression of disease. Patients with 

EBC should be treated with Herzuma 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 Herzuma 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 Herzuma 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. 



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Missed doses  

 

If the patient has missed a dose of Herzuma by one week or less, then the usual maintenance dose 

(weekly regimen: 2 mg/kg; three-weekly regimen: 6 mg/kg) should be administered as soon as 

possible. The patient who missed the dose should 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 Herzuma by more than one week, a re-loading dose of Herzuma 

should be administered over approximately 90 minutes (weekly regimen: 4 mg/kg; three-weekly 

regimen: 8 mg/kg) as soon as possible. Subsequent Herzuma maintenance doses (weekly regimen: 

2 mg/kg; three-weekly regimen 6 mg/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 Herzuma in the paediatric population. 

 

Method of administration  

 

Herzuma loading dose should be administered as a 90-minute intravenous infusion. It should not be 

administered as an intravenous push or bolus. Herzuma intravenous infusion should be administered 

by a health-care 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 Herzuma intravenous formulation before administration, see 

section 6.6. 

 

4.3 Contraindications 

 

 Hypersensitivity to trastuzumab, murine proteins, or to any of the excipients listed in 
section 6.1. 

 Severe dyspnoea at rest due to complications of advanced malignancy or requiring 
supplementary oxygen therapy. 

 

4.4 Special warnings and precautions for use 

 

Traceability 

 

In order to improve the 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). 



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Currently no data from clinical trials are available on re-treatment of patients with previous exposure 

to Herzuma in the adjuvant setting. 

 

Cardiac dysfunction 

 

General considerations 

 

Patients treated with Herzuma 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 Herzuma, 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 Herzuma. A careful risk-benefit assessment should be made before deciding to 

treat with Herzuma. 

 

Trastuzumab may persist in the circulation for up to 7 months after stopping Herzuma treatment based 

on population pharmacokinetic analysis of all available data (see section 5.2). Patients who receive 

anthracyclines after stopping Herzuma may possibly be at increased risk of cardiac dysfunction. If 

possible, physicians should avoid anthracycline-based therapy for up to 7 months after stopping 

Herzuma. 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 

Herzuma therapy has been seen.  

 

The safety of continuation or resumption of Herzuma in patients who experience cardiac dysfunction 

has not been prospectively studied. If 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 declined further, or symptomatic CHF has 

developed, discontinuation of Herzuma 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. 

 

If symptomatic cardiac failure develops during Herzuma 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  

  

Herzuma and anthracyclines should not be given concurrently in combination in the MBC setting. 



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Patients with MBC who have previously received anthracyclines are also at risk of cardiac dysfunction 

with Herzuma treatment, although the risk is lower than with concurrent use of Herzuma 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 Herzuma. In patients who receive anthracycline-containing 

chemotherapy further monitoring is recommended, and should occur yearly up to 5 years from the last 

administration of Herzuma, 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 

 

Herzuma 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, Herzuma 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 Herzuma 

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. 

 



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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 cardiac failure/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 and hypersensitivity  

 

Serious IRRs to Herzuma 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 Herzuma (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 Herzuma (see section 4.3). Caution should be exercised for pneumonitis, 

especially in patients being treated concomitantly with taxanes. 

 

4.5 Interaction with other medicinal products and other forms of interaction 

 



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No formal medicinal product interaction studies have been performed. Clinically significant 

interactions between Herzuma 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 intravenous loading dose followed by 6 mg/kg q3w or 2 mg/kg q1w intravenous, 

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 a single-arm study JP16003 of trastuzumab (4 mg/kg intravenous loading dose and 2 mg/kg 

intravenous weekly) and docetaxel (60 mg/m2 intravenous) 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 intravenous) 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. 

 

4.6 Fertility, pregnancy and lactation 

 

Women of childbearing potential 



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Women of childbearing potential should be advised to use effective contraception during treatment 

with Herzuma 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 Herzuma, or if a patient 

becomes pregnant while receiving Herzuma or within 7 months following the last dose of Herzuma, 

close monitoring by a multidisciplinary team is desirable. 

 

Breast-feeding 

 

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 Herzuma therapy 

and for 7 months after the last dose. 

 

Fertility 

 

There is no fertility data available. 

 

4.7 Effects on ability to drive and use machines 

 

Herzuma may have a minor influence on the ability to drive or use machines (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.  

 

4.8 Undesirable effects 

 

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.  

 



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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 

 

System organ class Adverse reaction Frequency 

Infections and infestations Infection Very common 

Nasopharyngitis Very common 

Neutropenic sepsis Common 

Cystitis Common 

Herpes zoster Common 

Influenza Common 

Sinusitis Common 

Skin infection Common 

Rhinitis Common 

Upper respiratory tract infection Common 

Urinary tract infection Common 

Erysipelas Common 

Cellulitis Common 

Pharyngitis Common 

Sepsis Uncommon 

Neoplasms benign, 

malignant and unspecified 

(incl. Cysts and polyps) 

Malignant neoplasm progression Not known 

Neoplasm progression Not known 

Blood and lymphatic 

system disorders 

Febrile neutropenia Very common 

Anaemia Very common 

Neutropenia Very common 

White blood cell count 

decreased/leukopenia 

Very common 

Thrombocytopenia  Very common 

Hypoprothrombinaemia Not known 

Immune thrombocytopenia Not known 

Immune system disorders Hypersensitivity Common 
+Anaphylactic reaction Not known 
+Anaphylactic shock Not known 

Metabolism and nutrition 

disorders 

Weight decreased/Weight loss Very common 

Anorexia Very common 

Tumour lysis syndrome Not known 

Hyperkalaemia Not known 

Psychiatric disorders Insomnia Very common 

Anxiety Common 

Depression Common 

Thinking abnormal Common 

Nervous system disorders 1Tremor Very common 

Dizziness Very common 

Headache Very common 

Paraesthesia Very common 

Dysgeusia Very common 

Peripheral neuropathy Common 

Hypertonia Common 



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System organ class Adverse reaction Frequency 

Somnolence Common 

Ataxia Common 

Paresis Rare 

Brain oedema Not known 

Eye disorders Conjunctivitis Very common 

Lacrimation increased Very common 

Dry eye Common 

Papilloedema Not known 

Retinal haemorrhage Not known 

Ear and labyrinth disorders Deafness Uncommon 

Cardiac disorders 1Blood pressure decreased Very common 
1Blood pressure increased Very common 
1Heart beat irregular Very common 
1Palpitation Very common 
1Cardiac flutter Very common 

Ejection fraction decreased* Very common 
+Cardiac failure (congestive) Common 
+1Supraventricular tachyarrhythmia Common 

Cardiomyopathy Common 

Pericardial effusion Uncommon 

Cardiogenic shock Not known 

Pericarditis Not known 

Bradycardia Not known 

Gallop rhythm present Not known 

Vascular disorders Hot flush Very common 
+1Hypotension Common 

Vasodilatation Common 

Respiratory, thoracic and 

mediastinal disorders 

+1Wheezing Very common 
+Dyspnoea Very common 

Cough Very common 

Epistaxis Very common 

Rhinorrhoea Very common 
+Pneumonia Common 

Asthma Common 

Lung disorder Common 
+Pleural effusion Common 

Pneumonitis Rare 
+Pulmonary fibrosis Not known 
+Respiratory distress Not known 
+Respiratory failure Not known 
+Lung infiltration  Not known 
+Acute pulmonary oedema Not known 
+Acute respiratory distress syndrome Not known 
+Bronchospasm Not known 
+Hypoxia Not known 
+Oxygen saturation decreased Not known 

Laryngeal oedema Not known 

Orthopnoea Not known 

Pulmonary oedema Not known 

Interstitial lung disease Not known 

Gastrointestinal disorders Diarrhoea Very common 

Vomiting Very common 

Nausea Very common 
1Lip swelling Very common 



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System organ class Adverse reaction Frequency 

Abdominal pain Very common 

Dyspepsia Very common 

Constipation Very common 

Stomatitis Very common 

Haemorrhoids Common 

Dry mouth Common 

Hepatobiliary disorders Hepatocellular injury Common 

Hepatitis Common 

Liver tenderness Common 

Jaundice Rare 

Hepatic failure Not known 

Skin and subcutaneous 

tissue disorders 

Erythema Very common 

Rash Very common 
1Swelling face Very common 

Alopecia Very common 

Nail disorder Very common 

Palmar-plantar erythrodysaesthesia 

syndrome 

Very common 

Acne Common 

Dry skin Common 

Ecchymosis Common 

Hyperhydrosis Common 

Maculopapular rash Common 

Pruritus Common 

Onychoclasis Common 

Dermatitis Common 

Urticaria Uncommon 

Angioedema Not known 

Musculoskeletal and 

connective tissue disorders 

Arthralgia Very common 
1Muscle tightness Very common 

Myalgia Very common 

Arthritis Common 

Back pain Common 

Bone pain Common 

Muscle spasms Common 

Neck Pain Common 

Pain in extremity Common 

Renal and urinary disorders Renal disorder Common 

Glomerulonephritis membranous Not known 

Glomerulonephropathy Not known 

Renal failure Not known 

Pregnancy, puerperium and 

perinatal conditions 

Oligohydramnios Not known 

Renal hypoplasia Not known 

Pulmonary hypoplasia Not known 

Reproductive system and 

breast disorders 

Breast inflammation/mastitis Common 

General disorders and 

administration site 

conditions 

Asthenia Very common 

Chest pain Very common 

Chills Very common 

Fatigue Very common 

Influenza-like symptoms Very common 

Infusion related reaction Very common 

Pain Very common 

Pyrexia Very common 



14 

System organ class Adverse reaction Frequency 

Mucosal inflammation Very common 

Peripheral oedema Very common 

Malaise Common 

Oedema Common 

Injury, poisoning and 

procedural complications 

Contusion Common 

+ 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 Herzuma 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, 



15 

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 hypoprothrombinemia 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 reporting system 

listed in Appendix V. 

 

4.9 Overdose 

 

There is no experience with overdose in human clinical trials. Single doses of Herzuma 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. 

 

 



16 

5. PHARMACOLOGICAL PROPERTIES 

 

5.1  Pharmacodynamic properties 

 

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

 

Herzuma 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 hybridisation (FISH) or chromogenic in situ hybridisation (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  

 

Herzuma 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 Herzuma 

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 

 

Score Staining pattern 
HER2 overexpression 

assessment 

0 
No staining is observed or membrane staining is 

observed in < 10% of the tumour cells. 
Negative 

1+ 

A faint/barely perceptible membrane staining is 

detected in > 10% of the tumour cells. The cells are 

only stained in part of their membrane.  
Negative 



17 

Score Staining pattern 
HER2 overexpression 

assessment 

2+ 
A weak to moderate complete membrane staining is 

detected in > 10% of the tumour cells.  
Equivocal 

3+ 
Strong complete membrane staining is detected in  

> 10% of the tumour cells. 
Positive 

 

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 hybridisation (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:  

 

Table 3 Recommended scoring system to evaluate the IHC staining patterns in gastric cancer 

 

Score 
Surgical specimen  

- staining pattern 

Biopsy specimen  

- staining pattern 

HER2 

overexpression 

assessment 

0 

No reactivity or membranous 

reactivity in < 10% of tumour 

cells  

No reactivity or membranous 

reactivity in any tumour cell  Negative 



18 

Score 
Surgical specimen  

- staining pattern 

Biopsy specimen  

- staining pattern 

HER2 

overexpression 

assessment 

1+ 

Faint ⁄ barely perceptible 

membranous reactivity in ≥ 10% 

of tumour cells; cells are 

reactive only in part of their 

membrane  

Tumour cell cluster with a faint ⁄ 

barely perceptible membranous 

reactivity irrespective of 

percentage of tumour cells 

stained  

Negative 

2+ 

Weak to moderate complete, 

basolateral or lateral 

membranous reactivity in 

≥ 10% of tumour cells  

Tumour cell cluster with a weak 

to moderate complete, 

basolateral or lateral 

membranous reactivity 

irrespective of percentage of 

tumour cells stained  

Equivocal 

3+ 

Strong complete, basolateral or 

lateral membranous reactivity in 

≥ 10% of tumour cells  

Tumour cell cluster with a 

strong complete, basolateral or 

lateral membranous reactivity 

irrespective of percentage of 

tumour cells stained  

Positive 

 

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  



19 

 

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 

 

Parameter Monotherapy Combination Therapy 

  Trastuzumab1 

 

 

N=172 

Trastuzumab 

plus 

paclitaxel2 

N=68 

Paclitaxel2 

 

 

N=77 

Trastuzumab 

plus 

docetaxel3 

N=92 

Docetaxel3 

 

 

N=94 

Response rate (95% 

CI)  
18% 

(13 - 25) 

49% 

(36 - 61) 

17% 

(9 - 27) 

61% 

(50 - 71) 

34% 

(25 - 45) 

Median duration of 

response (months)  

(95% CI)  

9.1 

(5.6 - 10.3) 

8.3 

(7.3-8.8) 

4.6 

(3.7-7.4) 

11.7 

(9.3 - 15.0) 

5.7 

(4.6 - 7.6) 

Median TTP 

(months) (95% CI)  
3.2 

(2.6 - 3.5) 

7.1 

(6.2 - 12.0) 

3.0 

(2.0 - 4.4) 

11.7 

(9.2 - 13.5) 

6.1 

(5.4 - 7.2) 

Median survival 

(months) (95% CI)  
16.4 

(12.3 - ne) 

24.8 

(18.6 - 33.7) 

17.9 

(11.2 - 23.8) 

31.2 

(27.3 - 40.8) 

22.74 

(19.1 - 30.8) 

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. estrogen-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: 

 

Table 5 Efficacy results from the non-comparative monotherapy and combination therapy studies 

 

Parameter Monotherapy Combination Therapy 

 

Trastuzumab1 

 

N=105 

Trastuzumab2 

 

N=72 

Trastuzumab 

plus paclitaxel3 

N=32 

Trastuzumab 

plus 

docetaxel4 

N=110 

Response rate  

(95% CI)  
24% 

(15 - 35) 

27% 

(14 - 43) 

59% 

(41 - 76) 

73% 

(63 - 81) 

Median duration of 

response (months) 

(range)  

10.1 

(2.8 - 35.6) 

7.9 

(2.1 - 18.8) 

10.5 

(1.8 - 21) 

13.4 

(2.1 - 55.1) 



20 

Parameter Monotherapy Combination Therapy 

 

Trastuzumab1 

 

N=105 

Trastuzumab2 

 

N=72 

Trastuzumab 

plus paclitaxel3 

N=32 

Trastuzumab 

plus 

docetaxel4 

N=110 

Median TTP (months) 

(95% CI)  
3.4 

(2.8 - 4.1) 

7.7 

(4.2 - 8.3) 

12.2 

(6.2 - ne) 

13.6 

(11 - 16) 

Median survival 

(months)  

(95% CI)  

ne ne ne 
47.3 

(32 - ne) 

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, estrogen receptor and progesterone receptor negative, histological 

and/or nuclear grade 2 - 3, or age < 35 years. 



21 

 

The efficacy results from the BO16348 trial following 12 months* and 8 years** median follow-up 

are summarised in Table 6:  

 

Table 6 Efficacy results from study BO16348 

 

 Median follow-up  

12 months* 

Median follow-up  

8 years** 

Parameter 
Observation 

N=1693 

Trastuzumab 

1 Year 

N = 1693 

Observation  

N= 1697*** 

Trastuzumab 

1 Year 

N = 1702*** 

Disease-free survival 

- No. patients with event 
- No. patients without event  
P-value versus observation 

Hazard ratio versus observation 

 

219 (12.9%) 127 (7.5%) 

1474 (87.1%) 1566 (92.5%) 

< 0.0001 

0.54 

 

570 (33.6%) 471 (27.7%) 

1127 (66.4%) 1231 (72.3%) 

< 0.0001 

0.76 

Recurrence-free survival 

- No. patients with event 
- No. patients without event  
P-value versus observation 

Hazard ratio versus observation 

 

208 (12.3%) 113 (6.7%) 

1485 (87.7%) 1580 (93.3%) 

< 0.0001 

0.51 

 

506 (29.8%) 399 (23.4%) 

1191 (70.2%) 1303 (76.6%) 

< 0.0001 

0.73 

Distant disease-free survival 

- No. patients with event 
- No. patients without event  
P-value versus observation 

Hazard ratio versus observation 

 

184 (10.9%) 99 (5.8%) 

1508 (89.1%) 1594 (94.6%) 

< 0.0001 

0.50 

 

488 (28.8%) 399 (23.4%) 

1209 (71.2%) 1303 (76.6%) 

< 0.0001 

0.76 

Overall survival (death) 

- No. patients with event 
- No. patients without event  
P-value versus observation 

Hazard ratio versus observation 

 

40 (2.4%) 31 (1.8%) 

1653 (97.6%) 1662 (98.2%) 

0.24 

0.75 

 

350 (20.6%) 278 (16.3%) 

1347 (79.4%) 1424 (83.7%) 

0.0005 

0.76 

*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 randomised 

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%).  

 



22 

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 N9831 trials at the time 

of the definitive analysis of DFS* are summarised 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* 

 

Parameter 
AC→P 

(n=1679) 

AC→PH 

(n=1672) 

Hazard ratio vs 

AC→P (95% CI) 

p-value 

Disease-free survival 

No. patients with event (%) 

 

261 (15.5) 

 

133 (8.0) 

 

0.48 (0.39, 0.59) 

p<0.0001 

Distant recurrence 

No. patients with event 

 

193 (11.5) 

 

96 (5.7) 

 

0.47 (0.37, 0.60) 

p<0.0001 

Death (OS event): 

No. patients with event 

 

92 (5.5) 

 

62 (3.7) 

 

0.67 (0.48, 0.92) 

p=0.014** 

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→PH 



23 

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 

summarised in Table 8 below: 

 

Table 8 Final overall survival analysis from the joint analysis of trials NSABP B-31 and NCCTG 

N9831 

 

Parameter 
AC→P 

(N=2032) 

AC→PH 

(N=2031) 

p-value versus 

AC→P 

Hazard ratio 

versus 

AC→P 

(95% CI) 

Death (OS event): 

No. patients with event (%) 

 

418 (20.6%) 

 

289 (14.2%) 

 

< 0.0001 

 

0.64 

(0.55, 0.74) 
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 day 1 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 summarised 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 

 

Parameter 
AC→D 

(n=1073) 

AC→DH 

(n=1074) 

Hazard ratio vs 

AC→D (95% CI) 

p-value 

Disease-free survival 

No. patients with event 

 

195 

 

134 

 

0.61 (0.49, 0.77) 

p<0.0001 



24 

Parameter 
AC→D 

(n=1073) 

AC→DH 

(n=1074) 

Hazard ratio vs 

AC→D (95% CI) 

p-value 

Distant recurrence 

No. patients with event 

 

144 

 

95 

 

0.59 (0.46, 0.77) 

p<0.0001 

Death (OS event) 

No. patients with event 

 

80 

 

49 

 

0.58 (0.40, 0.83) 

p=0.0024 

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 

 

Parameter 
AC→D 

(n=1073) 

DCarbH 

(n=1074) 

Hazard ratio vs 

AC→D (95% CI) 

p-value 

Disease-free survival 

No. patients with event 

 

195 

 

145 

 

0.67 (0.54, 0.83) 

p=0.0003 

Distant recurrence 

No. patients with event 

 

144 

 

103 

 

0.65 (0.50, 0.84) 

p=0.0008 

Death (OS event) 

No. patients with event 

 

80 

 

56 

 

0.66 (0.47, 0.93) 

p=0.0182 

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 BCIRG 006 study, 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 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 BCIRG 006 clinical studies combining DFS events and symptomatic cardiac events 

 

Parameter 

AC→PH 

(vs. AC→P) 

(NSABP B-31 and 

NCCTG N9831)* 

AC→DH 

(vs. AC→D) 

(BCIRG 006) 

DCarbH 

(vs. AC→D) 

(BCIRG 006) 

Primary efficacy analysis 

DFS hazard ratios 

(95% CI) 

p-value 

 

0.48 

(0.39, 0.59) 

p<0.0001 

 

0.61 

(0.49, 0.77) 

p<0.0001 

 

0.67 

(0.54, 0.83) 

p=0.0003 

Long term follow-up efficacy    



25 

Parameter 

AC→PH 

(vs. AC→P) 

(NSABP B-31 and 

NCCTG N9831)* 

AC→DH 

(vs. AC→D) 

(BCIRG 006) 

DCarbH 

(vs. AC→D) 

(BCIRG 006) 

analysis
** 

DFS hazard ratios 

(95% CI) 

p-value 

 

0.61 

(0.54, 0.69) 

p<0.0001 

 

0.72 

(0.61, 0.85) 

p<0.0001 

 

0.77 

(0.65, 0.90) 

p=0.0011 

Post-hoc exploratory analysis 

with DFS and symptomatic 

cardiac events 

Long term follow-up
** 

 
hazard ratios 

(95% CI) 

 

 

 

 

0.67 

(0.60, 0.75) 

 

 

 

 

0.77 

(0.66, 0.90) 

 

 

 

 

0.77 

(0.66, 0.90) 

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) 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 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 60mg/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 summarised in Table 12. The median duration of 

follow-up in the trastuzumab arm was 3.8 years. 



26 

 

Table 12 Efficacy results from MO16432 

 

Parameter 

Chemo + 

trastuzumab 

(n=115) 

Chemo only 

(n=116) 
 

Event-free survival  

 

No. patients with event 

 

46 

 

59 

Hazard ratio 

(95% CI) 

0.65 (0.44, 0.96) 

p=0.0275 

Total pathological complete 

response* (95% CI) 

40% 

(31.0, 49.6) 

20.7% 

(13.7, 29.2) 
p=0.0014 

Overall survival 

 

No. patients with event 

 

22 

 

33 

Hazard ratio 

(95% CI) 

0.59 (0.35, 1.02) 

p=0.0555 
* 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 summarised in Table 13:  

 

Table 13 Efficacy results from BO18225 

 

Parameter 
FP 

N = 290 

FP + H 

N = 294 
HR (95% CI) p-value 

Overall survival, median months  11.1 13.8 0.74 (0.60 - 0.91) 0.0046 

Progression-free survival,  

median months  
5.5 6.7 0.71 (0.59 - 0.85) 0.0002 

Time to disease progression,  

median months  
5.6 7.1 0.70 (0.58 - 0.85) 0.0003 

Overall response rate, % 34.5% 47.3% 1.70a (1.22 - 2.38) 0.0017 

Duration of response, median 

months  
4.8 6.9 0.54 (0.40 - 0.73) < 0.0001 

FP + H: Fluoropyrimidine/cisplatin + trastuzumab  

FP: Fluoropyrimidine/cisplatin  

a: Odds ratio  
 



27 

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 randomisation to the date of death from any cause. At the time of 

the analysis a total of 349 randomised 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). 

 

5.2 Pharmacokinetic properties 

 

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 non-linear elimination parameter values were 8.81 mg/day for the maximum elimination rate 

(Vmax) and 8.92 μg/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 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 

(steady-state), 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 

 

Regimen 
Primary tumour 

type 
N 

Cmin 

(μg/mL) 

Cmax 

(μg/mL) 

AUC0-21days 

(μg.day/mL) 



28 

Regimen 
Primary tumour 

type 
N 

Cmin 

(μg/mL) 

Cmax 

(μg/mL) 

AUC0-21days 

(μg.day/mL) 

8mg/kg + 

6mg/kg q3w 

MBC 805 
28.7 

(2.9 - 46.3) 

182 

(134 - 280) 

1376 

(728 - 1998) 

EBC 390 
30.9 

(18.7 - 45.5) 

176 

(127 - 227) 

1390 

(1039 - 1895) 

AGC 274 
23.1 

(6.1 - 50.3) 

132 

(84.2 - 225) 

1109 

(588 - 1938) 

4mg/kg +  

2mg/kg qw 

MBC 805 
37.4 

(8.7 - 58.9) 

76.5 

(49.4 - 114) 

1073 

(597 - 1584) 

EBC 390 
38.9 

(25.3 - 58.8) 

76.0 

(54.7 - 104) 

1074 

(783 - 1502) 

 

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 

 

Regimen 
Primary tumour 

type 
N 

Cmin,ss* 

(μg/mL) 

Cmax,ss** 

(μg/mL) 

AUCss, 0-21days 

(μg.day/mL) 

Time to 

steady-

state 

*** 

(week) 

8mg/kg + 

6mg/kg q3w 

MBC 805 
44.2 

(1.8 - 85.4) 

179 

(123 - 266) 

1736 

(618 - 2756) 
12 

EBC 390 
53.8 

(28.7 - 85.8) 

184 

(134 - 247) 

1927 

(1332 - 2771) 
15 

AGC 274 
32.9 

(6.1 - 88.9) 

131 

(72.5 -251) 

1338 

(557 - 2875) 
9 

4mg/kg + 

2mg/kg qw 

MBC 805 
63.1 

(11.7 - 107) 

107 

(54.2 - 164) 

1710 

(581 - 2715) 
12 

EBC 390 
72.6 

(46 - 109) 

115 

(82.6 - 160) 

1893 

(1309 - 2734) 
14 

*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 

 

Regimen 
Primary  

tumour type 
N 

Total CL range from 

Cmax,ss to Cmin,ss 

(L/day) 

t1/2 range from  

Cmax,ss to Cmin,ss 

(day) 

8mg/kg + 

6mg/kg q3w 

MBC 805 0.183 - 0.302 15.1 - 23.3 

EBC 390 0.158 - 0.253 17.5 - 26.6 

AGC 274 0.189 - 0.337 12.6 - 20.6 

4mg/kg +  

2mg/kg qw 

MBC 805 0.213 - 0.259 17.2 - 20.4 

EBC 390 0.184 - 0.221 19.7 - 23.2 

 

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 μg/mL (approximately 3% of the population predicted Cmin,ss, or about 97% 

washout) by 7 months. 

 



29 

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. 

 

5.3 Preclinical safety data 
 

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. 

Herzuma 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 Herzuma, 

or to determine its effects on fertility in males. 

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 
 

L-histidine hydrochloride 

L-histidine 

α,α-trehalose dihydrate 

Polysorbate 20 

 

6.2 Incompatibilities 
 

This medicinal product must not be mixed or diluted with other medicinal products except those 

mentioned under section 6.6. 

 

This medicinal product must not be diluted with glucose solutions since these cause aggregation of the 

protein. 

 

6.3 Shelf life 

 

150 mg Unopened vial 

 

6 years. 

 

420 mg Unopened vial 

 

6 years. 

 

Aseptic reconstitution and dilution 

 

After aseptic reconstitution with sterile water for injection, chemical and physical stability of the 

reconstituted solution has been demonstrated for 7 days at 2ºC - 8ºC.  

 

After aseptic dilution in polyvinylchloride, polyethylene or polypropylene bags containing sodium 

chloride 9 mg/mL (0.9%) solution for injection, chemical and physical stability of Herzuma has been 

demonstrated for up to 30 days at 2ºC – 8ºC, and 24 hours at temperatures not exceeding 30ºC. 

 



30 

From a microbiological point of view, the reconstituted solution and Herzuma infusion solution should 

be used immediately.  If not used immediately, in-use storage times and conditions prior to use are the 

responsibility of the user, and would not normally be longer than 24 hours at 2°C to 8°C, unless 

reconstitution and dilution have taken place under controlled and validated aseptic conditions. 

 

6.4 Special precautions for storage 

 

Store in a refrigerator (2ºC - 8ºC).  

 

Do not freeze the reconstituted solution. 

 

For storage conditions after reconstitution of the medicinal product, see section 6.3 and 6.6. 

 

6.5 Nature and contents of container  

 

Herzuma 150 mg powder for concentrate for solution for infusion 

 

A 20 mL clear glass type I vial with fluroTec-coated butyl rubber stopper containing 150 mg of 

trastuzumab. 

 

Each carton contains one vial. 

 

Herzuma 420 mg powder for concentrate for solution for infusion 

 

A 50 mL clear glass type I vial with butyl rubber stopper containing 420 mg of trastuzumab. 

 

Each carton contains one vial. 

 

6.6 Special precautions for disposal and other handling 
 

Appropriate aseptic technique should be used for reconstitution and dilution procedures. 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.  

 

Aseptic preparation, handling and storage:  

 

Aseptic handling must be ensured when preparing the infusion. Preparation should be:  

 performed under aseptic conditions 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 
 

Herzuma 150 mg powder for concentrate for solution for infusion 

 

Each vial of Herzuma is reconstituted with 7.2 mL of sterile water for injection (not supplied). Use of 

other reconstitution solvents should be avoided.  

This yields a 7.4 mL solution for single-dose use, containing approximately 21 mg/mL trastuzumab, at 

a pH of approximately 6.0. A volume overage of 4% ensures that the labelled dose of 150 mg can be 

withdrawn from each vial.  

 

Herzuma 420 mg powder for concentrate for solution for infusion 

 

Each vial of Herzuma is reconstituted with 20 mL of sterile water for injection (not supplied). Use of 

other reconstitution solvents should be avoided.  



31 

This yields a 21 mL solution for single-dose use, containing approximately 21 mg/mL trastuzumab, at 

a pH of approximately 6.0. A volume overage of 4% ensures that the labelled dose of 420 mg can be 

withdrawn from each vial. 

 

Herzuma should be carefully handled during reconstitution. Causing excessive foaming during 

reconstitution or shaking the reconstituted solution may result in problems with the amount of 

Herzuma that can be withdrawn from the vial.  

 

The reconstituted solution should not be frozen. 

 

Instructions for aseptic reconstitution 

 

1) Using a sterile syringe, slowly inject the appropriate volume (as noted above) of sterile water 

for injection in the vial containing the lyophilised Herzuma, directing the stream into the 

lyophilised cake.  

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 Herzuma results in a colourless to pale yellow 

transparent solution and should be essentially free of visible particulates.  

 

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 250 mL of 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.  

 

Herzuma is for single-use only, as the product contains no preservatives. Any unused medicinal 

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

 

No incompatibilities between Herzuma and polyvinylchloride, polyethylene or polypropylene bags 

have been observed. 

 

 

7. MARKETING AUTHORISATION HOLDER 

 

Celltrion Healthcare Hungary Kft.  

1062 Budapest 

Váci út 1-3. WestEnd Office Building B torony 

Hungary 

 



32 

 

8. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/17/1257/001 

EU/1/17/1257/002 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 

Date of first authorisation: 9 February 2018 

Date of latest renewal: 

 

 

10. DATE OF REVISION OF THE TEXT 

 

Detailed information on this medicinal product is available on the website of the European Medicines 

Agency http://www.ema.europa.eu. 

 



33 

 

 

 

 

ANNEX II 

 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 

MANUFACTURER RESPONSIBLE FOR BATCH RELEASE  

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



34 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 

MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturer of the biological active substance 

CELLTRION INC. 

20 Academy -ro 51 beon-gil 

Yeonsu-gu 

22014 Incheon 

REPUBLIC OF KOREA 

 

Name and address of the manufacturer responsible for batch release 

Biotech Services International Limited 

Biotec House, Central Park, Western Avenue 

Bridgend Industrial Estate 

Bridgend 

CF31 3RT 

UNITED KINGDOM 

 

Units 2100, 2110, 2120 and 2130 

Phase 18, Central Park 

Bridgend Industrial Estate,  

Bridgend, CF31 3TY,  

UNITED KINGDOM 

 

Millmount Healthcare Ltd. 
Block 7 
City North Business Campus  
Stamullen, Co. Meath K32 YD60 
IRELAND 
 

The printed package leaflet of the medicinal product must state the name and address of the 

manufacturer responsible for the release of the concerned batch. 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 

Characteristics, section 4.2). 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  

 Periodic safety update reports  

The requirements for submission of periodic safety update reports for this medicinal product are set 

out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 

2001/83/EC and any subsequent updates published on the European medicines web-portal. 

 



35 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 Risk Management Plan (RMP) 

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 

agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent 

updates of the RMP. 

An updated RMP should be submitted: 

 At the request of the European Medicines Agency. 

 Whenever the risk management system is modified, especially as the result of new 
information being received that may lead to a significant change to the benefit/risk profile 

or as the result of an important (pharmacovigilance or risk minimisation) milestone being 

reached. 



36 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 



37 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 



38 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Herzuma 150 mg powder for concentrate for solution for infusion 

trastuzumab 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

The vial contains 150 mg trastuzumab. After reconstitution, 1 mL concentrate contains 21 mg of 

trastuzumab. 

 

 

3. LIST OF EXCIPIENTS 

 

Excipients: L-histidine hydrochloride, L-histidine, polysorbate 20, α,α-trehalose dihydrate. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Powder for concentrate for solution for infusion 

1 vial 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

For intravenous use only after reconstitution and dilution. 

Read the package leaflet before use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP: 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

Store in a refrigerator (2ºC - 8ºC). 

 

 



39 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Celltrion Healthcare Hungary Kft.  

1062 Budapest 

Váci út 1-3. WestEnd Office Building B torony 
Hungary 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/17/1257/001 

 

 

13. BATCH NUMBER 

 

Lot: 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

Medicinal product subject to medical prescription 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Herzuma 150 mg 

 

 

17. UNIQUE IDENTIFIER - 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC:  

SN:  

NN: 

 

 



40 

 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 

VIAL LABEL 

 

 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 

 

Herzuma 150 mg powder for concentration for solution for infusion 

trastuzumab 

For intravenous use only 

 

 

2. METHOD OF ADMINISTRATION 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 

 

 

6. OTHER 

 

 



41 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Herzuma 420 mg powder for concentrate for solution for infusion 

trastuzumab 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

The vial contains 420 mg trastuzumab. After reconstitution, 1 mL concentrate contains 21 mg of 

trastuzumab. 

 

 

3. LIST OF EXCIPIENTS 

 

Excipients: L-histidine hydrochloride, L-histidine, polysorbate 20, α,α-trehalose dihydrate. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Powder for concentrate for solution for infusion 

1 vial 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

For intravenous use only after reconstitution and dilution. 

Read the package leaflet before use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP: 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

Store in a refrigerator (2ºC - 8ºC). 

 

 



42 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Celltrion Healthcare Hungary Kft.  

1062 Budapest 

Váci út 1-3. WestEnd Office Building B torony 
Hungary 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/17/1257/002 

 

 

13. BATCH NUMBER 

 

Lot: 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

Medicinal product subject to medical prescription 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Herzuma 420 mg 

 

 

17. UNIQUE IDENTIFIER - 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC:  

SN:  

NN: 

 

 



43 

 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 

VIAL LABEL 

 

 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 

 

Herzuma 420 mg powder for concentration for solution for infusion 

trastuzumab 

For intravenous use only 

 

 

2. METHOD OF ADMINISTRATION 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 

 

 

6. OTHER 

 

 

 



44 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 



45 

Package leaflet: Information for the user 
 

Herzuma 150 mg powder for concentrate for solution for infusion 

trastuzumab 

 

This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 

for how to report side effects. 

 

Read all of this leaflet carefully before you start using this medicine because it contains 

important information for you. 

 

 Keep this leaflet. You may need to read it again.  
 If you have any further questions, ask your doctor or pharmacist. 
 If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 

 

What is in this leaflet 

 

1. What Herzuma is and what it is used for  

2. What you need to know before you use Herzuma  

3. How to use Herzuma  

4. Possible side effects  

5. How to store Herzuma  

6. Contents of the pack and other information 

 

 

1. What Herzuma is and what it is used for 

 

Herzuma contains the active substance trastuzumab, which is a monoclonal antibody. Monoclonal 

antibodies attach to specific proteins or antigens. Trastuzumab is designed to bind selectively to an 

antigen called human epidermal growth factor receptor 2 (HER2). HER2 is found in large amounts on 

the surface of some cancer cells where it stimulates their growth. When Herzuma binds to HER2 it 

stops the growth of such cells and causes them to die. 

 

Your doctor may prescribe Herzuma for the treatment of breast and gastric cancer when: 

 

 you have early breast cancer, with high levels of a protein called HER2. 
 you have metastatic breast cancer (breast cancer that has spread beyond the original tumour) 

with high levels of HER2. Herzuma may be prescribed in combination with the chemotherapy 

medicine paclitaxel or docetaxel as first treatment for metastatic breast cancer or it may be 

prescribed alone if other treatments have proved unsuccessful. It is also used in combination 

with medicines called aromatase inhibitors with patients with high levels of HER2 and hormone 

receptor-positive metastatic breast cancer (cancer that is sensitive to the presence of female sex 

hormones). 

 you have metastatic gastric cancer with high levels of HER2, when it is in combination with the 
other cancer medicines capecitabine or 5-fluorouracil and cisplatin. 

 

 

2. What you need to know before you use Herzuma 

 

Do not take Herzuma if: 
 you are allergic to trastuzumab, to murine (mouse) proteins or any of the other ingredients of 

this medicine (listed in section 6). 

 you have severe breathing problems at rest due to your cancer or if you need oxygen treatment. 
 



46 

Warnings and precautions  

 

Your doctor will closely supervise your therapy.  

 

Heart checks 

 

Treatment with Herzuma alone or with a taxane may affect the heart, especially if you have ever used 

an anthracycline (taxanes and anthracyclines are two other kinds of medicine used to treat cancer). The 

effects may be moderate to severe and could cause death. Therefore, your heart function will be 

checked before, during (every three months) and after (up to two to five years) treatment with 

Herzuma. If you develop any signs of heart failure (inadequate pumping of blood by the heart), your 

heart function may be checked more frequently (every six to eight weeks), you may receive treatment 

for heart failure or you may have to stop Herzuma treatment. 

 

Talk to your doctor, pharmacist or nurse before using Herzuma if: 

 

 you have had heart failure, coronary artery disease, heart valve disease (heart murmurs), high 
blood pressure, taken any high blood pressure medicine or are currently taking any high blood 

pressure medicine. 

 

 you have ever had or are currently using a medicine called doxorubicin or epirubicin (medicines 
used to treat cancer). These medicines (or any other anthracyclines) can damage heart muscle 

and increase the risk of heart problems with trastuzumab. 

 

 you suffer from breathlessness, especially if you are currently using a taxane. Trastuzumab can 
cause breathing difficulties, especially when it is first given. This could be more serious if you 

are already breathless. Very rarely, patients with severe breathing difficulties before treatment 

have died when they were given trastuzumab. 

 

 you have ever had any other treatment for cancer. 
 

If you receive Herzuma with any other medicine to treat cancer, such as paclitaxel, docetaxel, an 

aromatase inhibitor, capecitabine, 5-fluorouracil, or cisplatin you should also read the patient 

information leaflets for these products. 

 

Children and adolescents 

 

Herzuma is not recommended for anyone under the age of 18 years. 

 

Other medicines and Herzuma 

 

Tell your doctor, pharmacist or nurse if you are taking, have recently taken or may take any other 

medicines.  

 

It may take up to 7 months for Herzuma to be removed from the body. Therefore you should tell your 

doctor, pharmacist or nurse that you have had Herzuma if you start any new medicine in the 7 months 

after stopping treatment. 

 

Pregnancy 

 

 If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor, 
pharmacist or nurse for advice before taking this medicine. 

 You should use effective contraception during treatment with Herzuma and for at least 7 months 
after treatment has ended. 

 Your doctor will advise you of the risks and benefits of taking Herzuma during pregnancy. In 
rare cases, a reduction in the amount of (amniotic) fluid that surrounds the developing baby 

within the womb has been observed in pregnant women receiving Herzuma. This condition may 



47 

be harmful to your baby in the womb and has been associated with the lungs not developing 

fully resulting in foetal death. 

 

Breast-feeding 

 

Do not breast-feed your baby during Herzuma therapy and for 7 months after the last dose of Herzuma 

as Herzuma may pass to your baby through your breast milk. 

 

Ask your doctor or pharmacist for advice before taking any medicine. 

 

Driving and using machines 

 

Herzuma may affect your ability to drive a car or operate machines. If during treatment you 

experience symptoms, such as chills or fever, you should not drive or use machines until these 

symptoms disappear.  

 

 

3. How to use Herzuma 

 

Before starting the treatment your doctor will determine the amount of HER2 in your tumour. Only 

patients with a large amount of HER2 will be treated with Herzuma. Herzuma should only be given by 

a doctor or nurse. Your doctor will prescribe a dose and treatment regimen that is right for you. The 

dose of Herzuma depends on your body weight. 

 

Herzuma is given as an intravenous infusion (“drip”) directly into your veins. The first dose of your 

treatment is given over 90 minutes and you will be observed by a health professional while it is being 

given in case you have any side effects. If the first dose is well tolerated the next doses may be given 

over 30 minutes (see section 2 under “Warnings and precautions”). The number of infusions you 

receive will depend on how you respond to the treatment. Your doctor will discuss this with you. 

 

In order to prevent medication errors it is important to check the vial labels to ensure that the medicine 

being prepared and given is Herzuma (trastuzumab) and not trastuzumab emtansine.  

 

For early breast cancer, metastatic breast cancer and metastatic gastric cancer, Herzuma is given every 

3 weeks. Herzuma may also be given once a week for metastatic breast cancer. 

 

If you stop using Herzuma 

 

Do not stop using this medicine without talking to your doctor first. All doses should be taken at the 

right time every week or every three weeks (depending on your dosing schedule). This helps your 

medicine work as well as it can.  

 

It may take up to 7 months for Herzuma to be removed from your body. Therefore your doctor may 

decide to continue to check your heart functions, even after you finish treatment.  

 

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 

 

 

4. Possible side effects 
 

Like all medicines, this medicine can cause side effects, although not everybody gets them. Some of 

these side effects may be serious and may lead to hospitalisation.  

 

During a Herzuma infusion, chills, fever and other flu like symptoms may occur. These are very 

common (may affect more than 1 in 10 people). Other infusion-related symptoms are: feeling sick 

(nausea), vomiting, pain, increased muscle tension and shaking, headache, dizziness, breathing 

difficulties, wheezing, high or low blood pressure, heart rhythm disturbances (palpitations, heart 



48 

fluttering or irregular heart beat), swelling of the face and lips, rash and feeling tired. Some of these 

symptoms can be serious and some patients have died (see section 2 under “Warnings and 

precautions”). 

 

These effects mainly occur with the first intravenous infusion (“drip” into your vein) and during the 

first few hours after the start of the infusion. They are usually temporary. You will be observed by a 

health care professional during the infusion and for at least six hours after the start of the first infusion 

and for two hours after the start of other infusions. If you develop a reaction, they will slow down or 

stop the infusion and may give you treatment to counteract the side effects. The infusion may be 

continued after the symptoms improve. 

 

Occasionally, symptoms start later than six hours after the infusion begins. If this happens to you, 

contact your doctor immediately. Sometimes, symptoms may improve and then get worse later.  

 

Serious side effects 

Other side effects can occur at any time during treatment with Herzuma, not just related to an infusion. 

Tell a doctor or nurse straight away, if you notice any of the following side effects:  

 

 Heart problems can sometimes occur during treatment and occasionally after treatment has 

stopped and can be serious. They include weakening of the heart muscle possibly leading to heart 

failure, inflammation  of the lining around the heart and heart rhythm disturbances. This can lead 

to symptoms such as breathlessness (including breathlessness at night), cough, fluid retention 

(swelling) in the legs or arms, palpitations (heart fluttering or irregular heart beat) (see 2. Heart 

checks).  

 

Your doctor will monitor your heart regularly during and after treatment but you should tell your 

doctor immediately if you notice any of the above symptoms. 

 

 Tumour lysis syndrome (a group of metabolic complications occurring after cancer treatment 

characterized by high blood levels of potassium and phosphate, and low blood levels of calcium). 

Symptoms may include kidney problems (weakness, shortness of breath, fatigue and confusion), 

heart problems (fluttering of the heart or a faster or slower heartbeat), seizures, vomiting or 

diarrhoea and tingling in the mouth, hands or feet 

 

If you experience any of the above symptoms when your treatment with Herzuma has finished, you 

should see your doctor and tell them that you have previously been treated with Herzuma. 

 

Very common side effects (may affect more than 1 in 10 people): 

 

 infections 

 diarrhoea 

 constipation 

 heartburn (dyspepsia) 

 fatigue 

 skin rashes 

 chest pain 

 abdominal pain 

 joint pain 

 low counts of red blood cells and white blood cells (which help fight infection) sometimes with 
fever 

 muscle pain 

 conjunctivitis 

 watery eyes 

 nose bleeds 

 runny nose 

 hair loss 



49 

 tremor 

 hot flush 

 dizziness 

 nail disorders 

 weight loss 

 loss of appetite 

 inability to sleep (insomnia) 

 altered taste 

 low platelet count 

 bruising 

 numbness or tingling of the fingers and toes 

 redness, swelling or sores in your mouth and/or throat 

 pain, swelling, redness or tingling of hands and/or feet 

 breathlessness 

 headache 

 cough 

 vomiting 

 nausea 
 

Common side effects (may affect up to 1 in 10 people): 

 

 allergic reactions  dry mouth and skin 

 throat infections  dry eyes 

 bladder and skin infections  sweating 

 shingles  feeling weak and unwell 

 inflammation of the breast  anxiety 

 inflammation of the liver  depression 

 kidney disorders  abnormal thinking 

 increased muscle tone or tension  
(hypertonia) 

 asthma 

 infection of lungs 

 pain in the arms and/or legs  lung disorders 

 itchy rash  back pain 

 sleepiness (somnolence)  neck pain 

 haemorrhoids  bone pain 

 itchiness  acne 
  leg cramps 

 

Uncommon side effects (may affect up to 1 in 100 people): 

 

 deafness 

 bumpy rash 

 blood infection 
 

Rare side effects (may affect up to 1 in 1000 people): 

 

 muscle weakness 

 jaundice 

 inflammation or scarring of the lungs 
 

Other side effects that have been reported with Herzuma use (frequency cannot be estimated from 

the available data): 

 

 abnormal or impaired blood clotting 

 anaphylactic reactions 

 high potassium levels 



50 

 swelling of the brain 

 swelling or bleeding at the back of the eyes 

 shock 

 swelling of the lining of the heart 

 slow heart rate 

 abnormal heart rhythm 

 respiratory distress 

 respiratory failure 

 acute accumulation of fluid in the lungs 

 acute narrowing of the airways 

 abnormally low oxygen levels in the blood 

 difficulty in breathing when lying flat 

 liver damage/failure 

 swelling of the face, lips and throat 

 kidney failure 

 abnormally low levels of fluid around baby in womb 

 failure of the lungs of the baby to develop in the womb 

 abnormal development of the kidneys of the baby in the womb 
 

Some of the side effects you experience may be due to your underlying cancer. If you receive 

Herzuma in combination with chemotherapy, some of them may also be due to the chemotherapy.  

 

If you get any side effects, talk to your doctor, pharmacist or nurse. 

 

Reporting of side effects 

 

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 

effects not listed in this leaflet. You can also report side effects directly via the national reporting 

system listed in Appendix V. By reporting side effects you can help provide more information on the 

safety of this medicine. 

 

 

5. How to store Herzuma 

 

Keep this medicine out of the sight and reach of children. 

 

Do not use this medicine after the expiry date which is stated on the outer carton and on the vial label 

after EXP. The expiry date refers to the last day of that month. 

 

Store in a refrigerator (2ºC - 8ºC). 

 

Infusion solutions should be used immediately after dilution. Do not use Herzuma if you notice any 

particulate matter or discoloration prior to administration. 

 

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to 

throw away medicines you no longer use. These measures will help protect the environment. 

 

 

6. Contents of the pack and other information 

 

What Herzuma contains  

 

 The active substance is trastuzumab. Each vial contains 150 mg trastuzumab that has to be 
dissolved in 7.2 mL of water for injection. The resulting solution contains approximately 

21 mg/mL trastuzumab. 

 



51 

 The other ingredients are L-histidine hydrochloride, L-histidine, α,α-trehalose dihydrate, 
polysorbate 20. 

 

What Herzuma looks like and contents of the pack 

 

Herzuma is a powder for concentrate for solution for intravenous infusion, which is supplied in a glass 

vial with a rubber stopper containing 150 mg of trastuzumab. The powder is a white to pale yellow 

pellet. Each carton contains 1 vial of powder. 

 

Marketing Authorisation Holder 
 

Celltrion Healthcare Hungary Kft.  

1062 Budapest 

Váci út 1-3. WestEnd Office Building B torony 
Hungary 

 

Manufacturer 
 

Biotec Services International Ltd. 

Biotec House  

Central Park 

Western Avenue  

Bridgend Industrial Estate  

Bridgend, CF31 3RT 

United Kingdom 

 

Millmount Healthcare Ltd. 
Block 7 
City North Business Campus  

Stamullen, Co. Meath K32 YD60 
Ireland 

 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder: 

 

België/Belgique/Belgien 

Mundipharma CVA 

Tél/Tel: + 32 15 45 1180 

 

Lietuva 

EGIS PHARMACEUTICALS PLC atstovybė 

Tel.: +370 5 231 4658 

 

България 

EGIS Bulgaria EOOD 

Teл.: + 359 2 987 6040 

 

Luxembourg/Luxemburg 
Mundipharma CVA 

Tél/Tel: + 32 15 45 1180 

 

Česká republika 

EGIS Praha, spol. s r.o 

Tel: + 420 227 129 111 

 

Magyarország 

Egis Gyógyszergyár Zrt. 

Tel.: + 36 1 803 5555 

 

Danmark 

Orion Pharma A/S  

Tlf: + 45 86 14 00 00 

 

Malta 
Medical Logistics Ltd. 

Tel: +356 2755 9990 

 

Deutschland 

Mundipharma GmbH 

Tel: +49 (0) 69 506029 000 

 

Nederland 
Mundipharma Pharmaceuticals B.V 

Tel: + 31 33 450 8270 

 

Eesti 

Orion Pharma Eesti OÜ  
Norge 
Orion Pharma AS 



52 

Tel: + 372 6 644 550 

 

Tlf: + 47 40 00 42 10 

 

España 
Kern Pharma, S.L. 

Tel: +34 93 700 2525 

 

Ö sterreich 
Astro-Pharma GmbH 

Tel: +43 1 97 99 860 

 

Ελλάδα 

ΒΙΑΝΕΞ Α.Ε. 

Τηλ: +30 210 8009111 - 120 

 

Polska 

EGIS Polska Sp. z o.o. 

Tel.: + 48 22 417 9200 

 

France 

CELLTRION HEALTHCARE FRANCE SAS 

Tél.: +33 (0)1 71 25 27 00 

 

Portugal 
PharmaKERN Portugal - Produtos 

Farmacêuticos, Sociedade Unipessoal, Lda. 

Tel: +351 214 200 290 

 

 

Hrvatska 

Oktal Pharma d.o.o. 

Tel: +385 1 6595 777 

 

România 

Egis Pharmaceuticals PLC Romania 

Tel: + 40 21 412 0017 

 

Ireland 
Mundipharma Pharmaceuticals Limited 

Tel: +353 1 2063800 

 

Slovenija 

OPH Oktal Pharma d.o.o. 

Tel.: +386 1 519 29 22 

 

Ísland 
Vistor hf.  

Sími: +354 535 7000 

 

Slovenská republika 

EGIS SLOVAKIA spol. s r.o 

Tel: +421 2 3240 9422 

 

Italia 
Mundipharma Pharmaceuticals Srl 

Tel: +39 02 31 82 88 1 

 

Suomi/Finland 
Orion Pharma 

Puh/Tel: + 358 10 4261 

 

Κύπρος 

C.A. Papaellinas Ltd 

Τηλ: +357 22741741 

 

Sverige 

Orion Pharma AB 

Tel: + 46 8 623 64 40 

 

Latvija 

EGIS Pharmaceuticals PLC pārstāvniecība 

Latvijā 

Tālr.: +371 67613859 

 

United Kingdom 
NAPP Pharmaceuticals Ltd. 

Tel: +44 (0) 1223 424444 

 

 

 

This leaflet was last revised in <{MM/YYYY}>. 

 

Other sources of information 

 

Detailed information on this medicine is available on the European Medicines Agency web site: 

http://www.ema.europa.eu 

 



53 

This leaflet is available in all EU/EEA languages on the European Medicines Agency website.  

 

The following information is intended for medical or healthcare professionals only 

 

Always keep this medicine in the closed original pack at a temperature of 2ºC - 8ºC in a refrigerator.  

 

Appropriate aseptic technique should be used for reconstitution and dilution procedures. 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.  

 

A vial of Herzuma aseptically reconstituted with sterile water for injections (not supplied) is 

chemically and physically stable for 7 days at 2ºC - 8ºC after reconstitution and must not be frozen.  

 

After aseptic dilution in polyvinylchloride, polyethylene or polypropylene bags containing sodium 

chloride 9 mg/mL (0.9 %) solution for injection, chemical and physical stability of Herzuma has been 

demonstrated for up to 30 days at 2 oC – 8oC, and 24 hours at temperatures not exceeding 30°C. 

 

From a microbiological point of view, the reconstituted solution and Herzuma infusion solution should 

be used immediately. If not used immediately, in-use storage times and conditions prior to use are the 

responsibility of the user, and would not normally be longer than 24 hours at 2°C to 8°C, unless 

reconstitution and dilution have taken place under controlled and validated aseptic conditions. 

 
Aseptic preparation, handling and storage:  

 

Aseptic handling must be ensured when preparing the infusion. Preparation should be:  

 performed under aseptic conditions 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 
 

Each vial of Herzuma is reconstituted with 7.2 mL of sterile water for injections (not supplied). Use of 

other reconstitution solvents should be avoided. This yields a 7.4 mL solution for single-dose use, 

containing approximately 21 mg/mL trastuzumab. A volume overage of 4% ensures that the labelled 

dose of 150 mg can be withdrawn from each vial.  

 

Herzuma should be carefully handled during reconstitution. Causing excessive foaming during 

reconstitution or shaking the reconstituted Herzuma may result in problems with the amount of 

Herzuma that can be withdrawn from the vial.  

 

Instructions for aseptic reconstitution:  

 

1) Using a sterile syringe, slowly inject 7.2 mL of sterile water for injections in the vial containing the 

lyophilised Herzuma, directing the stream into the lyophilised 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 Herzuma results in a colourless to pale yellow 

transparent solution and should be essentially free of visible particulates.  

 

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: 



54 

 

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 a 

polyvinylchloride, polyethylene or polypropylene infusion bag containing 250 mL of 0.9% sodium 

chloride solution. Do not use with glucose-containing solutions. The bag should be gently inverted to 

mix the solution in order to avoid foaming. Parenteral solutions should be inspected visually for 

particulates and discoloration prior to administration.  

 

 



55 

Package leaflet: Information for the user 
 

Herzuma 420 mg powder for concentrate for solution for infusion 

trastuzumab 

 

This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 

for how to report side effects. 

 

Read all of this leaflet carefully before you start using this medicine because it contains 

important information for you. 

 

 Keep this leaflet. You may need to read it again.  
 If you have any further questions, ask your doctor or pharmacist. 
 If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 

 

What is in this leaflet 

 

1. What Herzuma is and what it is used for  

2. What you need to know before you use Herzuma  

3. How to use Herzuma  

4. Possible side effects  

5. How to store Herzuma  

6. Contents of the pack and other information 

 

 

1. What Herzuma is and what it is used for 

 

Herzuma contains the active substance trastuzumab, which is a monoclonal antibody. Monoclonal 

antibodies attach to specific proteins or antigens. Trastuzumab is designed to bind selectively to an 

antigen called human epidermal growth factor receptor 2 (HER2). HER2 is found in large amounts on 

the surface of some cancer cells where it stimulates their growth. When Herzuma binds to HER2 it 

stops the growth of such cells and causes them to die. 

 

Your doctor may prescribe Herzuma for the treatment of breast and gastric cancer when: 

 

 you have early breast cancer, with high levels of a protein called HER2. 
 you have metastatic breast cancer (breast cancer that has spread beyond the original tumour) 

with high levels of HER2. Herzuma may be prescribed in combination with the chemotherapy 

medicine paclitaxel or docetaxel as first treatment for metastatic breast cancer or it may be 

prescribed alone if other treatments have proved unsuccessful. It is also used in combination 

with medicines called aromatase inhibitors with patients with high levels of HER2 and hormone 

receptor-positive metastatic breast cancer (cancer that is sensitive to the presence of female sex 

hormones). 

 you have metastatic gastric cancer with high levels of HER2, when it is in combination with the 
other cancer medicines capecitabine or 5-fluorouracil and cisplatin. 

 

 

2. What you need to know before you use Herzuma 

 

Do not take Herzuma if: 
 you are allergic to trastuzumab, to murine (mouse) proteins or any of the other ingredients of 

this medicine (listed in section 6). 

 you have severe breathing problems at rest due to your cancer or if you need oxygen treatment. 
 



56 

Warnings and precautions  

 

Your doctor will closely supervise your therapy.  

 

Heart checks 

 

Treatment with Herzuma alone or with a taxane may affect the heart, especially if you have ever used 

an anthracycline (taxanes and anthracyclines are two other kinds of medicine used to treat cancer). The 

effects may be moderate to severe and could cause death. Therefore, your heart function will be 

checked before, during (every three months) and after (up to two to five years) treatment with 

Herzuma. If you develop any signs of heart failure (inadequate pumping of blood by the heart), your 

heart function may be checked more frequently (every six to eight weeks), you may receive treatment 

for heart failure or you may have to stop Herzuma treatment. 

 

Talk to your doctor, pharmacist or nurse before using Herzuma if: 

 

 you have had heart failure, coronary artery disease, heart valve disease (heart murmurs), high 
blood pressure, taken any high blood pressure medicine or are currently taking any high blood 

pressure medicine. 

 

 you have ever had or are currently using a medicine called doxorubicin or epirubicin (medicines 
used to treat cancer). These medicines (or any other anthracyclines) can damage heart muscle 

and increase the risk of heart problems with trastuzumab. 

 

 you suffer from breathlessness, especially if you are currently using a taxane. Trastuzumab can 
cause breathing difficulties, especially when it is first given. This could be more serious if you 

are already breathless. Very rarely, patients with severe breathing difficulties before treatment 

have died when they were given trastuzumab. 

 

 you have ever had any other treatment for cancer. 
 

If you receive Herzuma with any other medicine to treat cancer, such as paclitaxel, docetaxel, an 

aromatase inhibitor, capecitabine, 5-fluorouracil, or cisplatin you should also read the patient 

information leaflets for these products. 

 

Children and adolescents 

 

Herzuma is not recommended for anyone under the age of 18 years. 

 

Other medicines and Herzuma 

 

Tell your doctor, pharmacist or nurse if you are taking, have recently taken or may take any other 

medicines.  

 

It may take up to 7 months for Herzuma to be removed from the body. Therefore you should tell your 

doctor, pharmacist or nurse that you have had Herzuma if you start any new medicine in the 7 months 

after stopping treatment. 

 

Pregnancy 

 

 If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor, 
pharmacist or nurse for advice before taking this medicine. 

 You should use effective contraception during treatment with Herzuma and for at least 7 months 
after treatment has ended. 

 Your doctor will advise you of the risks and benefits of taking Herzuma during pregnancy. In 
rare cases, a reduction in the amount of (amniotic) fluid that surrounds the developing baby 

within the womb has been observed in pregnant women receiving Herzuma. This condition may 



57 

be harmful to your baby in the womb and has been associated with the lungs not developing 

fully resulting in foetal death. 

 

Breast-feeding 

 

Do not breast-feed your baby during Herzuma therapy and for 7 months after the last dose of Herzuma 

as Herzuma may pass to your baby through your breast milk. 

 

Ask your doctor or pharmacist for advice before taking any medicine. 

 

Driving and using machines 

 

Herzuma may affect your ability to drive a car or operate machines. If during treatment you 

experience symptoms, such as chills or fever, you should not drive or use machines until these 

symptoms disappear.  

 

 

3. How to use Herzuma 

 

Before starting the treatment your doctor will determine the amount of HER2 in your tumour. Only 

patients with a large amount of HER2 will be treated with Herzuma. Herzuma should only be given by 

a doctor or nurse. Your doctor will prescribe a dose and treatment regimen that is right for you. The 

dose of Herzuma depends on your body weight. 

 

Herzuma is given as an intravenous infusion (“drip”) directly into your veins. The first dose of your 

treatment is given over 90 minutes and you will be observed by a health professional while it is being 

given in case you have any side effects. If the first dose is well tolerated the next doses may be given 

over 30 minutes (see section 2 under “Warnings and precautions”). The number of infusions you 

receive will depend on how you respond to the treatment. Your doctor will discuss this with you. 

 

In order to prevent medication errors it is important to check the vial labels to ensure that the medicine 

being prepared and given is Herzuma (trastuzumab) and not trastuzumab emtansine.  

 

For early breast cancer, metastatic breast cancer and metastatic gastric cancer, Herzuma is given every 

3 weeks. Herzuma may also be given once a week for metastatic breast cancer. 

 

If you stop using Herzuma 

 

Do not stop using this medicine without talking to your doctor first. All doses should be taken at the 

right time every week or every three weeks (depending on your dosing schedule). This helps your 

medicine work as well as it can.  

 

It may take up to 7 months for Herzuma to be removed from your body. Therefore your doctor may 

decide to continue to check your heart functions, even after you finish treatment.  

 

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 

 

 

4. Possible side effects 
 

Like all medicines, this medicine can cause side effects, although not everybody gets them. Some of 

these side effects may be serious and may lead to hospitalisation.  

 

During a Herzuma infusion, chills, fever and other flu like symptoms may occur. These are very 

common (may affect more than 1 in 10 people). Other infusion-related symptoms are: feeling sick 

(nausea), vomiting, pain, increased muscle tension and shaking, headache, dizziness, breathing 

difficulties, wheezing, high or low blood pressure, heart rhythm disturbances (palpitations, heart 



58 

fluttering or irregular heart beat), swelling of the face and lips, rash and feeling tired. Some of these 

symptoms can be serious and some patients have died (see section 2 under “Warnings and 

precautions”). 

 

These effects mainly occur with the first intravenous infusion (“drip” into your vein) and during the 

first few hours after the start of the infusion. They are usually temporary. You will be observed by a 

health care professional during the infusion and for at least six hours after the start of the first infusion 

and for two hours after the start of other infusions. If you develop a reaction, they will slow down or 

stop the infusion and may give you treatment to counteract the side effects. The infusion may be 

continued after the symptoms improve. 

 

Occasionally, symptoms start later than six hours after the infusion begins. If this happens to you, 

contact your doctor immediately. Sometimes, symptoms may improve and then get worse later.  

 

Serious side effects 

Other side effects can occur at any time during treatment with Herzuma, not just related to an infusion. 

Tell a doctor or nurse straight away, if you notice any of the following side effects:  

 

 Heart problems can sometimes occur during treatment and occasionally after treatment has 

stopped and can be serious. They include weakening of the heart muscle possibly leading to heart 

failure, inflammation  of the lining around the heart and heart rhythm disturbances. This can lead 

to symptoms such as breathlessness (including breathlessness at night), cough, fluid retention 

(swelling) in the legs or arms, palpitations (heart fluttering or irregular heart beat) (see 2. Heart 

checks).  

 

Your doctor will monitor your heart regularly during and after treatment but you should tell your 

doctor immediately if you notice any of the above symptoms. 

 

 Tumour lysis syndrome (a group of metabolic complications occurring after cancer treatment 

characterized by high blood levels of potassium and phosphate, and low blood levels of calcium). 

Symptoms may include kidney problems (weakness, shortness of breath, fatigue and confusion), 

heart problems (fluttering of the heart or a faster or slower heartbeat), seizures, vomiting or 

diarrhoea and tingling in the mouth, hands or feet 

 

If you experience any of the above symptoms when your treatment with Herzuma has finished, you 

should see your doctor and tell them that you have previously been treated with Herzuma. 

 

Very common side effects (may affect more than 1 in 10 people): 

 

 infections 

 diarrhoea 

 constipation 

 heartburn (dyspepsia) 

 fatigue 

 skin rashes 

 chest pain 

 abdominal pain 

 joint pain 

 low counts of red blood cells and white blood cells (which help fight infection) sometimes with 
fever 

 muscle pain 

 conjunctivitis 

 watery eyes 

 nose bleeds 

 runny nose 

 hair loss 



59 

 tremor 

 hot flush 

 dizziness 

 nail disorders 

 weight loss 

 loss of appetite 

 inability to sleep (insomnia) 

 altered taste 

 low platelet count 

 bruising 

 numbness or tingling of the fingers and toes 

 redness, swelling or sores in your mouth and/or throat 

 pain, swelling, redness or tingling of hands and/or feet 

 breathlessness 

 headache 

 cough 

 vomiting 

 nausea 
 

Common side effects (may affect up to 1 in 10 people): 

 

 allergic reactions  dry mouth and skin 

 throat infections  dry eyes 

 bladder and skin infections  sweating 

 shingles  feeling weak and unwell 

 inflammation of the breast  anxiety 

 inflammation of the liver  depression 

 kidney disorders  abnormal thinking 

 increased muscle tone or tension  
(hypertonia) 

 asthma 

 infection of lungs 

 pain in the arms and/or legs  lung disorders 

 itchy rash  back pain 

 sleepiness (somnolence)  neck pain 

 haemorrhoids  bone pain 

 itchiness  acne 
  leg cramps 

 

Uncommon side effects (may affect up to 1 in 100 people): 

 

 deafness 

 bumpy rash 

 blood infection 
 

Rare side effects (may affect up to 1 in 1000 people): 

 

 muscle weakness 

 jaundice 

 inflammation or scarring of the lungs 
 

Other side effects that have been reported with Herzuma use (frequency cannot be estimated from 

the available data): 

 

 abnormal or impaired blood clotting 

 anaphylactic reactions 

 high potassium levels 



60 

 swelling of the brain 

 swelling or bleeding at the back of the eyes 

 shock 

 swelling of the lining of the heart 

 slow heart rate 

 abnormal heart rhythm 

 respiratory distress 

 respiratory failure 

 acute accumulation of fluid in the lungs 

 acute narrowing of the airways 

 abnormally low oxygen levels in the blood 

 difficulty in breathing when lying flat 

 liver damage/failure 

 swelling of the face, lips and throat 

 kidney failure 

 abnormally low levels of fluid around baby in womb 

 failure of the lungs of the baby to develop in the womb 

 abnormal development of the kidneys of the baby in the womb 
 

Some of the side effects you experience may be due to your underlying cancer. If you receive 

Herzuma in combination with chemotherapy, some of them may also be due to the chemotherapy.  

 

If you get any side effects, talk to your doctor, pharmacist or nurse. 

 

Reporting of side effects 

 

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 

effects not listed in this leaflet. You can also report side effects directly via the national reporting 

system listed in Appendix V. By reporting side effects you can help provide more information on the 

safety of this medicine. 

 

 

5. How to store Herzuma 

 

Keep this medicine out of the sight and reach of children. 

 

Do not use this medicine after the expiry date which is stated on the outer carton and on the vial label 

after EXP. The expiry date refers to the last day of that month. 

 

Store in a refrigerator (2ºC - 8ºC). 

 

Infusion solutions should be used immediately after dilution. Do not use Herzuma if you notice any 

particulate matter or discoloration prior to administration. 

 

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to 

throw away medicines you no longer use. These measures will help protect the environment. 

 

 

6. Contents of the pack and other information 

 

What Herzuma contains  

 

 The active substance is trastuzumab. Each vial contains 420 mg trastuzumab that has to be 
dissolved in 20 mL of water for injection. The resulting solution contains approximately 

21 mg/mL trastuzumab. 

 



61 

 The other ingredients are L-histidine hydrochloride, L-histidine, α,α-trehalose dihydrate, 
polysorbate 20. 

 

What Herzuma looks like and contents of the pack 

 

Herzuma is a powder for concentrate for solution for intravenous infusion, which is supplied in a glass 

vial with a rubber stopper containing 420 mg of trastuzumab. The powder is a white to pale yellow 

pellet. Each carton contains 1 vial of powder. 

 

Marketing Authorisation Holder 
 

Celltrion Healthcare Hungary Kft.  

1062 Budapest 

Váci út 1-3. WestEnd Office Building B torony 
Hungary 

 

Manufacturer 
 

Biotec Services International Ltd. 

Biotec House  

Central Park 

Western Avenue  

Bridgend Industrial Estate  

Bridgend, CF31 3RT 

United Kingdom 

 

Millmount Healthcare Ltd. 
Block 7 
City North Business Campus  

Stamullen, Co. Meath K32 YD60 
Ireland 

 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder: 

 

België/Belgique/Belgien 

Mundipharma CVA 

Tél/Tel: + 32 15 45 1180 

 

Lietuva 

EGIS PHARMACEUTICALS PLC atstovybė 

Tel.: +370 5 231 4658 

 

България 

EGIS Bulgaria EOOD 

Teл.: + 359 2 987 6040 

 

Luxembourg/Luxemburg 
Mundipharma CVA 

Tél/Tel: + 32 15 45 1180 

 

Česká republika 

EGIS Praha, spol. s r.o 

Tel: + 420 227 129 111 

 

Magyarország 

Egis Gyógyszergyár Zrt. 

Tel.: + 36 1 803 5555 

 

Danmark 

Orion Pharma A/S  

Tlf: + 45 86 14 00 00 

 

Malta 
Medical Logistics Ltd. 

Tel: +356 2755 9990 

 

Deutschland 

Mundipharma GmbH 

Tel: +49 (0) 69 506029 000 

 

Nederland 
Mundipharma Pharmaceuticals B.V 

Tel: + 31 33 450 8270 

 

Eesti 

Orion Pharma Eesti OÜ  
Norge 
Orion Pharma AS 



62 

Tel: + 372 6 644 550 

 

Tlf: + 47 40 00 42 10 

 

España 
Kern Pharma, S.L. 

Tel: +34 93 700 2525 

 

Ö sterreich 
Astro-Pharma GmbH 

Tel: +43 1 97 99 860 

 

Ελλάδα 

ΒΙΑΝΕΞ Α.Ε. 

Τηλ: +30 210 8009111 - 120 

 

Polska 

EGIS Polska Sp. z o.o. 

Tel.: + 48 22 417 9200 

 

France 

CELLTRION HEALTHCARE FRANCE SAS 

Tél.: +33 (0)1 71 25 27 00 

 

Portugal 
PharmaKERN Portugal - Produtos 

Farmacêuticos, Sociedade Unipessoal, Lda. 

Tel: +351 214 200 290 

 

 

Hrvatska 

Oktal Pharma d.o.o. 

Tel: +385 1 6595 777 

 

România 

Egis Pharmaceuticals PLC Romania 

Tel: + 40 21 412 0017 

 

Ireland 
Mundipharma Pharmaceuticals Limited 

Tel: +353 1 2063800 

 

Slovenija 

OPH Oktal Pharma d.o.o. 

Tel.: +386 1 519 29 22 

 

Ísland 
Vistor hf.  

Sími: +354 535 7000 

 

Slovenská republika 

EGIS SLOVAKIA spol. s r.o 

Tel: +421 2 3240 9422 

 

Italia 
Mundipharma Pharmaceuticals Srl 

Tel: +39 02 31 82 88 1 

 

Suomi/Finland 
Orion Pharma 

Puh/Tel: + 358 10 4261 

 

Κύπρος 

C.A. Papaellinas Ltd 

Τηλ: +357 22741741 

 

Sverige 

Orion Pharma AB 

Tel: + 46 8 623 64 40 

 

Latvija 

EGIS Pharmaceuticals PLC pārstāvniecība 

Latvijā 

Tālr.: +371 67613859 

 

United Kingdom 
NAPP Pharmaceuticals Ltd. 

Tel: +44 (0) 1223 424444 

 

 

 

This leaflet was last revised in <{MM/YYYY}>. 

 

Other sources of information 

 

Detailed information on this medicine is available on the European Medicines Agency web site: 

http://www.ema.europa.eu 

 



63 

This leaflet is available in all EU/EEA languages on the European Medicines Agency website.  

 

The following information is intended for medical or healthcare professionals only 

 

Always keep this medicine in the closed original pack at a temperature of 2ºC - 8ºC in a refrigerator.  

 

Appropriate aseptic technique should be used for reconstitution and dilution procedures. 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.  

 

A vial of Herzuma aseptically reconstituted with sterile water for injections (not supplied) is 

chemically and physically stable for 7 days at 2ºC - 8ºC after reconstitution and must not be frozen.  

 

After aseptic dilution in polyvinylchloride, polyethylene or polypropylene bags containing sodium 

chloride 9 mg/mL (0.9 %) solution for injection, chemical and physical stability of Herzuma has been 

demonstrated for up to 30 days at 2 oC – 8oC, and 24 hours at temperatures not exceeding 30°C. 

 

From a microbiological point of view, the reconstituted solution and Herzuma infusion solution should 

be used immediately. If not used immediately, in-use storage times and conditions prior to use are the 

responsibility of the user, and would not normally be longer than 24 hours at 2°C to 8°C, unless 

reconstitution and dilution have taken place under controlled and validated aseptic conditions. 
 

Aseptic preparation, handling and storage:  

Aseptic handling must be ensured when preparing the infusion. Preparation should be:  

 performed under aseptic conditions 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 

 

Each vial of Herzuma is reconstituted with 20 mL of sterile water for injections (not supplied). Use of 

other reconstitution solvents should be avoided. This yields a 21 mL solution for single-dose use, 

containing approximately 21 mg/mL trastuzumab. A volume overage of 4% ensures that the labelled 

dose of 420 mg can be withdrawn from each vial. 

 

Herzuma should be carefully handled during reconstitution. Causing excessive foaming during 

reconstitution or shaking the reconstituted Herzuma may result in problems with the amount of 

Herzuma that can be withdrawn from the vial.  

 

Instructions for aseptic reconstitution:  

 

1) Using a sterile syringe, slowly inject 20 mL of sterile water for injections in the vial containing the 

lyophilised Herzuma, directing the stream into the lyophilised 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 Herzuma results in a colourless to pale yellow 

transparent solution and should be essentially free of visible particulates.  

 

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: 

 



64 

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 a 

polyvinylchloride, polyethylene or polypropylene infusion bag containing 250 mL of 0.9% sodium 

chloride solution. Do not use with glucose-containing solutions. The bag should be gently inverted to 

mix the solution in order to avoid foaming. Parenteral solutions should be inspected visually for 

particulates and discoloration prior to administration.  

 



65 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX IV 

 

SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS 

OF THE MARKETING AUTHORISATION(S) 

 

 

 

 

 

 



66 

 

Scientific conclusions 

 

Taking into account the PRAC Assessment Report on the PSUR(s) for trastuzumab, the scientific 

conclusions of CHMP are as follows:  

 

Although the number of cases identified by a search of the safety database and meeting the Cairo-

Bishop criteria for diagnosis was low, it is endorsed that a contributing factor of trastuzumab to 

tumour lysis syndrome (TLS) could not be excluded. Although there are some limitations when 

using Cairo-Bishop criteria for diagnosis leading to underestimation of the number of cases, the 

update of the Product Information to include TLS with a frequency unknown is endorsed, because 

trastuzumab is a potent mediator of antibody-dependent cell-mediated cytotoxicity (ADCC). 

Therefore, from the mechanism of action there is evidence that trastuzumab can cause tumour lysis 

syndrome. One case of tumour lysis syndrome with trastuzumab administration as monotherapy 

lends further support. 

 

The CHMP agrees with the scientific conclusions made by the PRAC. 

 

Grounds for the variation to the terms of the marketing authorisation(s) 

 

On the basis of the scientific conclusions for trastuzumab the CHMP is of the opinion that the 

benefit-risk balance of the medicinal product(s) containing trastuzumab is unchanged subject to the 

proposed changes to the product information 

 

The CHMP recommends that the terms of the marketing authorisation(s) should be varied. 

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
	SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS OF THE MARKETING AUTHORISATION(S)