Perjeta

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
  



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1. NAME OF THE MEDICINAL PRODUCT 
 
Perjeta 420 mg concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
One 14 ml vial of concentrate contains 420 mg of pertuzumab at a concentration of 30 mg/ml. 
After dilution, one ml of solution contains approximately 3.02 mg of pertuzumab for the initial dose 
and approximately 1.59 mg of pertuzumab for the maintenance dose (see section 6.6). 
 
Pertuzumab is a humanised IgG1 monoclonal antibody produced in mammalian (Chinese hamster 
ovary) cells by recombinant DNA technology. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Concentrate for solution for infusion. 
Clear to slightly opalescent, colourless to pale yellow, liquid. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Early breast cancer 
Perjeta is indicated for use in combination with trastuzumab and chemotherapy in: 

• the neoadjuvant treatment of adult patients with HER2-positive, locally advanced, 
inflammatory, or early stage breast cancer at high risk of recurrence (see section 5.1) 

• the adjuvant treatment of adult patients with HER2-positive early breast cancer at high risk of 
recurrence (see section 5.1) 

 
Metastatic breast cancer 
Perjeta is indicated for use in combination with trastuzumab and docetaxel in adult patients with 
HER2-positive metastatic or locally recurrent unresectable breast cancer, who have not received 
previous anti-HER2 therapy or chemotherapy for their metastatic disease. 
 
4.2 Posology and method of administration 
 
Perjeta should only be initiated under the supervision of a physician experienced in the administration 
of anti-cancer agents. Perjeta should be administered by a healthcare professional prepared to manage 
anaphylaxis and in an environment where full resuscitation facilities are immediately available. 
 
Posology 
 
Patients treated with Perjeta must have HER2-positive tumour status, defined as a score of 3+ by 
immunohistochemistry (IHC) and/or a ratio of ≥ 2.0 by in situ hybridisation (ISH) assessed by a 
validated test. 
 
To ensure accurate and reproducible results, the testing must be performed in a specialised laboratory, 
which can ensure validation of the testing procedures. For full instructions on assay performance and 
interpretation please refer to the package leaflets of validated HER2 testing assays. 
 
The recommended initial loading dose of pertuzumab is 840 mg administered as a 60 minute 
intravenous infusion, followed every 3 weeks thereafter by a maintenance dose of 420 mg 



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administered over a period of 30 to 60 minutes. An observation period of 30 - 60 minutes is 
recommended after completion of each infusion.  The observation period should be completed prior to 
any subsequent infusion of trastuzumab or chemotherapy (see section 4.4). 
 
Perjeta and trastuzumab should be administered sequentially and not mixed in the same infusion bag. 
Perjeta and trastuzumab can be given in any order. When administered with Perjeta the  
recommendation is to follow a 3 weekly schedule for trastuzumab administered as either: 
 

• an IV infusion with an initial loading dose of trastuzumab 8 mg/kg body weight followed 
every 3 weeks thereafter by a maintenance dose of 6 mg/kg body weight 

or  
• a fixed subcutaneous dose of trastuzumab by injection (600 mg) every 3 weeks irrespective of 

the patient’s body weight. 
 
In patients receiving a taxane, Perjeta and trastuzumab should be administered prior to the taxane.  
 
When administered with Perjeta, docetaxel can be started at 75 mg/m2, and subsequently escalated to 
100 mg/m2 depending on the chosen regimen and tolerability of the initial dose. Alternatively, 
docetaxel can be given at 100 mg/m2 on a 3 weekly schedule from the start, again depending on the 
chosen regimen. If a carboplatin-based regimen is used, the recommended dose for docetaxel is 75 
mg/m2 throughout (no dose escalation). When administered with Perjeta in the adjuvant setting, the 
recommended dose of paclitaxel is 80 mg/m2 once weekly for 12 weekly cycles. 
 
In patients receiving an anthracycline-based regimen, Perjeta and trastuzumab should be administered 
following completion of the entire anthracycline regimen (see section 4.4).  
 
Metastatic breast cancer 
 
Perjeta should be administered in combination with trastuzumab and docetaxel . Treatment with 
Perjeta and trastuzumab may continue until disease progression or unmanageable toxicity even if 
treatment with docetaxel is discontinued. 
 
Early breast cancer 
 
In the neoadjuvant setting, Perjeta should be administered for 3 to 6 cycles in combination with 
trastuzumab and chemotherapy, as part of a complete treatment regimen for early breast cancer (see 
section 5.1).  
 
In the adjuvant setting, Perjeta should be administered in combination with trastuzumab for a total of 
one year (up to 18 cycles or until disease recurrence, or unmanageable toxicity, whichever occurs first) 
as part of a complete regimen for early breast cancer and regardless of the timing of surgery.  
Treatment should include standard anthracycline- and/or taxane-based chemotherapy. Perjeta and 
trastuzumab should start on Day 1 of the first taxane-containing cycle and should continue even if 
chemotherapy is discontinued.  
 
Delayed or missed doses 
 
For recommendations on delayed or missed doses, please refer to Table 1 below. 
 



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Table 1 Recommendations regarding delayed or missed doses 
 
Time between two 
sequential 
infusions 

Perjeta  trastuzumab 
IV SC 

< 6 weeks The 420 mg dose of 
pertuzumab should be 
administered as soon as 
possible. Do not wait 
until the next planned 
dose. Thereafter, revert to 
the original planned 
schedule. 

The 6 mg/kg dose of 
trastuzumab IV should 
be administered as soon 
as possible. Do not wait 
until the next planned 
dose. Thereafter, revert 
to the original planned 
schedule. 
 

The fixed dose of 
600mg trastuzumab 
SC should be 
administered as soon 
as possible.  
Do not wait until the 
next planned dose. 
 

≥ 6 weeks The 840 mg loading dose 
of pertuzumab should be 
re-administered as a 60 
minute infusion, followed 
by a maintenance dose of 
420 mg IV administered 
every 3 weeks thereafter. 

The loading dose of 
8 mg/kg of trastuzumab 
IV should be re- 
administered over 
approximately 
90 minutes, followed by 
a maintenance dose of 
6 mg/kg IV administered 
every 3 weeks thereafter. 

 
Dose modification 
Dose reductions are not recommended for Perjeta or trastuzumab.  For details regarding trastuzumab, 
please refer to the summary of product characteristics (SmPC).  
 
Patients may continue therapy during periods of reversible chemotherapy-induced myelosuppression 
but they should be monitored carefully for complications of neutropenia during this time. For 
docetaxel and other chemotherapy dose modifications, see relevant SmPC. 
 
If trastuzumab treatment is discontinued, treatment with Perjeta should be discontinued.  
 
Left ventricular dysfunction  
Perjeta and trastuzumab should be withheld for at least 3 weeks for any signs and symptoms 
suggestive of congestive heart failure. Perjeta should be discontinued if symptomatic heart failure is 
confirmed (see section 4.4 for more details). 
 
Patients with metastatic breast cancer 
 
Patients should have a pre-treatment left ventricular ejection fraction (LVEF) of ≥ 50%. Perjeta and 
trastuzumab should be withheld for at least 3 weeks for: 
 

• a drop in LVEF to less than 40%  
 
• a LVEF of 40%-45% associated with a fall of ≥ 10% points below pre-treatment value. 

 
Perjeta and trastuzumab may be resumed if the LVEF has recovered to > 45%, or to 40-45% 
associated with a difference of < 10% points below pre-treatment values.  
 



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Patients with early breast cancer 
 
Patients should have a pre-treatment LVEF of ≥ 55% (≥ 50% after completion of the anthracycline 
component of chemotherapy, if given). Perjeta and trastuzumab should be withheld for at least 3 
weeks for:  
 

• a drop in LVEF to less than 50% associated with a fall of  ≥ 10% points below pre-treatment 
values. 

 
Perjeta and trastuzumab may be resumed if the LVEF has recovered to ≥50% or to a difference of 
< 10% points below pre-treatment values.  
 
Elderly patients 
No overall differences in efficacy of Perjeta were observed in patients ≥ 65 and < 65 years of age. No 
dose adjustment is necessary in the elderly population ≥ 65 years of age. Limited data are available in 
patients > 75 years of age. Please see section 4.8 for assessment of safety of Perjeta in elderly patients. 
 
Renal impairment 
Dose adjustments of pertuzumab are not needed in patients with mild or moderate renal impairment. 
No dose recommendations can be made for patients with severe renal impairment because of the 
limited pharmacokinetic data available (see section 5.2). 
 
Hepatic impairment 
The safety and efficacy of Perjeta have not been studied in patients with hepatic impairment.  No 
specific dose recommendations can be made. 
 
Paediatric population 
The safety and efficacy of Perjeta in children and adolescents below 18 years of age have not been 
established. There is no relevant use of Perjeta in the paediatric population in the indication of breast 
cancer. 
 
Method of administration 
 
Perjeta is administered intravenously by infusion. It should not be administered as an intravenous push 
or bolus. For instructions on dilution of Perjeta prior to administration, see sections 6.2 and 6.6. 
 
For the initial dose, the recommended infusion period is 60 minutes. If the first infusion is well 
tolerated, subsequent infusions may be administered over a period of 30 minutes to 60 minutes (see 
section 4.4). 
 
Infusion reactions 
 
The infusion rate may be slowed or interrupted if the patient develops an infusion reaction (see section 
4.8). The infusion may be resumed when symptoms abate. Treatment including oxygen, beta agonists, 
antihistamines, rapid i.v. fluids and antipyretics may also help alleviate symptoms.  
 
Hypersensitivity reactions/anaphylaxis  
 
The infusion should be discontinued immediately and permanently if the patient experiences a NCI-
CTCAE Grade 4 reaction (anaphylaxis), bronchospasm or acute respiratory distress syndrome (see 
section 4.4). 
 



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4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
4.4 Special warnings and precautions for use  
 
Traceability 
 
In order to improve the traceability of biological medicinal products, the name and batch number of 
the administered product should be clearly recorded. 
 
Left ventricular dysfunction (including congestive heart failure) 
 
Decreases in LVEF have been reported with medicinal products that block HER2 activity, including 
Perjeta. The incidence of symptomatic left ventricular systolic dysfunction (LVD) [congestive heart 
failure] was higher in patients treated with Perjeta in combination with trastuzumab and chemotherapy 
compared with trastuzumab and chemotherapy . Patients who have received prior anthracyclines or 
prior radiotherapy to the chest area may be at higher risk of LVEF declines. The majority of cases of 
symptomatic heart failure reported in the adjuvant setting were in patients who received anthracycline-
based chemotherapy (see section 4.8). 
 
Perjeta has not been studied in patients with: a pre-treatment LVEF value of < 50%; a prior history of 
congestive heart failure (CHF); LVEF declines to < 50% during prior trastuzumab adjuvant therapy; or 
conditions that could impair left ventricular function such as uncontrolled hypertension, recent 
myocardial infarction, serious cardiac arrhythmia requiring treatment or a cumulative prior 
anthracycline exposure to > 360 mg/m2 of doxorubicin or its equivalent. 
 
Assess LVEF prior to initiation of Perjeta and at regular intervals during treatment with Perjeta (e.g. 
once during neoadjuvant treatment and every 12 weeks in the adjuvant or metastatic setting) to ensure 
that LVEF is within normal limits. If the LVEF has declined as indicated in section 4.2 and has not 
improved, or has declined further at the subsequent assessment, discontinuation of Perjeta and 
trastuzumab should be strongly considered, unless the benefits for the individual patient are deemed to 
outweigh the risks.  
 
Cardiac risk should be carefully considered and balanced against the medical need of the individual 
patient before use of Perjeta with an anthracycline. Based on the pharmacological actions of  
HER2-targeted agents and anthracyclines, the risk of cardiac toxicity might be expected to be higher 
with concomitant use of Perjeta and anthracyclines than with sequential use.  
 
Sequential use of Perjeta (in combination with trastuzumab and a taxane) has been evaluated following 
the epirubicin or doxorubicin component of many anthracycline-based regimens in the APHINITY 
and BERENICE studies. However, only limited safety data are available on concurrent use of Perjeta 
and an anthracycline. In the TRYPHAENA study, Perjeta was given concurrently with epirubicin, as 
part of the FEC (5-fluorouracil, epirubicin, cyclophosphamide) regimen (see sections 4.8 and 5.1). 
Only chemotherapy-naive patients were treated and they received low cumulative doses of epirubicin 
(up to 300 mg/m2). In this study, cardiac safety was similar to that observed in patients given the same 
regimen but with Perjeta administered sequentially (following FEC chemotherapy). 
 
Infusion reactions 
 
Perjeta has been associated with infusion reactions, including events with a fatal outcome (see section 
4.8). Close observation of the patient during and for 60 minutes after the first infusion and during and 
for 30-60 minutes after subsequent infusions of Perjeta is recommended. If a significant infusion 
reaction occurs, the infusion should be slowed down or interrupted and appropriate medical therapies 
should be administered. Patients should be evaluated and carefully monitored until complete 
resolution of signs and symptoms. Permanent discontinuation should be considered in patients with 



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severe infusion reactions. This clinical assessment should be based on the severity of the preceding 
reaction and response to administered treatment for the adverse reaction (see section 4.2). 
 
Hypersensitivity reactions/anaphylaxis 
 
Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity, including 
anaphylaxis and events with a fatal outcome, has been observed with Perjeta (see section 4.8). 
Medicinal products to treat such reactions, as well as emergency equipment, should be available for 
immediate use. Perjeta must be permanently discontinued in case of NCI-CTCAE Grade 4 
hypersensitivity reactions (anaphylaxis), bronchospasm or acute respiratory distress syndrome (see 
section 4.2).  
 
Febrile neutropenia 
 
Patients treated with Perjeta, trastuzumab and docetaxel are at increased risk of febrile neutropenia 
compared with patients treated with placebo, trastuzumab and docetaxel, especially during the first 3 
cycles of treatment (see section 4.8). In the CLEOPATRA trial in metastatic breast cancer, nadir 
neutrophil counts were similar in Perjeta-treated and placebo-treated patients. The higher incidence of 
febrile neutropenia in Perjeta-treated patients was associated with the higher incidence of mucositis 
and diarrhoea in these patients. Symptomatic treatment for mucositis and diarrhoea should be 
considered. No events of febrile neutropenia were reported after cessation of docetaxel. 
 
Diarrhoea 
 
Perjeta may elicit severe diarrhoea. Diarrhoea is most frequent during concurrent administration with 
taxane therapy. Elderly patients (> 65 years) have a higher risk of diarrhoea compared with younger 
patients (< 65 years). Treat diarrhoea according to standard practice and guidelines. Early intervention 
with loperamide, fluids and electrolyte replacement should be considered, particularly in elderly 
patients, and in case of severe or prolonged diarrhoea.  Interruption of treatment with pertuzumab 
should be considered if no improvement in the patient’s condition is achieved. When the diarrhoea is 
under control treatment with pertuzumab may be reinstated. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No pharmacokinetic (PK) interactions were observed between pertuzumab and trastuzumab, or 
between pertuzumab and docetaxel in a sub-study of 37 patients in the randomised, pivotal trial 
CLEOPATRA in metastatic breast cancer. In addition, in the population PK analysis, no evidence of a 
drug-drug interaction has been shown between pertuzumab and trastuzumab or between pertuzumab 
and docetaxel. This absence of drug-drug interaction was confirmed by pharmacokinetic data from the 
NEOSPHERE and APHINITY studies. 
 
Five studies evaluated the effects of pertuzumab on the PK of co-administered cytotoxic agents, 
docetaxel, paclitaxel, gemcitabine, capecitabine, carboplatin and erlotinib. There was no evidence of 
any PK interaction between pertuzumab and any of these agents. The PK of pertuzumab in these 
studies was comparable to those observed in single-agent studies. 
 
4.6 Fertility, pregnancy and lactation 
 
Contraception  
 
Women of childbearing potential should use effective contraception while receiving Perjeta and for 6 
months following the last dose of pertuzumab. 
 
Pregnancy 
 
There is limited amount of data from the use of pertuzumab in pregnant women.  
Studies in animals have shown reproductive toxicity (see section 5.3). 



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Perjeta is not recommended during pregnancy and in women of childbearing potential not using 
contraception.  
 
Breast-feeding 
 
Because human IgG is secreted in human milk and the potential for absorption and harm to the infant 
is unknown, a decision should be made to discontinue breast-feeding or to discontinue treatment, 
taking into account the benefit of breast-feeding for the child and the benefit of Perjeta therapy for the 
woman (see section 5.2). 
 
Fertility 
 
No specific fertility studies in animals have been performed to evaluate the effect of pertuzumab. In 
repeated dose toxicity studies in cynomolgus monkeys, no definitive conclusions could be drawn on 
the adverse effect on male reproductive organs. No adverse reactions were observed in sexually 
mature female cynomolgus monkeys exposed to pertuzumab (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
On the basis of reported adverse reactions, Perjeta has a minor influence on the ability to drive or use 
machines. Dizziness may occur during treatment with Perjeta (see section 4.8). Patients experiencing 
infusion reactions should be advised not to drive and use machines until symptoms abate.  
 
4.8 Undesirable effects  
 
Summary of the safety profile 
 
The safety of Perjeta has been evaluated in more than 6,000 patients in Phase I, II, and III trials in 
patients with various malignancies and predominantly treated with Perjeta in combination with other 
antineoplastic agents. Those studies included the pivotal trials CLEOPATRA (n=808), NEOSPHERE 
(n=417), TRYPHAENA (n=225), and APHINITY (n=4804) [pooled in Table 2]. The safety of Perjeta 
was generally consistent across studies, although the incidence and most common adverse drug 
reactions (ADRs) varied depending on whether Perjeta was administered as monotherapy or with 
concomitant anti-neoplastic agents.  
 
Tabulated list of adverse reactions 
 
Table 2 summarizes the ADRs from the Perjeta-treated groups of the following pivotal clinical trials: 

• CLEOPATRA, in which Perjeta was given in combination with docetaxel and trastuzumab to 
patients with metastatic breast cancer (n=453) 

• NEOSPHERE (n=309) and TRYPHAENA (n=218), in which neoadjuvant Perjeta was given 
in combination with trastuzumab and chemotherapy to patients with locally advanced, 
inflammatory, or early breast cancer 

• APHINITY, in which adjuvant Perjeta was given in combination with trastuzumab and 
anthracycline-based or non-anthracycline-based, taxane-containing chemotherapy to patients 
with early breast cancer (n=2364) 

 
In addition, ADRs reported in the post-marketing setting are included in Table 2. As Perjeta was used 
with trastuzumab and chemotherapy in these trials, it is difficult to ascertain the causal relationship of 
an adverse event to a particular medicinal product.  
 



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The ADRs are listed below by MedDRA system organ class (SOC) and categories of frequency:  
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 and SOC, ADRs are presented in the order of decreasing seriousness. 
 
The most common ADRs (≥30%) from this pooled data were diarrhoea, alopecia, nausea, fatigue, 
neutropenia, and vomiting. The most common NCI-CTCAE Grade 3-4 ADRs (≥10%) were 
neutropenia and febrile neutropenia. 
 
Table 2 Summary of ADRs in patients treated with Perjeta in clinical trials^, and in the Post-

marketing setting†   
 

System organ class Very Common Common Uncommon Rare 

Infections and infestations Nasopharyngitis Paronychia  
Upper respiratory tract 
infection  
 

  

Blood and lymphatic 
system 
disorders 

Febrile neutropenia* 
Neutropenia  
Leucopenia  
Anaemia 

   

Immune system disorders Infusion reaction°°, * Hypersensitivity°, * 
Drug hypersensitivity°, 
* 

Anaphylactic reaction°, 
* 

Cytokine release 
syndrome°° 

Metabolism and nutrition 
disorders  

Decreased appetite    Tumour lysis 
syndrome† 

Psychiatric disorders Insomnia     

Nervous system disorders  Neuropathy peripheral 
Headache   
Dysgeusia 
Peripheral sensory 
neuropathy 
Dizziness 
Paraesthesia 

    

Eye disorders Lacrimation increased    

Cardiac disorders  Left ventricular 
dysfunction ** 

Cardiac failure 
congestive** 

 

Vascular disorders Hot flush    

Respiratory, thoracic and 
mediastinal disorders  

Cough  
Epistaxis 
Dyspnoea 

 Interstitial lung disease  
Pleural effusion  
 

 

Gastrointestinal disorders  Diarrhoea  
Vomiting   
Stomatitis  
Nausea  
Constipation  
Dyspepsia  
Abdominal pain 

   



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System organ class Very Common Common Uncommon Rare 

Skin and subcutaneous 
tissue disorders  

Alopecia  
Rash  
Nail disorder  
Pruritus  
Dry skin 

   

Musculoskeletal and 
connective tissue disorders  

Myalgia  
Arthralgia  
Pain in extremity 

   

General disorders and 
administration site 
conditions  

Mucosal inflammation 
Oedema peripheral 
Pyrexia  
Fatigue  
Asthenia  

Chills 
Pain 
Oedema 

  

^  Table 2 shows pooled data from the overall treatment period in CLEOPATRA (data cutoff 11 February 2014; 
median number of cycles of Perjeta was 24); and from the neoadjuvant  treatment period in NEOSPHERE 
(median number of cycles of Perjeta was 4, across all treatment arms) and TRYPHAENA (median number of 
cycles of Perjeta was 3 – 6 across treatment arms) and from the treatment period of APHINITY (median number 
of cycles of Perjeta was 18).      
 
* ADRs with a fatal outcome have been reported.   
** For the overall treatment period across the 4 studies. The incidence of left ventricular dysfunction and cardiac 

failure congestive reflect the MedDRA Preferred Terms reported in the individual studies. 
° Hypersensitivity/anaphylactic reaction is based on a group of terms. 
°° Infusion reaction includes a range of different terms within a time window, see “Description of selected 

adverse reactions” below.  
† ADRs reported in the post marketing setting- 
 
Description of selected adverse reactions 
 
Left ventricular dysfunction (LVD) 
In the pivotal trial CLEOPATRA in metastatic breast cancer, the incidence of LVD during study 
treatment was higher in the placebo-treated group than in the Perjeta-treated group (8.6% and 6.6%, 
respectively). The incidence of symptomatic LVD was also lower in the Perjeta-treated group (1.8% in 
the placebo-treated group vs. 1.5% in the Perjeta-treated group) (see section 4.4).  
 
In the neoadjuvant trial NEOSPHERE, in which patients received 4 cycles of Perjeta as neoadjuvant 
treatment, the incidence of LVD (during the overall treatment period) was higher in the Perjeta, 
trastuzumab and docetaxel-treated group (7.5%) compared to the trastuzumab and docetaxel-treated 
group (1.9%). There was one case of symptomatic LVD in the Perjeta and trastuzumab-treated group.  
In the neoadjuvant trial TRYPHAENA, the incidence of LVD (during the overall treatment period) 
was 8.3% in the group treated with Perjeta plus trastuzumab and FEC (5-fluorouracil, epirubicin, 
cyclophosphamide) followed by Perjeta plus trastuzumab and docetaxel; 9.3% in the group treated 
with Perjeta plus trastuzumab and docetaxel following FEC; and 6.6% in the group treated with 
Perjeta in combination with TCH (docetaxel, carboplatin and trastuzumab). The incidence of 
symptomatic LVD (congestive heart failure) was 1.3% in the group treated with Perjeta plus 
trastuzumab and docetaxel following FEC (this excludes a patient who experienced symptomatic LVD 
during FEC treatment prior to receiving Perjeta plus trastuzumab and docetaxel) and also 1.3% in the 
group treated with Perjeta in combination with TCH. No patients in the group treated with Perjeta plus 
trastuzumab and FEC followed by Perjeta plus trastuzumab and docetaxel experienced symptomatic 
LVD. 
 
In the neoadjuvant period of the BERENICE trial, the incidence of NYHA Class III/IV symptomatic 
LVD (congestive heart failure according to NCI-CTCAE v.4) was 1.5% in the group treated with dose 
dense doxorubicin and cyclophosphamide (AC) followed by Perjeta plus trastuzumab and paclitaxel 
and none of the patients (0%) experienced symptomatic LVD in the group treated with FEC followed 
by Perjeta in combination with trastuzumab and docetaxel. The incidence of asymptomatic LVD 



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(ejection fraction decrease according to NCI-CTCAE v.4) was 7% in the group treated with dose 
dense AC followed by Perjeta plus trastuzumab and paclitaxel and 3.5% in the group treated with FEC 
followed by Perjeta plus trastuzumab and docetaxel. 
 
In APHINITY, the incidence of symptomatic heart failure (NYHA class III or IV) with a LVEF 
decline of at least 10% points from baseline and to <50% was <1% (0.6% of Perjeta-treated patients vs 
0.3% of placebo-treated patients). Of the patients who experienced symptomatic heart failure, 46.7% 
of Perjeta-treated patients and 57.1% of placebo-treated patients had recovered (defined as 2 
consecutive LVEF measurements above 50%) at the data cutoff. The majority of the events were 
reported in anthracycline-treated patients. Asymptomatic or mildly symptomatic (NYHA class II) 
declines in LVEF of at least 10% points from baseline and to <50% were reported in 2.7% of Perjeta-
treated patients and 2.8% of placebo-treated patients, of whom 79.7% of Perjeta-treated patients and 
80.6% of placebo-treated patients had recovered at the data cutoff.  
 
Infusion reactions 
An infusion reaction was defined in the pivotal trials as any event reported as hypersensitivity, 
anaphylactic reaction, acute infusion reaction or cytokine release syndrome occurring during an 
infusion or on the same day as the infusion. In the pivotal trial CLEOPATRA, the initial dose of 
Perjeta was given the day before trastuzumab and docetaxel to allow for the examination of Perjeta-
associated reactions. On the first day when only Perjeta was administered, the overall frequency of 
infusion reactions was 9.8% in the placebo-treated group and 13.2% in the Perjeta-treated group, with 
the majority of infusion reactions being mild or moderate. The most common infusion reactions 
(≥ 1.0%) in the Perjeta-treated group were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity 
and vomiting. 
 
During the second cycle when all medicinal products were administered on the same day, the most 
common infusion reactions in the Perjeta-treated group (≥ 1.0%) were fatigue, dysgeusia, drug 
hypersensitivity, myalgia and vomiting (see section 4.4). 
 
In neoadjuvant and adjuvant trials, Perjeta was administered on the same day as other study treatments 
in all cycles. Infusion reactions occurred in 18.6% - 25.0% of patients on the first day of Perjeta 
administration (in combination with trastuzumab and chemotherapy). The type and severity of events 
were consistent with those observed in CLEOPATRA at the cycles when Perjeta was given on the 
same day as trastuzumab and docetaxel, with the majority of reactions being mild or moderate in 
severity. 
 
Hypersensitivity reactions/anaphylaxis 
In the pivotal trial CLEOPATRA in metastatic breast cancer, the overall frequency of investigator 
reported hypersensitivity/anaphylaxis events during the entire treatment period was 9.3% in the 
placebo-treated group and 11.3% in the Perjeta-treated group, of which 2.5% and 2.0% were  
NCI-CTCAE Grade 3-4, respectively. Overall, 2 patients in the placebo-treated group and 4 patients in 
the Perjeta-treated group experienced events described as anaphylaxis by the investigator (see section 
4.4).  
 
Overall, the majority of hypersensitivity reactions were mild or moderate in severity and resolved 
upon treatment. Based on modifications made to the study treatment, most reactions were assessed as 
secondary to docetaxel infusions. 
 
In the neoadjuvant and adjuvant trials, hypersensitivity/anaphylaxis events were consistent with those 
observed in CLEOPATRA. In NEOSPHERE, two patients in the Perjeta and docetaxel-treated group 
experienced anaphylaxis. In both the TRYPHAENA and APHINITY trials, the overall frequency of 
hypersensitivity/anaphylaxis was highest in the Perjeta and TCH treated group (13.2% and 7.6%, 
respectively), of which 2.6% and 1.3% of events, respectively, were NCI-CTCAE Grade 3-4. 
 
Febrile neutropenia 
In the pivotal trial CLEOPATRA, the majority of patients in both treatment groups experienced at 
least one leucopenic event (63.0% of patients in the Perjeta-treated group and 58.3% of patients in the 



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placebo-treated group), of which the majority were neutropenic events (see section 4.4). Febrile 
neutropenia occurred in 13.7% of Perjeta-treated patients and 7.6% of placebo-treated patients. In both 
treatment groups, the proportion of patients experiencing febrile neutropenia was highest in the first 
cycle of therapy and declined steadily thereafter. An increased incidence of febrile neutropenia was 
observed among Asian patients in both treatment groups compared with patients of other races and 
from other geographic regions. Among Asian patients, the incidence of febrile neutropenia was higher 
in the Perjeta-treated group (25.8%) compared with the placebo-treated group (11.3%). 
 
In the NEOSPHERE trial, 8.4% of patients treated with neoadjuvant Perjeta, trastuzumab and 
docetaxel experienced febrile neutropenia compared with 7.5% of patients treated with trastuzumab 
and docetaxel. In the TRYPHAENA trial, febrile neutropenia occurred in 17.1% of patients treated 
with neoadjuvant Perjeta + TCH, and 9.3% of patients treated with neoadjuvant Perjeta, trastuzumab 
and docetaxel following FEC. In TRYPHAENA, the incidence of febrile neutropenia was higher in 
patients who received six cycles of Perjeta compared with patients who received three cycles of 
Perjeta, independent of the chemotherapy given. As in the CLEOPATRA trial, a higher incidence of 
neutropenia and febrile neutropenia was observed among Asian patients compared with other patients 
in both neoadjuvant trials. In NEOSPHERE, 8.3% of Asian patients treated with neoadjuvant Perjeta, 
trastuzumab and docetaxel experienced febrile neutropenia compared with 4.0% of Asian patients 
treated with neoadjuvant trastuzumab and docetaxel. 
 
In the APHINITY trial, febrile neutropenia occurred in 12.1% of Perjeta-treated patients and 11.1% of 
placebo-treated patients. As in the CLEOPATRA, TRYPHAENA, and NEOSPHERE trials, a higher 
incidence of febrile neutropenia was observed among Perjeta-treated Asian patients compared with 
other races in the APHINITY trial (15.9% of Perjeta-treated patients and 9.9% of placebo-treated 
patients). 
 
Diarrhoea 
In the pivotal trial CLEOPATRA in metastatic breast cancer, diarrhoea occurred in 68.4% of Perjeta-
treated patients and 48.7% of placebo-treated patients (see section 4.4). Most events were mild to 
moderate in severity and occurred in the first few cycles of treatment. The incidence of NCI-CTCAE 
Grade 3-4 diarrhoea was 9.3% in Perjeta-treated patients vs 5.1% in placebo-treated patients. The 
median duration of the longest episode was 18 days in Perjeta-treated patients and 8 days in placebo-
treated patients. Diarrhoeal events responded well to proactive management with anti-diarrhoeal 
agents. 
 
In the NEOSPHERE trial, diarrhoea occurred in 45.8% of patients treated with neoadjuvant Perjeta, 
trastuzumab and docetaxel compared with 33.6% of patients treated with trastuzumab and docetaxel. 
In the TRYPHAENA trial, diarrhoea occurred in 72.3% of patients treated with neoadjuvant 
Perjeta+TCH and 61.4% of patients treated with neoadjuvant Perjeta, trastuzumab and docetaxel 
following FEC. In both studies most events were mild to moderate in severity.  
 
In the APHINITY trial, a higher incidence of diarrhoea was reported in the Perjeta-treated arm 
(71.2%) compared to the placebo arm (45.2%).  Grade ≥ 3 diarrhoea was reported in 9.8% of patients 
in the Perjeta arm vs. 3.7% in the placebo arm. The majority of the reported events were Grade 1 or 2 
in severity. The highest incidence of diarrhoea (all Grades) was reported during the targeted 
therapy+taxane chemotherapy period (61.4% of patients in the Perjeta arm vs. 33.8% of patients in the 
placebo arm).The incidence of diarrhoea was much lower after chemotherapy cessation, affecting 
18.1% of patients in the Perjeta arm vs. 9.2% of patients in the placebo arm in the post-chemotherapy 
targeted therapy period. 
 
Rash 
In the pivotal trial CLEOPATRA in metastatic breast cancer, rash occurred in 51.7% of Perjeta-treated 
patients, compared with 38.9% of placebo-treated patients. Most events were Grade 1 or 2 in severity, 
occurred in the first two cycles, and responded to standard therapies, such as topical or oral treatment 
for acne. 
 



13 

In the NEOSPHERE trial, rash occurred in 40.2% of patients treated with neoadjuvant Perjeta, 
trastuzumab and docetaxel compared with 29.0% of patients treated with trastuzumab and docetaxel. 
In the TRYPHAENA trial, rash occurred in 36.8% of patients treated with neoadjuvant Perjeta + TCH 
and 20.0% of patients treated with neoadjuvant Perjeta, trastuzumab and docetaxel following FEC. 
The incidence of rash was higher in patients who received six cycles of Perjeta compared with patients 
who received three cycles of Perjeta, independent of the chemotherapy given. 
 
In the APHINITY trial, the adverse event of rash occurred in 25.8% of patients in Perjeta arm vs.  
20.3% of patients in placebo arm. The majority of rash events were Grade 1 or 2. 
 
Laboratory abnormalities 
In the pivotal trial CLEOPATRA in metastatic breast cancer, the incidence of NCI-CTCAE v.3 Grade 
3-4 neutropenia was balanced in the two treatment groups (86.3% of Perjeta-treated patients and 
86.6% of placebo-treated patients, including 60.7% and 64.8% Grade 4 neutropenia, respectively). 
 
In the NEOSPHERE trial, the incidence of NCI-CTCAE v.3 Grade 3-4 neutropenia was 74.5% in 
patients treated with neoadjuvant Perjeta, trastuzumab and docetaxel compared with 84.5% in patients 
treated with trastuzumab and docetaxel, including 50.9% and 60.2% Grade 4 neutropenia, respectively. 
In the TRYPHAENA trial, the incidence of NCI-CTCAE v.3 Grade 3-4 neutropenia was 85.3% in 
patients treated with neoadjuvant Perjeta + TCH and 77.0% in patients treated with neoadjuvant 
Perjeta, trastuzumab and docetaxel following FEC, including 66.7% and 59.5% Grade 4 neutropenia, 
respectively.  
 
In the APHINITY trial, the incidence of NCI-CTCAE v.4 Grade 3-4 neutropenia was 40.6% in 
patients treated with Perjeta, trastuzumab and chemotherapy compared with 39.1% in patients treated 
with placebo, trastuzumab and chemotherapy, including 28.3% and 26.5% Grade 4 neutropenia, 
respectively. 
 
Elderly Patients 
 
The incidence of the following all grade adverse events was at least 5% higher in patients ≥ 65 years 
of age, compared to patients < 65 years of age: decreased appetite, anaemia, weight decreased, 
asthenia, dysgeusia, peripheral neuropathy, hypomagnesemia and diarrhoea. Limited data are available 
in patients > 75 years of age.  
 
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 
 
The maximum tolerated dose of pertuzumab has not been determined. In clinical trials, single doses 
higher than 25 mg/kg (1727 mg) have not been tested. 
 
In case of overdose, patients must be closely monitored for signs or symptoms of adverse reactions 
and appropriate symptomatic treatment instituted. 
 
 

https://www.ema.europa.eu/documents/template-form/appendix-v-adverse-drug-reaction-reporting-details_en.doc


14 

5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC13 
 
Mechanism of action 
 
Pertuzumab is a recombinant humanised monoclonal antibody that specifically targets the extracellular 
dimerization domain (subdomain II) of the human epidermal growth factor receptor 2 protein (HER2), 
and thereby, blocks ligand-dependent heterodimerisation of HER2 with other HER family members, 
including EGFR, HER3 and HER4. As a result, pertuzumab inhibits ligand-initiated intracellular 
signalling through two major signal pathways, mitogen-activated protein (MAP) kinase and 
phosphoinositide 3-kinase (PI3K). Inhibition of these signalling pathways can result in cell growth 
arrest and apoptosis, respectively. In addition, pertuzumab mediates antibody-dependent cell-mediated 
cytotoxicity (ADCC). 
 
While pertuzumab alone inhibited the proliferation of human tumour cells, the combination of 
pertuzumab and trastuzumab significantly augmented antitumour activity in HER2-overexpressing 
xenograft models. 
 
Clinical efficacy and safety 
 
The efficacy of Perjeta in HER2-positive breast cancer is supported by a randomised phase III trial and 
a single-arm phase II trial in metastatic breast cancer, two randomised neoadjuvant phase II  trials in 
early breast cancer (one controlled), a non-randomised neoadjuvant phase II trial, and a randomised 
phase III trial in the adjuvant setting. 
 
HER2 overexpression was determined at a central laboratory and defined as a score of 3+ by IHC or 
an ISH amplification ratio ≥2.0 in the trials outlined below. 
 
Metastatic breast cancer  
 
Perjeta in combination with trastuzumab and docetaxel 
CLEOPATRA (WO20698) is a multicentre, randomised, double-blind, placebo-controlled phase III 
clinical trial conducted in 808 patients with HER2-positive metastatic or locally recurrent unresectable 
breast cancer. Patients with clinically important cardiac risk factors were not included (see section 4.4). 
Due to the exclusion of patients with brain metastases no data are available on Perjeta activity on brain 
metastases. There is very limited data available in patients with unresectable locally recurrent disease. 
Patients were randomised 1:1 to receive placebo + trastuzumab + docetaxel or Perjeta + trastuzumab + 
docetaxel.  
 
Perjeta and trastuzumab were given at standard doses in a 3-weekly regimen. Patients were treated 
with Perjeta and trastuzumab until disease progression, withdrawal of consent or unmanageable 
toxicity. Docetaxel was given as an initial dose of 75 mg/m2 as an intravenous infusion every three 
weeks for at least 6 cycles. The dose of docetaxel could be escalated to 100 mg/m2 at the investigator’s 
discretion if the initial dose was well tolerated.  
 
The primary endpoint of the study was progression-free survival (PFS) as assessed by an independent 
review facility (IRF) and defined as the time from the date of randomisation to the date of disease 
progression or death (from any cause) if the death occurred within 18 weeks of the last tumour 
assessment. Secondary efficacy endpoints were overall survival (OS), PFS (investigator-assessed), 
objective response rate (ORR), duration of response, and time to symptom progression according to 
the FACT B Quality of Life questionnaire. 
 
Approximately half the patients in each treatment group had hormone receptor-positive disease 
(defined as oestrogen receptor (ER) positive and/or progesterone receptor (PgR) positive) and 



15 

approximately half of the patients in each treatment group had received prior adjuvant or neoadjuvant 
therapy. Most of these patients had received prior anthracycline therapy and 11% of all patients had 
received prior trastuzumab. A total of 43% of patients in both treatment groups had previously 
received radiotherapy. Patients’ median LVEF at baseline was 65.0% (range 50% – 88%) in both 
groups.  
 
The efficacy results from the CLEOPATRA study are summarised in Table 3. A statistically 
significant improvement in IRF-assessed PFS was demonstrated in the Perjeta-treated group compared 
with the placebo-treated group. The results for investigator-assessed PFS were similar to those 
observed for IRF-assessed PFS.  
 
Table 3  Summary of efficacy from CLEOPATRA study 
 
Parameter  Placebo+  

trastuzumab 
+ docetaxel 

n=406 

Perjeta+  
trastuzumab 
+ docetaxel 

n=402 

HR 
(95% CI) 

 

p-value 

Progression-Free Survival  
(independent review) – primary 
endpoint* 
 
no. of patients with an event 
Median months 

 
 
 
 

242 (59%) 
12.4 

 
 
 
 

191 (47.5%) 
18.5 

 
 
 
 

0.62 
[0.51;0.75] 

 
 
 
 

<0.0001 

Overall Survival - secondary 
endpoint** 
 
no. of patients with an event 
Median months 

 
 
 

221 (54.4%) 
40.8 

 
 
 

168 (41.8%) 
56.5 

 
 
 

0.68 
[0.56;0.84] 

 
 
 

0.0002 

Objective Response Rate 
(ORR)^ - secondary endpoint 
no. of patients with measurable 
disease 
Responders***                                       
95% CI for ORR            
Complete response (CR)                             
Partial Response (PR)                             
Stable disease (SD)                                
Progressive disease (PD)                           

 
 
 

336 
233 (69.3%) 
[64.1; 74.2] 
14 (4.2%) 

219 (65.2%) 
70 (20.8%) 
28 (8.3%) 

 
 
 

343 
275 (80.2%) 
[75.6; 84.3] 
19 (5.5%) 

256 (74.6%) 
50 (14.6%) 
13 (3.8 %) 

 
 
 

Difference 
in ORR: 
10.8% 

[4.2,17.5] 

 
 
 

0.0011 

Duration of Response †^ 
n= 
Median weeks  
95% CI for Median 

 
233 
54.1 

[46;64] 

 
275 
87.6 

[71;106] 

  

* Primary progression-free survival analysis, cutoff date 13th May 2011. 
** Event-driven final overall survival analysis, cutoff date 11th February 2014. 
*** Patients with best overall response of confirmed CR or PR by RECIST. 
† Evaluated in patients with Best Overall Response of CR or PR. 
^ Objective response rate and duration of response are based on IRF-assessed tumour assessments. 
 
Consistent results were observed across pre-specified patient subgroups including the subgroups based 
on stratification factors of geographic region and prior adjuvant/neoadjuvant therapy or de novo 
metastatic breast cancer (see Figure 1). A post hoc exploratory analysis revealed that for patients who 
had received prior trastuzumab (n = 88), the hazard ratio for IRF-assessed PFS was 0.62 (95% CI 0.35, 
1.07), compared with 0.60 (95% CI 0.43, 0.83) for patients who had received prior therapy which did 
not include trastuzumab (n = 288). 
 



16 

Figure 1 IRF-assessed PFS by patient subgroup 
 

 
 

The event-driven final analysis of OS was performed when 389 patients had died (221 in the placebo-
treated group and 168 in the Perjeta-treated group). The statistically significant OS benefit in favour of 
the Perjeta-treated group, previously observed at an interim analysis of OS (performed one year after 
the primary analysis), was maintained (HR 0.68, p = 0.0002 log-rank test). The median time to death 
was 40.8 months in the placebo-treated group and 56.5 months in the Perjeta-treated group (see Table 
3, Figure 2). 
 
A descriptive analysis of OS performed at the end of the study when 515 patients had died (280 in the 
placebo-treated group and 235 in the Perjeta-treated group) showed that the statistically significant OS 
benefit in favour of the Perjeta-treated group was maintained over time after a median follow-up of 99 
months (HR 0.69, p < 0.0001 log-rank test; median time to death 40.8 months [placebo-treated group] 
versus 57.1 months [Perjeta-treated group]). Landmark survival estimates at 8 years were 37% in the 
Perjeta-treated group and 23% in the placebo-treated group. 
 



17 

Figure 2 Kaplan-Meier Curve of Event-Driven Overall Survival 
 

 

HR= hazard ratio; CI= confidence interval; Pla= placebo; Ptz= pertuzumab (Perjeta); T= trastuzumab (Herceptin); D= docetaxel. 

 
No statistically significant differences were found between the two treatment groups in Health Related 
Quality of Life as assessed by FACT-B TOI-PFB scores.  
 
Additional supportive clinical trial information 
 
BO17929 - single-arm trial in metastatic breast cancer 
 
BO17929 was a phase II, non-randomised study in patients with metastatic breast cancer whose 
tumours had progressed during treatment with trastuzumab. Treatment with Perjeta and trastuzumab 
resulted in a response rate of 24.2%, with a further 25.8% of patients experiencing stabilisation of 
disease lasting at least 6 months, indicating that Perjeta is active following progression on 
trastuzumab.   
 
Early Breast Cancer 
 
Neoadjuvant Treatment 
 
In the neoadjuvant setting, locally advanced and inflammatory breast cancers are considered as high-
risk irrespective of hormone receptor status. In early stage breast cancer, tumor size, grade, hormone 
receptor status and lymph node metastases should be taken into account in the risk assessment. 
 
The indication in the neoadjuvant treatment of breast cancer is based on demonstration of an 
improvement in pathological complete response rate, and trends to improvement in disease-free 
survival that nevertheless do not establish or precisely measure a benefit with regard to long-term 
outcomes, such as overall survival or disease-free survival.  
 
NEOSPHERE (WO20697)  
 
NEOSPHERE is a phase II, multicentre, multinational randomised controlled trial with Perjeta and 
was conducted in 417 adult female patients with newly diagnosed, early, inflammatory or locally 
advanced HER2-positive breast cancer (T2-4d; primary tumour > 2cm in diameter) who had not 



18 

received prior trastuzumab, chemotherapy or radiotherapy. Patients with metastases, bilateral breast 
cancer, clinically important cardiac risk factors (see section 4.4) or LVEF < 55% were not included. 
The majority of patients were less than 65 years old.  
 
Patients were randomised to receive one of the following neoadjuvant regimens for 4 cycles prior to 
surgery:  
 

• Trastuzumab plus docetaxel  
• Perjeta plus trastuzumab and docetaxel 
• Perjeta plus trastuzumab 
• Perjeta plus docetaxel.  

 
Randomisation was stratified by breast cancer type (operable, locally advanced, or inflammatory) and 
ER or PgR positivity. 
   
Pertuzumab was given intravenously at an initial dose of 840 mg, followed by 420 mg every three 
weeks. Trastuzumab was given intravenously at an initial dose of 8 mg/kg, followed by 6 mg/kg every 
three weeks. Docetaxel was given intravenously at an initial dose of 75 mg/ m2 followed by 75 mg/ m2 
or 100 mg/ m2 (if tolerated) every 3 weeks. Following surgery all patients received 3 cycles of 5-
fluorouracil (600 mg/m2), epirubicin (90 mg/m2), cyclophosphamide (600 mg/m2) (FEC) given 
intravenously every three weeks, and trastuzumab administered intravenously every three weeks to 
complete one year of therapy. Patients who only received Perjeta plus trastuzumab prior to surgery 
subsequently received both FEC and docetaxel post surgery. 
 
The primary endpoint of the study was pathological complete response (pCR) rate in the breast 
(ypT0/is).  Secondary efficacy endpoints were clinical response rate, breast conserving surgery rate 
(T2-3 tumours only), disease-free survival (DFS), and PFS. Additional exploratory pCR rates included 
nodal status (ypT0/isN0 and ypT0N0). 
 
Demographics were well balanced (median age was 49-50 years, the majority were caucasian (71%)) 
and all patients were female. Overall 7% of patients had inflammatory breast cancer, 32% had locally 
advanced breast cancer and 61% had operable breast cancer.  Approximately half the patients in each 
treatment group had hormone receptor-positive disease (defined as ER positive and/or PgR positive).  
 
The efficacy results are presented in Table 4. A statistically significant  improvement in pCR rate 
(ypT0/is) was observed in patients receiving Perjeta plus trastuzumab and docetaxel compared to 
patients receiving trastuzumab and docetaxel (45.8% vs 29.0%, p value = 0.0141). A consistent pattern 
of results was observed regardless of pCR definition. The difference in pCR rate is considered likely 
to translate into a clinically meaningful difference in long term outcomes and is supported by positive 
trends in PFS (HR 0.69, 95% CI 0.34, 1.40) and DFS (HR 0.60, 95% CI 0.28, 1.27).  
 
The pCR rates as well as the magnitude of benefit with Perjeta (Perjeta plus trastuzumab and docetaxel 
compared to patients receiving trastuzumab and docetaxel) were lower in the subgroup of patients with 
hormone receptor-positive tumours (difference of 6% in pCR in the breast) than in patients with 
hormone receptor-negative tumours (difference of 26.4% in pCR in the breast).  
pCR rates were similar in patients with operable versus locally advanced disease. There were too few 
patients with inflammatory breast cancer to draw any firm conclusions but the pCR rate was higher in 
patients who received Perjeta plus trastuzumab and docetaxel. 
 



19 

TRYPHAENA (BO22280) 
 
TRYPHAENA is a multicentre, randomised phase II clinical trial conducted in 225 adult female 
patients with HER2-positive locally advanced, operable, or inflammatory breast cancer (T2-4d; 
primary tumour  > 2cm in diameter) who had not received prior trastuzumab, chemotherapy or 
radiotherapy.  Patients with metastases, bilateral breast cancer, clinically important cardiac risk factors 
(see section 4.4) or LVEF  <  55% were not included. The majority of patients were less than 65 years 
old. Patients were randomised to receive one of three neoadjuvant regimens prior to surgery as 
follows:  
 

• 3 cycles of FEC followed by 3 cycles of docetaxel, all given concurrently with Perjeta and 
trastuzumab 

• 3 cycles of FEC alone followed by 3 cycles of docetaxel, with trastuzumab and Perjeta given 
concurrently 

• 6 cycles of TCH in combination with Perjeta.  
 

Randomisation was stratified by breast cancer type (operable, locally advanced, or inflammatory) and 
ER and /or PgR positivity.  
 
Pertuzumab was given intravenously at an initial dose of 840 mg, followed by 420 mg every three 
weeks.  Trastuzumab was given intravenously at an initial dose of 8 mg/kg, followed by 6 mg/kg 
every three weeks.  FEC (5-fluorouracil [500 mg/m2], epirubicin [100 mg/m2], cyclophosphamide 
[600 mg/m2]) were given intravenously every three weeks for 3 cycles.  Docetaxel was given as an 
initial dose of 75 mg/m2 IV infusion every three weeks with the option to escalate to 100 mg/m2 at the 
investigator’s discretion if the initial dose was well tolerated.  However, in the group treated with 
Perjeta in combination with TCH, docetaxel was given intravenously at 75 mg/m2 (no escalation was 
permitted) and carboplatin (AUC 6) was given intravenously every three weeks. Following surgery all 
patients received trastuzumab to complete one year of therapy. 
 
The primary endpoint of this study was cardiac safety during the neoadjuvant treatment period of the 
study.  Secondary efficacy endpoints were pCR rate in the breast (ypT0/is), DFS, PFS and OS.  
 
Demographics were well balanced between arms (median age was 49-50 years, the majority were 
Caucasian [77%]) and all patients were female. Overall 6% of patients had inflammatory breast cancer, 
25% had locally advanced breast cancer and 69% had operable breast cancer. Approximately half the 
patients in each treatment group had ER-positive and/or PgR-positive disease. 
 
Compared with published data for similar regimens without pertuzumab, high pCR rates were 
observed in all 3 treatment arms (see Table 4). A consistent pattern of results was observed regardless 
of pCR definition used. The pCR rates were lower in the subgroup of patients with hormone receptor-
positive tumours (range 46.2% to 50.0%) than in patients with hormone receptor-negative tumours 
(range 65.0% to 83.8%). 
 
pCR rates were similar in patients with operable and locally advanced disease. There were too few 
patients with inflammatory breast cancer to draw any firm conclusions.  
 



20 

Table 4 NEOSPHERE (WO20697) and TRYPHAENA (BO22280): Overview of efficacy 
(Intent to Treat Population)  

 
 NEOSPHERE (WO20697) TRYPHAENA (BO22280) 

Parameter 

Trastuzum
ab 

+Docetaxel 
N=107 

Perjeta+ 
Trastuzuma

b+ 
Docetaxel 

N=107 

Perjeta+ 
Trastuzuma

b 
N=107 

Perjeta 
+Docetaxel 

N=96 

Perjeta+ 
Trastuzumab+ 

FEC 
Perjeta+ 

Trastuzumab
+ 

Docetaxel 
N=73 

FEC 
Perjeta+ 

Trastuzumab
+ 

Docetaxel 
N=75 

Perjeta 
+TCH 
N=77 

pCR rate in 
the breast 
(ypT0/is) 
n (%) 
[95% CI]1 

31 (29.0%) 
[20.6; 38.5] 

49 (45.8%) 
[36.1; 55.7] 

18 (16.8%) 
[10.3; 25.3] 

23 (24.0%) 
[15.8; 33.7] 

45 (61.6%) 
[49.5; 72.8] 

43 (57.3%) 
[45.4; 68.7] 

51 (66.2%) 
[54.6; 76.6] 

Difference 
in pCR 
rates2 

[95% CI]3 

 
+16.8 % 

[3.5; 30.1] 
-12.2 % 

[-23.8; -0.5] 
-21.8 % 

[-35.1; -8.5] 
NA NA NA 

p-value 
(with 
Simes corr. 
for CMH 
test)4 

 

0.0141 
(vs. 

Trastuzumab
+Docetaxel) 

0.0198 
(vs. 

Trastuzumab
+Docetaxel) 

0.0030 
(vs Perjeta+ 

Trastuzumab+
Docetaxel) 

NA NA NA 

pCR rate in 
the breast 
and lymph 
node 
(ypT0/is 
N0) 
n (%) 
[95% CI] 

23 (21.5%) 
[14.1; 30.5] 

42 (39.3%) 
[30.3; 49.2] 

12 (11.2%) 
[5.9; 18.8] 

17 (17.7%) 
[10.7; 26.8] 

41 (56.2%) 
[44.1; 67.8] 

41 (54.7%) 
[42.7; 66.2] 

49 (63.6%) 
[51.9; 74.3] 

ypT0 N0  
n (%) 
[95% CI] 

13 (12.1%) 
[6.6; 19.9] 

35 (32.7%) 
[24.0; 42.5] 

6 (5.6%) 
[2.1; 11.8] 

13 (13.2%) 
[7.4; 22.0] 

37 (50.7%) 
[38.7; 62.6] 

34 (45.3%) 
[33.8; 57.3] 

40 (51.9%) 
[40.3; 63.5] 

Clinical 
Response5 

79 (79.8%) 89 (88.1%) 69 (67.6%) 65 (71.4%) 67 (91.8%) 71 (94.7%) 69 (89.6%) 

FEC: 5-fluorouracil, epirubicin, cyclophosphamide; TCH: docetaxel, carboplatin and trastuzumab, CMH: 
Cochran–Mantel–Haenszel 
1. 95% CI for one sample binomial using Pearson-Clopper method. 
2. Treatment Perjeta+Trastuzumab+Docetaxel and Perjeta+Trastuzumab are compared to Trastuzumab+ 
Docetaxel while Perjeta+Docetaxel  is compared to Perjeta+Trastuzumab+Docetaxel. 
3. Approximate 95% CI for difference of two response rates using Hauck-Anderson method. 
4. p-value from Cochran-Mantel-Haenszel  test, with Simes multiplicity adjustment. 
5. Clinical response represents patients with a best overall response of CR or PR during the neoadjuvant period 
(in the primary breast lesion). 
 



21 

BERENICE (WO29217) 
 
BERENICE is a non-randomized, open-label, multicentre, multinational, Phase II trial conducted in 
401 patients with HER2-positive locally advanced, inflammatory, or early-stage breast cancer (with 
primary tumours > 2cm in diameter or node-positive disease). 
 
The BERENICE study included two parallel groups of patients. Patients considered suitable for 
neoadjuvant treatment with trastuzumab plus anthracycline/taxane-based chemotherapy were allocated 
to receive one of the two following regimens prior to surgery as follows:  
 

• Cohort A - 4 cycles of two weekly dose-dense doxorubicin and cyclophosphamide followed 
by 4 cycles of Perjeta in combination with trastuzumab and paclitaxel. 

• Cohort B - 4 cycles of FEC followed by 4 cycles of Perjeta in combination with trastuzumab 
and docetaxel.  

 
Following surgery all patients received Perjeta and trastuzumab intravenously every 3 weeks to 
complete 1 year of therapy. 
 
The primary endpoint of the BERENICE trial is cardiac safety in the neoadjuvant period of the trial. 
The primary endpoint of cardiac safety, i.e. the incidence of NYHA Class III/IV LVD and LVEF 
declines, was consistent with previous data in the neoadjuvant setting (see section 4.4. and 4.8). 
 
Adjuvant Treatment 
 
In the adjuvant setting, based on data from the APHINITY study, HER2-positive early breast cancer 
patients at high risk of recurrence are defined as those with lymph node-positive or hormone receptor-
negative disease. 
 
APHINITY (BO25126)  
 
APHINITY is a multicentre, randomised, double-blind, placebo-controlled Phase III trial conducted in 
4804 patients with HER2-positive early breast cancer who had their primary tumour excised prior to 
randomisation. Patients were then randomised to receive Perjeta or placebo, in combination with 
adjuvant trastuzumab and chemotherapy. Investigators selected one of the following anthracycline-
based or non-anthracycline-based chemotherapy regimens for individual patients: 
 

• 3 or 4 cycles of FEC or 5-fluorouracil, doxorubicin and cyclophosphamide (FAC), followed 
by 3 or 4 cycles of docetaxel or 12 cycles of weekly paclitaxel 

• 4 cycles of AC or epirubicin and cyclophosphamide (EC), followed by 3 or 4 cycles of 
docetaxel or 12 cycles of weekly paclitaxel  

• 6 cycles of docetaxel in combination with carboplatin   
 

Pertuzumab and trastuzumab were administered intravenously (see section 4.2) every 3 weeks starting 
on Day 1 of the first taxane-containing cycle, for a total of 52 weeks (up to 18 cycles) or until 
recurrence, withdrawal of consent or unmanageable toxicity. Standard doses of 5-fluorouracil, 
epirubicin, doxorubicin, cyclophosphamide, docetaxel, paclitaxel and carboplatin were administered. 
After completion of chemotherapy, patients received radiotherapy and/or hormone therapy as per local 
clinical standard. 
 
The primary endpoint of the study was invasive disease-free survival (IDFS), defined as the time from 
randomisation to first occurrence of ipsilateral local or regional invasive breast cancer recurrence, 
distant recurrence, contralateral invasive breast cancer, or death from any cause. Secondary efficacy 
endpoints were IDFS including second primary non-breast cancer, overall survival (OS), disease-free 
survival (DFS), recurrence-free interval (RFI) and distant recurrence-free interval (DRFI). 



22 

 
Demographics were well balanced between the two treatment arms. The median age was 51 years, and 
over 99% of patients were female. The majority of patients had node-positive (63%) and/or hormone 
receptor-positive disease (64%), and were Caucasian (71%). 
 
After a median follow-up of 45.4 months, the APHINITY study showed a 19% (hazard ratio [HR] = 
0.81; 95% CI 0.66, 1.00 p-value 0.0446) reduction in risk of recurrence or death in patients 
randomised to receive Perjeta compared with patients randomised to receive placebo. 
 
The efficacy results from the APHINITY trial are summarised in Table 5 and in Figure 3. 
 
Table 5  Overall Efficacy: ITT Population 
 

 

Perjeta + trastuzumab 
+ Chemotherapy 
N=2400 

Placebo + 
trastuzumab + 
Chemotherapy 
N=2404 

Primary Endpoint  
Invasive Disease Free Survival (IDFS)   
Number (%) of patients with event  171 (7.1%) 210 (8.7%) 
HR [95% CI] 0.81 [0.66, 1.00] 
p-value (Log-Rank test, stratified1) 0.0446 
3 year event-free rate2 [95% CI]  94.1 [93.1, 95.0] 93.2 [92.2, 94.3] 
Secondary Endpoints1  
IDFS including second primary non-breast 
cancer  
Number (%) of patients with event  189 (7.9%) 230 (9.6%) 
HR [95% CI] 0.82 [0.68, 0.99] 
p-value (Log-Rank test, stratified1) 0.0430 
3 year event-free rate2 [95% CI]  93.5 [92.5, 94.5] 92.5 [91.4, 93.6] 
Disease Free Survival (DFS)   
Number (%) of patients with event 192 (8.0%) 236 (9.8%) 
HR [95% CI] 0.81 [0.67, 0.98] 
p-value (Log-Rank test, stratified1) 0.0327 
3 year event-free rate2 [95% CI] 93.4 [92.4, 94.4] 92.3 [91.2, 93.4] 
Overall Survival (OS)3  
Number (%) of patients with event 80 (3.3%) 89 (3.7%) 
HR [95% CI] 0.89 [0.66, 1.21] 
p-value (Log-Rank test, stratified1) 0.4673 
3 year event-free rate2 [95% CI] 97.7 [97.0, 98.3] 97.7 [97.1, 98.3] 
Key to abbreviations (Table 5): HR: Hazard Ratio; CI: Confidence Interval  
1. All analyses stratified by nodal status, protocol version, central hormone receptor status, and adjuvant 
chemotherapy regimen.                                                          
2. 3-year event-free rate derived from Kaplan-Meier estimates. 
3. Data from first interim analysis.  
 



23 

Figure 3 Kaplan-Meier Curve of Invasive Disease Free Survival  
 

 
IDFS= invasive disease free survival; CI= confidence interval; Pla= placebo; Ptz= pertuzumab (Perjeta); T= trastuzumab. 
 
The estimate of IDFS at 4-years was 92.3% in the Perjeta-treated group versus 90.6% in the placebo-
treated group. At the time of the estimate the median follow-up was 45.4 months. 
 
Results of Subgroup Analysis  
 
At the time of the primary analysis, the benefits of Perjeta were more apparent in subgroups of patients 
a high risk of recurrence: patients with node-positive or hormone receptor-negative disease (see table 
6). 
 



24 

Table 6  Efficacy results in subgroups by nodal status and hormone receptor status1 
 
 
 
Population 

Number of IDFS events/Total N (%) Unstratified HR 
(95% CI) Perjeta + 

trastuzumab + 
chemotherapy 

Placebo +  
trastuzumab + 
chemotherapy 

Nodal status 
   Positive 139/1503 

(9.2%) 
181/1502 
(12.1%) 

0.77 
(0.62, 0.96) 

   Negative  32/897 
(3.6%) 

29/902 
(3.2%) 

1.13 
(0.68, 1.86) 

Hormone receptor 
status 

   

   Negative 71/864 
(8.2%) 

91/858 
(10.6%) 

0.76 
(0.56, 1.04) 

   Positive 100/1536 
(6.5%) 

119/1546 
(7.7%) 

0.86 
(0.66, 1.13) 

1 Prespecified subgroup analyses without adjusting for multiple comparisons, therefore, results are considered 
descriptive. 
 
Estimates of IDFS rates in the lymph node- positive subgroup were 92.0% versus 90.2% at 3 years and 
89.9% vs. 86.7% at 4 years in Perjeta-treated patients versus placebo-treated patients, respectively. In 
the lymph node- negative subgroup, estimates of IDFS rates were 97.5% versus 98.4% at 3 years and 
96.2% versus 96.7% at 4 years in Perjeta-treated patients versus placebo-treated patients, respectively. 
In the hormone receptor-negative subgroup, estimates of IDFS rates were 92.8% versus 91.2% at 3 
years and 91.0% versus 88.7% at 4 years in Perjeta-treated patients versus placebo-treated patients, 
respectively. In the hormone receptor-positive subgroup estimates of IDFS rates were 94.8% versus 
94.4% at 3 years and 93.0% versus 91.6% at 4 years in Perjeta-treated patients versus placebo-treated 
patients, respectively.  
 
Patient Reported Outcomes (PRO) 
 
Secondary endpoints included the assessment of patient-reported global health status, role and 
physical function, and treatment symptoms using the EORTC QLQ-C30 and EORTC QLQ-BR23 
questionnaires. In the analyses of patient-reported outcomes, a 10-point difference was considered 
clinically meaningful.  
 
Patients’ physical function, global health status and diarrhoea scores showed a clinically meaningful 
change during chemotherapy in both treatment arms. The mean decrease from baseline at that time for 
physical function was -10.7 (95% CI-11.4, -10.0) in the Perjeta arm and -10.6 (95% CI -11.4, -9.9) in 
the placebo arm; global health status was -11.2 (95% CI -12.2, -10.2) in the Perjeta arm and -10.2 
(95% CI -11.1,-9.2) in the placebo arm. Change in diarrhoea symptoms increased to +22.3 (95% CI 
21.0, 23.6) in the Perjeta arm versus +9.2 (95% CI 8.2, 10.2) in the placebo arm.  
 
Thereafter in both arms physical function and global health status scores returned to baseline levels 
during targeted treatment. Diarrhoea symptoms returned to baseline after HER2 therapy in the Perjeta-
arm. The addition of Perjeta to trastuzumab plus chemotherapy did not affect patients’ overall role 
function over the course of the study.  
 
Immunogenicity 
 
Patients in the pivotal trial CLEOPATRA were tested at multiple time-points for anti-drug antibodies 
(ADA) to Perjeta. 3.3% (13/389 patients) of Perjeta-treated patients and 6.7% (25/372 patients) of 
placebo-treated patients tested positive for ADA. In BERENICE, 4.1% (16/392) of the patients treated 
with Perjeta tested positive for ADA.  None of these patients experienced 
anaphylactic/hypersensitivity reactions that were clearly related to ADA. 



25 

 
Paediatric population 
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
Perjeta in all subsets of the paediatric population in breast cancer (see section 4.2 for information on 
paediatric use). 
 
5.2 Pharmacokinetic properties 
 
A population pharmacokinetic analysis was performed with data from 481 patients across different 
clinical trials (phase I, II and III) with various types of advanced malignancies who had received 
Perjeta as a single agent or in combination at pertuzumab doses ranging from 2 to 25 mg/kg 
administered every 3 weeks as a 30-60 minutes intravenous infusion. 
 
Absorption 
 
Perjeta is administered as an intravenous infusion.  
 
Distribution 
 
Across all clinical studies, the volume of distribution of the central (Vc) and the peripheral (Vp) 
compartment in the typical patient, was 3.11 litres and 2.46 litres, respectively. 
 
Biotransformation 
 
The metabolism of pertuzumab has not been directly studied. Antibodies are cleared principally by 
catabolism. 
 
Elimination 
 
The median clearance (CL) of pertuzumab was 0.235 litres/day and the median half-life was 18 days. 
 
Linearity/non-linearity 
 
Pertuzumab displayed linear pharmacokinetics within the recommended dose range. 
 
Elderly patients 
 
Based on the population pharmacokinetic analysis, no significant difference was observed in the 
pharmacokinetics of pertuzumab between patients < 65 years (n=306) and patients ≥ 65 years (n=175). 
 
Renal impairment  
 
No dedicated renal impairment trial for Perjeta has been conducted. Based on the results of the 
population pharmacokinetic analysis, pertuzumab exposure in patients with mild (creatinine clearance 
[CLcr] 60 to 90 ml/min, N=200) and moderate renal impairment (CLcr 30 to 60 ml/min, N=71) was 
similar to that in patients with normal renal function (CLcr greater than 90 ml/min, N=200). No 
relationship between CLcr and pertuzumab exposure was observed over the range of CLcr (27 to 
244 ml/min). 
 
Other special populations 
 
The population PK analysis suggested no PK differences based on age, gender and ethnicity (Japanese 
versus non-Japanese). Baseline albumin and lean body weight were the most significant covariates 
influencing CL. CL decreased in patients with higher baseline albumin concentrations and increased in 
patients with greater lean body weight. However sensitivity analyses performed at the recommended 
dose and schedule of Perjeta showed that at the extreme values of these two covariates, there was no 



26 

significant impact on the ability to achieve target steady-state concentrations identified in preclinical 
tumour xenograft models. Therefore, there is no need to adjust the dosage of pertuzumab based on 
these covariates. 
  
The PK results of pertuzumab in the NEOSPHERE and APHINITY studies were consistent with the 
predictions from the previous population PK model. No differences in pertuzumab PK were observed 
in patients with early breast cancer compared to patients with metastatic breast cancer. 
 
5.3 Preclinical safety data 
 
No specific fertility studies in animals have been performed to evaluate the effect of pertuzumab. No 
definitive conclusion on adverse effects can be drawn on the male reproductive organs in cynomolgus 
monkey repeated dose toxicity study. 
 
Reproductive toxicology studies have been conducted in pregnant cynomolgus monkeys (Gestational 
Day (GD) 19 through to GD 50) at initial doses of 30 to 150 mg/kg followed by bi-weekly doses of 
10 to 100 mg/kg. These dose levels resulted in clinically relevant exposures of 2.5 to 20-fold greater 
than the recommended human dose, based on Cmax. Intravenous administration of pertuzumab from 
GD19 through GD50 (period of organogenesis) was embryotoxic, with dose-dependent increases in 
embryo-foetal death between GD25 to GD70. The incidences of embryo-foetal loss were 33, 50, and 
85% for pregnant female monkeys treated with bi-weekly pertuzumab doses of 10, 30, and 100 mg/kg, 
respectively (2.5 to 20-fold greater than the recommended human dose, based on Cmax). At Caesarean 
section on GD100, oligohydramnios, decreased relative lung and kidney weights and microscopic 
evidence of renal hypoplasia consistent with delayed renal development were identified in all 
pertuzumab dose groups. In addition, consistent with foetal growth restrictions, secondary to 
oligohydramnios, lung hypoplasia (1 of 6 in 30 mg/kg and 1 of 2 in100 mg/kg groups), ventricular 
septal defects (1 of 6 in 30 mg/kg group), thin ventricular wall (1 of 2 in 100 mg/kg group) and minor 
skeletal defects (external - 3 of 6 in 30 mg/kg group) were also noted.  Pertuzumab exposure was 
reported in offspring from all treated groups, at levels of 29% to 40% of maternal serum levels at 
GD100.  
 
In cynomolgus monkeys, weekly intravenous administration of pertuzumab at doses up to 
150 mg/kg/dose was generally well tolerated. With doses of 15 mg/kg and higher, intermittent mild 
treatment-associated diarrhoea was noted. In a subset of monkeys, chronic dosing (7 to 26 weekly 
doses) resulted in episodes of severe secretory diarrhoea. The diarrhoea was managed (with the 
exception of euthanasia of one animal, 50 mg/kg/dose) with supportive care including intravenous 
fluid replacement therapy. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Glacial acetic acid 
L-Histidine 
Sucrose 
Polysorbate 20 
Water for injections 
 
6.2 Incompatibilities 
 
Glucose (5%) solution should not be used to dilute Perjeta since it is chemically and physically 
unstable in such solutions. 
 
This medicinal product must not be mixed with other medicinal products except those mentioned in 
section 6.6. 
 



27 

6.3 Shelf life 
 
Unopened vial  
 
2 years.  
 
Diluted solution 
 
Chemical and physical in-use stability has been demonstrated for 24 hours at 30°C.  
From a microbiological point of view, the product 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 normally not be longer than 24 hours at 2°C to 8°C, unless dilution has taken place in 
controlled and validated aseptic conditions.  
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C-8°C). 
 
Do not freeze.  
 
Keep the vial in the outer carton in order to protect from light. 
 
For storage conditions after dilution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
Vial (Type I glass) with a stopper (butyl rubber) containing 14 ml of solution.  
 
Pack of 1 vial. 
 
6.6 Special precautions for disposal and other handling 
 
Perjeta does not contain any antimicrobial preservative. Therefore, care must be taken to ensure the 
sterility of the prepared solution for infusion and should be prepared by a healthcare professional.  
 
Perjeta is for single use only. 
 
The vial must not be shaken. 14 ml of Perjeta concentrate should be withdrawn from the vial and 
diluted into a 250 ml PVC or non-PVC polyolefin infusion bag of sodium chloride 9 mg/ml (0.9%) 
solution for infusion. After dilution, one ml of solution should contain approximately 3.02 mg of 
pertuzumab (840 mg/278 ml) for the initial dose where two vials are required and approximately 
1.59 mg of pertuzumab (420 mg/264  ml) for the maintenance dose where one vial is required.  
The bag should be gently inverted to mix the solution in order to avoid foaming. 
 
Parenteral medicinal products should be inspected visually for particulates and discolouration prior to 
administration. If particulates or discoloration are observed, the solution should not be used. Once the 
infusion is prepared it should be administered immediately (see section 6.3).  
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
Perjeta is compatible with polyvinylchloride (PVC) or non-PVC polyolefin bags including 
polyethylene. 
 
 



28 

7. MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/13/813/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 4th March 2013 
Date of latest renewal: 8th December 2017 
 
 
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. 
  

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


29 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 

 
 



30 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturer of the biological active substance(s)  
Genentech, Inc. 
1000 New Horizons Way 
Vacaville, CA 95688-9431 
USA 
 
Name and address of the manufacturer responsible for batch release 
Roche Pharma AG 
Emil-Barell-Strasse 1 
D-79639 Grenzach-Whylen 
Germany 
 
 
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 subsquent updates published on the European medicines web-portal. 
 
 
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 agreeed  
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.  

 
• Obligation to conduct post-authorisation measures 
 
The MAH shall complete, within the stated timeframe, the following measures: 
 
Description Due date 
MO28047 (PERUSE)  
A multicenter, open-label, single-arm study of pertuzumab in combination with 
trastuzumab and a taxane in first line treatment of patients with HER2- positive 
advanced (metastatic or locally recurrent) breast cancer 
 

September 
2020 

  



31 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



32 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



33 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Perjeta 420 mg concentrate for solution for infusion 
pertuzumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One 14 ml vial contains 420 mg of pertuzumab at a concentration of 30 mg/ml. 
 
 
3. LIST OF EXCIPIENTS 
 
Glacial acetic acid, L-histidine, sucrose and polysorbate 20. 
Water for injections 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate for solution for infusion 
420 mg/14 ml 
1 x 14 ml 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For intravenous use after dilution 
Do not shake 
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 
Do not freeze 
Keep the vial in the outer carton in order to protect from light  



34 

 
 
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 
 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/13/813/001 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  
  



35 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Perjeta 420 mg concentrate for solution for infusion 
pertuzumab 
IV 
 
 
2. METHOD OF ADMINISTRATION 
 
For intravenous use after dilution 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
420 mg/14 ml 
 
 
6. OTHER 
 

  



36 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



37 

Package Leaflet: Information for the user 
 

Perjeta 420 mg concentrate for solution for infusion 
pertuzumab 

 
Read all of this leaflet carefully before you start being given 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 nurse.  
• If you get any side effects, talk to your doctor or nurse. This includes any possible side effects 

not listed in this leaflet. See section 4. 
 
What is in this leaflet:  
 
1. What Perjeta is and what it is used for 
2. What you need to know before you are given Perjeta 
3. How you are given Perjeta  
4. Possible side effects 
5. How to store Perjeta 
6. Contents of the pack and other information 
 
 
1. What Perjeta is and what it is used for 
 
Perjeta contains the active substance pertuzumab and is used to treat adult patients with breast cancer 
when: 
• The breast cancer has been identified to be of the “HER2-positive” form – your doctor will 

test you for this. 
• The cancer has spread to other parts of the body such as the lungs or liver (metastasised) and 

has not previously been treated with anticancer medicines (chemotherapy) or other medicines 
designed to attach to HER2, or else the cancer has come back in the breast after previous 
treatment. 

• The cancer has not spread to other parts of the body and treatment is going to be given before 
surgery takes place (treatment before surgery is called neoadjuvant therapy) 

• The cancer has not spread to other parts of the body and treatment is going to be given after 
surgery (treatment after surgery is called adjuvant therapy) 

 
As well as Perjeta you will also receive trastuzumab and medicines called chemotherapy Information 
about these medicines is described in separate package leaflets. Ask your doctor or nurse to give you 
information about these other medicines. 
 
How Perjeta works 
 
Perjeta is a type of medicine called a “monoclonal antibody” which attaches itself to specific targets in 
your body and on the cancer cells.  
 
Perjeta recognises and attaches to a target 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 Perjeta attaches to the HER2 cancer cells, it may slow or stop the cancer cells from growing, or 
may kill them. 
 
 



38 

2. What you need to know before you are given Perjeta 
 
You must not be given Perjeta 
 
• If you are allergic to pertuzumab, or to any of the other ingredients of this medicine (listed in 

section 6). 
 
If you are not sure, talk to your doctor or nurse before you are given Perjeta. 
 
Warnings and precautions 
 
Treatment with Perjeta may affect the heart.  Talk to your doctor or nurse before you are given Perjeta: 
• If you have ever had heart problems (such as heart failure, treatment for serious irregular 

heartbeats, uncontrolled high blood pressure, recent heart attack), your heart function will be 
checked before and during treatment with Perjeta and your doctor will run tests to check if 
your heart is working properly.  

• If you have ever had heart problems during previous treatment with trastuzumab. 
• If you have ever had a chemotherapy medicine from the class called anthracyclines, e.g. 

doxorubicin or epirubicin – these medicines can damage heart muscle and increase the risk of 
heart problems with Perjeta. 

 
If any of the above applies to you (or you are not sure), talk to your doctor or nurse before you are 
given Perjeta. See section 4 “Serious side effects” for more details about signs of heart problems to 
look out for. 
 
Infusion reactions 
Infusion reactions, allergic or anaphylactic (more severe allergic) reactions can happen. Your doctor or 
nurse will check for side effects during your infusion and for 30 to 60 minutes afterwards. If you get 
any serious reaction, your doctor may stop treatment with Perjeta. Very rarely, patients have died due 
to anaphylactic reactions during Perjeta infusion. See section 4 “Serious side effects” for more details 
about infusion reactions to look out for during the infusion and thereafter.  
 
Febrile neutropenia (Low white blood cells with fever) 
When Perjeta is given with other cancer treatments (trastuzumab and chemotherapy), the number of 
white blood cells may drop and fever (raised temperature) may develop. If you have inflammation of 
the digestive tract (e.g.sore mouth or diarrhoea) you may be more likely to develop this side effect. 
 
Diarrhoea 
Treatment with Perjeta may cause severe diarrhoea. Patients over 65 years of age have a higher risk of 
diarrhoea compared with patients younger than 65 years of age. Diarrhoea is a condition where your 
body produces more watery stools than normal. If you experience severe diarrhoea while receiving 
your anti-cancer treatment, your doctor may start you on anti-diarrhoeal treatment and may stop your 
treatment with Perjeta until the diarrhoea is under control.  
 
Use in children and adolescents 
Perjeta should not be given to patients under the age of 18 years because there is no information on 
how it works in this age group. 
 
Use in the elderly 
Patients over 65 years of age who are treated with Perjeta are more likely to experience side effects 
such as reduced appetite, decrease in the number of red blood cells, weight loss, feeling tired, loss or 
altered taste, weak, numb, tingling or prickling sensations mainly affecting the feet and legs and 
diarrhoea, compared to patients younger than 65 years of age. 
 
Other medicines and Perjeta 
Tell your doctor or nurse if you are taking, have recently taken or might take any other medicines.  
 



39 

Pregnancy and breast-feeding 
Before starting treatment, you must tell your doctor or nurse if you are pregnant or breast-feeding, or if 
you think you may be pregnant or are planning to have a baby. They will advise you about the benefits 
and risks for you and your baby of taking Perjeta while you are pregnant. 
 
• Tell your doctor straight away, if you get pregnant during treatment with Perjeta or during the 

6 months after stopping treatment. 
• Ask your doctor about whether you can breast-feed during or after treatment with Perjeta. 
 
Perjeta may harm the unborn baby. You should use effective contraception during treatment with 
Perjeta and for 6 months after stopping treatment. Talk to your doctor about the best contraception for 
you. 
 
Driving and using machines 
Perjeta may have a minor effect on you being able to drive or use machines. However, if you get any 
dizziness, infusion reactions, allergic or anaphylactic reactions, wait until these have gone away before 
driving or using machines. 
 
Sodium  
Perjeta contains less than 1 mmol of sodium per dose, i.e. it is essentially sodium-free. 
 
 
3. How you are given Perjeta 
 
Being given this medicine 
 
Perjeta will be given to you by a doctor or nurse in a hospital or clinic. 
• It is given by a drip into a vein (intravenous infusion) once every three weeks. 
• The amount of medicine you are given and how long the infusion will last are different for the 

first dose and following doses.  
• The number of infusions you will be given depends on how you respond to treatment and 

whether you are receiving treatment before or after surgery (neoadjuvant or adjuvant therapy) 
or for disease which has spread. 

• Perjeta is given with other cancer treatments (trastuzumab andchemotherapy). 
 
For the first infusion: 
• You will be given 840 mg of Perjeta over 60 minutes. Your doctor or nurse will check for side 

effects during your infusion and for 60 minutes afterwards. 
• You will also be given trastuzumab and chemotherapyl. 
 
For all following infusions, if the first infusion was well tolerated: 
• You will be given 420 mg of Perjeta over 30 to 60 minutes. Your doctor or nurse will check 

for side effects during your infusion and for 30 to 60 minutes afterwards. 
• You will also be given trastuzumab and chemotherapy. 
 
For further information on dosing of trastuzumab and chemotherapy (which can cause side effects as 
well), please refer to the package leaflet for these products. If you have questions about these 
medicines, please ask your doctor or nurse.  
 
If you forget to have Perjeta 
If you forget or miss your appointment to receive Perjeta make another appointment as soon as 
possible. If it has been 6 weeks or more since your last visit a higher Perjeta dose of 840 mg will be 
given to you. 
 



40 

If you stop having Perjeta 
Do not stop having this medicine without talking to your doctor first. It is important that you are given 
all the infusions that have been recommended. 
 
If you have any further questions on the use of this medicine, ask your doctor or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Serious side effects 
Tell a doctor or nurse straight away, if you notice any of the following side effects:  
• Very severe or persistent diarrhoea (7 or more stools per day). 
• A decrease in the number or low amount of white blood cells (shown in a blood test), with or 

without fever, which may increase the risk of an infection. 
• Infusion reactions with symptoms that can either be mild or more severe and may include 

feeling sick (nausea), fever, chills, feeling tired, headache, loss of appetite, joint and muscle 
pains, and hot flushes.  

• Allergic and anaphylactic (more severe allergic) reactions with symptoms that may include 
swelling of your face and throat, with difficulty in breathing. Very rarely, patients have died 
due to anaphylactic reactions during Perjeta infusion.   

• Heart problems (heart failure) with symptoms that can include cough, shortness of breath, and 
swelling (fluid retention) in your legs or arms.  

• Tumour lysis syndrome (a condition which may happen when cancer cells die quickly, 
causing changes in blood levels of minerals and metabolites shown in a blood test). Symptoms 
may include kidney problems (weakness, shortness of breath, fatigue and confusion), heart 
problems (fluttering of the heart of a faster or slower heartbeat), seizures, vomiting or 
diarrhoea and tingling in the mouth, hands or feet 

 
Tell a doctor or nurse straight away, if you notice any of the side effects above.  
 
Other side effects include: 
 
Very common (may affect more than 1 in 10 people): 
• Diarrhoea 
• Hair loss 
• Feeling sick or being tired 
• Rash 
• Inflammation of your digestive tract (e.g. sore mouth) 
• Decrease in the number of red blood cells – shown in a blood test 
• Joint or muscle pain, muscle weakness 
• Constipation 
• Reduced appetite 
• Loss of or altered taste 
• Fever  
• Swollen ankles or other body parts due to your body retaining too much water 
• Not being able to sleep 
• Hot flushes  
• Weak, numb, tingling or prickling sensations mainly affecting the feet and legs  
• Nose bleeds 
• Cough 
• Heartburn 
• Dry, itchy or acne like skin 
• Nail problems  



41 

• Sore throat, red, sore or runny nose, flu-like symptoms and fever 
• Producing more tears 
• Fever associated with dangerously low levels of a type of white blood cell (neutrophils) 
• Pain in the body, arms, legs, and belly 
• Shortness of breath 
• Feeling dizzy 
 
Common (may affect up to 1 in 10 people): 
• A feeling of numbness, prickling or tingling in feet or hands; sharp jabbing, throbbing, 

freezing or burning pain; feeling pain from something which should not be painful such as a 
light touch; less able to feel changes in heat or cold; loss of balance or coordination 

• Inflammation of the nail bed where the nail and skin meet  
• Infection of the ear, nose or throat 
• Condition in which the left ventricle of the heart is functionally impaired with or without 

symptoms  
 
Uncommon (may affect up to 1 in 100 people): 
• Chest symptoms such as a dry cough or breathlessness (possible signs of interstitial lung 

disease, a condition of damage to the tissues around the air sacs in the lungs) 
• Fluid around the lungs causing difficulty in breathing 
 
If you experience any of the above symptoms after treatment with Perjeta has been stopped, you 
should consult your doctor immediately and inform him or her that you have previously been treated 
with Perjeta. 
 
Some of the side effects which you get may be due to your breast cancer. If you are given Perjeta with 
trastuzumab and chemotherapy at the same time, some side effects may also be due to these other 
medicines. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor 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 Perjeta 
 
Perjeta will be stored by the health professionals at the hospital or clinic. The storage details  
are as follows: 
• 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 after EXP. 

The expiry date refers to the last day of that month. 
• Store in a refrigerator (2°C-8°C).  
• Do not freeze. 
• Keep the vial in the outer carton in order to protect from light. 
• Do not use this medicine if you notice any particles in the liquid or it is the wrong colour 

(please see section 6).  
• Do not throw away any medicines via wastewater or household waste. Ask your pharmacist 

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

 
 

https://www.ema.europa.eu/documents/template-form/appendix-v-adverse-drug-reaction-reporting-details_en.doc


42 

6. Contents of the pack and other information 
 
What Perjeta contains 
• The active substance is pertuzumab. Each vial contains a total of 420 mg pertuzumab at a 

concentration of 30 mg/ml 
• The other ingredients are glacial acetic acid, L-histidine, sucrose, polysorbate 20 and water for 

injections 
 
What Perjeta looks like and contents of the pack 
Perjeta is a concentrate for solution for infusion. It is a clear to slightly pearly (opalescent), colourless 
to pale yellow liquid. It is supplied in a glass vial containing 14 ml concentrate. 
Each pack contains one vial. 
 
Marketing Authorisation Holder 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
Manufacturer 
Roche Pharma AG  
Emil-Barell-Strasse 1 
D-79639 Grenzach-Wyhlen 
Germany  
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
N.V. Roche S.A. 
Tél/Tel: +32 (0) 2 525 82 11 
 

Lietuva 
UAB “Roche Lietuva” 
Tel: +370 5 2546799 
 

България 
Рош България ЕООД 
Тел: +359 2 818 44 44 
 

Luxembourg/Luxemburg 
(Voir/siehe Belgique/Belgien) 
 

Česká republika 
Roche s. r. o. 
Tel: +420 - 2 20382111 
 

Magyarország 
Roche (Magyarország) Kft. 
Tel: +36 - 23 446 800 
 

Danmark 
Roche a/s 
Tlf: +45 - 36 39 99 99 
 

Malta 
(See Ireland) 
 

Deutschland 
Roche Pharma AG 
Tel: +49 (0) 7624 140 
 

Nederland 
Roche Nederland B.V. 
Tel: +31 (0) 348 438050 
 

Eesti 
Roche Eesti OÜ 
Tel: + 372 - 6 177 380 
 

Norge 
Roche Norge AS 
Tlf: +47 - 22 78 90 00 
 

Ελλάδα 
Roche (Hellas) A.E.  
Τηλ: +30 210 61 66 100 
 

Österreich 
Roche Austria GmbH 
Tel: +43 (0) 1 27739 
 



43 

España 
Roche Farma S.A. 
Tel: +34 - 91 324 81 00 
 

Polska 
Roche Polska Sp.z o.o. 
Tel: +48 - 22 345 18 88 
 

France 
Roche 
Tél: +33  (0)1 47 61 40 00 
 

Portugal 
Roche Farmacêutica Química, Lda 
Tel: +351 - 21 425 70 00 
 

Hrvatska 
Roche d.o.o. 
Tel: + 385 1 47 22 333 
 

România 
Roche România S.R.L. 
Tel: +40 21 206 47 01 
 

Ireland 
Roche Products (Ireland) Ltd. 
Tel: +353 (0) 1 469 0700 
 

Slovenija 
Roche farmacevtska družba d.o.o. 
Tel: +386 - 1 360 26 00 
 

Ísland  
Roche a/s 
c/o Icepharma hf 
Sími: +354 540 8000 
 

Slovenská republika  
Roche Slovensko, s.r.o. 
Tel: +421 - 2 52638201 
 

Italia 
Roche S.p.A. 
Tel: +39 - 039 2471 

Suomi/Finland 
Roche Oy  
Puh/Tel: +358 (0) 10 554 500 
 

Kύπρος  
Γ.Α.Σταμάτης & Σια Λτδ. 
Τηλ: +357 - 22 76 62 76 
 

Sverige 
Roche AB 
Tel: +46 (0) 8 726 1200 
 

Latvija 
Roche Latvija SIA 
Tel: +371 - 6 7039831 
 

United Kingdom 
Roche Products Ltd. 
Tel: +44 (0) 1707 366000 
 

 
This leaflet was last revised in.  
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu  

 


	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