Phesgo

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 
 
 
  



2 

This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Phesgo 600 mg/600 mg solution for injection  
Phesgo 1200 mg/600 mg solution for injection  
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Phesgo 600 mg/600 mg solution for injection  
 
One vial of 10 mL solution contains 600 mg of pertuzumab and 600 mg of trastuzumab.  
Each mL of solution contains 60 mg of pertuzumab and 60 mg of trastuzumab 
 
Phesgo 1200 mg/600 mg solution for injection  
 
One vial of 15 mL solution contains 1200 mg of pertuzumab and 600 mg of trastuzumab.  
Each mL of solution contains 80 mg of pertuzumab and 40 mg of trastuzumab 
 
Pertuzumab and trastuzumab are humanised immunoglobulin (Ig)G1 monoclonal antibodies produced 
in mammalian (Chinese hamster ovary) cells by recombinant deoxyribonucleic acid (DNA) 
technology. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection.  
 
Clear to opalescent solution, colourless to slightly brownish, pH 5.2-5.8, osmolality of 270-370 and 
275-375 mOsmol/kg for the 1200 mg/600 mg and 600 mg/600 mg solutions, respectively. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Early breast cancer (EBC) 
 
Phesgo is indicated for use in combination with 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 (MBC) 
 
Phesgo is indicated for use in combination with 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. 
 



3 

4.2 Posology and method of administration 
 
Phesgo should only be initiated under the supervision of a physician experienced in the administration 
of anti-cancer agents. Phesgo should be administered by a healthcare professional prepared to manage 
anaphylaxis and in an environment where full resuscitation facilities are immediately available (see 
section 4.4).  
 
In order to prevent medication errors, it is important to check the vial label to ensure that the medicinal 
product being prepared and administered is Phesgo.  
 
Posology 
 
Patients treated with Phesgo 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 hybridization (ISH), assessed by a 
validated test. 
 
To ensure accurate and reproducible results, the testing must be performed in a specialized laboratory, 
which can ensure validation of the testing procedures. For full instructions on assay performance and 
interpretation, please refer to the package leaflet of validated HER2 testing assays. 
 
For Phesgo dose recommendations in early and metastatic breast cancer please refer to Table 1.  
 
Table 1: Phesgo recommended dosing and administration  
 

 Dose (irrespective of 
body weight)  

Approximate duration of 
subcutaneous injection  

Observation time ab 

Loading dose 1200 mg pertuzumab/ 
600 mg trastuzumab  

8 minutes 30 minutes 

Maintenance dose 
(every 3 weeks)  

600 mg pertuzumab/ 
600 mg trastuzumab 

5 minutes 15 minutes 

aPatients should be observed for injection-related reactions and hypersensitivity reactions  
bObservation period should start following administration of Phesgo and be completed prior to any 
subsequent administration of chemotherapy  
 
In patients receiving a taxane, Phesgo should be administered prior to the taxane.  
 
When administered with Phesgo, the recommended initial dose of docetaxel is 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 Phesgo 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, Phesgo should be administered following 
completion of the entire anthracycline regimen (see section 4.4). 
 
Metastatic breast cancer  
 
Phesgo should be administered in combination with docetaxel. Treatment with Phesgo may continue 
until disease progression or unmanageable toxicity even if treatment with docetaxel is discontinued 
(see section 4.4). 
 
Early breast cancer  



4 

 
In the neoadjuvant setting, Phesgo should be administered for 3 to 6 cycles in combination with 
chemotherapy, as part of a complete treatment regimen for early breast cancer (see section 5.1). 
 
In the adjuvant setting, Phesgo should be administered 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. Phesgo should start on Day 1 of the first taxane-
containing cycle and should continue even if chemotherapy is discontinued. 
 
Delayed or missed doses 
 
If the time between two sequential injections is: 

• less than 6 weeks, the maintenance dose of Phesgo 600 mg/600 mg should be administered as soon 
as possible. Thereafter, continue with the 3-weekly schedule. 

• 6 weeks or more, a loading dose of Phesgo 1200 mg/600 mg should be re-administered followed 
by maintenance dose of Phesgo 600 mg/600 mg every 3 weeks thereafter. 

 
Dose modifications 
 
Dose reductions are not recommended for Phesgo. Discontinuation of treatment with Phesgo may be 
needed at the discretion of the physician. 
 
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 summary of product 
characteristics (SmPC).  
 
Left ventricular dysfunction 
 
Phesgo should be withheld for at least 3 weeks for any signs and symptoms suggestive of congestive 
heart failure. Phesgo 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 %. Phesgo 
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.  

 
Phesgo 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. 
 
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).  
 
Phesgo 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.  
 
Phesgo may be resumed if the LVEF has recovered to ≥ 50 % or to a difference of < 10 % points 
below pre-treatment values. 
 
Special populations 



5 

 
Elderly  
 
No overall differences in efficacy of Phesgo were observed in patients ≥ 65 and < 65 years of age. No 
dose adjustment of Phesgo is required in patients ≥ 65 years of age. Limited data are available in 
patients > 75 years of age. 
 
Please see section 4.8 for assessment of safety in elderly patients.   
 
Renal impairment 
 
Dose adjustments of Phesgo 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 (PK) data available (see section 5.2). 
 
Hepatic impairment 
 
The safety and efficacy of Phesgo have not been studied in patients with hepatic impairment. Patients 
with hepatic impairment are unlikely to require Phesgo dose adjustment. No specific dose adjustment 
are recommended (see section 5.2). 
 
Paediatric population 
 
The safety and efficacy of Phesgo in children and adolescents below 18 years of age have not been 
established. There is no relevant use of Phesgo in the paediatric population in the indication of breast 
cancer. 
 
Method of administration  
 
Phesgo should be administered as a subcutaneous injection only. Phesgo is not intended for 
intravenous administration.  
 
The injection site should be alternated between the left and right thigh only. New injections should be 
given at least 2.5 cm from the previous site on healthy skin and never into areas where the skin is red, 
bruised, tender, or hard. The dose should not be split between two syringes or between two sites of 
administration. During the treatment course with Phesgo, other medicinal products for subcutaneous 
administration should preferably be injected at different sites.  
 
The loading dose and maintenance dose should be administered over 8 and 5 minutes, respectively. 
 
An observation period of 30 minutes after completion of Phesgo loading dose and 15 minutes after 
completion of the maintenance dose is recommended for injection-related reactions (see sections 4.4 
and 4.8). 
 
Injection-related reactions  
The injection may be slowed or paused if the patient experiences injection-related symptoms (see 
section 4.4 and section 4.8). Treatment including oxygen, beta agonists, antihistamines, rapid 
intravenous fluids and antipyretics may also help alleviate systemic symptoms. 
 
Hypersensitivity reactions /anaphylaxis 
The injection 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 and section 4.8). 
 
For instructions on use and handling of the medicinal product before administration, see section 6.6. 
 
4.3 Contraindications 



6 

 
Hypersensitivity to the active substances 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 the 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 
pertuzumab and trastuzumab. The incidence of symptomatic left ventricular systolic dysfunction 
(LVD [congestive heart failure]) was higher in patients treated with pertuzumab in combination with 
trastuzumab and chemotherapy compared to trastuzumab and chemotherapy. In the adjuvant setting, 
the majority of cases of symptomatic heart failure reported were in patients who received 
anthracycline-based chemotherapy (see section 4.8). Patients who have received prior anthracyclines 
or prior radiotherapy to the chest area may be at higher risk of LVEF declines based on studies with 
intravenous pertuzumab in combination with trastuzumab and chemotherapy. 

Patients with history of serious cardiac illness or medical conditions, history of ventricular 
dysrhythmias or risk factors for ventricular dysrhythmias were excluded from the (neo-)adjuvant EBC 
pivotal trial FEDERICA with Phesgo. 

Phesgo has not been studied in patients with: a pretreatment LVEF value of < 55 % (EBC) or < 50 % 
(MBC); a prior history of congestive heart failure (CHF); 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. In addition, pertuzumab in combination with trastuzumab and chemotherapy has not been 
studied in patients with decreases in LVEF < 50 % during prior trastuzumab adjuvant therapy.  
 
Assess LVEF prior to initiation of Phesgo and at regular intervals during treatment (e.g. once during 
neoadjuvant treatment and every 12 weeks in the adjuvant and 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 Phesgo 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 Phesgo 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 Phesgo and anthracyclines than with sequential use. 
 
Sequential use of Phesgo (in combination with a taxane) has been evaluated following the doxorubicin 
component of two anthracycline-based regimens in the FEDERICA study while sequential use of 
intravenous pertuzumab (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. Only limited safety data are available on concurrent use of  intravenous 
pertuzumab in combination with trastuzumab and an anthracycline. In the TRYPHAENA study, 
intravenous pertuzumab in combination with trastuzumab 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 pertuzumab administered sequentially (following FEC chemotherapy). 
 
Injection-related reactions/infusion-related reactions (IRRs)  
 



7 

Phesgo has been associated with injection-related reactions (see section 4.8). Injection-related 
reactions were defined as any systemic reaction with symptoms such as fever, chills, headache, likely 
due to a release of cytokines occurring within 24 hour of administration of Phesgo. Close observation 
of the patient during and for 30 minutes after administration of the loading dose and during and for 
15 minutes following the administration of the maintenance dose of Phesgo is recommended. If a 
significant injection-related reaction occurs, the injection should be slowed down or paused 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 severe injection-related 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). Although fatal outcomes resulting from injection-related reactions have not 
been observed with Phesgo, caution should be exercised, as fatal infusion related-reactions have been 
associated with intravenous pertuzumab in combination with intravenous trastuzumab and 
chemotherapy. 
 
Hypersensitivity reactions/anaphylaxis  
 
Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity reactions, 
including anaphylaxis and events with fatal outcomes, have been observed with pertuzumab in 
combination with trastuzumab and chemotherapy (see section 4.8). The majority of anaphylactic 
reactions occurred within the first 6-8 cycles of treatment when pertuzumab and trastuzumab were 
given in combination with chemotherapy. Medicinal products to treat such reactions, as well as 
emergency equipment, should be available for immediate use. Phesgo must be permanently 
discontinued in case of NCI-CTCAE Grade 4 hypersensitivity reactions (anaphylaxis), bronchospasm 
or acute respiratory distress syndrome (see section 4.2). Phesgo is contraindicated in patients with 
known hypersensitivity to pertuzumab, trastuzumab or to any of its excipients (see section 4.3).  
 
Febrile neutropenia 
 
Patients treated with Phesgo in combination with a taxane are at increased risk of febrile neutropenia.  
 
Patients treated with intravenous pertuzumab in combination with 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 pertuzumab-treated and placebo-
treated patients. The higher incidence of febrile neutropenia in pertuzumab-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 
 
Phesgo 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 Phesgo should be 
considered if no improvement in the patient’s condition is achieved. When the diarrhoea is under 
control treatment with Phesgo may be reinstated. 
 



8 

Pulmonary events 
 
Severe pulmonary events have been reported with the use of trastuzumab in the post-marketing 
setting. These events have occasionally been fatal. In addition, cases of interstitial lung disease 
including lung infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis, pleural 
effusion, respiratory distress, acute pulmonary oedema and respiratory insufficiency have been 
reported. Risk factors associated with interstitial lung disease include prior or concomitant therapy 
with other anti-neoplastic therapies known to be associated with it such as taxanes, gemcitabine, 
vinorelbine and radiation therapy. These events may occur as part of an infusion-related reaction or 
with a delayed onset. Patients experiencing dyspnoea at rest due to complications of advanced 
malignancy and comorbidities may be at increased risk of pulmonary events. Therefore, these patients 
should not be treated with Phesgo. Caution should be exercised for pneumonitis, especially in patients 
being treated concomitantly with taxanes. 
 
Excipients 
 
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 
‘sodium-free’. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No formal drug interaction studies have been performed.  
 
Pertuzumab 
 
No 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 PK 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. 
 
Trastuzumab 
 
No formal drug interaction studies have been performed. Clinically significant interactions between 
trastuzumab and the concomitant medicinal products used in clinical trials have not been observed. 
 
Effect of trastuzumab on the pharmacokinetics of other antineoplastic agents  
 
PK data from studies BO15935 and M77004 in women with HER2-positive metastatic breast cancer 
suggested that exposure to paclitaxel and doxorubicin (and their major metabolites 6-α 
hydroxylpaclitaxel, POH, and doxorubicinol, DOL) was not altered in the presence of trastuzumab 
(8 mg/kg or 4 mg/kg intravenous loading dose followed by 6 mg/kg q3w or 2 mg/kg q1w intravenous, 
respectively). However, trastuzumab may elevate the overall exposure of one doxorubicin metabolite, 
(7-deoxy-13 dihydro-doxorubicinone, D7D). The bioactivity of D7D and the clinical impact of the 
elevation of this metabolite were unclear.  
 
Data from study JP16003, a single-arm study of trastuzumab (4 mg/kg intravenous loading dose and 
2 mg/kg intravenous weekly) and docetaxel (60 mg/m2 intravenous) in Japanese women with 
HER2-positive metastatic breast cancer, suggested that concomitant administration of trastuzumab had 
no effect on the single dose pharmacokinetics of docetaxel. Study JP19959 was a substudy of 
BO18255 (ToGA) performed in male and female Japanese patients with advanced gastric cancer to 



9 

study the pharmacokinetics of capecitabine and cisplatin when used with or without trastuzumab. The 
results of this substudy suggested that the exposure to the bioactive metabolites (e.g. 5-FU) of 
capecitabine was not affected by concurrent use of cisplatin or by concurrent use of cisplatin plus 
trastuzumab. However, capecitabine itself showed higher concentrations and a longer half-life when 
combined with trastuzumab. The data also suggested that the pharmacokinetics of cisplatin were not 
affected by concurrent use of capecitabine or by concurrent use of capecitabine plus trastuzumab.  
 
PK data from Study H4613g/GO01305 in patients with metastatic or locally advanced inoperable 
HER2-positive cancer suggested that trastuzumab had no impact on the PK of carboplatin. 
 
Effect of antineoplastic agents on trastuzumab pharmacokinetics  
 
By comparison of simulated serum trastuzumab concentrations after trastuzumab monotherapy 
(4 mg/kg loading/2 mg/kg q1w intravenous) and observed serum concentrations in Japanese women 
with HER2-positive metastatic breast cancer (study JP16003) no evidence of a PK effect of concurrent 
administration of docetaxel on the pharmacokinetics of trastuzumab was found. Comparison of PK 
results from two Phase II studies (BO15935 and M77004) and one Phase III study (H0648g) in which 
patients were treated concomitantly with trastuzumab and paclitaxel and two Phase II studies in which 
trastuzumab was administered as monotherapy (W016229 and MO16982), in women with 
HER2-positive MBC indicates that individual and mean trastuzumab trough serum concentrations 
varied within and across studies but there was no clear effect of the concomitant administration of 
paclitaxel on the pharmacokinetics of trastuzumab.  
 
Comparison of trastuzumab PK data from Study M77004 in which women with HER2-positive 
metastatic breast cancer were treated concomitantly with trastuzumab, paclitaxel and doxorubicin to 
trastuzumab PK data in studies where trastuzumab was administered as monotherapy (H0649g) or in 
combination with anthracycline plus cyclophosphamide or paclitaxel (Study H0648g), suggested no 
effect of doxorubicin and paclitaxel on the pharmacokinetics of trastuzumab. 
Pharmacokinetic data from Study H4613g/GO01305 suggested that carboplatin had no impact on the 
PK of trastuzumab. 
 
The administration of concomitant anastrozole did not appear to influence the pharmacokinetics of 
trastuzumab. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential/contraception 
 
Women of childbearing potential should use effective contraception while receiving Phesgo and for 
7 months following the last dose. 
 
Pregnancy 
 
In animal studies pertuzumab has shown reproductive toxicity. There is only a limited amount of data 
from the use of pertuzumab in pregnant women. 
 
From animal studies, it is not known whether trastuzumab can affect reproductive capacity (see 
section 5.3).  However, in the post-marketing setting, cases of foetal renal growth and/or function 
impairment in association with oligohydramnios, some of which resulted in fatal pulmonary 
hypoplasia of the foetus, have been reported in pregnant women receiving trastuzumab. 
 
Based on the aforementioned animal studies and post-marketing data, Phesgo should therefore be 
avoided during pregnancy unless the potential benefit for the mother outweighs the potential risk to 
the foetus. Women who become pregnant should be advised of the possibility of harm to the foetus. If 
a pregnant woman is treated with Phesgo, or if a patient becomes pregnant while receiving Phesgo or 



10 

within 7 months following the last dose of Phesgo, close monitoring by a multidisciplinary team is 
desirable.  
 
Breast-feeding 
 
As human IgG is secreted into human milk and the potential for absorption and harm to the infant is 
unknown, women should not breast-feed during Phesgo therapy and for at least 7 months following 
the last dose. 
 
Fertility 
 
Pertuzumab 
 
No specific fertility studies in animals have been performed to evaluate the effect of pertuzumab. No 
adverse effects on male and female reproductive organs were observed in repeat-dose toxicity studies 
of pertuzumab for up to six-month duration in cynomolgus monkeys (see section 5.3).  
 
Trastuzumab 
 
Reproduction studies conducted in cynomolgus monkeys with trastuzumab revealed no evidence of 
impaired fertility in female cynomolgus monkeys (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
Phesgo has minor influence on the ability to drive and use machines (see section 4.8). Patients 
experiencing injection-related reactions or dizziness (see section 4.4) should be advised not to drive 
and use machines until symptoms abate. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
The most common ADRs (≥ 30 %) reported in patients treated with Phesgo or intravenous pertuzumab 
in combination with trastuzumab and chemotherapy were alopecia, diarrhoea, nausea, anemia, 
asthenia and arthralgia.  
 
The most common serious adverse events (SAE) (≥ 1 %) reported in patients treated with Phesgo or 
intravenous pertuzumab in combination with trastuzumab were febrile neutropenia, cardiac failure, 
pyrexia, neutropenia, neutropenic sepsis, neutrophil count decreased and pneumonia.  
 
The safety profile of Phesgo was overall consistent to the known safety profile of intravenous 
pertuzumab in combination with trastuzumab, with an additional ADR of injection site reaction 
(14.9 % vs. 0.4 %). 
 
Tabulated list of adverse reactions  
 
The safety of pertuzumab in combination with trastuzumab has been evaluated in 3344 patients with 
HER2-positive breast cancer s in the pivotal trials CLEOPATRA, NEOSPHERE, TRYPHAENA and 
APHINITY. It was generally consistent across studies, although the incidence and most common 
adverse drug reaction (ADRs) varied depending on whether pertuzumab in combination with 
trastuzumab were administered with or without concomitant anti-neoplastic agents. 
 



11 

The safety of Phesgo has been evaluated in 248 patients with HER2-positive early breast cancer in the 
pivotal trial FEDERICA. 
 
Table 2 presents ADRs that have been reported in association with the use of intravenous pertuzumab 
in combination with trastuzumab and chemotherapy in the below mentioned pivotal clinical trials 
(n= 3344) and in the post-marketing setting. Additionally, an ADR specific to the Phesgo route of 
administration that has been reported in the FEDERICA study, is included in table 2. 
 

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

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

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

• FEDERICA, in which Phesgo (n= 248) or intravenous pertuzumab and trastuzumab (n= 252) 
was given in combination with chemotherapy to patients with early breast cancer 

 
As pertuzumab is used in combination with trastuzumab and chemotherapy, it is difficult to ascertain 
the causal relationship of an adverse reaction to a particular medicinal product.  
 
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. 
 



12 

Table 2 Summary of ADRs in patients treated with pertuzumab, trastuzumab in pivotal 
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 
 

   

Skin and subcutaneous 
tissue disorders  

Alopecia  
Rash  
Nail disorder  
Pruritus  
Dry skin 

   

Musculoskeletal and 
connective tissue disorders  

Myalgia  
Arthralgia  
Pain in extremity 

   



13 

System organ class Very Common Common Uncommon Rare 

General disorders and 
administration site 
conditions  

Mucosal inflammation 
Oedema peripheral 
Pyrexia  
Fatigue   
Asthenia 
Injection site 
reaction°°°  

Chills 
Pain 
Oedema 

  

^  Table 2 shows pooled data from the overall treatment period in CLEOPATRA (data cut off 11 February 2014; 
median number of cycles of pertuzumab was 24); and from the neoadjuvant treatment period in NEOSPHERE 
(median number of cycles of pertuzumab was 4, across all treatment arms) and TRYPHAENA (median number 
of cycles of  pertuzumab was 3-6 across treatment arms); and from the treatment period of APHINITY(median 
number of cycles of pertuzumab was 18). Additionally, Table 2 shows an ADR specific to the Phesgo route of 
administration that has been reported in the FEDERICA study (median number of cycles of  Phesgo was 7). 
* Including ADRs with a fatal outcome have been reported.   
** For the overall treatment period across the 4 studies (CLEOPATRA, NEOSPHERE, TRYPHAENA, 

APHINITY). 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, defined as any systemic events 

reported as hypersensitivity, anaphylactic reaction, acute infusion reaction or cytokine release syndrome 
occurring during an infusion or within 24 hours of the infusion. 

°°°Observed with Phesgo only 
† ADRs reported in the post marketing setting- 
 
Description of selected adverse reactions 
 
Left ventricular dysfunction 
 
Phesgo in combination with chemotherapy 
 
In the pivotal trial FEDERICA, 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 1.2 % of Phesgo treated 
patients vs 0.8 % of intravenous pertuzumab and trastuzumab-treated patients. Of the patients who 
experienced symptomatic heart failure, none of the Phesgo-treated patients had recovered at the data 
cut-off and one patient was withdrawn from Phesgo due to an event of symptomatic heart failure. 
Asymptomatic or mildly symptomatic (NYHA class II) declines in LVEF of at least 10 %-points from 
baseline and to < 50 % (confirmed by secondary LVEF) were reported in 0.8 % of Phesgo-treated 
patients and 4 % of intravenous pertuzumab and trastuzumab-treated patients, of whom one of the 
Phesgo-treated patients had recovered at the data cut-off and two patients were withdrawn from 
Phesgo (see sections 4.2 and 4.4).  
 
Pertuzumab intravenous in combination with trastuzumab and chemotherapy 
 
In the pivotal trial CLEOPATRA, the incidence of LVD during study treatment was higher in the 
placebo-treated group than the pertuzumab-treated group (8.6 % and 6.6 %, respectively). The 
incidence of symptomatic LVD was also lower in the pertuzumab treated group (1.8 % in the placebo-
treated group vs. 1.5 % in the pertuzumab-treated group) (see section 4.4).  
 
In the neoadjuvant trial NEOSPHERE, in which patients received four cycles of pertuzumab as 
neoadjuvant treatment, the incidence of LVD (during the overall treatment period) was higher in the 
pertuzumab, 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 pertuzumab and 
trastuzumab-treated group.  



14 

 
In the neoadjuvant trial TRYPHAENA, the incidence of LVD (during the overall treatment period) 
was 8.3 % in the group treated with pertuzumab plus trastuzumab and FEC (5-fluorouracil, epirubicin, 
cyclophosphamide) followed by pertuzumab plus trastuzumab and docetaxel; 9.3 % in the group 
treated with pertuzumab plus trastuzumab and docetaxel following FEC; and 6.6 % in the group 
treated with pertuzumab in combination with TCH (docetaxel, carboplatin and trastuzumab). The 
incidence of symptomatic LVD (congestive heart failure) was 1.3 % in the group treated with 
pertuzumab plus trastuzumab and docetaxel following FEC (this excludes a patient who experienced 
symptomatic LVD during FEC treatment prior to receiving pertuzumab plus trastuzumab and 
docetaxel) and also 1.3 % in the group treated with pertuzumab in combination with TCH. No patients 
in the group treated with pertuzumab plus trastuzumab and FEC followed by pertuzumab 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 pertuzumab plus trastuzumab and 
paclitaxel and none of the patients (0 %) experienced symptomatic LVD in the group treated with FEC 
followed by pertuzumab in combination with trastuzumab and docetaxel. The incidence of 
asymptomatic LVD (ejection fraction decrease according to NCI-CTCAE v.4) was 7 % in the group 
treated with dose dense AC followed by pertuzumab plus trastuzumab and paclitaxel and 3.5 % in the 
group treated with FEC followed by pertuzumab 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 pertuzumab-treated 
patients vs 0.3 % of placebo-treated patients). Of the patients who experienced symptomatic heart 
failure, 46.7 % of pertuzumab-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 pertuzumab-treated patients and 2.8 % of placebo-treated patients, of whom 79.7 % of pertuzumab-
treated patients and 80.6 % of placebo-treated patients had recovered at the data cutoff. 
 
Injection/infusion-related reactions 
 
Phesgo in combination with chemotherapy 
 
In the pivotal trial FEDERICA, an injection/infusion-related reaction was defined as any systemic 
reaction reported within 24 hours of Phesgo or intravenous pertuzumab in combination with 
trastuzumab administration (see sections 4.2 and 4.4). 
 
Injection-related reactions were reported in 0.8 % of Phesgo treated patients and infusion related 
reactions were reported in 10.7 % of intravenous pertuzumab and trastuzumab-treated patients. Most 
of the systemic injection/infusion related reactions seen with Phesgo or intravenous pertuzumab and 
trastuzumab were chills, pyrexia or vomiting. 
 
Injection site reactions were defined as any local reaction reported within 24 hours of Phesgo 
administration were reported in 14.9 % of Phesgo treated patients and were all grade 1 or 2 events. 
Most of the local injection site reactions seen with Phesgo were either injection site pain or injection 
site erythema. 
 
Pertuzumab intravenous in combination with trastuzumab and chemotherapy 



15 

 
An administration-related 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 pertuzumab was given the day before trastuzumab and docetaxel to allow for the examination 
of pertuzumab associated reactions. On the first day when only pertuzumab was administered, the 
overall frequency of infusion-related reactions was 9.8 % in the placebo-treated group and 13.2 % in 
the pertuzumab-treated group, with the majority of reactions being mild or moderate. The most 
common infusion-related reactions (≥ 1.0 %) in the pertuzumab-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 related reactions (≥ 1.0 %) in the pertuzumab-treated group were fatigue, drug 
hypersensitivity, dysgeusia, hypersensitivity, myalgia, and vomiting (see section 4.4).  
 
In neoadjuvant and adjuvant trials, pertuzumab was administered on the same day as the other study 
treatment. Infusion-related reactions occurred in 18.6 %-25.0 % of patients on the first day of 
pertuzumab administration (in combination with trastuzumab and chemotherapy). The type and 
severity of events were consistent with those observed in CLEOPATRA, with a majority of reactions 
being mild or moderate in severity. 
 
Hypersensitivity reactions/anaphylaxis 
 
Phesgo in combination with chemotherapy 
 
In the pivotal trial FEDERICA, the overall frequency of hypersensitivity/anaphylaxis reported events 
related to HER2-targeted therapy was 1.6 % in the Phesgo-treated patients vs. 1.2 % in the intravenous 
pertuzumab and trastuzumab-treated patients, of which none were NCI-CTCAE (version 4.0) grade 
3-4 (see section 4.4). One patient experienced a hypersensitivity/anaphylaxis event during or 
immediately after administration of Phesgo; at the first cycle which led to withdrawal from therapy 
(see sections 4.2 and 4.4). 
 
Pertuzumab intravenous in combination with trastuzumab and chemotherapy 
 
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 pertuzumab-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 pertuzumab-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 pertuzumab and docetaxel-treated 
group experienced anaphylaxis. In both the TRYPHAENA and APHINITY trials, the overall 
frequency of hypersensitivity/anaphylaxis was highest in the pertuzumab 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. 
 



16 

Febrile neutropenia 
 
Phesgo in combination with chemotherapy 
 
In the pivotal trial FEDERICA, febrile neutropenia occurred in 6.5 % of Phesgo -treated patients and 
5.6 % of intravenous pertuzumab and trastuzumab-treated patients.  
 
As in intravenous pertuzumab and trastuzumab pivotal trials, a higher incidence of febrile neutropenia 
was observed among intravenous pertuzumab and trastuzumab -treated Asian patients (13.0 %), 
similarly, the incidence of febrile neutropenia in Phesgo-treated Asian patients was also higher 
(13.7 %).  
 
Pertuzumab intravenous in combination with trastuzumab and chemotherapy 
 
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 pertuzumab-treated group and 58.3 % of patients 
in the placebo-treated group), of which the majority were neutropenic events (see section 4.4). Febrile 
neutropenia occurred in 13.7 % of pertuzumab-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 Pertuzumab-treated group (25.8 %) compared with the placebo-treated group (11.3 %). 
 
In the NEOSPHERE trial, 8.4 % of patients treated with neoadjuvant pertuzumab, 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 pertuzumab + TCH, and 9.3 % of patients treated with neoadjuvant pertuzumab, 
trastuzumab and docetaxel following FEC. In TRYPHAENA, the incidence of febrile neutropenia was 
higher in patients who received six cycles of pertuzumab compared with patients who received three 
cycles of pertuzumab, 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 pertuzumab, 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 pertuzumab-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 pertuzumab-treated Asian patients 
compared with other races in the APHINITY trial (15.9 % of pertuzumab-treated patients and 9.9 % of 
placebo-treated patients). 
 
Diarrhoea 
 
Phesgo in combination with chemotherapy 
 
In the pivotal trial FEDERICA diarrhoea occurred in 61.7 % of Phesgo-treated patients and 59.1 % of 
intravenous pertuzumab and trastuzumab-treated patients. Grade ≥ 3 diarrhoea was reported in 7.3 % 
of patients in the Phesgo arm vs. 5.2 % in the intravenous pertuzumab and trastuzumab 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 and taxane chemotherapy period (57.7 % of patients 
in the Phesgo-treated arm vs. 53.6 % of patients in the intravenous pertuzumab and trastuzumab-
treated arm)-(see section 4.4).  
 



17 

Pertuzumab intravenous in combination with trastuzumab and chemotherapy 
 
In the pivotal trial CLEOPATRA in metastatic breast cancer, diarrhoea occurred in 68.4 % of 
pertuzumab-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 pertuzumab-treated patients vs. 5.1 % in placebo-treated 
patients. The median duration of the longest episode was 18 days in pertuzumab-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 
pertuzumab, 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 pertuzumab+TCH and 61.4 % of patients treated with neoadjuvant pertuzumab, 
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 pertuzumab-treated arm 
(71.2 %) compared to the placebo arm (45.2 %).  Grade ≥ 3 diarrhoea was reported in 9.8 % of 
patients in the pertuzumab 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 pertuzumab 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 pertuzumab arm vs. 9.2 % of patients in the placebo arm 
in the post-chemotherapy targeted therapy period. 
 
Rash 
 
Phesgo in combination with chemotherapy 
 
In the pivotal trial FEDERICA rash occurred in 18.1 % of Phesgo-treated patients and 21.8 % of 
intravenous pertuzumab and trastuzumab-treated patients. The majority of rash events were Grade 1 or 
2. 
 
Pertuzumab intravenous in combination with trastuzumab and chemotherapy 
 
In the pivotal trial CLEOPATRA in metastatic breast cancer, rash occurred in 51.7 % of pertuzumab-
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. 
 
In the NEOSPHERE trial, rash occurred in 40.2 % of patients treated with neoadjuvant pertuzumab, 
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 pertuzumab + 
TCH and 20.0 % of patients treated with neoadjuvant pertuzumab, trastuzumab and docetaxel 
following FEC. The incidence of rash was higher in patients who received six cycles of pertuzumab 
compared with patients who received three cycles of pertuzumab, independent of the chemotherapy 
given. 
 
In the APHINITY trial, the adverse reaction of rash occurred in 25.8 % of patients in pertuzumab arm 
vs. 20.3 % of patients in placebo arm. The majority of rash events were Grade 1 or 2. 
 



18 

Laboratory abnormalities 
 
Phesgo in combination with chemotherapy 
 
In the pivotal trial FEDERICA, the incidence of NCI-CTCAE v.4 Grade 3-4 neutropenia was balanced 
in the two treatment groups (14.5 % of Phesgo -treated patients and 13.9 % of intravenous pertuzumab 
and trastuzumab-treated patients). 
 
Pertuzumab intravenous in combination with trastuzumab and chemotherapy 
 
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 pertuzumab-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 pertuzumab, 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 pertuzumab+ TCH and 77.0 % in patients treated with 
neoadjuvant pertuzumab, 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 pertuzumab, 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. 
 
Immunogenicity 
 
As with all therapeutic proteins, there is the potential for an immune response to pertuzumab and 
trastuzumab in patients treated with Phesgo.  
 
In the FEDERICA study, the incidence of treatment-emergent anti-pertuzumab and anti-trastuzumab 
antibodies was 3 % (7/237) and 0.4 % (1/237), respectively, in patients treated with intravenous 
pertuzumab and trastuzumab.  
 
The incidence of treatment-emergent anti-pertuzumab, anti-trastuzumab, and anti-vorhyaluronidase 
alfa antibodies was 4.8 % (11/231), 0.9 % (2/232), and 0.9 % (2/225), respectively, in patients treated 
with Phesgo. Among patients that tested positive to anti-pertuzumab antibodies, neutralizing anti-
pertuzumab antibodies were detected in one patient treated with intravenous pertuzumab and 
trastuzumab and in one patient treated with Phesgo. Among patients that tested positive to anti-
trastuzumab antibodies, neutralizing anti-trastuzumab antibodies were detected in one patient treated 
with Phesgo. 
 
The incidence of anti-pertuzumab and anti-trastuzumab antibodies detected at any time point 
(including baseline) was 7.1 % (18/252) and 1.2 % (3/252), respectively, in patients treated with 
intravenous pertuzumab and trastuzumab.  
 
The incidence of anti-pertuzumab, anti-trastuzumab, and anti-vorhyaluronidase alfa antibodies 
detected at any time point (including baseline) was 8.5 % (21/248), 2.4 % (6/248), and 6.7 % (16/240), 
respectively, in patients treated with Phesgo. Among patients that tested positive to anti-pertuzumab 
antibodies, neutralizing anti-pertuzumab antibodies were detected in two patients treated with 
intravenous pertuzumab and trastuzumab and in two patients treated with Phesgo. Among patients that 



19 

tested positive to anti-trastuzumab antibodies, neutralizing anti-trastuzumab antibodies were detected 
in one patient treated with Phesgo. 
 
The clinical relevance of the development of anti-pertuzumab, anti-trastuzumab or anti-
vorhyaluronidase alfa antibodies after treatment with Phesgo is unknown. 
 
Elderly patients 
 
In FEDERICA, no overall differences in safety of Phesgo were observed in patients ≥ 65 and < 65 
years of age.  
 
However, in the pivotal pertuzumab clinical trials with intravenous pertuzumab in combination with 
trastuzumab, decreased appetite, anemia, weight decreased, asthenia, dysgeusia, neuropathy 
peripheral, hypomagnesemia and diarrhea, occurred with an incidence of ≥ 5 % higher in patients ≥ 65 
years of age (n= 418) compared to patients < 65 years of age (n= 2926).  
 
Limited clinical trial data are available in patients > 75 years of age treated with Phesgo or intravenous 
pertuzumab and trastuzumab. Post-marketing data shows no differences in safety of pertuzumab in 
combination with trastuzumab in patients ≥ 65 and < 65 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 highest Phesgo dose tested is 1200 mg pertuzumab/600 mg trastuzumab. In case of overdose, 
patients must be closely monitored for signs or symptoms of adverse reactions and appropriate 
symptomatic treatment instituted. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XY02 
 
Mechanism of action  
 
Phesgo contains pertuzumab and trastuzumab which provides the therapeutic effect of this medicinal 
product and vorhyaluronidase alfa, an enzyme used to increase the dispersion and absorption of co-
formulated substances when administered subcutaneously. 
 
Pertuzumab and trastuzumab are recombinant humanised IgG1 monoclonal antibodies which target 
the human epidermal growth factor receptor 2 (HER2). Both substances bind to distinct HER2 
subdomains without competing and have complementary mechanisms for disrupting HER2 signalling: 
 

• Pertuzumab specifically targets the extracellular dimerization domain (subdomain II) of HER2 
and thereby blocks ligand-dependent heterodimerization of HER2 with other HER family 
members, including epidermal growth factor receptor (EGFR), HER3 and HER4. As a result, 
pertuzumab inhibits ligand-activated intracellular signalling through two major signalling 
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 

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


20 

 
• Trastuzumab binds to sub-domain IV, of the extracellular domain of the HER2 protein to 

inhibit the ligand-independent, HER2 mediated proliferation and survival signals in human 
tumour cells that over express HER2.   

 
Additionally, both substances mediate antibody-dependent cell-mediated cytotoxicity (ADCC). In 
vitro, both pertuzumab and trastuzumab ADCC are exerted preferentially on HER2-overexpressing 
cancer cells compared with cancer cells that do not overexpress HER2. 
 
Clinical efficacy and safety 
 
This section is presenting the clinical experience from Phesgo fixed dose combination of pertuzumab 
and trastuzumab and from intravenous pertuzumab in combination with trastuzumab in patients with 
HER2 overexpressing early and metastatic breast cancer.  
 
Clinical experience of Phesgo fixed dose combination of pertuzumab and trastuzumab in patients with 
HER2 positive early breast cancer  
 
The clinical experience of Phesgo is based on data from a Phase III clinical trial (FEDERICA 
WO40324) in patients with HER2 overexpressing early breast cancer. 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 trial outlined below. 
 
FEDERICA is an open-label, multicenter, randomized study conducted in 500 patients with HER2-
positive early breast cancer that is operable or locally advanced (including inflammatory) with a 
tumour size > 2 cm or node-positive in the neoadjuvant and adjuvant setting. Patients were 
randomized to receive 8 cycles of neoadjuvant chemotherapy with concurrent administration of 
4 cycles of either Phesgo or intravenous pertuzumab and trastuzumab during cycles 5-8.  Investigators 
selected one of the two following neoadjuvant chemotherapy for individual patients:  
 

• 4 cycles of doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) every 2 weeks 
followed by paclitaxel (80 mg/m2) weekly for 12 weeks  

• 4 cycles of doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) every 3 weeks 
followed by 4 cycles of docetaxel (75 mg/m2 for the first cycle and then 100 mg/m2 at 
subsequent cycles at the investigator’s discretion) every 3 weeks  

 
Following surgery, patients continued therapy with Phesgo or intravenous pertuzumab and 
trastuzumab as treated prior to surgery for an additional 14 cycles, to complete 18 cycles of HER2 
targeted therapy. Patients also received adjuvant radiotherapy and endocrine therapy as per local 
practice. In adjuvant period, substitution of intravenous trastuzumab for subcutaneous trastuzumab 
was permitted at investigator discretion. HER2-targeted therapy was administered every 3 weeks 
according to Table 3 as follows:  
 
Table 3: Dosing and administration of Phesgo, intravenous pertuzumab, intravenous 
trastuzumab, and subcutaneous trastuzumab  
 

Medicinal 
Products  

Administration Dose 
Loading Maintenance  

Phesgo Subcutaneous injection 1200 mg/600 mg 600 mg/600 mg 
Pertuzumab Intravenous infusion 840 mg 420 mg 
Trastuzumab Intravenous infusion 8 mg/kg 6 mg/kg 
Trastuzumab  Subcutaneous injection  600 mg 

 
FEDERICA was designed to demonstrate non-inferiority of the pertuzumab Cycle 7 (i.e., pre-dose 
Cycle 8) serum Ctrough of pertuzumab within Phesgo compared with intravenous pertuzumab (primary 
endpoint). Additional secondary endpoints included non-inferiority of the Cycle 7 serum trastuzumab 
Ctrough of trastuzumab within Phesgo compared with intravenous trastuzumab, efficacy (locally 



21 

assessed total pathological complete response, tpCR), and safety outcomes. Demographics were well 
balanced between the two treatment arms and the median age of patients treated in the study was 
51 years. The majority of patients had hormone receptor-positive disease (61.2 %), node-positive 
disease (57.6 %), and were Caucasian (65.8 %). 
 
For non-inferiority of the pertuzumab and trastuzumab exposures from Phesgo refer to section 5.2. For 
safety profile refer to section 4.8. 
 
The analysis of secondary efficacy endpoint, tpCR (locally assessed), defined as an absence of 
invasive disease in the breast and axilla (ypT0/is, ypN0) is shown in Table 4.  
 
Table 4: Summary of total pathological complete response (tpCR)  
 
 Phesgo    

 (n= 248) 
Intravenous 
pertuzumab + 
trastuzumab 
(n= 252) 

tpCR (ypT0/is, ypN0) 148 (59.7 %)  150 (59.5 %)  
Exact 95 % CI for tpCR rate1   (53.28; 65.84)   (53.18; 65.64)   
Difference in tpCR rate (subcutaneous minus intravenous 
arm) 

0.15  

95 % CI for the difference in tpCR2 rate - 8.67 to 8.97  
1 Confidence interval for one sample binomial using Pearson-Clopper method 
2 Hauck-Anderson continuity correction has been used in this calculation 
 
Clinical experience of intravenous pertuzumab in combination with trastuzumab in HER2 positive 
breast cancer 
 
The clinical experience of intravenous pertuzumab in combination with trastuzumab is based on data 
from two randomised neoadjuvant phase II trials in early breast cancer (one controlled), a non-
randomised neoadjuvant phase II trial, a randomised phase III trial in the adjuvant setting and a 
randomised phase III trial and a single-arm phase II trial in metastatic breast cancer. 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. 
 
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, tumour 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 (DFS) that nevertheless do not establish or precisely measure a benefit with regard to long-
term outcomes, such as overall survival (OS) or DFS.  
 
NEOSPHERE (WO20697)  
 
NEOSPHERE is a phase II, multicentre, multinational randomised controlled trial with pertuzumab 
and was conducted in 417 adult female patients with newly diagnosed, early, inflammatory or locally 
advanced HER2-positive breast cancer (T2-4d; primary tumour > 2 cm 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.  
 



22 

Patients were randomised to receive one of the following neoadjuvant regimens for 4 cycles prior to 
surgery:  
 

• Trastuzumab plus docetaxel  
• Pertuzumab plus trastuzumab and docetaxel 
• Pertuzumab plus trastuzumab 
• Pertuzumab plus docetaxel.  

 
Randomisation was stratified by breast cancer type (operable, locally advanced, or inflammatory) and 
oestrogen receptor (ER) or progesterone (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 pertuzumab 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), DFS, and progression-free survival (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 pertuzumab 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 (hazard ratio [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 pertuzumab (pertuzumab 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 pertuzumab plus trastuzumab and docetaxel. 
 



23 

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 > 2 cm 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 pertuzumab 
and trastuzumab 

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

• 6 cycles of TCH in combination with pertuzumab.  
 

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 intravenous 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 pertuzumab 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 5). 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.  
 



24 

Table 5 NEOSPHERE (WO20697) and TRYPHAENA (BO22280): Overview of efficacy 
(Intent to treat population)  

 
 NEOSPHERE (WO20697) TRYPHAENA (BO22280) 

Parameter 

Trastuzu
mab 

+docetax
el 

N= 107 

Pertuzuma
b+ 

trastuzuma
b+ 

docetaxel 
N= 107 

Pertuzuma
b+ 

trastuzuma
b 

N= 107 

Pertuzuma
b 

+docetaxel 
N= 96 

Pertuzumab+ 
trastuzumab

+ 
FEC 

pertuzumab
+ 

trastuzumab
+ 

docetaxel 
N= 73 

FEC 
Pertuzumab

+ 
trastuzumab

+ 
docetaxel 

N= 75 

Pertuzumab 
+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. 

pertuzumab+ 
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 pertuzumab+trastuzumab+docetaxel and pertuzumab+trastuzumab are compared to Trastuzumab+ 
Docetaxel while pertuzumab+docetaxel is compared to pertuzumab+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). 



25 

 
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 > 2 cm 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 pertuzumab in combination with trastuzumab and paclitaxel. 

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

 
Following surgery all patients received pertuzumab 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 sections 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 pertuzumab 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, OS, DFS, recurrence-free interval 
(RFI) and distant recurrence-free interval (DRFI). 
 



26 

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 % (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 
pertuzumab compared with patients randomised to receive placebo. 
 
The efficacy results from the APHINITY trial are summarised in Table 6 and in Figure 1. 
 
Table 6  Overall efficacy: Intent to treat population  
 

 

Pertuzumab + 
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 6): 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.  
 



27 

Figure 1 Kaplan-Meier curve of invasive disease free survival  
 

 
IDFS= invasive disease free survival; CI= confidence interval; Pla= placebo; Ptz= pertuzumab ; T= trastuzumab. 
 
The estimate of IDFS at 4-years was 92.3 % in the pertuzumab-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 pertuzumab were more apparent in subgroups of 
patients a high risk of recurrence: patients with node-positive or hormone receptor-negative disease 
(see table 7). 
 
Table 7  Efficacy results in subgroups by nodal status and hormone receptor status1 

 
 
 
Population 

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

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. 



28 

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 pertuzumab-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 pertuzumab-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 pertuzumab-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 
pertuzumab-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 pertuzumab 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 
pertuzumab 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 pertuzumab 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 
pertuzumab arm. The addition of pertuzumab to trastuzumab plus chemotherapy did not affect 
patients’ overall role function over the course of the study.  
 
Metastatic breast cancer  
 
Pertuzumab 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 pertuzumab 
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 
pertuzumab + trastuzumab + docetaxel.  
 
Pertuzumab and trastuzumab were given at standard doses in a 3-weekly regimen. Patients were 
treated with pertuzumab 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 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 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 ER-positive and/or PgR-positive) and approximately half of the patients in each treatment 
group had received prior adjuvant or neoadjuvant therapy. Most of these patients had received prior 



29 

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 8. A statistically 
significant improvement in IRF-assessed PFS was demonstrated in the pertuzumab-treated group 
compared with the placebo-treated group. The results for investigator-assessed PFS were similar to 
those observed for IRF-assessed PFS.  
 
Table 8  Summary of efficacy from CLEOPATRA study  
 

Parameter  Placebo+  
trastuzumab 
+ docetaxel 

n= 406 

Pertuzumab
+  

trastuzumab 
+ docetaxel 

n= 402 

HR 
(95 % CI) 

 

p-value 

Progression-free furvival  
(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, 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 2). 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). 
 



30 

Figure 2 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 pertuzumab-treated group). The statistically significant OS benefit in 
favour of the pertuzumab-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 pertuzumab-treated 
group (see Table 8, Figure 3). 
 
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 pertuzumab-treated group) showed that the statistically 
significant OS benefit in favour of the pertuzumab-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 [pertuzumab-treated group]). Landmark 
survival estimates at 8 years were 37 % in the pertuzumab-treated group and 23 % in the placebo-
treated group. 
 



31 

Figure 3 Kaplan-Meier curve of event-driven overall survival 
 

 

HR= hazard ratio; CI= confidence interval; Pla= placebo; Ptz= pertuzumab ; T= trastuzumab; 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.  
 
Paediatric population 
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
Phesgo in all subsets of the paediatric population in breast cancer (see section 4.2 for information on 
paediatric use). 
 
5.2 Pharmacokinetic properties 
 
The PK results for the primary endpoint of pertuzumab Cycle 7 Ctrough (i.e., pre-dose cycle 8), showed 
non-inferiority of pertuzumab within Phesgo (geometric mean 88.7 mcg/mL) compared to intravenous 
pertuzumab (geometric mean 72.4 mcg/mL) with a geometric mean ratio of 1.22 (90 % CI: 1.14-1.31). 
The lower boundary of the two-sided 90 % confidence interval for the geometric mean ratio of 
pertuzumab within Phesgo and intravenous pertuzumab was 1.14, i.e., greater than the predefined 
margin of 0.8. 
 
The PK results for the secondary endpoint, trastuzumab Cycle 7 Ctrough (i.e., predose Cycle 8), showed 
non-inferiority of trastuzumab within Phesgo (geometric mean 57.5 mcg/mL) compared to intravenous 
trastuzumab (geometric mean 43.2 mcg/mL) with a geometric mean ratio of 1.33 (90 % CI: 
1.24-1.43). 
 
Absorption 
 
The median maximum serum concentration (Cmax) of pertuzumab within Phesgo and time to maximal 
concentration (Tmax) were 157 mcg/mL and 3.82 days, respectively. Based on population PK analysis, 
the absolute bioavailability was 0.712 and the first-order absorption rate (Ka) is 0.348 (1/day).  
 



32 

The median Cmax of trastuzumab within Phesgo and Tmax were 114 mcg/mL and 3.84 days, 
respectively. Based on population PK analysis, the absolute bioavailability was 0.771 and the Ka is 
0.404 (1/day).   
 
Distribution 
 
Based on population PK analysis, the volume of distribution of the central (Vc) compartment of 
pertuzumab within Phesgo in the typical patient, was 2.77 litres.  
 
Based on population PK analysis, the Vc compartment of subcutaneous trastuzumab in the typical 
patient, was 2.91 litres. 
 
Biotransformation 
 
The metabolism of Phesgo has not been directly studied. Antibodies are cleared principally by 
catabolism.  
 
Elimination 
 
Based on population PK analysis, the clearance of pertuzumab within Phesgo was 0.163 L/day and the 
elimination half-life (t1/2) was approximately 24.3 days. 
 
Based on population PK analysis, the clearance of trastuzumab within Phesgo was 0.111 L/day.  
Trastuzumab is estimated to reach concentrations that are < 1 mcg/mL (approximately 3 % of the 
population predicted Cmin,ss, or about 97 % washout) in at least 95 % patients 7 months after the last 
dose. 
 
Elderly patients 
 
No studies have been conducted to investigate the pharmacokinetics of Phesgo in elderly patients.  
 
In population PK analyses of pertuzumab within Phesgo and intravenous pertuzumab, age was not 
found to significantly affect PK of pertuzumab. 
 
In population PK analyses of subcutaneous or intravenous trastuzumab, age has been shown to have 
no effect on the disposition of trastuzumab. 
 
Renal impairment 
  
No studies have been conducted to investigate the pharmacokinetics of Phesgo in patients with renal 
impairment.  
 
Based on population PK analyses of pertuzumab within Phesgo and intravenous pertuzumab, renal 
impairment was shown not to affect pertuzumab exposure; however, only limited data from patients 
with severe renal impairment were included in population pharmacokinetic analyses. 
 
In a population PK analysis of subcutaneous and intravenous trastuzumab, renal impairment was shown 
not to affect trastuzumab disposition. 
 
Hepatic impairment 
 
No formal PK study has been conducted in patients with hepatic impairment. Based on population PK 
analyses of pertuzumab within Phesgo, mild hepatic impairment was shown not to affect pertuzumab 
exposure. However, only limited data from patients with mild hepatic impairment were included in 
population PK analyses. IgG1 molecules such as pertuzumab and trastuzumab are catabolised by 
widely distributed proteolytic enzymes not restricted to hepatic tissue. Therefore, changes in hepatic 
function are unlikely to have an effect on the elimination of pertuzumab and trastuzumab. 



33 

 
 
5.3 Preclinical safety data 
 
No dedicated studies were conducted with the combination of subcutaneous pertuzumab, trastuzumab, 
and vorhyaluronidase alfa. 
 
Pertuzumab  
 
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.  
 
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 subcutaneous 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 (4- to 35-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 in 100 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.  
 
Subcutaneous pertuzumab (250 mg/kg/week for 4 weeks) and intravenous pertuzumab (up to 150 
mg/kg weekly for up to 26 weeks) was well tolerated in cynomolgus monkeys (binding species), 
except for the development of diarrhoea. With intravenous pertuzumab doses of 15 mg/kg and higher, 
intermittent mild treatment-associated diarrhoea was noted. In a subset of monkeys, chronic dosing 
(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. 
 
Trastuzumab  
 
Reproduction studies have been conducted in Cynomolgus monkeys via the intravenous route at doses 
up to 16 times that of the human maintenance trastuzumab dose in Phesgo of 600 mg formulation and 
have revealed no evidence of impaired fertility or harm to the foetus. Placental transfer of trastuzumab 
during the early (days 20-50 of gestation) and late (days 120-150 of gestation) foetal development 
period was observed.  
 
There was no evidence of acute or multiple dose-related toxicity in studies of up to 6 months, or 
reproductive toxicity in teratology, female fertility or late gestational toxicity/placental transfer 
studies. Trastuzumab is not genotoxic. A study of trehalose, a major formulation excipient did not 
reveal any toxicities.  
 
No long-term animal studies have been performed to establish the carcinogenic potential of 
trastuzumab, or to determine its effects on fertility in males. 
 
A study conducted in lactating Cynomolgus monkeys administered intravenous trastuzumab doses up 
to 16 times that of the human maintenance dose of 600 mg trastuzumab in the Phesgo formulation 
demonstrated that trastuzumab is secreted in the milk post partum. The exposure to trastuzumab in 



34 

utero and the presence of trastuzumab in the serum of infant monkeys was not associated with any 
adverse effects on their growth or development from birth to 1 month of age. 
 
Hyaluronidase  
 
Hyaluronidase is found in most tissues of the human body. Non-clinical data for recombinant human 
hyaluronidase reveal no special hazard for humans based on conventional studies of repeated dose 
toxicity including safety pharmacology endpoints. Reproductive toxicology studies with 
vorhyaluronidase alfa revealed embryofetal toxicity in mice at high systemic exposure, but did not 
show teratogenic potential. 
 
A single dose study in rabbits and a 13-week repeat dose toxicity study in Cynomolgus monkeys were 
conducted with trastuzumab subcutaneous formulation. The rabbit study was performed to specifically 
examine local tolerance aspects. The 13-week study was performed to confirm that the change to the 
subcutaneous route of administration and the use of the excipient vorhyaluronidase alfa did not have 
an effect on the trastuzumab safety characteristics. Trastuzumab subcutaneous formulation was locally 
and systemically well tolerated. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Vorhyaluronidase alfa  
L-histidine 
L-histidine hydrochloride monohydrate 
α,α-trehalose dihydrate 
Sucrose 
L-methionine 
Polysorbate 20 (E432) 
Water for injections 
 
6.2 Incompatibilities 
 
Phesgo is a ready to use solution which should not be mixed or diluted with other products. 
 
6.3 Shelf life 
 
18 months.  
 
Once transferred from the vial to the syringe the medicinal product is physically and chemically stable 
for 28 days at 2 °C-8 °C protected from light and for 24 hours (cumulative time in the vial and the 
syringe) at ambient temperature (maximum 30 °C) in diffused daylight.  
 
As Phesgo does not contain any antimicrobial-preservative, from a microbiological point of view, the 
medicinal 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 preparation of the syringe 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. 
 



35 

For storage conditions of the opened medicinal product, see sections 6.3 and 6.6. 
 
6.5 Nature and contents of container   
 
Phesgo 600 mg/600 mg solution for injection 
 
Pack of one 15 mL type I borosilicate glass vial tapered with fluororesin-laminated rubber stopper, 
containing 10 mL solution of 600 mg of pertuzumab and 600 mg of trastuzumab. 
The stopper is sealed with aluminium and covered by an orange plastic flip-off cap. 
 
Phesgo 1200 mg/600 mg solution for injection 
 
Pack of one 20 mL type I borosilicate glass vial tapered with fluororesin-laminated rubber stopper, 
containing 15 mL solution of 1200 mg of pertuzumab and 600 mg of trastuzumab.  
The stopper is sealed with aluminum and covered by a cool green plastic flip-off cap.  
 
6.6 Special precautions for disposal and other handling 
 
Phesgo should be inspected visually to ensure there is no particulate matter or discolouration prior to 
the administration. If particulate matter or discoloration is observed the vial should be discarded per 
local disposal guidelines. 
 
Do not shake the vial. 
 
A syringe, a transfer needle and an injection needle are needed to withdraw Phesgo solution from the 
vial and inject it subcutaneously. Phesgo may be injected using hypodermic injection needles with 
gauges between 25G-27G and lengths between 3/8"(10 mm)-5/8"(16 mm). Phesgo is compatible with 
stainless steel, polypropylene, polycarbonate, polyethylene, polyurethane, polyvinyl chloride and 
fluorinated ethylene polypropylene. 
 
As Phesgo does not contain any antimicrobial-preservative, from a microbiological point of view, the 
medicinal product should be used immediately. If not used immediately, preparation should take place 
in a controlled and validated aseptic conditions. After transfer of the solution to the syringe, it is 
recommended to replace the transfer needle by a syringe closing cap to avoid drying of the solution in 
the needle and not compromise the quality of the medicinal product. Label the syringe with the peel-
off sticker. The hypodermic injection needle must be attached to the syringe immediately prior to 
administration followed by volume adjustment to 15 mL if Phesgo 1200 mg/600 mg is used or 10 mL 
if Phesgo 600 mg/600 mg is used. 
 
Phesgo is for single use only. Any unused medicinal product or waste material should be disposed of 
in accordance with local requirements.  
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH 
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/20/1497/001 (1200 mg/600 mg) 
EU/1/20/1497/002 (600 mg/600 mg) 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 



36 

 
 
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 
  



37 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
ANNEX II 

 
A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE 

SUBSTANCES 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 

 



38 

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

 
Name and address of the manufacturers of the biological active substances 
 
Pertuzumab  
 
Genentech, Inc. 
1000 New Horizons Way  
Vacaville, CA 95688-9431  
USA 
 
Trastuzumab  
 
Roche Diagnostics GmbH  
Nonnenwald 2  
82377 Penzberg 
Germany  
 
Roche Singapore Technical Operations Pte. Ltd. 
10 Tuas Bay Link  
637394 Singapore  
Singapore 
 
Name and address of the manufacturer responsible for batch release 
 
Roche Pharma AG 
Emil-Barell-Strasse 1  
79639 Grenzach-Wyhlen  
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 (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of 
Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC 
and any subsequent updates published on the European medicines web-portal. 
 
The marketing authorisation holder (MAH) shall submit the first PSUR for this product within 
6 months following authorisation.  
 
 



39 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT   

 
• Risk management plan (RMP) 

 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance 
activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the 
marketing authorisation and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk profile or 
as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached. 

 
  



40 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



41 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



42 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Phesgo  600 mg/600 mg solution for injection 
 
pertuzumab/trastuzumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One vial contains 600 mg of pertuzumab and 600 mg of trastuzumab in 10 mL solution. 
 
 
3. LIST OF EXCIPIENTS 
 
Vorhyaluronidase alfa 
L-histidine  
L-histidine hydrochloride monohydrate 
α,α-trehalose dihydrate  
sucrose  
polysorbate 20  
L-Methionine 
water for injections 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection  
600 mg/600 mg in 10 mL  
1 vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For subcutaneous use only 
 
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 
 
 



43 

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 
 
 
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/1/20/1497/002 
 
 
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. 
 
 



44 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC  
SN  
NN 
  



45 

 
 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Phesgo  600 mg/600 mg solution for injection 
 
pertuzumab/trastuzumab 
 
For subcutaneous use only 
 
 
2. METHOD OF ADMINISTRATION 
 
For subcutaneous use only 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
600 mg/600 mg in 10 mL 
 
 
6. OTHER 
 
 
 
  



46 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Phesgo 1200 mg/600 mg solution for injection 
 
pertuzumab/trastuzumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One vial contains 1200 mg of pertuzumab and 600 mg of trastuzumab in 15 mL solution. 
 
 
3. LIST OF EXCIPIENTS 
 
Vorhyaluronidase alfa 
L-histidine  
L-histidine hydrochloride monohydrate 
α,α-trehalose dihydrate  
sucrose  
polysorbate 20  
L-Methionine 
water for injections 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection  
1200 mg/600 mg in 15 mL 
1 vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For subcutaneous use only 
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 



47 

 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator  
Do not freeze  
Keep the vial in the outer carton in order to protect from light 
 
 
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/1/20/1497/001 
 
 
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  



48 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Phesgo 1200 mg/600 mg solution for injection 
pertuzumab/trastuzumab 
For subcutaneous use only 
 
 
2. METHOD OF ADMINISTRATION 
 
For subcutaneous use only 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
1200 mg/600 mg in 15 mL 
 
 
6. OTHER 
 
 
  



49 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 
 
 



50 

Package leaflet: Information for the user 
 

Phesgo 600 mg/600 mg solution for injection 
Phesgo 1200 mg/600 mg solution for injection 

pertuzumab/trastuzumab 
 

This medicine is subject to additional monitoring. This will allow quick identification of new 
safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects. 
 
Read all of this leaflet carefully before you are 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, pharmacist or nurse. 
• If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Phesgo is and what it is used for  
2. What you need to know before you are given Phesgo  
3. How you are given Phesgo 
4. Possible side effects  
5. How to store Phesgo 
6. Contents of the pack and other information 
 
 
1. What Phesgo is and what it is used for 
 
Phesgo is a cancer medicine that contains two active substances: pertuzumab and trastuzumab. 

• Pertuzumab and trastuzumab are ‘monoclonal antibodies’. They are designed to attach to a 
specific target on cells called “human epidermal growth factor receptor 2” (HER2). 

• HER2 is found in large amounts on the surface of some cancer cells and stimulates their 
growth.   

• By attaching to HER2 on cancer cells, pertuzumab and trastuzumab slow down their growth, 
or kill them. 

 
Phesgo is available in two different strengths. See section 6 for more information. 

 
Phesgo is used to treat adult patients with breast cancer that is of the “HER2-positive” type – your 
doctor will test you for this. It can be used when: 

• the cancer has spread to other parts of the body such as the lungs or liver (metastasised), or the 
cancer has come back in the breast and the area around breast, but cannot be operated, and no 
treatment with cancer medicines (chemotherapy) or other medicines designed to attach to 
HER2 has been given. 

• the cancer has not spread to other parts of the body, and treatment is going to be  given either 
before surgery (neoadjuvant therapy) or after surgery (adjuvant therapy). 
 

As part of your treatment with Phesgo you will also receive other medicines called chemotherapy. 
Information about these medicines is described in separate package leaflets. Ask your doctor, 
pharmacist or nurse to give you information about these other medicines. 
 
 
2. What you need to know before you are given Phesgo 
 



51 

You must not be given Phesgo  
 

• if you are allergic to pertuzumab, trastuzumab, or to any of the other ingredients of this 
medicine (listed in section 6). 

If you are not sure, talk to your doctor, pharmacist or nurse before you are given Phesgo 
 
Warnings and precautions  
 
Heart problems 
 
Treatment with Phesgo may affect the heart. Talk to your doctor, pharmacist or nurse before you are 
given Phesgo if: 

• you have ever had heart problems (such as heart failure, treatment for serious irregular heart 
beats, uncontrolled high blood pressure, recent heart attack).Your doctor will run tests to 
check if your heart is working properly before and during treatment with Phesgo. 

• you have ever had heart problems during previous treatment with a medicine containing 
trastuzumab. 

• you have ever had a chemotherapy medicine from the class of cancer medicines called 
anthracyclines, e.g. doxorubicin or epirubicin – these medicines can damage heart muscle and 
increase the risk of heart problems with Phesgo. 

• you have ever had a radiotherapy to the chest area, as it can increase the risk of heart 
problems.  

If any of the above applies to you (or you are not sure), talk to your doctor or nurse before you are 
given Phesgo. See section 4 “Serious side effects” for more details about signs of heart problems to 
look out for. 
 
Injection reactions 
 
A reaction to the injection can happen. These are allergic reactions and can be severe. 
 
If you get any serious reaction, your doctor may stop treatment with Phesgo. See section 4 ‘‘Serious 
side effects’’ for more details about injection related reactions to look out for during the injection and 
thereafter. 
 
Your doctor or nurse will check for side effects during your injection and for: 

• 30 minutes after the first injection of Phesgo.  
• 15 minutes after subsequent injection of Phesgo.  

If you get any serious reaction, your doctor may stop treatment with Phesgo.  
 
Low levels of white blood cells and fever (Febrile neutropenia)  
 
When Phesgo is given with chemotherapy medicines, the number of white blood cells may drop and 
fever 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. If the fever persists for several days, this may be a sign 
of worsening of your condition and you should contact your physician. 
 
Diarrhoea 
 
Treatment with Phesgo 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.  If you get severe diarrhoea during 
your cancer treatment, your doctor may give you medicines to control diarrhoea. Your doctor may also 
stop your treatment with Phesgo until the diarrhoea is under control. 
 



52 

Children and adolescents 
 
Phesgo 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. 
 
Elderly patients over 65 
 
Patients over 65 years of age are more likely to get side effects such as reduced appetite, decrease in 
the number of red blood cells, weight loss, tiredness, loss or altered taste, weakness, numbness, 
tingling or prickling sensations mainly affecting the feet and legs and diarrhoea, compared to patients 
younger than 65 years of age. 
 
Other medicines and Phesgo 
Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other 
medicines. 
 
Pregnancy, breast-feeding and contraception 
Before starting treatment, you must tell your doctor, pharmacist 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 discuss with 
you the benefits and risks for you and your baby of taking Phesgo while you are pregnant. 
 

• Tell your doctor straight away, if you get pregnant during treatment with Phesgo or during the 
7 months after stopping treatment. Phesgo may harm the unborn baby. You should use 
effective contraception during treatment with Phesgo and for 7 months after stopping 
treatment. 

• Ask your doctor about whether you can breast-feed during or after treatment with Phesgo.  
 
Driving and using machines 
Phesgo may affect your ability to drive  or operate machines. If during treatment you experience 
symptoms, such as feeling dizzy, chills, fever or any injection or allergic reactions as described in 
section 4, you should not drive or use machines until these symptoms disappear. 
 
Phesgo contains Sodium 
Phesgo contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially sodium-free. 
 
 
3. How you are given Phesgo 
 
Phesgo will be given to you by a doctor or nurse in a hospital or clinic as an injection under your skin 
(subcutaneous injection). 

• Injections will be given every three weeks. 
• You will get the injection first in one thigh and then in the other. You will keep getting the 

injection in one thigh then the other. 
• Your doctor or nurse will make sure that each injection is given in a new place (at least 2.5 cm 

away from any previous place of injection), and where the skin is not red, bruised, tender or 
hard. 

• Different places for injection should be used for other medicines. 
 

 
Start of the treatment (loading dose)  

•  Phesgo 1200 mg/600 mg will be given under your skin over 8 minutes. Your doctor or nurse 
will check for side effects during your injection and for 30 minutes afterwards. 

• You will also be given chemotherapy 
 



53 

Subsequent injections (maintenance doses), which will be given if the first injection have not caused 
severe side effects:  

• Phesgo 600 mg/600 mg will be given under your skin over 5 minutes. Your doctor or nurse 
will check for side effects during your injection and for 15 minutes afterwards. 

• You will also be given chemotherapy, depending on the doctor’s prescription. 
• The number of injections you will be given depends on: 

•  how you respond to treatment 
•  whether you are having treatment before surgery or after surgery or for disease which 

has spread. 
 

For further information on loading and maintenance dose see section 6. 
For further information on dosing of chemotherapy (which can cause side effects as well), please read 
the package leaflet for these medicines. If you have questions about them, please ask your doctor, 
pharmacist or nurse. 
 
If you forget to have Phesgo 
If you miss your appointment to have Phesgo make another appointment as soon as possible. 
Depending on how much time passed between the two visits, your doctor will decide which strength 
of Phesgo to give you.  
 
If you stop having Phesgo 
Do not stop your treatment with this medicine without talking to your doctor first. It is important that 
you are given the full course of injections at the right time every three weeks. This helps your 
medicine work as well as it can. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Serious side effects 
 
Tell a doctor or nurse straight away, if you notice any of the following side effects: 
• Heart problems: a slower or faster heart beat than usual or fluttering of the heartand symptoms that 
can include cough, shortness of breath, and swelling (fluid retention) in your legs or arms. 
• Injection related reactions: these may be mild or more severe and may include feeling sick, fever, 
chills, feeling tired, headache, loss of appetite, joint and muscle pains, and hot flushes. 
• Diarrhoea: these may be mild or moderate but can be very severe or long-lasting diarrhoea, passing 
7 or more watery stools in a day. 
• Low number of white blood cells as shown in a blood test. This may or may not be with a fever. 
• Allergic reactions: swelling of your face and throat, with difficulty in breathing, this may be a sign 
of a serious allergic reaction. 
• Tumour lysis syndrome (where cancer cells die quickly). Symptoms may include: 

• kidney problems - signs include weakness, shortness of breath, fatigue and confusion, 
• heart problems - signs include fluttering of the heart or a faster or slower heart beat,  
• seizures (fits), 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 
 
Very common (may affect more than 1 in 10 people): 
• Hair loss 
• Rash 
• Inflammation of your digestive tract (e.g. sore mouth) 
• Decrease in the number of red blood cells as shown in a blood test 



54 

• Muscle weakness 
• Constipation 
• Loss of taste, or a change in the way things taste 
• Not being able to sleep 
• Weak, numb, tingling or prickling sensations mainly affecting the feet and legs 
• Nose bleeds 
• Heartburn 
• Dry, itchy or acne like skin 
• Pain at the injection site, reddened skin (erythema) and bruising at the injection site  
• Nail problems, such as discoloration like white or dark streaks or change in nail color 
• Sore throat, red, sore or runny nose, flu-like symptoms and fever which may lead to infection of the 
ear, nose or throat 
• Producing more tears 
• Pain in the body, arms, legs, and belly 
 
Common (may affect up to 1 in 10 people): 
• A feeling of numbness, prickling or tingling in your hands 
• Sharp jabbing, throbbing, freezing or burning pain 
• Feeling pain from something which should not be painful, such as a light touch 
• Reduced ability to feel changes in temperature 
• Loss of balance or coordination 
• Inflammation of the nail bed where the nail and skin meet 
• Condition in which the left part of the heart is not working properly 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 get any of the side effects above, talk to your doctor, nurse or pharmacist. 
 
If you get any of the above after treatment with Phesgo has been stopped, you should get in touch with 
your doctor immediately and say that you have previously been treated with Phesgo. 
 
Some of the side effects which you get may be due to your breast cancer. If you are given Phesgo with 
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, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Phesgo 
 
Phesgo 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 and the vial 

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. 
• Once the vial is open, use the solution immediately. Do not use this medicine if you notice any 

particles in the liquid or it is the wrong colour (see section 6). 

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


55 

• 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 protect the 
environment. 

 
 
6. Contents of the pack and other information 
 
What Phesgo contains  
The active substances are pertuzumab and trastuzumab.  

• Maintenance dose: One vial of 10 mL solution contains 600 mg of pertuzumab and 600 mg 
of trastuzumab. Each mL contains 60 mg of pertuzumab and 60 mg of trastuzumab. 

• Loading dose: One vial of 15 mL solution contains 1200 mg of pertuzumab and 600 mg of 
trastuzumab. Each mL contains 80 mg of pertuzumab and 40 mg of trastuzumab. 

 
The other ingredients are vorhyaluronidase alfa, L-histidine, L-histidine hydrochloride monohydrate, 
α,α-trehalose dihydrate, sucrose, L-methionine, polysorbate 20 and water for injections (see section 2 
“Phesgo contains sodium”). 
 
What Phesgo looks like and contents of the pack 
 
Phesgo is a solution for injection. It is a clear to opalescent solution, colourless to slightly brown 
supplied in a glass vial. Each pack contains one vial with either 10 mL or 15 mL solution. 
 
Marketing Authorisation Holder 
Roche Registration GmbH 
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
Manufacturer  
Roche Pharma AG 
Emil-Barell-Strasse 1  
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 
Ροχηε σ. ρ. Ο. 
Τελ: +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) 



56 

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 

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 4722 333 
 
Ireland 
Roche Products (Ireland) Ltd. 
Tel: +353 (0) 1 469 0700 

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

Κύπρος 
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 <{month YYYY}>. 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 
This leaflet is available in all EU/EEA languages on the European Medicines Agency website.  
 

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

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCES 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